Humatrope - Lilly Clinical Trial Registry

Transcription

Return to list of Lilly drugs
Humatrope (LY137998)
These clinical study results are supplied for informational purposes only in the interests of scientific disclosure. They are not intended to substitute for the FDA-approved
package insert or other approved labeling. The approved drug label can be found at http://pi.Lilly.com/us/humatrope-pi.pdf
Therapeutic
Area
Endocrinology
Alias
Trial Title
Trial
Phase
3/4
Endocrinology
B9R-MC-GDCH Idiopathic Short Stature
Endocrinology
B9R-MC-GDCHb Idiopathic Short Stature
843b Humatrope® in Non-Growth Hormone-Deficient Children with Short Stature
3
4
Endocrinology
Turner Syndrome
Trial ID
817/ Humatrope Treatment to Final Height in Turner Syndrome
4419
818 Investigation of the Safety and Efficacy of Growth Hormone Replacement
Therapy in Adults with Previously Treated Childhood Growth Hormone
Deficiency
824 Use of Biosynthetic Human Growth Hormone (Humatrope®) in Short Children
with Chronic Renal Failure
843 Humatrope® in Non-Growth Hormone-Deficient Children with Short Stature
Endocrinology
B9R-CA-GDCT
Indication
B9R-EW-E005/6 Adult Replacement Growth
Hormone Deficiency
B9R-FP-0909
Chronic Renal Insufficiency
The Effect of Chronic Somatropin Treatment on Bone Mineral Density in
Patients Diagnosed with Adult-Onset Growth Hormone Deficiency
3
3
3
Endocrinology
B9R-US-GDEO
Adult Replacement Growth
Hormone Deficiency
883
Endocrinology
B9R-MC-GDFN
SHOX Deficiency
3
Endocrinology
B9R-JE-K01A
Hormone Deficiency
2704 Efficacy and Safety of Somatropin Treatment in Pediatric Subjects with SHOX
Disorder and SHOX-Deficient Turner Syndrome
2889 Placebo-Controlled Double Blind Study Of LY137998 [Somatropin
(Recombinant DNA Origin)] In Adults With Growth Hormone Deficiency
Endocrinology
B9R-IT-GDFT
Growth Hormone Deficiency
4
Endocrinology
B9R-JE-K02A
Hormone Deficiency
5123 The Genetics and Neuroendocrinology in Children with GHD: A Part of
GeNeSIS
5300 Long-Term Clinical Study Of LY137998 [Somatropin (Recombinant DNA
Origin)] In Adults With Growth Hormone Deficiency
Endocrinology
B9R-JE-K03A
Hormone Deficiency
6018 Extended Clinical Study of LY137998 [Somatropin (Recombinant DNA Origin)]
In Adults with Growth Hormone Deficiency
3
3
3/4
Endocrinology
B9R-EW-GDGB Small for Gestational Age
6581 Optimization of Growth Hormone Treatment in Short Children Born Small for
Gestational Age Based on a Growth Prediction Model: The OPTIMA Trial
3
Endocrinology
B9R-EW-E003/4 Adult Replacement Growth
Hormone Deficiency
Z007 Investigation of the Safety and Efficacy of Growth Hormone Replacement
Therapy in Adults with Growth Hormone Deficiency Arising in Adult Life
3
Z009 The Efficacy and Safety of Biosynthetic Authentic Human Growth Hormone in
Short Prepubertal Children with Normal Growth Hormone Response to
Standard Provocation Tests
3
Endocrinology
B9R-EW-E001
Idiopathic Short Stature
Page 1 of 2
Humatrope (LY137998)
These clinical study results are supplied for informational purposes only in the interests of scientific disclosure. They are not intended to substitute for the FDA-approved
package insert or other approved labeling. The approved drug label can be found at http://pi.Lilly.com/us/humatrope-pi.pdf
Endocrinology
B9R-JE-6001
Achondroplasia
Z019 Evaluation of Growth Promoting Effect and Safety of Growth Hormone in
Achondroplasia
Page 2 of 2
3
Return to list of Humatrope studies
CT Registry ID# 0817/4419
Page 1
Summary ID# 0817/4419
Clinical Study Summary: Study B9R-CA-GDCT
Core Study and Addenda
Humatrope Treatment to Final Height
in Turner Syndrome
Date summary approved by Lilly: 24 November 2008
Title of Study: Humatrope Treatment to Final Height in Turner Syndrome
Investigator(s): This multicenter study included 13 principal investigators.
Study Center(s): This study was conducted at 13 study centers in 1 country.
Length of Study:
Phase of Development:
Date of first patient visit: 06 February 1989
Phase 3 at study initiation
Date of last patient visit: 05 December 2007
Phase 4 at study completion
Objectives:
Core Study
Primary Objective: To determine the efficacy of Humatrope in promoting linear growth to final height
in girls with Turner syndrome.
Secondary Objective: To determine the antigenicity and other measures of clinical safety of
Humatrope in patients with Turner syndrome.
Addendum 1:
Objective: To provide to patients who were randomized to the Control group of the Core Study and
who discontinued from the study on or after 19 December 1997 the option to receive Humatrope treatment
if judged appropriate by their physician.
Addendum 2:
Objectives: 1) to collect true final height data; 2) to evaluate hearing, tympanic membrane function,
and other specific areas of interest with respect to the safety of growth hormone therapy in Turner
syndrome; and 3) to evaluate pancreatic beta cell function, as assessed by measurement of parameters of
glucose metabolism.
Addendum 3:
Objectives: to determine the parental origin of the retained X chromosome of an appropriate subset of
patients and to determine whether this held any predictive value for spontaneous growth or response to
growth hormone therapy.
Somatropin rDNA
Copyright © 2008 Eli Lilly and Company. All rights reserved.
Page 2
Study Design: Study B9R-CA-GDCT (hereafter referred to as the Core Study) was initiated as a Phase 3
outpatient, randomized, parallel, controlled comparison of the outcomes of Humatrope treatment versus
non-treatment (hereafter referred to as the Control group, or simply, Control) to final height in patients with
Turner syndrome. Patients in the Control group received no injections; patients in the treatment group
(hereafter referred to as the Humatrope group) received Humatrope (50 µg/kg/dose) by subcutaneous
injection 6 times per week (total weekly dose 0.3 mg/kg). Patients in both groups received ethinyl estradiol
(escalating doses from 2.5 to 20 µg daily) after age 13, and medroxyprogesterone acetate (10-mg tablets 10
days each month) after age 15. Patients in both groups were to continue on study until attainment of final
height (defined as the last height measurement when the patient’s bone age was at least 14 years and height
velocity was less than 2.0 cm/year, based on height measurements performed at least 6 months apart;
Figure 1).
B 9 R - C A - G D C T C o re S tu d y D e s ig n
C o n tro l n = 78
(N o T r ea tm en t)
R a n d o m iz atio n
F ina l
H eigh t
H u m atr o p e n = 7 6
(5 0 µg /k g /d a y x 6 d a ys/w k; 0 .3 0 m g /kg /w k )
V is it
1
2
3
4
5
6
7
M o nth
0
3
6
9
12
15
18
e tc .
F ina l
H eigh t
Figure 1. Study design.
Patients who had been randomized to the Control group in the Core Study and who remained in the study
until 19 December 1997 were given the option to receive Humatrope through Protocol Amendment (f) or
Protocol Addendum 1. In addition, some Control patients discontinued the Core Study and received
growth hormone treatment outside the study; a number of these patients participated in follow-up through
Protocol Addendum 2 (Figure 2).
All Randomized
As-Randomized Humatrope
As-Randomized Control
Never
Received GH
GH Outside
Study
As-Treated Control
Humatrope in
Amendment (f)
Humatrope in
Addendum 1
As-Treated GH
Abbreviations: GH = growth hormone.
Figure 2. Participant flow diagram.
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Number of Patients:
Planned: 100 (50 Control; 50 Humatrope)
Randomized: 154 (78 Control; 76 Humatrope)
Completed Core Study: 104 (43 Control; 61 Humatrope)
Entered Addendum 1: 2 (2 Control; 0 Humatrope)
Completed Addendum 1: 2 (2 Control; 0 Humatrope)
Entered Addendum 2: 76 (28 Control; 48 Humatrope)
Completed Addendum 2: 49 (18 Control; 31 Humatrope)
Participated in Addendum 3: 57 (20 Control; 37 Humatrope)
Main Inclusion Criteria:
• Females with a diagnosis of Turner syndrome
• Chronological age 7 years to less than 13 years
• Prepubertal (Tanner stage I breast development)
• Height less than or equal to the 10th percentile for sex and age of the general population (United
States National Center for Health Statistics standards, 1976)
• Prestudy height velocity less than 6 cm/year based on measurements obtained at least 6 months
apart
• In hypothyroid patients, normal thyroid function tests over the 6-month period prior to enrollment
• Provision of signed informed consent by parent(s) or legal guardian(s)
Main Exclusion Criteria:
• Prior treatment with growth hormone
• Presence of a Y chromosome component in the karyotype with gonads in situ
• Diabetes mellitus or other clinically significant systemic disease
• History of malignancy
Study Drug Dosage and Mode of Administration:
The study drug was Humatrope (somatropin [rDNA for injection]; recombinant human growth hormone
[GH]).
As-Randomized Treatment Groups
The As-Randomized Non-Treatment Control group (hereafter referred to as the Control group) was
randomized to receive no injections (no active growth-promoting treatment). This group includes all
patients who were randomized to the Non-Treatment Control group (no Humatrope) at Study GDCT entry,
whether or not they subsequently received Humatrope or another brand of GH by any mechanism.
The As-Randomized Humatrope-Treated group (hereafter referred to as the As-Randomized Humatrope
group, abbreviated when necessary to AR Humatrope) was randomized to receive Humatrope 0.05 mg/kg
(50 µg/kg) by subcutaneous injection 6 times per week (0.3 mg/kg total weekly dose). The weekly
Humatrope dose was not to exceed 15 mg. This group includes all patients who were randomized to the
Humatrope group at Study GDCT entry, whether or not they actually received Humatrope.
As-Treated Treatment Groups
Several patients changed from Control to GH treatment outside the Core Study; in particular, some patients
participated in Addendum 1, which provided the option of GH treatment to former Controls. Additionally,
some patients who were randomized to Humatrope did not choose to continue in the Core Study and did
not ever receive GH but contributed data in follow-up. To facilitate analysis according to treatment
actually received, “As-Treated” groups are also defined.
The As-Treated No-GH group (abbreviated when necessary to AT No GH) group includes all patients who
were randomized in the Core Study and received no form of GH either during or outside the study.
(continued)
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As-Treated Treatment Groups (concluded)
The As-Treated GH-Treated group (hereafter referred to as the As-Treated GH group, abbreviated when
necessary to AT GH) group includes all patients, irrespective of their randomization group, who received
Humatrope at any time during the study or any brand of GH outside the study.
Additional Study Medications (Both As-Randomized Treatment Groups)
In addition, patients in both treatment groups who had no clinical evidence of ovarian function received
orally administered sex hormone replacement therapy (ethinyl estradiol 5.0-µg tablets and
medroxyprogesterone acetate 10-mg tablets) on a standardized schedule according to the following criteria:
1.
2.
3.
Patients at least 13 years of age who had been followed in the study for at least 12 months began
estrogen replacement with ethinyl estradiol 2.5 µg daily;
Patients at least 14 years of age, but not yet 15 years of age, received ethinyl estradiol 5.0 µg daily;
After 1 year of treatment with ethinyl estradiol 5.0 µg, a cyclic hormone replacement regimen was
initiated. The regimen comprised ethinyl estradiol 20 µg daily from Days 1 through 24, accompanied
by medroxyprogesterone acetate 10 mg on Days 15 through 24. Both drugs were suspended on
Day 24; the cycle was reinitiated on the first day of the following month.
Duration of Treatment or Study Participation: The Core Study was approved in 1988 with an initial
treatment (or follow-up) duration of 18 months, to be extended by 12-month blocks to final height, based
on interim study results. The protocol was amended in 1992 (Amendment [d]) to provide a definition of
final height (annualized growth rate <2.0 cm/year based on at least 6 months’ growth data and a bone age
≥14 years) as the criterion to determine patient completion of the Core Study.
Ethinyl estradiol and medroxyprogesterone acetate were to be taken as described above, until study
completion (or beyond, at the discretion of the investigator).
Variables:
Efficacy:
• Height standard deviation score (SDS; according to general female population standards of the
National Center for Health Statistics [NHCS] [Kuczmarski et al. 2000]), hereafter abbreviated as
Height SDS [NCHS]
• Change in height SDS [NHCS]
• Height SDS (according to the Turner syndrome standards of Lyon et al. 1985), hereafter abbreviated
as Height SDS [Lyon]
• Change in height SDS [Lyon]
• Height (cm)
• Change in height (cm)
Safety:
• Adverse events
• Measures of middle ear and hearing function
• Measures of glucose metabolism (fasting blood glucose, fasting insulin, hemoglobin A1C)
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Evaluation Methods:
Populations:
The All Randomized Population is defined as all patients randomized in the Core Study, whether or not
they received any study drug, or had a post-baseline visit.
The Final Height Population is defined as those patients who fulfilled any of the following criteria:
•
•
•
Had a height measurement available after annualized height velocity had fallen below 2 cm/year,
based on measurements at least 6 months apart, and after bone age (according to the central reader)
was 14 years or greater (protocol completion criteria);
Declared “Protocol Complete” by the investigator (whether or not formal protocol completion criteria
were met); or
Had a height measurement available after bone age of 15 years or chronological age of 17 years.
Safety Population
Patients in the All Randomized Population who either received any study medication or had post-baseline
safety data.
Treated-As-Randomized Population
Patients in the All Randomized Population who at each observed time point maintained the treatment to
which they were assigned at randomization.
Glucose 4-Year Population
Patients in the Safety Population who were followed for at least 4 years without GH treatment (if never
treated with GH) or who received GH for a total of 4 years (if ever treated with GH).
Statistical Methods, Efficacy: Because the intent of the protocol was to establish both the principle of a
GH-treatment effect in patients with Turner syndrome, and its magnitude in patients who completed
treatment, the primary efficacy analysis consists of 2 components: intent-to-treat analysis of gain in height
in the All Randomized Population (to inferentially establish presence of a GH effect) and Final Height
analysis in the Final Height Population (for estimation of magnitude of GH effect).
Height and change-in-height analyses are performed using SDS, based on the US general population female
standards (Kuczmarski et al. 2000) and the published Turner syndrome standards (Lyon et al. 1985). These
SDS variables are referred to as Height SDS [NCHS] and Height SDS [Lyon].
Height SDS is calculated on each scale as:
• age-specific values, based on height and age at the time of measurement, and
• adult-standard values (last available height, irrespective of age, converted to SDS for height at
20 years of age [that is, adult height]).
Both height and change in height from baseline to last measurement are assessed with age-specific SDS.
For patients in the Final Height Population, last measurement of height is additionally assessed in
centimeters (cm) and adult SDS.
(continued)
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Statistical Methods, Efficacy (concluded)
The presence or absence of a treatment effect of Humatrope upon height is determined by an intent-to-treat
analysis, contrasting the treatments to which the patients were randomized. Specifically, the primary
inferential analysis tests for difference between As-Randomized Treatment groups in the mean change in
age-specific height SDS [NCHS], from baseline to last available height measurement, in the All
Randomized Population.
In the presence of a treatment effect, the magnitude of treatment effect is estimated by an analysis of
patients for whom true final height data are available, contrasting the treatments actually received by the
patients. Specifically, the primary estimation analysis computes the difference between As-Treated
Treatment Groups in the mean age-specific height SDS [NCHS], at last available height measurement, in
the Final Height Population.
Primary and secondary efficacy variables are evaluated in an analysis of covariance (ANCOVA) model that
includes explanatory variables of baseline height SDS [Lyon], baseline age, treatment, baseline height SDS
[Lyon] by treatment interaction, and baseline age by treatment interaction. Baseline height SDS [Lyon]
and treatment are retained as design factors; other terms are removed from the model if not significant at
p<0.05. P-values are given for the difference of least squares (LS) means between treatment groups based
on Type III sums of squares in the ANCOVA model.
Statistical Methods, Safety: Analyses of adverse events are performed using the Safety Population, using
As-Randomized treatment groups when analyzing the Core Study, and using As-Treated treatment groups
when analyzing Addendum 2 data. To avoid confounding the safety data because of the change in
treatment assignment of a number of patients after they had completed their participation in the Core Study,
the Treated-as-Randomized Population is used to summarize the adverse events when analyzing the
study as a whole (Core Baseline to Addendum 2 Endpoint). Treatment-emergent adverse events (TEAEs)
are summarized at the patient level by counts and percentages of each occurring Medical Dictionary for
Drug Regulatory Activities (MedDRA) Lower Level Term (LLT), for terms with prevalence ≥5% in either
treatment group. In addition, using an a priori classification of events into categories of special interest,
occurrences at the patient level are compared between treatment groups, by counts and percentages, in the
Treated-as-Randomized Population over the study as a whole. Targeted adverse events were collected
by questionnaire during Addendum 2; numbers of occurrences at the patient level are compared for each
event term by a Fisher Exact test between As-Treated treatment groups.
All middle ear and hearing analyses are performed on patients in the All Randomized Population who had
a hearing examination performed. Because each patient who ever received GH had been treated by the
time her hearing examination was performed, hearing analyses are performed with As-Treated treatment
groups. The audiologists’ qualitative assessments of normality or abnormality of middle ear and hearing
data are evaluated by summarizing the number and percentage of patients with normal versus abnormal (or
unknown) results for each of the following: (i) impedance tympanometry, (ii) pure tone audiometry, and
(iii) speech audiometry. Additionally, for each of these tests, an analysis is performed of an objectively
calculated criterion of normality, based on published references (King et al. 2007; Moscicki et al. 1985).
All hearing analyses are evaluated with a Fisher Exact test of the number of abnormal results among
evaluable results, between As-Treated treatment groups.
(continued)
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Statistical Methods, Safety (concluded):
Addendum 2 collected additional targeted safety endpoints and laboratory data that were not collected in
the Core Study. Safety data specifically from Addendum 2 (Addendum 2 Baseline to Addendum 2
Endpoint) are analyzed using the Safety Population, with the As-Treated treatment groups. When safety
data from Addendum 2 are integrated for analysis with safety data from the Core Study, the Treated-AsRandomized Population is used.
Analyses of glucose metabolism data presented here focus on patients in the Glucose 4-year Population,
to address specific questions of interest identified in the protocol. Mean fasting blood glucose, fasting
insulin, and hemoglobin A1C are tabulated at multiple analysis time points between Core Baseline and
Addendum 2 last measurement. Change from Core Baseline to Addendum 2 Maximum, and Change from
Core Last Measurement to Addendum 2 Maximum in each analyte are examined in an analysis of variance
(ANOVA) model with a term for treatment. For both the Core Study (during treatment) and the Addendum
(post-GH follow-up), the number of patients crossing specific clinically relevant cutpoints is tabulated, and
tested between treatment groups by a Fisher Exact test, for glucose metabolism parameters of interest.
Patient Disposition
Table 1 provides the numbers of patients available for analyses of efficacy and safety
variables.
Table 1.
Summary of Patient Disposition
All Analysis Populations
B9R-CA-GDCT
------------------------------------------------------------------------------As-Randomized As-Randomized
Control
Humatrope
Total
------------------------------------------------------------------------------All Randomized Patients
78 (100%)
76 (100%)
154 (100%)
Safety Population
66 (84.6%)
75 (98.7%)
141 (91.6%)
Treated As Randomized
54 (69.2%)
74 (97.4%)
128 (83.1%)
Glucose Safety Population 1-year
60 (76.9%)
73 (96.1%)
133 (86.4%)
Glucose Safety Population 4-year
51 (65.4%)
59 (77.6%)
110 (71.4%)
Final Height Population
58 (74.4%)
72 (94.7%)
130 (84.4%)
-------------------------------------------------------------------------------The total number of patients randomized was used to calculate the percentages.
Program Location: SMDISA1.sas
Output Location: SMDISA11.txt
Data Location: Analysis_Data_Sets (COMMON)
Table 2 presents patient disposition and reasons for discontinuation. Of the 154 patients
randomized in the study, 104 (67.5%) were declared protocol complete by the
investigator. The most common reason for study discontinuation prior to protocol
completion was patient decision (n=22; 14.3%).
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Table 2.
Page 8
Patient Disposition and Reasons for Discontinuation
All Randomized Population
B9R-CA-GDCT
--------------------------------------------------------------------------------As-Randomized As-Randomized
Control
Humatrope
Total
--------------------------------------------------------------------------------All Randomized Population
78 (100%)
76 (100%)
154 (100%)
Declared Protocol Complete
43 (55.1%)
61 (80.3%)
104 (67.5%)
Discontinued Before Completion
35 (44.9%)
15 (19.7%)
50 (32.5%)
Withdrew Before Visit 1
11 (14.1%)
1 ( 1.3%)
12 ( 7.8%)
Discontinued at or Beyond Visit 1
Patient Decision
14 (17.9%)
8 (10.5%)
22 (14.3%)
Entry Criteria Exclusion
3 ( 3.8%)
1 ( 1.3%)
4 ( 2.6%)
Protocol Violation
3 ( 3.8%)
1 ( 1.3%)
4 ( 2.6%)
Lost to Follow-up
3 ( 3.8%)
0 ( 0.0%)
3 ( 1.9%)
Adverse Event
0 ( 0.0%)
2 ( 2.6%)
2 ( 1.3%)
Lack Of Efficacy
0 ( 0.0%)
2 ( 2.6%)
2 ( 1.3%)
Death
1 ( 1.3%)
0 ( 0.0%)
1 ( 0.6%)
---------------------------------------------------------------------------------Notes:
Frequencies are presented as number (percent). Percentages are calculated
relative to total number of randomized patients within treatment group.
Reasons for patient discontinuation at or beyond Visit 1 are listed in
descending order of frequency for the total patient population.
Data Location: Analysis_Data_Sets (ALL_M)
Of the 130 patients included in the Final Height Population, 108 (83.1%) fulfilled the
formal protocol definition of final height (Table 3). An additional 22 patients either were
declared protocol complete by the investigator, or had height measurements available at
or beyond chronological age 17 or bone age 15.
Table 3.
Completion Criteria Summary
B9R-CA-GDCT
Control
Humatrope
Total
--------------------------------------------------------------------------------Final Height Population
58 (100%)
72 (100%)
130 (100%)
Declared Protocol Complete
43 (74.1%)
61 (84.7%)
104 (80.0%)
by Investigator
Fulfilled Protocol Definition
43 (74.1%)
65 (90.3%)
108 (83.1%)
of Protocol Completion
Height Measurement Available
53 (91.4%)
66 (91.7%)
119 (91.5%)
at CA 17 or BA 15
---------------------------------------------------------------------------------CA = Chronological Age, BA = Bone Age.
Data Location: Analysis_Data_Sets (COMMON)
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Of the 154 patients who entered the Core Study, 76 (49.4%) returned for long-term
follow-up in Addendum 2, and 49 (31.8%) completed Addendum 2 (Table 4).
Table 4.
Patient Participation in Core Study and Addenda
B9R-CA-GDCT
---------------------------------------------------------------------As-Randomized As-Randomized
Number of Patients
Control
Humatrope
Total
---------------------------------------------------------------------Core Study
Started
78 (100%)
76 (100%)
154 (100%)
Completed
43 (55.1%)
61 (80.3%)
104 (67.5%)
Addendum 1
Started
2 ( 2.6%)
NA
2 ( 1.3%)
Completed
2 ( 2.6%)
NA
2 ( 1.3%)
Addendum 2
Started
28 (35.9%)
48 (63.2%)
76 (49.4%)
Completed
18 (23.1%)
31 (40.8%)
49 (31.8%)
Addendum 3
Participated
20 (25.6%)
37 (48.7%)
57 (37.0%)
Hearing Examination
Test Performed
25 (32.1%)
47 (61.8%)
72 (46.8%)
----------------------------------------------------------------------Program Location: SMDISA4.sas
Data Location: Analysis_Data_Sets (ALL_M)
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Efficacy Analyses
There were no statistically significant differences in baseline characteristics between
treatment groups for either the All Randomized Population (Table 5) or the Final
Height Population (Table 6).
Table 5.
Summary of Patient Characteristics at Core Study Baseline
B9R-CA-GDCT
As-Randomized
As-Randomized
Control
Humatrope
p-value
Age (years)
10.46 ± 1.77
10.36 ± 1.80
0.709
Height (cm)
120.06 ± 8.26
119.84 ± 8.45
0.872
−3.25 ± 0.82
−3.21 ± 0.82
0.796
Height SDS [NCHS]¹
−0.13 ± 0.86
−0.10 ± 0.88
0.809
Height SDS [Lyon]²
Pre-treatment height velocity (cm/year)
4.08 ± 1.01
4.23 ± 1.10
0.418
2
0.27 ± 0.69
0.35 ± 0.74
0.509
Pre-treatment height velocity SDS [Ranke]
160.02 ± 6.04
161.42 ± 6.06
0.172
Target height³ (cm)
−0.51 ± 0.93
−0.29 ± 0.93
0.173
Target height³ SDS NCHS [adult]
Bone age (years)
8.57 ± 1.51
8.79 ± 1.42
0.373
Bone age delay (years)
−1.89 ± 1.28
−1.57 ± 1.16
0.134
Weight (kg)
27.03 ± 7.78
26.69 ± 7.78
0.788
Weight SDS
−1.75 ± 1.16
−1.80 ± 1.30
0.789
18.44 ± 3.37
18.24 ± 3.35
0.713
Body mass index (kg/m²)
Body mass index SDS
0.27 ± 0.82
0.18 ± 0.97
0.547
Karyotype 45,X (%)
61.5
59.2
0.702
Caucasian / Asian / other (%)
80.6 / 10.4 / 9.0
88.0 / 8.0 / 4.0
0.111
Stature stratum: lower / middle / upper (%)
21.8 / 39.7 / 38.5
23.7 / 36.8 / 39.5
0.936
Abbreviations: SDS = standard deviation score; NCHS = National Center for Health Statistics.
¹US general population female reference standard [Kuczmarski et al. 2000]
²Turner syndrome reference standard for height [Lyon et al. 1985] and height velocity [Ranke et al. 1988]
³Target height is the sex-adjusted average of parents’ heights (also referred to as midparental height).
Frequencies of categorical variables are analyzed using a Fisher Exact test for the distribution across all
categories in the data; means of continuous variables are analyzed using a type III Sum of Squares
analysis of variance (ANOVA): PROC GLM model=treatment.
Program Location: SMBSCA1.sas
Output Location: SMBSCA11.txt
Data Location: Analysis_Data_Sets (EFFICACY)
Characteristics
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Table 6.
Page 11
Summary of Patient Characteristics at Core Study Baseline
B9R-CA-GDCT
As-Randomized
As-Randomized
Control
Humatrope
p-value
Age (years)
10.57 ± 1.72
10.39 ± 1.80
0.557
Height (cm)
120.48 ± 7.74
119.84 ± 8.49
0.657
−3.23 ± 0.84
−3.24 ± 0.83
0.988
Height SDS [NCHS]¹
−0.13 ± 0.87
−0.12 ± 0.89
0.967
Height SDS [Lyon]²
Pre-treatment height velocity (cm/year)
4.18 ± 1.00
4.22 ± 1.12
0.823
2
0.35 ± 0.68
0.34 ± 0.75
0.955
Pre-treatment height velocity SDS [Ranke]
160.14 ± 5.94
161.34 ± 6.14
0.268
Target height³ (cm)
−0.49 ± 0.92
−0.31 ± 0.95
0.268
Target height³ SDS NCHS [adult]
Bone age (years)
8.64 ± 1.46
8.80 ± 1.43
0.538
Bone age delay (years)
−1.95 ± 1.37
−1.55 ± 1.18
0.089
Weight (kg)
27.38 ± 8.04
26.86 ± 7.84
0.712
Weight SDS
−1.74 ± 1.16
−1.78 ± 1.33
0.834
Body mass index (kg/m²)
18.58 ± 3.64
18.36 ± 3.37
0.726
Body mass index SDS
0.27 ± 0.84
0.22 ± 0.97
0.778
Karyotype 45,X (%)
60.3
58.3
0.453
Caucasian / Asian / other (%)
78.6 / 10.7 / 10.7
87.5 / 8.3 / 4.2
0.072
Stature stratum: lower / middle / upper (%)
22.4 / 41.4 / 36.2
25.0 / 34.7 / 40.3
0.750
Abbreviations: SDS = standard deviation score; NCHS = National Center for Health Statistics.
¹US general population female reference standard [Kuczmarski et al. 2000]
²Turner syndrome reference standard for height [Lyon et al. 1985] and height velocity [Ranke et al. 1988]
³Target height is the sex-adjusted average of parents’ heights (also referred to as midparental height).
Frequencies of categorical variables are analyzed using a Fisher Exact test for the distribution across all
categories in the data; means of continuous variables are analyzed using a type III Sum of Squares analysis
of variance (ANOVA): PROC GLM model=treatment.
Program Location: SMBSCA1.sas
Output Location: SMBSCA12.txt
Characteristics
Table 7 presents a summary of the primary efficacy analyses. In the intent-to-treat
analysis, a statistically significant difference was demonstrated for Change in Height SDS
[NCHS] between As-Randomized treatment groups in the All Randomized Population
(p<0.001, primary inferential analysis). In the efficacy analysis, for the Final Height
Population according to As-Treated treatment groups, final Height SDS [NCHS] was
1.0 SDS (95% confidence interval [CI]: 0.9, 1.2) greater for the GH group than for the No
GH group (primary estimation analysis).
Somatropin rDNA
Somatropin rDNA
Table 7.
Summary of Primary Efficacy Analyses, Height SDS [NCHS]
Inferential Analysis in All Randomized Population with As-Randomized Treatment Groups
Estimation Analysis in Final Height Population with As-Treated Treatment Groups
B9R-CA-GDCT
Intent-to-Treat Analysis (Primary Inferential Analysis)
Change in Height SDS [NCHS], Baseline to Last Measurement
As-Randomized
As-Randomized
Control
Humatrope
n
LS Mean
SE
n
LS Mean
78
0.09
0.07
76
0.97
SE
0.07
LS Means
Difference and 95% CI
p-value
0.9 (0.7, 1.1)
<0.001a
Efficacy Analysis (Primary Estimation Analysis)
Height SDS [NCHS], Last Measurement After Attainment of Final Height
As-Treated
As-Treated
LS Means
p-value
No GH
GH
Difference and 95% CI
n
LS Mean
SE
n
LS Mean
SE
48
−3.30
0.07
82
−2.25
0.05
1.0 (0.9, 1.2)b
<0.001
Abbreviations: ANCOVA = analysis of covariance; SDS = standard deviation score; NCHS = National Center for Health Statistics; LS = least squares; SE =
standard error; CI = confidence interval; GH = growth hormone.
Each analysis uses an ANCOVA model that includes explanatory variables of baseline height SDS [Lyon], baseline age, treatment, baseline height SDS [Lyon]
by treatment interaction, and baseline age by treatment interaction. Baseline height SDS [Lyon] and treatment are retained as design factors; other terms are
removed from the model if not significant at p<0.05. P-values are given for the difference of LS means between treatment groups based on Type III sums of
squares in the ANCOVA model.
a
The p-value from the primary inferential analysis is used to establish existence of a treatment effect. Source: SMEFFA13.
b
The LS means difference from the primary estimation analysis is the principal estimate of magnitude of treatment effect. Source: SMEFFA12.
Page 12
Page 13
The average age of the patients at final height was 20 years for the As-Randomized
Control group and 21 years for the As-Randomized Humatrope group, after
approximately 4.7 and 5.3 years of participation in the Core Study, respectively. Eleven
(19%) of the patients randomized to Control ultimately received GH (Table 8).
Table 8.
Temporal Characteristics at Last Measurement
B9R-CA-GDCT
As-Randomized
As-Randomized
Control
Humatrope
n
Mean ± SD
n
Mean ± SD
Age (years)
58
20.05 ± 3.62
72
20.97 ± 3.42
Time on Core Study (years)
58
4.72 ± 2.34
72
5.31 ± 1.95
Total follow-up time (years)
58
9.48 ± 3.79
72
10.58 ± 3.61
8
3.64 ± 0.94
71
5.38 ± 1.86
Duration of GH (years)a
Abbreviations: SD = standard deviation; GH = growth hormone.
a
Eleven patients who were randomized to Control ultimately received GH; duration of GH treatment is
unknown for 3 patients.
Program Location: SMEFFA1.sas
Output Location: SMEFFA11.txt
Characteristics
Analysis of the Final Height Population according to the As-Randomized treatment
groups showed a difference of 0.8 SDS in the mean in adult Height SDS (NCHS). The
corresponding difference between treatment groups for mean attained height was 5.4 cm.
Mean bone age was approximately 15 years for both groups (Table 9).
Somatropin rDNA
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Table 9.
Auxological Characteristics at Last Measurement
B9R-CA-GDCT
As-Randomized
As-Randomized
LS Means
Characteristics
Control
Humatrope
Difference
p-value
n
LS Mean
SE
n
LS Mean
SE
and 95% CI
Height (cm)
58
143.11
0.50
72
148.51
0.44
5.4 (4.1, 6.7)
<0.001
Height SDS [NCHS AS]
58
−3.08
0.08
72
−2.25
0.07
0.8 (0.6, 1.0)
<0.001
Height SDS [NCHS adult]
58
−3.10
0.08
72
−2.28
0.07
0.8 (0.6, 1.0)
<0.001
Height SDS [Lyon AS]
58
0.17
0.08
72
0.93
0.07
0.8 (0.6, 1.0)
<0.001
Height SDS [Lyon adult]
58
0.02
0.07
72
0.82
0.07
0.8 (0.6, 1.0)
<0.001
Height (cm), change from baseline
58
23.00
0.49
72
28.39
0.44
5.4 (4.1, 6.7)
<0.001
Height SDS [NCHS AS], change from baseline
58
0.15
0.08
72
0.99
0.08
0.8 (0.6, 1.1)
<0.001
Height SDS [Lyon AS], change from baseline
58
0.29
0.08
72
1.05
0.07
0.8 (0.6, 1.0)
<0.001
Bone Age (years)
57
14.83
0.15
72
14.89
0.13
0.1 (−0.3, 0.5)
0.775
Weight (kg)
56
49.36
1.70
72
56.81
1.50
7.5 (3.0, 11.9)
0.001
Weight SDS
56
−1.23
0.18
72
−0.30
0.16
0.9 (0.4, 1.4)
<0.001
BMI (kg/m²)
56
24.45
0.68
72
25.78
0.60
1.3 (−0.5, 3.1)
0.142
BMI SDS [NCHS AS]
56
0.59
0.10
72
0.81
0.09
0.2 (−0.1, 0.5)
0.125
BMI SDS [NCHS AS], change from baseline
56
0.35
0.09
72
0.59
0.08
0.2 (−0.0, 0.5)
0.056
Abbreviations: LS = least squares; SE = standard error; CI = confidence interval; SDS = standard deviation score; NCHS = US general population female
reference standard [Kuczmarski et al. 2000]; AS = age-specific; Lyon = Turner syndrome reference standard [Lyon et al. 1985]; BMI = body mass index.
squares in the ANCOVA model. Source: SMEFFA11.
Page 14
Page 15
The average age of the patients at final height was 20 years for the As-Treated No GH
group and 21 years for the As-Treated GH group after approximately 5.1 and 5.0 years of
participation in the Core Study, respectively (Table 10).
Table 10.
Temporal Characteristics at Last Measurement
B9R-CA-GDCT
As-Treated
As-Treated
No GH
GH
n
Mean ± SD
n
Mean ± SD
Age (years)
48
19.94 ± 3.64
82
20.92 ± 3.43
Time on Core Study (years)
48
5.08 ± 2.27
82
5.03 ± 2.09
Total follow-up time (years)
48
9.14 ± 3.80
82
10.65 ± 3.57
0
NA
79
5.21 ± 1.86
Duration of GH (years)a
Abbreviations: SD = standard deviation; GH = growth hormone; NA = Not applicable.
a
Eleven patients who were randomized to Control ultimately received GH; duration of GH treatment is
unknown for 3 patients.
Program Location: SMEFFA1.sas
Output Location: SMEFFA12.txt
Characteristics
Analysis of the Final Height Population according to the As-Treated treatment groups
showed a difference of 1.0 SDS in the mean age-specific Height SDS (NCHS), and a
difference of 1.1 SDS in mean adult Height SDS (NCHS). The corresponding difference
between groups for mean attained height was 6.9 cm. Mean bone age was approximately
15 years for both groups (Table 11).
Somatropin rDNA
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Table 11.
Auxological Characteristics at Last Measurement
B9R-CA-GDCT
As-Treated
As-Treated
LS Means
Characteristics
No GH
GH
Difference
p-value
n
LS Mean
SE
n
LS Mean
SE
and 95% CI
Height (cm)
48
141.63
0.47
82
148.52
0.36
6.9 (5.7, 8.1)
<0.001
Height SDS [NCHS AS]
48
−3.30
0.07
82
−2.25
0.05
1.0 (0.9, 1.2)a
<0.001
Height SDS [NCHS adult]
48
−3.33
0.07
82
−2.27
0.05
1.1 (0.9, 1.2)
<0.001
Height SDS [Lyon AS]
48
−0.02
0.08
82
0.92
0.06
0.9 (0.7, 1.1)
<0.001
Height SDS [Lyon adult]
48
−0.20
0.07
82
0.82
0.05
1.0 (0.9, 1.2)
<0.001
Height (cm), change from baseline
48
21.53
0.47
82
28.38
0.36
6.8 (5.7, 8.0)
<0.001
Height SDS [NCHS AS], change from baseline
48
−0.09
0.08
82
0.99
0.06
1.1 (0.9, 1.3)
<0.001
Height SDS [Lyon AS], change from baseline
48
0.10
0.08
82
1.05
0.06
0.9 (0.7, 1.1)
<0.001
Bone age (years)
47
14.87
0.17
82
14.86
0.13
0.0 (−0.4, 0.4)
0.992
Weight (kg)
46
49.10
1.89
82
56.05
1.42
7.0 (2.3, 11.6)
0.004
Weight SDS
46
−1.37
0.20
82
−0.33
0.15
1.0 (0.5, 1.5)
<0.001
BMI (kg/m²)
46
24.16
0.75
82
25.78
0.56
1.6 (−0.2, 3.5)
0.084
BMI SDS [NCHS AS]
46
0.52
0.11
82
0.82
0.09
0.3 (0.0, 0.6)
0.042
BMI SDS [NCHS AS], change from baseline
46
0.41
0.11
82
0.52
0.08
0.1 (−0.2, 0.4)
0.440
Abbreviations: GH = growth hormone; LS = least squares; SE = standard error; CI = confidence interval; SDS = standard deviation score; NCHS = US general
population female reference standard [Kuczmarski et al. 2000]; AS = age-specific; Lyon = Turner syndrome reference standard [Lyon et al. 1985]; BMI = body
mass index.
a
The LS Means difference from this primary estimation analysis is the principal estimate of magnitude of treatment effect.
squares in the ANCOVA model. Source: SMEFFA12.
Page 16
Page 17
Safety Analyses
Table 12 provides an overview of adverse events reported in this study for patients in the
Treated-As-Randomized Population. One Control patient for whom a serious adverse
event was reported is not included in Table 12, because the patient received GH after
participating in the Core Study and is therefore excluded from the Treated-AsRandomized Population; this patient’s serious adverse event occurred during the Core
Study, prior to GH therapy. In addition, 1 patient had an event of shortness of breath
(dyspnea) that was not designated as serious when initially reported by the study site.
The diagnosis for this event was later changed to asthma and the event outcome was
changed to serious on the basis of threat to life; however, this change was not reflected in
the study database, and this patient is therefore not included in the data provided below
for serious adverse events.
Table 12.
Summary of Adverse Events for Overall Study
B9R-CA-GDCT Core Baseline to Addendum 2 Endpoint
Control
Humatrope
Total
54 (100%)
74 (100%)
128 (100%)
--------------------------------------------------------------------------------Type of Adverse Event
Death
1 ( 1.9%)
0 ( 0.0%)
1 ( 0.8%)
Serious
10 (18.5%)
22 (29.7%)
32 (25.0%)
Resulted in Discontinuation from
0 ( 0.0%)
2 ( 2.7%)
2 ( 1.6%)
Study
Event of Special Interest
47 (87.0%)
73 (98.6%)
120 (93.8%)
Treatment-emergent
53 (98.1%)
74 (100%)
127 (99.2%)
---------------------------------------------------------------------------------N = number of patients in treatment group; n = number of patients in treatment
group for whom event was reported. Frequencies are presented as number
(percent). Percentages are relative to Treated-As-Randomized population,
within column.
A serious event was defined as an event that resulted in any of the following
outcomes; death; threat to life; severe or permanent disability; hospitalization
or prolongation of hospital stay if the event occurred while the patient was
already hospitalized; other severe outcome (including cancer).
An event of special interest was defined as an event that either is known
to occur with increased frequency in patients with Turner syndrome, or is
listed in the product labeling for Humatrope.
A treatment-emergent adverse event was defined as any event that began after
baseline (Visit 1) or increased in severity after baseline. The numbers
represent patients for whom at least one treatment-emergent adverse event
was reported.
Program Location: FQAESA1.sas
Output Location: FQAESA11.txt
Data Location: Analysis_Data_Sets (EVENT)
Somatropin rDNA
Page 18
Serious Adverse Events
One patient in the As-Randomized Control group died as a result of a cardiac arrest
following rupture of an aortic aneurysm. Forty-three other serious adverse events were
reported for 33 patients: 11 patients in the As-Randomized Control group (including the
patient who later died, and 1 patient who received GH treatment after leaving the Core
Study) and 22 patients in the As-Randomized Humatrope group. These 43 events, which
were serious on the basis of hospitalization, are summarized below in 5 broad categories.
Because 5 of 33 patients had multiple hospitalizations, they are included in 2 distinct
categories; the remaining 28 patients are included in 1 category only.
•
Fifteen patients were hospitalized for 17 events that represented acute
illnesses, infections, injuries, or surgeries (Control, n=5: 2 patients,
appendicitis and appendectomy; 1 patient, ruptured aortic aneurysm;
1 patient, possible thrombophlebitis; 1 patient, pneumonia; Humatrope,
n=10: 2 patients, arm fractures; 2 patients, viral gastroenteritis/“stomach
flu”; 1 patient, acute psoriasis/pustular psoriasis [2 separate episodes];
1 patient, cellulitis; 1 patient, pyelonephritis; 1 patient, viral meningitis;
1 patient, dehydration and wrist fracture [2 separate events]; and 1 patient,
otitis media).
•
Seven patients were hospitalized for 10 events of surgery related to ear,
nose, and throat conditions (Control, n=1: 1 patient, teeth extraction;
Humatrope, n=6: 1 patient, adenoidectomy; 1 patient tympanoplasty and
mastoid operation [2 separate events]; 1 patient, mastoidectomy; 1 patient,
tympanoplasty, mastoidectomy, and nasal surgery; 1 patient,
tympanoplasty [1 event] and cholesteatoma resection [3 separate events];
and 1 patient, dental surgery).
•
Six patients were hospitalized for elective surgeries (Control, n=4:
1 patient, ureteral reimplantation; 1 patient, pectus excavatum repair;
1 patient, plastic surgery for pterygium colli; 1 patient, plastic surgery for
keloid scar removal; Humatrope, n=2: 1 patient, gonadectomy; and
1 patient, plastic surgery for pterygium colli).
•
Six patients were hospitalized for other surgeries or procedures (Control,
n=1: 1 patient, unspecified surgical procedure; Humatrope, n=5: 1 patient,
gastroscopy and colonoscopy; 1 patient, cystoscopy and pyelogram;
1 patient, strabismus repair; 1 patient, coarctation repair; and 1 patient,
ventriculo-peritoneal shunt revision).
•
Four patients were hospitalized for events that were significant for other
reasons (Control, n=1: 1 patient, idiopathic thrombocytopenic purpura;
Humatrope, n=3: 1 patient, iron deficiency anemia; 1 patient,
hypochromic, microcytic anemia; and 1 patient, cerebellar cyst).
Somatropin rDNA
Page 19
Treatment-Emergent Adverse Events
Table 13 presents TEAEs reported in ≥5% of patients in either group.
Table 13.
Treatment-Emergent Adverse Events (MedDRA LLT)
Reported for at least 5% of Patients in Either Group
Treated-As-Randomized Population, Events for Overall
Study
Control
Humatrope
Total
54 (100%)
74 (100%)
128 (100%)
--------------------------------------------------------------------------------Any Adverse Event
53 (98.1%)
74 (100%)
127 (99.2%)
Cold
39 (72.2%)
42 (56.8%)
81 (63.3%)
Headache
25 (46.3%)
46 (62.2%)
71 (55.5%)
Sore throat
28 (51.9%)
37 (50.0%)
65 (50.8%)
Fever
20 (37.0%)
36 (48.6%)
56 (43.8%)
Flu
20 (37.0%)
36 (48.6%)
56 (43.8%)
Vomiting
21 (38.9%)
29 (39.2%)
50 (39.1%)
Otitis media
13 (24.1%)
32 (43.2%)
45 (35.2%)
Cough
14 (25.9%)
27 (36.5%)
41 (32.0%)
Ear infection
12 (22.2%)
27 (36.5%)
39 (30.5%)
Rhinitis
11 (20.4%)
17 (23.0%)
28 (21.9%)
Head cold
9 (16.7%)
18 (24.3%)
27 (21.1%)
Upper respiratory infection
14 (25.9%)
13 (17.6%)
27 (21.1%)
Nasal congestion
8 (14.8%)
17 (23.0%)
25 (19.5%)
Diarrhea
11 (20.4%)
12 (16.2%)
23 (18.0%)
Flu syndrome
6 (11.1%)
15 (20.3%)
21 (16.4%)
Hypothyroidism
7 (13.0%)
13 (17.6%)
20 (15.6%)
Otitis externa
6 (11.1%)
13 (17.6%)
19 (14.8%)
Pharyngitis
8 (14.8%)
11 (14.9%)
19 (14.8%)
Abdominal pain
9 (16.7%)
9 (12.2%)
18 (14.1%)
Nausea
5 ( 9.3%)
13 (17.6%)
18 (14.1%)
Ear pain
3 ( 5.6%)
14 (18.9%)
17 (13.3%)
Upper respiratory tract infection
9 (16.7%)
8 (10.8%)
17 (13.3%)
Ear ache
6 (11.1%)
10 (13.5%)
16 (12.5%)
---------------------------------------------------------------------------------(continued)
Somatropin rDNA
Table 13.
Page 20
Study
(Continued)
Control
Humatrope
Total
54 (100%)
74 (100%)
128 (100%)
--------------------------------------------------------------------------------Rash
8 (14.8%)
8 (10.8%)
16 (12.5%)
Intermittent headache
3 ( 5.6%)
12 (16.2%)
15 (11.7%)
Throat infection
7 (13.0%)
8 (10.8%)
15 (11.7%)
Dental treatment
8 (14.8%)
6 ( 8.1%)
14 (10.9%)
Menstrual cramps
7 (13.0%)
7 ( 9.5%)
14 (10.9%)
Scoliosis
8 (14.8%)
6 ( 8.1%)
14 (10.9%)
Stomach ache
7 (13.0%)
7 ( 9.5%)
14 (10.9%)
Chickenpox
5 ( 9.3%)
8 (10.8%)
13 (10.2%)
Earache
5 ( 9.3%)
8 (10.8%)
13 (10.2%)
Stomach flu
6 (11.1%)
7 ( 9.5%)
13 (10.2%)
Streptococcal sore throat
4 ( 7.4%)
9 (12.2%)
13 (10.2%)
Bronchitis
5 ( 9.3%)
7 ( 9.5%)
12 ( 9.4%)
Eye infection
3 ( 5.6%)
9 (12.2%)
12 ( 9.4%)
Sinus congestion
5 ( 9.3%)
7 ( 9.5%)
12 ( 9.4%)
Cold symptoms
4 ( 7.4%)
7 ( 9.5%)
11 ( 8.6%)
Dizziness
4 ( 7.4%)
7 ( 9.5%)
11 ( 8.6%)
Tonsillitis
5 ( 9.3%)
6 ( 8.1%)
11 ( 8.6%)
Depression
4 ( 7.4%)
6 ( 8.1%)
10 ( 7.8%)
Impetigo
4 ( 7.4%)
6 ( 8.1%)
10 ( 7.8%)
Sinusitis
3 ( 5.6%)
7 ( 9.5%)
10 ( 7.8%)
Common cold
4 ( 7.4%)
5 ( 6.8%)
9 ( 7.0%)
Dry skin
1 ( 1.9%)
8 (10.8%)
9 ( 7.0%)
Gastroenteritis
2 ( 3.7%)
7 ( 9.5%)
9 ( 7.0%)
Hearing loss
2 ( 3.7%)
7 ( 9.5%)
9 ( 7.0%)
Knee pain
1 ( 1.9%)
8 (10.8%)
9 ( 7.0%)
---------------------------------------------------------------------------------(continued)
Somatropin rDNA
Table 13.
Page 21
Study
(Continued)
Control
Humatrope
Total
54 (100%)
74 (100%)
128 (100%)
--------------------------------------------------------------------------------Myringotomy
1 ( 1.9%)
8 (10.8%)
9 ( 7.0%)
Primary ovarian failure
4 ( 7.4%)
5 ( 6.8%)
9 ( 7.0%)
Eczema
4 ( 7.4%)
4 ( 5.4%)
8 ( 6.3%)
Hay fever
1 ( 1.9%)
7 ( 9.5%)
8 ( 6.3%)
Hypertension
1 ( 1.9%)
7 ( 9.5%)
8 ( 6.3%)
Stomach cramps
4 ( 7.4%)
4 ( 5.4%)
8 ( 6.3%)
Stomach pain
2 ( 3.7%)
6 ( 8.1%)
8 ( 6.3%)
Upset stomach
3 ( 5.6%)
5 ( 6.8%)
8 ( 6.3%)
Urinary tract infection
3 ( 5.6%)
5 ( 6.8%)
8 ( 6.3%)
Bladder infection
3 ( 5.6%)
4 ( 5.4%)
7 ( 5.5%)
Chest cold
0 ( 0.0%)
7 ( 9.5%)
7 ( 5.5%)
Congestion nasal
2 ( 3.7%)
5 ( 6.8%)
7 ( 5.5%)
Coughing
2 ( 3.7%)
5 ( 6.8%)
7 ( 5.5%)
Low back pain
4 ( 7.4%)
3 ( 4.1%)
7 ( 5.5%)
Mole excision
2 ( 3.7%)
5 ( 6.8%)
7 ( 5.5%)
Multiple allergies
1 ( 1.9%)
6 ( 8.1%)
7 ( 5.5%)
Myopia
3 ( 5.6%)
4 ( 5.4%)
7 ( 5.5%)
Naevus
2 ( 3.7%)
5 ( 6.8%)
7 ( 5.5%)
Throat sore
1 ( 1.9%)
6 ( 8.1%)
7 ( 5.5%)
Tympanoplasty
0 ( 0.0%)
7 ( 9.5%)
7 ( 5.5%)
Conjunctivitis
2 ( 3.7%)
4 ( 5.4%)
6 ( 4.7%)
Cramps menstrual
2 ( 3.7%)
4 ( 5.4%)
6 ( 4.7%)
Dysmenorrhea
2 ( 3.7%)
4 ( 5.4%)
6 ( 4.7%)
Nose bleed
1 ( 1.9%)
5 ( 6.8%)
6 ( 4.7%)
Osteopenia
4 ( 7.4%)
2 ( 2.7%)
6 ( 4.7%)
---------------------------------------------------------------------------------(continued)
Somatropin rDNA
Table 13.
Page 22
Study
(Concluded)
Control
Humatrope
Total
54 (100%)
74 (100%)
128 (100%)
--------------------------------------------------------------------------------Sinus infection
1 ( 1.9%)
5 ( 6.8%)
6 ( 4.7%)
Tooth extraction
3 ( 5.6%)
3 ( 4.1%)
6 ( 4.7%)
Accidental overdose
0 ( 0.0%)
5 ( 6.8%)
5 ( 3.9%)
Chest pain
4 ( 7.4%)
1 ( 1.4%)
5 ( 3.9%)
Dental surgery NOS
1 ( 1.9%)
4 ( 5.4%)
5 ( 3.9%)
Ear tube insertion
1 ( 1.9%)
4 ( 5.4%)
5 ( 3.9%)
Epistaxis
3 ( 5.6%)
2 ( 2.7%)
5 ( 3.9%)
Fatigue
4 ( 7.4%)
1 ( 1.4%)
5 ( 3.9%)
Head injury
3 ( 5.6%)
2 ( 2.7%)
5 ( 3.9%)
Ingrown toe nail
3 ( 5.6%)
2 ( 2.7%)
5 ( 3.9%)
Leg pain
1 ( 1.9%)
4 ( 5.4%)
5 ( 3.9%)
Nasal discharge
3 ( 5.6%)
2 ( 2.7%)
5 ( 3.9%)
Ache stomach
0 ( 0.0%)
4 ( 5.4%)
4 ( 3.1%)
Aortic dilatation
3 ( 5.6%)
1 ( 1.4%)
4 ( 3.1%)
Asthma
0 ( 0.0%)
4 ( 5.4%)
4 ( 3.1%)
Blood pressure high
3 ( 5.6%)
1 ( 1.4%)
4 ( 3.1%)
Ear discharge
0 ( 0.0%)
4 ( 5.4%)
4 ( 3.1%)
Pain
0 ( 0.0%)
4 ( 5.4%)
4 ( 3.1%)
Psoriasis
0 ( 0.0%)
4 ( 5.4%)
4 ( 3.1%)
Spotting vaginal
4 ( 7.4%)
0 ( 0.0%)
4 ( 3.1%)
Sensorineural hearing loss
3 ( 5.6%)
0 ( 0.0%)
3 ( 2.3%)
Tympanosclerosis
3 ( 5.6%)
0 ( 0.0%)
3 ( 2.3%)
within column.
Events are listed in order of overall frequency of occurrence for total
population.
MedDRA = Medical Dictionary for Regulatory Affairs, LLT = Lower Level Term.
A treatment-emergent adverse event was defined as any event that began after
baseline (Visit 1) or increased in severity after baseline. The numbers
represent patients for whom at least one treatment-emergent adverse event
was reported.
Somatropin rDNA
Page 23
Addendum 2 employed a targeted questionnaire to solicit the occurrence of certain
adverse events of special interest to patients with Turner syndrome or to those receiving
GH. There were no statistically significant differences between treatment groups for any
of these events (Table 14).
Table 14.
Targeted Adverse Events Collected by Questionnaire during
Addendum 2
Safety Population with Addendum 2 Data
B9R-CA-GDCT
-----------------------------------------------------------------------------As-Treated
As-Treated
No-GH
GH
Total
p-value
Safety Population
21 (100%)
55 (100%)
76 (100%)
-----------------------------------------------------------------------------Diabetes
0 ( 0.0%)
1 ( 1.8%)
1 ( 1.3%)
>0.999
High blood sugar
0 ( 0.0%)
1 ( 1.8%)
1 ( 1.3%)
>0.999
Middle ear infection
2 ( 9.5%)
13 (23.6%)
15 (19.7%)
0.212
Ear surgery
0 ( 0.0%)
3 ( 5.5%)
3 ( 3.9%)
0.556
Hearing loss
5 (23.8%)
17 (30.9%)
22 (28.9%)
0.778
Other ear problem
0 ( 0.0%)
3 ( 5.5%)
3 ( 3.9%)
0.556
Heart surgery
0 ( 0.0%)
0 ( 0.0%)
0 ( 0.0%)
Other heart problem
4 (19.0%)
5 ( 9.1%)
9 (11.8%)
0.251
High blood pressure
3 (14.3%)
8 (14.5%)
11 (14.5%)
>0.999
Edema
2 ( 9.5%)
10 (18.2%)
12 (15.8%)
0.492
New diagnosis of scoliosis
1 ( 4.8%)
0 ( 0.0%)
1 ( 1.3%)
0.276
Worsening of scoliosis already
0 ( 0.0%)
0 ( 0.0%)
0 ( 0.0%)
present
Surgery of scoliosis
0 ( 0.0%)
0 ( 0.0%)
0 ( 0.0%)
Limp
1 ( 4.8%)
1 ( 1.8%)
2 ( 2.6%)
0.479
Hip pain
1 ( 4.8%)
3 ( 5.5%)
4 ( 5.3%)
>0.999
Slipped capital femoral
0 ( 0.0%)
0 ( 0.0%)
0 ( 0.0%)
epiphysis
Other bone or joint problem
3 (14.3%)
12 (21.8%)
15 (19.7%)
0.538
Pressure/fluid on the brain
0 ( 0.0%)
2 ( 3.6%)
2 ( 2.6%)
>0.999
Frequent headache
2 ( 9.5%)
6 (10.9%)
8 (10.5%)
>0.999
Hyperthyroidism
0 ( 0.0%)
1 ( 1.8%)
1 ( 1.3%)
>0.999
Hypothyroidism
4 (19.0%)
10 (18.2%)
14 (18.4%)
>0.999
Development of new moles on
4 (19.0%)
7 (12.7%)
11 (14.5%)
0.484
the skin
Darkening or enlargement of
1 ( 4.8%)
7 (12.7%)
8 (10.5%)
0.432
moles already present on the
skin
Other surgery
3 (14.3%)
13 (23.6%)
16 (21.1%)
0.533
Other health problem
10 (47.6%)
19 (34.5%)
29 (38.2%)
0.306
-----------------------------------------------------------------------------N = number of patients in treatment group; n = number of patients in treatment
group for whom event was reported. Frequencies are presented as number (percent).
Percentages are relative to Safety Population with Addendum 2 data, within
column.
P-values calculated using Fisher Exact test.
Somatropin rDNA
Page 24
An additional analysis of spontaneously reported TEAEs was performed to aid in
detection of any potential safety signals. For this analysis, custom classifications were
prospectively defined for events that may have clinical significance for patients with
Turner syndrome or that may be associated with GH treatment (Table 15).
Table 15.
Events of Special Interest for Overall Study
Control
Humatrope
Total
54 (100%)
74 (100%)
128 (100%)
--------------------------------------------------------------------------------Event of Special Interest
47 (87.0%)
73 (98.6%)
120 (93.8%)
Headache
Otitis Media
Ear Disorder
Joint Disorder
Menstrual Disorder
Thyroid Disorder
Cardiovascular Disorder
Change in Cutaneous Nevi
Hearing Disorder
Scoliosis
Back Pain
Ear Tubes
Edema
Tympanic Membrane Disorder
Fracture
Bone Disorder
Tonsillectomy and/or Adenoidectomy
Liver Disorder
Lymphoid Tissue Hyperplasia
Diabetes Mellitus and Related
Lipid Disorder
Neoplasia
Raised Intracranial Pressure
25
22
10
9
13
12
9
8
5
8
7
3
4
4
4
4
1
3
1
1
0
0
0
(46.3%)
(40.7%)
(18.5%)
(16.7%)
(24.1%)
(22.2%)
(16.7%)
(14.8%)
( 9.3%)
(14.8%)
(13.0%)
( 5.6%)
( 7.4%)
( 7.4%)
( 7.4%)
( 7.4%)
( 1.9%)
( 5.6%)
( 1.9%)
( 1.9%)
( 0.0%)
( 0.0%)
( 0.0%)
50
52
35
23
19
17
18
19
15
8
8
12
10
10
9
4
7
2
4
2
3
1
1
(67.6%)
(70.3%)
(47.3%)
(31.1%)
(25.7%)
(23.0%)
(24.3%)
(25.7%)
(20.3%)
(10.8%)
(10.8%)
(16.2%)
(13.5%)
(13.5%)
(12.2%)
( 5.4%)
( 9.5%)
( 2.7%)
( 5.4%)
( 2.7%)
( 4.1%)
( 1.4%)
( 1.4%)
75
74
45
32
32
29
27
27
20
16
15
15
14
14
13
8
8
5
5
3
3
1
1
(58.6%)
(57.8%)
(35.2%)
(25.0%)
(25.0%)
(22.7%)
(21.1%)
(21.1%)
(15.6%)
(12.5%)
(11.7%)
(11.7%)
(10.9%)
(10.9%)
(10.2%)
( 6.3%)
( 6.3%)
( 3.9%)
( 3.9%)
( 2.3%)
( 2.3%)
( 0.8%)
( 0.8%)
within column.
For analysis of Events of Special Interest, custom classifications were prospectively
defined for events that may have clinical significance for patients with Turner
syndrome or that may be associated with GH treatment.
Events are listed in order of overall frequency of occurrence for total
population.
Somatropin rDNA
Somatropin rDNA
Middle Ear and Hearing Assessments
There were no statistically significant differences between treatment groups in audiologists’ assessments of any of 3 middle ear and
hearing evaluations (Table 16).
Table 16.
Audiometric Examination Normality, Audiologist Assessed
All Randomized Patients with Hearing Examination
B9R-CA-GDCT
--------------------------------------------------------------------------------------------------------------As-Treated
As-Treated
No GH
GH
Total
p-value
--------------------------------------------------------------------------------------------------------------Hearing Examination Performed
19
53
72
Audiometric Examination Normality Questions Answered
19 (100%)
53 (100%)
72 (100%)
Abnormal Pure Tone Audiometry, Hearing Threshold
10 (52.6%)
29 (54.7%)
39 (54.2%)
>0.999
Abnormal Speech Audiometry
3 (15.8%)
12 (22.6%)
15 (20.8%)
0.744
Abnormal Impedance Tympanogram
2 (10.5%)
18 (34.0%)
20 (27.8%)
0.073
---------------------------------------------------------------------------------------------------------------Each p-value is from a Fisher Exact test of the proportion of patients whose result was reported abnormal among
patients for whom the audiologist completed the normality assessment questions for 'Pure Tone Audiometry, Hearing
Threshold', 'Speech Audiometry', and 'Impedance Tympanogram'.
Program Location: FQHEAA1.sas
Output Location: FQHEAA11.txt
Data Location: Analysis_Data_Sets (AUDEXAM_NORM_AA)
Page 25
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There was no statistically significant difference between treatment groups in the audiologists’ overall assessment of hearing loss
(Table 17).
Table 17.
Overview of Hearing Loss, Audiologist Assessed, By Type
B9R-CA-GDCT
--------------------------------------------------------------------------------------------------------------As-Treated
As-Treated
No GH
GH
Total
p-value
19
53
72
Hearing Examination Normality Question Answered
19 (100%)
52 (100%)
71 (100%)
No Hearing Loss, Audiologist Assessment
7 (36.8%)
20 (38.5%)
27 (38.0%)
Hearing Loss, Audiologist Assessment
12 (63.2%)
32 (61.5%)
44 (62.0%)
>0.999
Conductive Hearing Loss
1 ( 5.3%)
7 (13.5%)
8 (11.3%)
Sensorineural Hearing Loss
8 (42.1%)
15 (28.8%)
23 (32.4%)
Conductive and Sensorineural (Mixed) Hearing Loss
2 (10.5%)
9 (17.3%)
11 (15.5%)
Unspecified Hearing Loss
1 ( 5.3%)
1 ( 1.9%)
2 ( 2.8%)
---------------------------------------------------------------------------------------------------------------The p-value on 'Hearing Loss, Audiologist Assessment' is from a Fisher Exact test, upon the proportion of
patients for whom the audiologist responded to an omnibus question regarding normality of the audiometric
examination.
Data Location: Analysis_Data_Sets (HEARLOSS_TYPE_AA)
Page 26
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There was no statistically significant difference between treatment groups in calculated determinations of test normality for pure tone
audiometry (Table 18), impedance tympanometry (Table 19), or speech audiometry (Table 20).
Table 18.
Overview of Hearing Loss, Calculated from Pure Tone Audiometry, By Type
B9R-CA-GDCT
------------------------------------------------------------------------------------------------------------------------As-Treated
As-Treated
No GH
GH
Total
p-value
------------------------------------------------------------------------------------------------------------------------Hearing Examination Performed
19
53
72
Evaluable Pure Tone Audiometry Data
17 (100%)
44 (100%)
61 (100%)
No Hearing Loss, Calculated
7 (41.2%)
20 (45.5%)
27 (44.3%)
Hearing Loss of Any Type, Calculated
10 (58.8%)
24 (54.5%)
34 (55.7%)
>0.999
Sensorineural Hearing Loss (SNHL)
5 (29.4%)
7 (15.9%)
12 (19.7%)
Conductive Hearing Loss (CHL)
0 ( 0.0%)
5 (11.4%)
5 ( 8.2%)
Mixed Hearing Loss Type I (MHL1)
2 (11.8%)
6 (13.6%)
8 (13.1%)
Mixed Hearing Loss Type II (MHL2)
1 ( 5.9%)
5 (11.4%)
6 ( 9.8%)
Unspecified Hearing Loss (UHL)
4 (23.5%)
7 (15.9%)
11 (18.0%)
Abnormal Pure Tone Average, Calculated
5 (29.4%)
19 (43.2%)
24 (39.3%)
0.391
-------------------------------------------------------------------------------------------------------------------------Pure Tone Audiometry data was considered evaluable if air conduction values were available for all frequencies from 250 to
8000 Hz for both ears, and the difference in hearing threshold between air conduction and bone conduction was >= -5 dB HL
in those cases in which bone conduction was tested. Abnormal hearing: air conduction > 20 dB HL at two adjacent frequencies
or air conduction > 30 dB HL at any individual frequency; sensorineural hearing loss (SNHL): air conduction threshold > 20
dB HL and air-bone gap <= 10 dB HL; conductive hearing loss (CHL): air conduction threshold > 20 dB HL, bone conduction
threshold <= 20 dB HL and air-bone gap > 10 dB HL; mixed hearing loss type 1 (MHL1): air conduction threshold > 20 dB HL
and bone threshold > 20 and air-bone gap > 10 dB HL; mixed hearing loss type 2 (MHL2): evidence of SNHL as defined in (2)
and CHL as defined in (3) in the same ear; unspecified hearing loss (UHL): abnormal hearing with none of SNHL, CHL, MHL1,
or MHL2 present.
The p-values on 'Hearing Loss Of Any Type, Calculated' and 'Abnormal Pure Tone Average' are from a Fisher Exact test,
as a proportion of patients with evaluable Pure Tone Audiometry data. In this table, an individual ear may have only
one Type of Hearing Loss. However, Type of Hearing Loss may be different in each ear of an individual patient, and so
categories are not mutually exclusive at the patient level.
Data Location: Analysis_Data_Sets (PURETONE_CALC)
Page 27
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Table 19.
Overview of Impedance Tympanometry, Calculated
B9R-CA-GDCT
-----------------------------------------------------------------------------------------------------------------As-Treated
As-Treated
No GH
GH
Total
p-value
-----------------------------------------------------------------------------------------------------------------Hearing Examination Performed
19
53
72
Evaluable Tympanogram
16 (100%)
42 (100%)
58 (100%)
Normal Tympanogram, Calculated
10 (62.5%)
17 (40.5%)
27 (46.6%)
Tympanogram Abnormality Of Any Type, Calculated
6 (37.5%)
25 (59.5%)
31 (53.4%)
0.153
Reduced Equivalent Ear Canal Volume (ECV)
1 ( 6.3%)
0 ( 0.0%)
1 ( 1.7%)
Increased Equivalent Ear Canal Volume (ECV)
3 (18.8%)
15 (35.7%)
18 (31.0%)
Reduced Tympanometric Peak Pressure (TPP)
0 ( 0.0%)
6 (14.3%)
6 (10.3%)
Reduced Static Admittance/Compliance (SA/C)
2 (12.5%)
8 (19.0%)
10 (17.2%)
Increased Static Admittance/Compliance (SA/C)
0 ( 0.0%)
6 (14.3%)
6 (10.3%)
------------------------------------------------------------------------------------------------------------------Impedance Tympanometry data is Evaluable if, in both ears, values are available for each of Equivalent Ear Canal
Volume (ECV),Tympanometric Peak Pressure (TPP), and Static Admittance/Compliance (SA/C). Types of tympanometry
abnormality are not mutually exclusive; therefore, an individual patient may be included in more than one
category.
The p-value for 'Tympanogram Abnormality Of Any Type, Calculated' is from a Fisher Exact test, as a proportion of
patients with abnormal findings among the patients with evaluable Impedance Tympanometry data.
Data Location: Analysis_Data_Sets (TYMPANOMETRY_CALC)
Page 28
Somatropin rDNA
Table 20.
Overview of Speech Audiometry, Calculated
B9R-CA-GDCT
--------------------------------------------------------------------------------------------------------------As-Treated
As-Treated
No GH
GH
Total
p-value
19
53
72
Evaluable Speech Audiometry
19 (100%)
50 (100%)
69 (100%)
Normal Speech Audiometry, Calculated
16 (84.2%)
41 (82.0%)
57 (82.6%)
Speech Audiometry Abnormality Of Any Type, Calculated
3 (15.8%)
9 (18.0%)
12 (17.4%)
>0.999
Abnormal Speech Reception Threshold
3 (15.8%)
9 (18.0%)
12 (17.4%)
Abnormal Speech Discrimination
1 ( 5.3%)
1 ( 2.0%)
2 ( 2.9%)
---------------------------------------------------------------------------------------------------------------Speech Audiometry data is Evaluable if, for both ears, values are available for Speech Reception
Threshold and Speech Discrimination.
The p-value for 'Speech Audiometry Abnormality Of Any Type, Calculated' is from a Fisher Exact test, as a
proportion of patients with evaluable Speech Audiometry data. Types of speech audiometry abnormality are not
mutually exclusive; therefore, an individual patient may be included in more than one category.
Data Location: Analysis_Data_Sets (SPEECHAUD_CALC)
Page 29
Somatropin rDNA
Measures of Glucose Metabolism
Fifty-six patients in the Safety Population who were followed for at least 4 years without GH treatment (if never treated) or who
received GH for a total of 4 years were included in this analysis of glucose metabolism data. Average values for fasting glucose and
hemoglobin A1C were within the normal range (ADA 2007) at all time points and were similar for both treatment groups (Table 21).
Table 21.
Glucose Metabolism – Descriptive Statistics
Treated-As-Randomized Patients in Glucose 4-Year Population
B9R-CA-GDCT Patients with Glucose Metabolism Data at Core Baseline and during Addendum 2
--------------------------------------------------------------------------------------------------Addendum 2
Core
Core Last
Addendum 2
Last
Addendum 2
Baseline
Measurement
Baseline
Measurement
Maximum
n mean ± SD
n mean ± SD
n mean ± SD
n mean ± SD
n mean ± SD
--------------------------------------------------------------------------------------------------Fasting Glucose
(mg/dL)
Control
20 79.8 ± 10.6
19 77.0 ± 9.4
20 83.4 ± 7.0
11 81.1 ± 7.3 20 85.3 ± 6.8
Humatrope
36 81.1 ± 10.3
36 80.4 ± 9.2
35 78.9 ± 13.4
26 83.0 ± 8.5 36 84.1 ± 8.3
Fasting Glucose
(mMol/L)
Control
Humatrope
20
36
4.4 ±
4.5 ±
0.6
0.6
19
36
4.3 ±
4.5 ±
0.5
0.5
20
35
4.6 ±
4.4 ±
0.4
0.7
11
26
4.5 ±
4.6 ±
0.4
0.5
20
36
4.7 ±
4.7 ±
0.4
0.5
Hemoglobin
A1C (%)
Control
Humatrope
20
36
4.8 ±
4.8 ±
0.5
0.5
19
36
4.9 ±
5.0 ±
0.6
0.4
20
34
5.0 ±
5.0 ±
0.5
0.4
11
24
4.6 ±
4.8 ±
0.5
0.4
20
36
5.0 ±
5.0 ±
0.5
0.4
--------------------------------------------------------------------------------------------------Core Last Measurement - last post-baseline measurement in core study
Addendum 2 Last Measurement - last measured value at Visit 202 or 203
Addendum 2 Maximum - maximum value measured at Visit 201, 202, or 203
Program Location: SMLABA1.sas
Output Location: SMLABA13.txt
Data Location: Analysis_Data_Sets (GLUMET)
Page 30
Somatropin rDNA
There were no statistically significant differences between treatment groups for changes in fasting blood glucose or hemoglobin A1C
(Table 22).
Table 22.
Glucose Metabolism – Inferential Statistics
Treated-As-Randomized Patients in Glucose 4-Year Population
B9R-CA-GDCT Patients with Glucose Metabolism Data at Core Baseline and during Addendum 2
----------------------------------------------------------------------------------------------------Change from Core Baseline
Change from Core Last Measurement
to Addendum 2 Maximum
to Addendum 2 Maximum
------------------------------------- ------------------------------------Treatment Effect¹
Treatment Effect
and 95% CI
p-value²
and 95% CI
p-value³
----------------------------------------------------------------------------------------------------Fasting Glucose (mg/dL)
-2.492 (-8.631, 3.646)
0.419
-5.071(-11.324, 1.183)
0.110
Fasting Glucose (mMol/L)
-0.138 (-0.479, 0.202)
-0.281 (-0.628, 0.066)
Hemoglobin A1C (%)
-0.007 (-0.199, 0.186)
0.945
-0.004 (-0.167, 0.160)
0.966
----------------------------------------------------------------------------------------------------¹ Treatment effect is difference in least squares means (Humatrope minus Control) from an ANOVA model with
a term for treatment
² p-value for treatment effect on change from Core Baseline to Addendum 2 Maximum
³ p-value for treatment effect on change from Core Last Measurement to Addendum 2 Maximum.
Page 31
Page 32
Eight Control patients and 9 Humatrope-treated patients had abnormal fasting blood
glucose values (≥100 mg/dL) at some time during the study. One patient in the
Humatrope group had fasting blood glucose of ≥126 mg/dL, consistent with the
American Diabetes Association (ADA) definition of diabetes (ADA 2007). Two of
16 Humatrope-treated patients who underwent modified oral glucose tolerance tests had
2-hour post-prandial glucose values consistent with the ADA definition of impaired
glucose tolerance (≥140 mg/dL). There were no statistically significant differences
between treatment groups for the proportion of patients with values above the defined
cutpoints (Table 23).
Table 23.
Glucose Metabolism Cutpoint Analysis, Core Study
Safety Population
B9R-CA-GDCT Patients who Participated in Core Study for
at Least 4 Years
----------------------------------------------------------------------------------Laboratory Test
Treatment
N
n (%)
p-value
----------------------------------------------------------------------------------Fasting Glucose >=100 mg/dL
Control
43
8 (18.6%)
>0.999
Humatrope
54
9 (16.7%)
Fasting Glucose >=100, <=125 mg/dL
Control
Humatrope
43
54
8 (18.6%)
8 (14.8%)
-
Fasting Glucose >=126 mg/dL
Control
Humatrope
43
54
0 ( 0.0%)
1 ( 1.9%)
-
2-Hour Post-Prandial Glucose >=140 mg/dL
Control
Humatrope
17
16
0 ( 0.0%)
2 (12.5%)
0.227
Hemoglobin A1C
Control
Humatrope
43
56
0 ( 0.0%)
2 ( 3.6%)
0.504
----------------------------------------------------------------------------------Abbreviations:
N = number of subjects with normal baseline data for Fasting Glucose and
Hemoglobin A1C
N = number of subjects with test performed for 2-Hour Post-Prandial Glucose
n = number of subjects with abnormal post-baseline at any time during Core Study
All p-values are from Fisher Exact test.
For Hemoglobin A1C, cutpoint until 11 May 1998 >=6.8%, from 19 May 1998 cutpoint
was >=6.1%.
Somatropin rDNA
Page 33
Of the 60 patients evaluated in long-term follow-up in Addendum 2 (at least 1 year after
treatment discontinuation for those who had received GH), 3 of 39 patients previously
treated with GH had fasting blood glucose values consistent with the ADA definition of
impaired fasting glucose (≥100 mg/dL; ADA 2007). Table 24 presents patients with
values above or below the defined clinically significant cutpoints for each glucose
metabolism parameter.
Table 24.
Glucose Metabolism Cutpoint Analysis, Post-GH Follow-up
Glucose 4-Year Population
B9R-CA-GDCT Patients with Glucose Metabolism Data
during Addendum 2
--------------------------------------------------------------------------------Laboratory Test
Treatment
N
n (%)
p-value
--------------------------------------------------------------------------------Fasting Glucose >=100 mg/dL
AT No-GH
21
0 ( 0.0%)
0.545
AT GH
39
3 ( 7.7%)
Fasting Glucose >=100, <=125 mg/dL
AT No-GH
AT GH
21
39
0 ( 0.0%)
3 ( 7.7%)
-
Fasting Glucose >=126 mg/dL
AT No-GH
AT GH
21
39
0 ( 0.0%)
0 ( 0.0%)
-
Fasting Insulin Laboratory >=35 µIU/mL
AT No-GH
AT GH
21
40
1 ( 4.8%)
2 ( 5.0%)
>0.999
Fasting Insulin Clinical >=20 µIU/mL
AT No-GH
AT GH
21
40
1 ( 4.8%)
2 ( 5.0%)
>0.999
Fasting Glucose/Insulin Ratio¹
<=4.5 mg/10^-4U
AT No-GH
AT GH
21
38
1 ( 4.8%)
3 ( 7.9%)
>0.999
QUICKI²<=0.30
AT No-GH
AT GH
21
39
1 ( 4.8%)
2 ( 5.1%)
>0.999
Hemoglobin A1C
AT No-GH
AT GH
21
40
0 ( 0.0%)
0 ( 0.0%)
-
--------------------------------------------------------------------------------Abbreviations: N = number of subjects with any Addendum 2 data, n = number
of subjects with an abnormal result at any time during Addendum 2
AT No-GH = As-Treated No-GH, AT GH = As-Treated GH
Fasting Insulin Laboratory = Cutpoint is laboratory-provided high limit of
normal range
Fasting Insulin Clinical = Exceeding cutpoint yields clinical suspicion of
insulin resistance
¹ Calculated only for patients with fasting blood <100 mg/dL (<5.6 mMol/L)
² QUICKI = Quantitative Insulin Sensitivity Check Index [Katz et al. 2000]
All p-values are from Fisher Exact test.
For Hemoglobin A1C, cutpoint until 11 May 1998 >=6.8%, from 19 May 1998 cutpoint
was >=6.1%.
Somatropin rDNA
Page 34
References
[ADA] American Diabetes Association. 2007. Standards of medical care in diabetes—
2007. Diabetes Care 30 Suppl 1:S4-S41.
Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ. 2000.
Quantitative insulin sensitivity check index: a simple, accurate method for assessing
insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402-2410.
King KA, Makishima T, Zalewski CK, Bakalov VK, Griffith AJ, Bondy CA, Brewer CC.
2007. Analysis of auditory phenotype and karyotype in 200 females with Turner
syndrome. Ear Hear 28(6):831-841.
Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z,
Curtin LR, Roche AF, Johnson CL. 2000. CDC growth charts: United States. Advance
data from vital and health statistics. No. 314:1-28. Hyattsville, Maryland: National
Center for Health Statistics.
Lyon AJ, Preece MA, Grant DB. 1985. Growth curve for girls with Turner syndrome.
Arch Dis Child 60(10):932-935.
Moscicki EK, Elkins EF, Baum HM, McNamara PM. 1985. Hearing loss in the elderly:
an epidemiologic study of the Framingham Heart Study Cohort. Ear Hear 6(4):184190.
[NCHS] National Center for Health Statistics. NCHS Growth Charts, 1976. Mon Vital
Stat Rep 25(3) Suppl. (HRA) 76-1120. Rockville, MD: Health Resources
Administration, 1976.
Ranke MB, Stubbe P, Majewski F, Bierich JR. 1988. Spontaneous growth in Turner’s
syndrome. Acta Paediatr Scand (Suppl) 343:22-30.
Somatropin rDNA
CT Registry ID#818
Page 1
Summary ID#818
Clinical Study Summary: Study B9R-EW-E005/6
Title of Study: Investigation of the Safety and Efficacy of Growth Hormone Replacement Therapy in
Adults with Previously Treated Childhood Growth Hormone Deficiency
Investigator(s): These multicenter studies included 8 principal investigators.
Study Center(s): This study was conducted at 8 study centers in 6 countries.
Length of Study: 29 months
Phase of Development: 3
Dates of patient enrollment: May 1992 to March 1993
Objectives:
Primary Objective: The primary objective of these studies was to ascertain efficacy of Humatrope®
(biosynthetic human growth hormone [hGH], LY137998, somatropin) replacement therapy for patients
with childhood-onset growth hormone deficiency (GHD) with respect to body composition and lipid
parameters.
Secondary Objectives: The secondary objectives of these studies were to determine efficacy and safety of
long-term treatment of GH-deficient adults with Humatrope, and to assess changes in insulin-like growth
factor levels and bone parameters.
Study Design:
Studies B9R-EW-E005 (E005) and B9R-EW-E006 (E006) were randomized, parallel, double-blind,
placebo-controlled studies involving 71 patients with childhood-onset GHD. Patients began a single-blind
placebo lead-in period for 1 month. Patients were then randomized to receive either Humatrope or placebo
for 6 months in a double-blind fashion (0-6 months), followed by 12 months of open-label growth hormone
(GH) therapy for all patients (6-18 months).
Number of Patients:
Planned: 50 patients per study (25 patients in each study treatment arm), for a total of 100 patients. Full
enrollment was not attained due to scarcity of patients.
Enrolled: 24 Study E005, 47 Study E006, 71 total.
Randomized: 22 Study E005, 45 Study E006, 67 total.
Study E005: 10 Humatrope, 12 placebo.
Study E006: 22 Humatrope, 23 placebo.
Completed:
Double-blind therapy (0-6 months): 28 Humatrope, 30 placebo, 58 total.
Entire study (0-18 months): 22 Humatrope, 26 placebo, 48 total.
Diagnosis and Main Criteria for Inclusion: Deficiency of GH arising and treated during childhood, but
not treated with GH and/or GH-releasing hormone in the previous 2 years. Deficiency demonstrated within
the last 2 years by a negative response to standard GH stimulations test (maximal peak less than 5 ng/mL).
Test Product, Dose, and Mode of Administration:
Mode of administration: A single subcutaneous injection in the evening.
Humatrope: Following the initial 1-month placebo lead-in period, an initial Humatrope 6.25 µg/kg/day
dose was given for 1 month and 12.5 µg/kg/day thereafter; 16 IU (5.92 mg) freeze-dried biosynthetic GH in
vials reconstituted with 8 mL diluent. To avoid unblinding the study code, all patients began the open-label
phase (Visit 5) at a dosage of 6.25 µg/kg/day Humatrope for 1 month and 12.5 µg/kg/day thereafter.
LY137998 (somatropin)
Approved: 23 March 2005
CT Registry ID#818
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Duration of Treatment:
Placebo (Placebo/hGH): 1-month lead-in for all patients, followed by 6 months double-blind for
randomized patients, followed by 12 months open-label hGH for all patients
Humatrope (hGH/hGH): 1-month lead-in for all patients, followed by 6 months double-blind for
randomized patients, followed by 12 months open-label hGH for all patients
Reference Therapy, Dose, and Mode of Administration: Placebo comprised of excipient in identical
vials reconstituted with 8 mL diluent and administered in a single subcutaneous injection in the evening.
Variables:
Efficacy:
Primary: Body composition (lean body mass, fat mass, and percent body fat) derived by bioelectrical
impedance measurement and skinfold thickness; and lipids (total cholesterol, high-density lipoprotein
[HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, very low-density lipoprotein [VLDL]
cholesterol), and triglyceride
Secondary: Concentration of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding
protein-3 (IGFBP-3); bone parameters (osteocalcin; urinary pyridinoline, and deoxypyridinoline) and
apolipoproteins A-1 and B
Safety: Adverse events, vital sign evaluation, oral glucose tolerance tests, thyroid hormone concentrations,
growth hormone antibodies, and clinical laboratory tests.
Health Outcomes: Total health-related quality of life scores by the Nottingham Health Profile.
Evaluation Methods:
Statistical: There are two studies, B9R-EW-E005 (E005) and B9R-EW-E006 (E006), included in this
report. The studies have been analyzed separately (as E005 and E006) and combined (as E005/6) for all
efficacy parameters and central laboratory safety parameters. The studies have been combined for analysis
of adverse events and local laboratory parameters.
In all tables, the group of patients treated with Humatrope throughout the 18-month period is referred to as
hGH/hGH, and the group of patients who were treated with placebo for the first 6 months followed by
Humatrope for the next 12 months is referred to as Placebo/hGH.
Analysis of variance (ANOVA) with terms for treatment, investigator, and treatment-by-investigator
interaction in the model, was used to compare Humatrope and placebo treatment over the first 6 months
after randomization (0-6 months) and baseline values with Humatrope treatment values at subsequent visits
(Visit 1 [baseline] for the hGH/hGH group and Visit 5 [6-month visit] for the Placebo/hGH group).
A p-value of ≤.05 was considered statistically significant, and a p-value of between 0.05 and 0.1 was
considered marginally significant and referred to as such in this report. With regard to health-related
quality of life as measured by the Nottingham Health Profile, a p-value of ≤0.01 was considered
statistically significant, and a p-value between 0.01 and 0.05 was considered marginally significant for
parametric and nonparametric analyses.
Health Outcomes: Three health-related quality of life questionnaires were used: the Hospital Anxiety and
Depression scale, the Nottingham Health Profile, and Activities of Daily Living. The Hospital Anxiety and
Depression scale was used at baseline only for the purpose of detecting significant mood or depression
disorders. The Activities of Daily Living scale was not analyzed due to poor reliability of this analog scale.
The Nottingham Health Profile has been used in populations of GH-deficient adults and is well validated in
multiple languages. There were no disease-specific questionnaires for GHD when these studies were
conducted.
Summary (on following pages)
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Summary
Disposition of Patients
Table 1.A summarizes the primary reasons for discontinuation during the 6-month
double-blind period, and Table 1.B summarizes the primary reasons for discontinuation
during the entire 18-month treatment period. Of the 71 patients enrolled, 67 patients
(94.4%) were randomized; 58 patients (81.7%) completed the double-blind treatment
period (Visits 2 to 5), and 48 patients (67.6%) completed the entire 18-month treatment
period (Visits 2 to 10). One patient was enrolled into Study E006 after the enrollment
cut-off date of March 1993. This patient’s data through Visit 7 was in the database for
analysis and is included this report. Visit 8 data for this patient was included in the
appendix of the original clinical study report for this study. Eighteen randomized patients
discontinued the studies early for the following reasons: adverse event (3), personal
conflict (6), protocol interim criteria not met (1), patient’s perception of lack of
efficacy (2), sponsor’s decision (2), lost to follow-up (3), and satisfactory response (1).
CT Registry ID#818
Table 1.
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Patient Disposition
Demographic and Other Baseline Characteristics
Table 2 summarizes the results for selected demographic measurements at baseline. The
2 treatment groups were similar with respect to the demographic parameters. There were
more men (73.1%) than women (26.9%) entered into the 2 combined studies, and the
balance was similar between the 2 treatment groups. All the patients were Caucasian,
with a mean age of 28.4 years (range: 18.0 to 48.2 years). There were no statistically
significant differences between the two treatment groups with respect to sex, age, or
height. For weight, patients randomized to hGH/hGH in Study E005 were marginally
significantly lighter than the Placebo/hGH group (p=.052), but in Study E006, the
patients randomized to hGH/hGH were statistically significantly heavier than the
Placebo/hGH group (p=.050). Thus, in the combined studies there was no statistically
significant difference between treatment groups (p=.470).
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Historical Diagnosis
The most commonly reported historical diagnoses are summarized in Table 3.
Secondary Conditions
The majority of patients had hypopituitarism associated with one or more of the
following: decreased gonadal function, hypothyroidism, and/or adrenal insufficiency.
Table 2.
Demographic Summary of All Randomized Patients
CT Registry ID#818
Table 3.
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Historical Diagnoses of All Randomized Patients
Study
E006
n
E005
E005/6
n
n
Idiopathic
Isolated Growth Hormone Deficiency
5
13
18
Growth Hormone plus TSH Deficiency
2
5
7
Growth Hormone plus LH/FSH Deficiency
1
3
4
Growth Hormone plus Diabetes Insipidus
0
1
1
Multiple Deficiency
12
18
30
Trauma, Empty Sella, Post-Tubercular Condition
1
3
4
Craniopharyngioma, Dysgerminoma
1
2
3
Total
22
45
67
Abbreviations: n = number of patients with each diagnosis; TSH = thyroid-stimulating hormone;
LH = luteinizing hormone; FSH = follicle-stimulating hormone.
Efficacy: Combined Studies (Studies E005/6)
Primary Efficacy: Body Composition
Tables 4 and 5 summarize actual and baseline-to-endpoint change in lean body mass and
fat mass, respectively, for the individual and combined studies. There was an increase in
lean body mass in Study E005, Study E006, and the combined Studies E005/6 for all
patients treated with Humatrope as compared with placebo in the 6-month blinded study
phase or to baseline in the long-term, open-label study phase. This therapeutic effect
persisted into the open-label period for the additional 12 months of study drug exposure.
Fat mass and percent body fat decreased significantly in both studies separately and
combined.
Table 6 summarizes actual and baseline-to-endpoint change in percent body fat. The
percent body fat demonstrates a statistically significant therapeutic effect of Humatrope
in all patients treated with Humatrope as compared with placebo in the 6-month blinded
study phase or to baseline in the long-term, open-label study phase. Exceptions (lack of
statistical significance for percent body fat) in the individual studies occurred only at the
18-month endpoint of Study E006.
Table 7 summarizes actual and baseline-to-endpoint change in the sum of skinfolds (sum
of measurements of skinfold thickness at four anatomic sites). The sum of skinfolds
demonstrated that local fat was reduced during Humatrope treatment. There was a mean
reduction of 14.35 mm in local fat in the Humatrope treated group compared to mean
reduction of 3.22 mm in local fat in the placebo treated group in the combined studies
(p=.036).
Table 4.
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Summary and Analysis of Lean Body Mass
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Table 5.
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Summary and Analysis of Fat Mass
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Table 6.
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Summary and Analysis of Percent Body Fat
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Table 7.
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Summary and Analysis of Sum of Skinfolds
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Primary Efficacy: Lipids
Tables 8 and 9 summarize actual and baseline-to-endpoint change in HDL cholesterol
and HDL/LDL ratio. These studies demonstrate modest effects on improving HDL
cholesterol and HDL/LDL ratio as compared with baseline but not with placebo. There
was a statistically significant increase from baseline in HDL cholesterol in the hGH/hGH
treatment group at 12-and 18-months treatment for the individual and combined studies,
which was not seen in the Placebo/hGH treated group after 6 months open label
treatment. The change from baseline in the HDL/LDL cholesterol ratio was statistically
significant at 6- and 18-months in Study E005. The hGH/hGH treatment group had a
mean increase of 0.12 in the HDL/LDL ratio at 6 months (p=.039) and a mean increase of
0.14 at 18 months (p=.023) in Study E005. In study E006, the hGH/hGH treatment group
had a mean increase of 0.20 (p=.006) at 18 months. In the combined studies, the
hGH/hGH treatment group had mean increases of 0.06 at 6 months (p=.005), 0.08 at 12
months (p=.015), and 0.18 at 18 months (p<.001). The Placebo/hGH treatment group
experienced a statistically significant change in HDL/LDL cholesterol ratio in the
combined studies with a mean increase of 0.20 (p=.048) at 6 months. Other lipid
parameters are not significantly influenced by Humatrope treatment. These results were
obtained from patients who continued an unrestricted diet and who experienced no
additional intervention or control measures of moderately elevated cholesterol or low
HDL cholesterol values during the course of the study.
Table 8.
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Summary and Analysis of HDL Cholesterol
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Table 9.
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Summary and Analysis of High-Density Lipoprotein/Low Density Liprprotein (HDL/LDL) Ratio
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Primary Efficacy: Health-Related Quality of Life
The Nottingham Health Profile was used to assess health-related quality of life in the
study population. The Nottingham Health Profile assesses 6 domains: Energy Level,
Emotional Reactions, Social Isolation, Sleep, Pain, and Physical Mobility. Betweengroup comparisons (nonparametric analyses) for the combined Studies E005/6
demonstrated a statistically significant improvement (p<.01), or decrease in discomfort,
in the domain of Social Isolation. However, a significant placebo effect can also be seen
in the domain of Energy Level during the first 6 months of the studies. As compared to
baseline, the long-term effect of Humatrope continued to show a significant effect
(p<.05) in the domain of Emotional Reactions.
Secondary Efficacy: Markers of Bone Metabolism
Due to poor assay validity, urinary pyridinoline and deoxypyridinoline values are not
presented in this summary.
Secondary Efficacy: Insulin-Like Growth Factor
Tables 10 and 11 show a statistically significant increases in IGF-I and IGFBP-3
occurred in the hGH/hGH treatment group compared with placebo and baseline at 6
months and compared to baseline at 18 months. The Placebo/hGH treated group did not
experience a significant increase in IGFBP-3 at 6 months, and changes in IGF-I were
inconsistent. There was a statistically significant between group difference for IGF-I and
IGFBP-3 at 6 months.
Table 10.
Summary of Baseline-to-Endpoint (6 Months) Change in IGF-I and IGFBP-3
hGH/hGH
Mean (SD)
Baseline Mean (SD)
Change
pEfficacy Parameter
N
Valuea
N
Study E005
IGF-I (ng/mL)
9
30.08 (17.44)
95.36 (70.01)
.004
11
IGFBP-3 (ng/mL)
9
1039.00 (367.64)
983.22 (713.84)
.008
12
Study E006
IGF-I (ng/mL)
22
74.64 (79.68)
135.00 (118.10)
<.001
22
IGFBP-3 (ng/mL)
22
1800.45 (1163.98)
1131.27 (874.01)
<.001
23
Studies E005/6
IGF-I (ng/mL)
31
60.71 (69.50)
123.49 (106.79)
<.001
33
IGFBP-3 (ng/mL)
31
1562.50 (1041.93)
1088.29 (821.75)
<.001
35
Abbreviations: IGF-I = insulin-like growth factor I; IGFBP-3 = insulin-like growth factor-binding
protein 3; N = number of patients with measurements; SD = standard deviation.
aWithin-group p-value for change from baseline.
bBetween-group p-value.
CT Registry ID#818
Placebo/hGH
Mean (SD)
Baseline Mean (SD)
Change
pValuea
pValueb
65.25 (57.68)
1747.33 (1078.44)
-16.73 (29.19)
77.08 (407.59)
.042
.637
<.001
.002
48.46 (37.81)
1516.78 (924.19)
10.04 (14.70)
24.35 (415.98)
.003
.390
<.001
<.001
54.39 (45.66)
1595.83 (970.19)
1.12 (23.92)
42.43 (407.87)
.378
.724
<.001
<.001
Page 15
Table 11.
Summary of Baseline-to-Endpoint (18 Months) Change in IGF-I and IGFBP-3
hGH/hGH Treatment Group
Baseline Mean (SD)
Mean (SD) Change
Efficacy Parameter
N
Study E005
IGF-I (ng/mL)
9
30.08 (17.44)
124.58 (96.09)
IGFBP-3 (ng/mL)
9
1039.00 (367.64)
1788.32 (1099.73)
Study E006
IGF-I (ng/mL)
22
74.64 (79.68)
127.64 (117.18)
IGFBP-3 (ng/mL)
22
1800.45 (1163.98)
1465.36 (1109.97)
Studies E005/6
IGF-I (ng/mL)
31
60.71 (69.50)
126.75 (109.89)
IGFBP-3 (ng/mL)
31
1562.50 (1041.93)
1559.13 (1098.70)
Abbreviations: IGF-I = insulin-like growth factor 1, IGFBP-3 =
insulin-like growth factor-binding protein 3; N = number of
patients with measurements; SD = standard deviation.
CT Registry ID#818
p-Valuea
.004
.004
<.001
<.001
<.001
<.001
Page 16
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Secondary Efficacy: Apolipoprotein A-1 and Apolipoprotein B
There were no statistically significant within- or between-treatment group changes from
baseline in either study separately or combined, for apolipoprotein A-I and
apolipoprotein B.
Efficacy by Subgroup Analyses
Subgroup analyses were performed on the main efficacy variables (lean body mass,
percent body fat, total cholesterol, HDL cholesterol, and sum of skinfolds). The
subgroups were sex, age, and percent body fat. There were no statistically significant
sex, age, or percent-body-fat group effects during the double-blind therapy of primary
efficacy parameters except for sex effects for sum of skinfolds, where males showed a
marginally significantly greater decrease from baseline than females (p=.051). There
were also no statistically significant sex, age, or percent-body-fat group effects for any
variable from baseline to endpoint in the hGH/hGH treatment group.
Efficacy by investigator demonstrated a consistent treatment effect in favor of Humatrope
for lean body mass and percent body fat. However, for sum of skinfolds, total
cholesterol, and HDL cholesterol, the direction of treatment effect was inconsistent
across the investigators.
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Safety
Deaths and Other Serious Adverse Events
There were no deaths reported for any patients participating in these studies.
A total of 3 serious adverse events (SAEs) were reported for 3 patients during the 18month study period, and one SAE was reported for a patient during the extension period
of the study. None of these SAEs was Humatrope related (Table 12).
Table 12.
Serious Adverse Events by Body System and Treatment
Period
Event
Digestive
Cholestatic Jaundice
Treatment
Group
Treatment
Period
Days on hGH
Therapya
Not randomized
Placebo lead-in
0
hGH/hGH
hGH
38
Metabolic and Nutritional
Liver Enzymes Elevated, Hepatitis C VirusPositive
Nervous/Musculoskeletal
Convulsion
Placebo/hGH
Placebo
Safety Reports Filed During the Extension Period
Accidental Injury, Surgical Procedure
Placebo/hGH
HGH/dailyb
Abbreviations: hGH = human growth hormone (Humatrope); lead-in = placebo lead-in.
aNumber of days of Humatrope treatment prior to reporting the serious adverse event.
bDaily Humatrope treatment.
0
426
Discontinuations Due to Adverse Events
A total of 3 patients discontinued prior to completion of the 18 months of these studies.
These patients were all receiving Humatrope at the time of discontinuation from the
studies for the following reasons: joint disorder after 246 days of therapy, hepatitis after
82 days of therapy, and edema after 42 days of therapy.
Table 13 lists, by body system, the number of patients reporting treatment-emergent
adverse events (TEAEs) with ≥5% overall incidence during Humatrope therapy. Of
those listed, the most frequently occurring adverse events (AEs) over the first 6 months
of treatment for Humatrope-treated patients were increased serum glutamic oxaloacetic
transaminase (SGOT) and flu syndrome. The most frequently occurring adverse event in
the group of patients treated with placebo for 6 months followed by Humatrope for 12
months were flu syndrome, pain and edema (each at 10%).
CT Registry ID#818
Table 13.
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Treatment-Emergent Adverse Events with ≥5% Overall
Incidence During Humatrope Treatment Listed
Alphabetically by Body System
Vital Sign Evaluation
There was a statistically significant difference between treatment groups at baseline for
supine systolic (p=.025) and diastolic blood pressure (p=.022) in the combined studies,
the hGH/hGH treatment group having a higher systolic and diastolic blood pressure than
the Placebo/hGH treatment group. There was also a statistically significant difference
between treatment groups at baseline for supine heart rate in Study E005. The hGH/hGH
treatment group had mean supine heart rate of 65.30 bpm compated to a mean supine
heart rate of 74.17 bpm in the placebo/hGH treatment group. Vital sign changes were
within the bounds of clinical normalcy. There was a statistically significant difference
between treatments groups in supine diastolic blood pressure in the combined studies.
The hGH/hGH treatment group had a mean decrease in diastolic blood pressure of –4.72
mm Hg compared a mean increase 1.54 mm Hg in the placebo/hGH treatment group
(p=.019). These potential benefits of Humatrope therapy in this population could not be
demonstrated long term. There were no adverse effects on vital signs.
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Clinical Laboratory Evaluation
The data from the clinical laboratory measurements were analyzed for categorical
distribution of results from baseline to endpoint, categorical distribution at endpoint, and
identification of patients with markedly abnormal laboratory results. At the 6-month
endpoint there was a statistically significant (p=.002) difference between Humatrope and
placebo-treated patients for the categorical shift to high values in alkaline phosphatase.
There were 8 patients in the Humatrope treated group who shifted from low or normal
alkaline phosphatase values at baseline to high values at the end of 6 months. This
difference reflects the effect of Humatrope on bone turnover.
Growth Hormone Antibody Formation
Serum samples from 64 of the 67 randomized patients in these studies were assayed.
Only 1 patient had a positive GH antibody test during the studies. This patient was
treated with Humatrope for the entire 18 months, and had a positive test at Visit 5
(6 months) and a subsequent negative test at Visit 10 (18 months). There was no
evidence of antibody-neutralizing effect.
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Summary ID#824
Clinical Study Summary: Study B9R-FP-0909
Title of Study: Use of Biosynthetic Human Growth Hormone (Humatrope ®) in Short Children with
Chronic Renal Failure
Study Center(s): This study was conducted at 2 study centers in one country.
Length of Study: 5 years, 7 months
Date first patient enrolled: 4 September 1990
Date last patient completed: 18 April 1996
Objectives: To determine the efficacy of human growth hormone (GH) on growth velocity in children
with chronic renal failure.
Study Design:
This was a two-centre, open-label study of the use of Humatrope therapy in children with growth
retardation due to chronic renal failure. It involved 28 prepubertal children who had renal failure which
was being treated either by conservative treatment (15 patients) or by dialysis (13 patients). At Visit 1
patients were enrolled, informed consent was to be obtained and entry criteria were determined. The time
interval between Visits 1 and 2 was variable depending on patient circumstances. Humatrope was supplied
to patients and therapy commenced at Visit 2. Efficacy and safety determinations were carried out at
3-monthly intervals (Visits 3 to 10) until patients had received 24 months of Humatrope therapy.
In 1993 it was decided on compassionate grounds that therapy would be extended for all children on
dialysis and for those still on conservative treatment whose inulin clearance was <35 ml/min/1.73m2 and
bone age was <9 years . Therapy was to continue until patients reached their final height and visits for
efficacy and safety determinations continued at 3-monthly intervals. For the purposes of this report a cutoff point was determined as 5 years (60 months) of study treatment and so this report summarises all data
from Visit 1 (baseline) until Visit 22 (60 month cut-off).
Number of Patients:
Planned: 50 patients
Randomized: Male 23, Female 5, Total 28
Completed (2-years): 18 patients
Completed (5-years): 6 patients
Diagnosis and Main Criteria for Inclusion: Chronic renal failure treated either by conservative treatment
or dialysis. Age >2 years; bone age <10 years (girls) or <12 years (boys); growth retardation as height
below -2 standard deviations (SD) or at -2 SD but loss of 2 SD immediately prior to study; diminished
growth velocity; positive response to GH stimulation test; normal glucose tolerance; informed consent.
Humatrope: 0.17 IU/kg/day, given once daily by subcutaneous injection
Duration of Treatment: Initially up to 2 years, extended to up to final height. Cut-off point for this report
was 5 years of Humatrope
Reference Therapy, Dose, and Mode of Administration: None
Somatropin
Copyright ©2005 Eli Lilly and Company. All rights reserved.
Approved: 15 June 2005
CT Registry ID#824
Page 2
Variables:
Efficacy-- Height standard deviation scores (SDS), growth velocity, bone age retardation, target and final
height, insulin-like growth factor-I and IGF binding protein-3
Safety-- Adverse event reporting, renal function, glucose tolerance tests, clinical safety laboratory results
Evaluation Methods:
Statistical: Analysis of variance and paired t-tests. All statistical tests were two-sided and were
performed at the 5% significance level. All confidence intervals were calculated at 95% and were also
two-sided.
Summary:
In this study the efficacy and safety of Humatrope therapy was assessed in a group of prepubertal patients who had serious underlying disease of chronic renal failure which was
causing growth retardation. Patients were either being treated by conservative therapy or
were on dialysis at study entry. The average duration of Humatrope therapy was shorter
for patients on dialysis because these patients progressed to kidney transplant earlier than
the conservative treatment patients.
Patient Disposition:
There were 28 children with growth retardation due to chronic renal failure enrolled in
this study between September 1990 and March 1991. One patient was entered in the
study but underwent a kidney transplant before enrolment and did not receive any study
drug. There were no patients who were enrolled but not assigned to Humatrope
treatment. The renal failure was being treated at the start of the study by either
conservative treatment (CT) or by dialysis (D) which was either haemodialysis or chronic
peritoneal dialysis. Patients who went from CT to D during the study continued
Humatrope treatment. Patients who underwent renal transplantation during the study
were withdrawn and Humatrope treatment was discontinued. For some patients who
received a kidney transplant, Humatrope therapy recommenced after transplantation but
no data collected after the transplant was included within the analysis of this study.
Humatrope treatment was extended until final height for children on dialysis and for
those on conservative treatment who had an inulin or creatinine clearance
<35 ml/min/1.73m2 and/or had bone age <9 years. The data cut-off point for this report
was at the end of 60 months (5 years) of Humatrope therapy. The patient disposition
through to the end of the 5th year of follow-up in this study is summarised in Table 1.
Somatropin
CT Registry ID#824
Table 1.
Page 3
Patient Disposition
Initial treatment
Discontinuationa
CT
D
Transplant
Other
Baseline
28 (100)
15 (100)
13 (100)
--1 Year Completed
25 (89)
15 (100)
10 (77)
--Discontinued
3 (11)
0
3 (23)
3
0
2 Year Completed
17 (61)
12 (80)
5 (38)
--Discontinued
11 (39)
3 (20)
8 (62)
9
2
3 Year Completed
14 (50)
11 (73)
3 (23)
--Discontinued
14 (50)
4 (27)
10 (77)
11
3
4 Year Completed
11 (39)
9 (60)
2 (15)
--Discontinued
17 (61)
6 (40)
11 (85)
12
5
5 Year Completed
6 (21)
6 (40)
0
--Discontinued
22 (79)
9 (60)
13 (100)
15
7
Abbreviations: CT = conservative treatment; D = dialysis.
a reasons for discontinuation were renal transplant or other (lost to follow-up, serious adverse event,
parental decision, lack of efficacy).
All
Of the 15 patients who were initially under CT when entered into this study, all
completed one year of treatment and 12 (80%) completed two years, although two of
these had changed treatment to dialysis. There were three patients initially under CT who
discontinued before completion of two years of Humatrope, each due to renal transplant.
There were six (40%) patients under CT who completed five years of Humatrope
treatment, although two of these were then being treated with dialysis and subsequently
received a renal transplant. Of the nine patients discontinued up to five years, only one
was discontinued for a reason other than transplant, which was a patient who withdrew
due to parental decision.
Of the 13 patients under D at the start of study, three (23%) were discontinued due to
renal transplant at less than ten months after starting Humatrope therapy. These three
patients re-started Humatrope therapy after the transplant but none of their data were
included in the efficacy analyses. After two years of Humatrope treatment only five
(38%) patients initially under D were still on therapy. Six of the eight patients who had
then discontinued did so due to renal transplants and the other two patients discontinued
due to lack of efficacy. No patients initially under D completed five years of therapy;
seven of the 13 discontinued due to renal transplant, three due to lack of efficacy, one due
to a serious adverse event of pancreatitis, one due to reaching final height and one moved
and was lost to follow-up.
Baseline Demographics:
There were 28 patients enrolled in the study at Visit 1 and who commenced Humatrope
therapy at Visit 2. Three of the patients discontinued from the study before completing
one year of treatment and are not included in any efficacy analysis. Therefore, the
baseline demographics and efficacy analyses are based on the 25 patients who completed
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CT Registry ID#824
Page 4
one year of Humatrope administration. The safety analyses are based on data from all
patients who entered the study.
The baseline characteristics of the children enrolled into this study are summarised in
Table 2.
Table 2.
Baseline Characteristics (mean ± SD)
CT
D
Total
(N = 15)
(N = 10)
(N=25)
Age (years)
8.9 ± 2.5
9.5 ± 4.0
9.1 ± 3.2
Sex ratio
Male (n (%))
13 (87)
7 (70)
20 (80)
Female (n (%))
2 (13)
3 (30)
5 (20)
2
Creatinine clearance (ml/min/1.73 m )
23.4 ± 11.6
Inulin clearance (ml/min/1.73 m2)
21.6 ± 5.3
Chronic renal failure duration (years)
7.5 ± 2.6
7.1 ± 4.0
7.3 ± 3.2
Dialysis duration (years)
3.6 ± 2.7
Height SDS
-3.13 ± 0.87
-3.82 ± 1.25
-3.41 ± 1.07
Growth velocity (cm)
4.1 ± 1.5
4.4 ± 2.3
4.2 ± 1.8
Growth velocity SDS
-2.77 ± 1.71
-2.19 ± 2.10
-2.54 ± 1.86
Bone age (years)
5.5 ± 1.9
6.0 ± 3.1
5.7 ± 2.4
Bone age retardation (CA-BA) (years)
3.0 ± 1.1
3.0 ± 1.4
3.0 ± 1.2
Abbreviations: BA = bone age; CA = chronological age; CT = conservative treatment; D = dialysis; SDS =
standard deviation score.
Efficacy Results:
Height SDS:
Efficacy was primarily assessed from changes in height standard deviation scores (SDS)
and growth velocity. Height was increased throughout Humatrope therapy with a
progressive increase in height SDS at each yearly timepoint assessed. At the last
measurement on Humatrope therapy the statistical analysis showed that the increase in
height from baseline was significant for the total population of patients evaluated. The
significant increases were consistent for patients given either conservative treatment or
dialysis at baseline. The summary and analysis for the mean absolute values and the
changes from baseline for height SDS for chronological age are shown in Table 3.
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Table 3.
Page 5
Summary and Analysis of Height SDS Absolute Values and
Changes from Baseline at Each Timepoint, mean ± SD
(median)
CT
D
Total
Baseline
n=15
n=10
n=25
Absolute
-3.13 ± 0.87 (-2.88)
-3.82 ± 1.25 (-3.87)
-3.41 ± 1.07 (-3.06)
1 Year
n=15
n=8
n=23
Absolute
-2.22 ± 0.95 (-1.94)
-3.46 ± 1.28 (-3.69)
-2.65 ± 1.21 (-2.18)
Change
0.93 ± 0.30 (0.86)
0.52 ± 0.41 (0.49)
0.78 ± 0.39 (0.85)
2 Year
n=12
n=4
n=16
Absolute
-1.83 ± 0.95 (-1.59)
-4.34 ± 0.27 (-4.28)
-2.45 ± 1.39 (-2.03)
Change
1.34 ± 0.38 (1.29)
0.47 ± 0.74 (0.72)
1.12 ± 0.60 (1.09)
3 Year
n=11
n=3
n=14
Absolute
-1.60 ± 1.00 (-1.24)
-4.32 ± 0.23 (-4.19)
-2.18 ± 1.46 (-1.57)
Change
1.52 ± 0.49 (1.45)
0.27 ± 0.98 (0.70)
1.25 ± 0.78 (1.33)
4 Year
n=9
n=1
n=10
Absolute
-1.20 ± 0.95 (-0.97)
-3.50 (-3.50)
-1.43 ± 1.16 (-1.02)
Change
1.67 ± 0.58 (1.67)
0.24 (0.24)
1.53 ± 0.71 (1.61)
5 Year
n=6
n=0
n=6
Absolute
-1.21 ± 1.24 (-0.92)
–
-1.21 ± 1.24 (-0.92)
Change
1.83 ± 0.80 (1.75)
–
1.83 ± 0.80 (1.75)
LMT
n=15
n=10
n=25
Absolute
-1.60 ± 1.16 (-1.34)
-3.23 ± 1.36 (-3.38)
-2.25 ± 1.46 (-2.18)
Change
1.54 ± 0.65 (1.31)
0.59 ± 0.56 (0.70)
1.16 ± 0.77 (1.11)
a
95%CI
1.18 to 1.89
0.19 to 1.00
0.84 to 1.47
p-valueb
<0.001
0.009
<0.001
Abbreviations: CI = confidence interval; CT = conservative treatment; D = dialysis; LMT = last
measurement on Humatrope therapy.
a 95% confidence interval for change from baseline.
b paired t-tests for within-group change from baseline.
The number and percent of patients with height SDS within the normal range at the
yearly timepoints from one to five years and at the last measurement on Humatrope
therapy are shown in Table 4. At baseline all patients had height SDS below the normal
range whereas at the last measurement on therapy 60% of the conservative treatment
patients and 20% of the dialysis patients had height SDS above -2. Overall, therefore,
there were 11 of 25 (44%) evaluable patients with height SDS greater than the lower limit
of normal.
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Table 4.
Page 6
Number and Percent of Patients Within the Normal Range
for Height SDS by Treatment Year
CT
D
Total
n/N
%
n/N
%
n/N
%
Baseline
0/15
0
0/10
0
0/25
0
1 year
8/15
53
1/8
13
9/23
39
2year
8/12
67
0/4
0
8/16
50
3 year
8/11
73
0/3
0
8/14
57
4 year
8/9
89
0/1
0
8/10
80
5 year
5/6
83
0/0
0
5/6
83
LMT
9/15
60
2/10
20
11/25
44
Abbreviations: CT = conservative treatment; D = dialysis; LMT = last measurement on Humatrope
therapy; n = number of patients with height SDS within normal range; N = number of patients
remaining in study at the timepoint.
Growth Velocity:
The summary and analysis for the mean absolute values and the changes from baseline
for growth velocity SDS for chronological age are shown in Table 5. Growth velocity
was also increased throughout Humatrope therapy and the statistical analysis for the last
measurement on Humatrope therapy showed that the increase from baseline was
significant for the total number of patients assessed. The increase to the last
measurement on therapy was slightly greater for the conservative treatment patients than
for the dialysis patients but was significant for both groups. For the total number of
evaluated patients the mean growth velocity calculated as SDS per year was above +2,
the upper limit of normal, for each yearly interval of Humatrope therapy. For those
patients who achieved final height during the study the difference between actual height
and target height was only 1.54 SDS (9.7 cm) (Table 6).
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Table 5.
Page 7
Summary and Analysis of Growth Velocity (SDS) Absolute
Values and Changes from Baseline at Each Timepoint, mean
± SD (median)
CT
D
Total
Baseline
n=15
n=10
n=25
Absolute
-2.77 ± 1.71 (-2.77)
-2.19 ± 2.10 (-2.10)
-2.54 ± 1.86 (-2.43)
1 Year
n=15
n=8
n=23
Absolute
5.60 ± 2.90 (5.69)
2.54 ± 3.29 (1.75)
4.53 ± 3.32 (5.10)
Change
8.37 ± 3.26 (8.84)
4.56 ± 4.62 (5.01)
7.04 ± 4.12 (8.63)
2 Year
n=12
n=4
n=16
Absolute
4.40 ± 2.90 (4.70)
2.15 ± 2.64 (1.73)
3.84 ± 2.93 (4.14)
Change
7.33 ± 2.62 (6.97)
4.37 ± 2.41 (3.75)
6.59 ± 2.82 (6.48)
3 Year
n=11
n=3
n=14
Absolute
3.51 ± 2.70 (3.17)
0.13 ± 2.08 (0.58)
2.79 ± 2.89 (2.84)
Change
6.39 ± 2.44 (6.05)
3.35 ± 0.69 (3.02)
5.74 ± 2.51 (5.23)
4 Year
n=9
n=1
n=10
Absolute
3.22 ± 2.58 (2.51)
2.02 (2.02)
3.10 ± 2.46 (2.47)
Change
6.18 ± 2.12 (5.70)
4.45 (4.45)
6.01 ± 2.07 (5.47)
5 Year
n=6
n=0
n=6
Absolute
3.41 ± 2.87 (2.57)
–
3.41 ± 2.87 (2.57)
Change
6.42 ± 2.64 (5.92)
–
6.42 ± 2.64 (5.92)
LMT
n=15
n=10
n=25
Absolute
3.14 ± 2.13 (2.86)
1.51 ± 3.00 (2.10)
2.49 ± 2.58 (2.26)
Change
5.91 ± 2.54 (6.14)
3.70 ± 3.67 (3.25)
5.02 ± 3.17 (5.59)
a
95%CI
4.50 to 7.31
1.08 to 6.32
3.72 to 6.33
p-valueb
<0.001
0.011
<0.001
a 95% confidence interval for change from baseline.
Table 6.
Summary of Target Height Minus Baseline (Visit 2), Last
Measurement on Humatrope Therapy and Final Heights,
mean ± SD (median)
CT
D
Total
Target -Baseline
n=15
n=9
n=24
(SDS)
2.83 ± 0.88 (2.85)
3.18 ± 1.12 (3.50)
2.96 ± 0.97 (3.05)
Target - LMT
n=15
n=9
n=24
(SDS)
1.30 ± 0.90 (1.15)
2.64 ± 1.05 (2.94)
1.80 ± 1.16 (1.74)
Target - Final
n=7
n=4
n=11
(cm)
10.2 ± 7.3 (6.5)
8.9 ± 6.0 (10.3)
9.7 ± 6.5 (10.0)
(SDS)
1.56 ± 1.15 (0.93)
1.49 ± 1.00 (1.72)
1.54 ± 1.05 (1.67)
Abbreviations: CT = conservative treatment; D = dialysis; LMT = last measurement on therapy; n =
number of evaluable patients; SDS = standard deviation score.
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Bone Age Retardation:
The summary and analysis of absolute values and changes from baseline for bone age
retardation are shown in Table 7. The retardation of bone age compared with
chronological age was also reduced by Humatrope therapy. For the last measurement on
therapy there was a significant reduction from baseline in retardation. This was mainly
due to a significant catch-up in bone age to the last measurement on therapy for the
conservative treatment patients since the reduction in bone age for the dialysis patients
did not reach significance. There were 56% of the patients who entered puberty during
the study although for the six patients who actually completed five years of the study
there were five (83%) who reached puberty.
Table 7.
Summary and Analysis of Bone Age Retardation as Absolute
Value and Change from Baseline at Each Timepoint, mean ± SD
(n)
CT
D
Total
Baseline
Absolute
3.02 ± 1.13 (14)
3.00 ± 1.43 (8)
3.01 ± 1.22 (22)
1 Year
Absolute
2.85 ± 1.17 (13)
2.87 ± 1.21 (8)
2.85 ± 1.16 (21)
Change
0.01 ± 0.65 (12)
-0.12 ± 0.31 (6)
-0.03 ± 0.55 (18)
2 Year
Absolute
2.61 ± 1.12 (12)
3.44 ± 0.69 (4)
2.82 ± 1.07 (16)
Change
-0.50 ± 0.99 (12)
0.13 ± 0.22 (2)
-0.41 ± 0.94 (14)
3 Year
Absolute
2.20 ± 0.91 (10)
3.01 ± 0.37 (2)
2.34 ± 0.89 (12)
Change
-0.68 ± 0.74 (10)
0.27 (1)
-0.59 ± 0.76 (11)
4 Year
Absolute
1.96 ± 0.96 (9)
– (0)
1.96 ± 0.96 (9)
Change
-0.81 ± 0.87 (9)
– (0)
-0.81 ± 0.87 (9)
5 Year
Absolute
1.70 ± 1.44 (5)
– (0)
1.70 ± 1.44 (5)
Change
-1.53 ± 1.33 (5)
– (0)
-1.53 ± 1.33 (5)
LMT
Absolute
2.01 ± 1.06 (14)
2.80 ± 1.02 (10)
2.34 ± 1.10 (24)
Change
-0.94 ± 1.16 (13)
-0.26 ± 0.52 (8)
-0.68 ± 1.01 (21)
95%CIa
-1.64 to -0.24
-0.69 to 0.18
-1.14 to -0.22
p-valueb
0.013
0.200
0.006
a 95% confidence interval for change from baseline for number of patients with evaluable data.
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Page 9
Insulin-Like Growth Factor-I (IGF-I) and IGF Binding Protein (IGFBP)-3
Concentrations:
The serum concentrations of the growth hormone-dependent factors, IGF-I and IGFBP-3,
are summarized in Table 8. The IGF-I concentration was very variable between patients
and overall the increase during Humatrope therapy was not very large. There was an
88.8% increase from baseline at the end of the first year for conservative treatment
patients but at the end of the second year the mean value was very similar to baseline.
The dialysis patients showed very little increase in the first year but a 151.1% increase in
the second year. The IGFBP-3 concentrations were also very variable and changed very
little from baseline values during Humatrope therapy.
Table 8.
Summary of Serum Concentrations of Insulin-Like Growth
Factor-I (IGF-I) and IGF Binding Protein-3 (IGFBP-3) as
Absolute Values (ng/ml) and Percent Changes from
Baseline, mean ± SD (median)
CT
D
Total
IGF-I
Baseline
n=15
n=9
n=24
absolute
192 ± 69 (194)
143 ± 33 (132)
174 ± 62 (153)
1 Year
n=10
n=3
n=13
absolute
311 ± 88 (303)
208 ± 64 (173)
287 ± 92 (282)
% change
88.8 ± 59.2 (71.3)
29.2 ± 16.4 (28.8)
75.1 ± 57.9 (61.3)
2 Year
n=10
n=4
n=14
absolute
207 ± 74 (178)
322 ± 69 (326)
240 ± 88 (237)
% change
12.0 ± 24.0 (17.9)
151.1 ± 60.5 (150.4)
51.8 ± 74.1 (29.1)
LMT
n=15
n=9
n=24
absolute
344 ±144 (334)
224 ± 101 (230)
299 ± 140 (276)
% change
93.7 ± 100.3 (52.1)
61.1 ± 68.5 (61.1)
81.5 ± 89.5 (56.6)
IGFBP-3
Baseline
n=15
n=9
n=24
absolute
5.2 ± 2.5 (4.2)
8.0 ± 1.3 (7.8)
6.3 ± 2.5 (5.7)
1 Year
n=10
n=3
n=13
absolute
6.2 ± 1.0 (6.3)
8.2 ± 1.0 (8.3)
6.7 ± 1.3 (6.5)
% change
49.6 ± 42.8 (43.7)
1.1 ± 24.6 (-11.9)
38.4 ± 43.9 (37.8)
2 Year
n=10
n=4
n=14
absolute
5.2 ± 1.5 (4.9)
5.9 ± 1.0 (5.4)
5.4 ± 1.4 (5.4)
% change
29.9 ± 36.4 (30.1)
-28.1 ± 16.5 (-27.7)
13.4 ± 41.5 (-4.2)
LMT
n=15
n=9
n=24
absolute
7.9 ± 2.7 (7.0)
7.2 ± 1.9 (7.4)
7.6 ± 2.4 (7.2)
% change
67.4 ± 73.0 (56.8)
-9.0 ± 25.0 (-10.1)
38.8 ± 69.9 (27.1)
Abbreviations: CT = conservative treatment; D = dialysis; LMT = last measurement on Humatrope
therapy.
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Safety:
No deaths were reported for any patient in the study. There were a high number of
serious adverse events but this was mainly due to the underlying disease of renal failure.
The number of patients reporting each serious adverse event, the frequency, and the
investigator’s classification of relationship to Humatrope therapy are summarized in
Table 9. Surgical procedures were reported for 25 (89.3%) patients but the majority of
these were kidney transplants. There were five events reported as possibly related to
Humatrope and each required hospitalisation. One was a kidney graft rejection which
occurred two to three months after Humatrope was stopped for the transplant. Two of the
events were headache and hypercalcemia which occurred when the patient received an
accidental overdose. The same patient previously had hypothyroidism which was
recorded by the investigator as possibly related to study drug. One event of pancreatitis
was reported as possibly related although the patient was taking concomitant sodium
valproate for epilepsy which is known to provoke pancreatitis.
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Table 9.
Page 11
Incidence (n) and Frequency (%) of Serious Adverse Events
for All Enrolled Patients and Relationship to Therapy
Overall
(N=28)
Surgical procedure
Creatinine clearance decreased
Fever
Immune system disorder
Infection
Pyelonephritis
Abdominal pain
Convulsion
Hernia
Leukocytosis
Rhinitis
Urinary tract infection
Vomiting
Abscess
Anorexia
Asthma
Bronchiolitis
Creatinine increased
Diarrhea
Dysuria
Epididymitis
Flank pain
Gastroenteritis
Headache
Hemiplegia
Herpes simplex
Hypercalcaemia
Hypertension
Hypokalaemia
Hypothyroidism
Kidney tubular disorder
Meningitis
Otitis
Overdose
Pancreatitis
Pharyngitis
Polyuria
Rash
Stomatitis
Syncope
Testis disorder
Thrombosis
Somatropin
n
25
9
6
5
4
3
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Related to Humatrope
%
89.3
32.1
21.4
17.9
14.3
10.7
7.1
7.1
7.1
7.1
7.1
7.1
7.1
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
n
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
1
0
0
1
0
0
0
0
1
0
0
0
0
0
0
0
%
–
–
–
3.6
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3.6
–
–
3.6
–
–
3.6
–
–
–
–
3.6
–
–
–
–
–
–
–
CT Registry ID#824
Page 12
Renal Function:
The data for creatinine clearance, inulin clearance, and the serum concentration of
creatinine are summarized in Table 10. Renal function determined from creatinine and
inulin clearance deteriorated during the study but it was not possible to determine
whether this was related to Humatrope therapy or the progression of the underlying renal
failure.
Table 10.
Baseline
absolute
1 Year
absolute
change
2 Years
absolute
change
Summary of Absolute Values and Change from Baseline for
Renal Function Tests During the Study, mean ± SD (median)
Creatinine clearance
(ml/min/1.73m2)
(n=10)
20.1 ± 11.2 (20.2)
(n=7)
27.0 ± 8.4 (26.0)
2.2 ± 9.3 (0.5)
(n=6)
13.9 ± 3.7 (15.1)
-11.1 ± 11.2 (-8.5)
Inulin clearance
(ml/min/1.73m2)
(n=12)
21.3 ± 5.7 (20.5)
(n=10)
17.9 ± 5.2 (17.0)
-3.1 ± 4.8 (-2.0)
(n=11)
13.5 ± 6.0 (12.0)
-7.3 ± 7.1 (-8.0)
Serum creatinine
(umol/L)
(n=15)
294 ± 159 (248)
(n=14)
266 ± 116 (272)
-34 ± 221 (8)
(n=12)
406 ± 168 (456)
160 ± 139 (164)
Glucose Tolerance Tests (OGTT):
The data from the oral glucose tolerance tests at one and two years of Humatrope therapy
are summarized in Table 11. There was no evidence of any decrease in glucose tolerance
during the study.
Table 11.
Baseline
absolute
1 Year
absolute
change
2 Years
absolute
change
Summary of Blood Glucose and Insulin Levels at Fasting
and 120 Minute of Oral Glucose Tolerance Tests
Glucose (mmol/L)
fasting
120 min
(n=18)
(n=27)
4.6 ± 0.5 (4.6)
5.8 ± 1.4 (6.0)
(n=22)
(n=17)
4.8 ± 0.9 (4.9)
6.6 ±1.8 (6.6)
0.2 ± 1.1 (0.2)
1.2 ± 2.4 (0.6)
(n=16)
(n=15)
4.8 ± 0.4 (4.8)
6.3 ± 1.9 (6.0)
0.6 ± 0.4 (0.6)
1.2 ± 2.4 (0.7)
Insulin (mU/L)
fasting
120 min
(n=12)
(n=25)
11.3 ± 10.2 (9.5)
36.0 ± 23.1 (30.0)
(n=20)
(n=16)
12.6 ± 6.7 (11.0)
41.2 ± 20.0 (36.5)
3.1 ± 8.4 (4.7)
9.1 ± 34.4 (19.0)
(n=14)
(n=15)
10.2 ± 4.8 (9.5)
38.4 ± 23.8 (28.0)
5.3 ± 7.0 (6.0)
4.0 ± 34.5 (4.5)
Clinical Safety Laboratory Tests:
A pre-stated normal range for each analyte was obtained from each local laboratory. The
measurements were evaluated for categorical distribution at baseline and at two years and
five years of Humatrope therapy, defining results as either within the normal laboratory
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range or as abnormal if outside of the normal range. There were no obvious trends in
distribution of any particular analyte with Humatrope therapy. There were no patients
who were discontinued from the study due to abnormal laboratory results and none of the
abnormal laboratory values were considered by the investigators to be clinically relevant
to Humatrope administration.
Vital Signs:
Vital signs determined in this study included supine systolic and diastolic blood pressures
and heart rate which were determined at baseline (Visit 1) and each study visit from
Visit 3 onwards. There were no obvious trends for changes in vital signs and no changes
in the determinations were considered by the investigators to be clinically significant or
relevant to Humatrope therapy.
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Page 1
Summary ID#843
Clinical Study Summary: Study B9R-MC-GDCH
Title of Study: Humatrope® in Non-Growth Hormone-Deficient Children with Short Stature*
Investigator(s): This multicenter study included three principal investigators.
Study Center(s): This study was conducted at two study centers in the United States.
Length of Study: 13 years and 1 month
Date first patient enrolled: January 1988
Date last patient completed: February 2001
Objectives:
Primary: The primary objective was to determine whether adult height was improved in pediatric patients
with idiopathic short stature (ISS)*, treated to final height with Humatrope, 0.222 mg/kg/wk.
Secondary:
• Determine whether lower leg growth during initial Humatrope therapy is predictive of the
long-term response to Humatrope.
• Determine the antigenicity and other measures of clinical safety of Humatrope in patients with
ISS.*
*Note: On 25 July 2003, the US Food and Drug Administration approved Humatrope for the long-term
treatment of ISS, also called non-growth hormone-deficient short stature. ISS will be used throughout this
document.
Study Design: This was a multicenter, double-blind, randomized, parallel, placebo-controlled study in
pediatric patients with ISS. The core study consisted of a screening period and a blinded treatment period.
The primary treatment period ended either when the patient reached final height or when the blinded
treatment period was terminated by Lilly. At the conclusion of the core, blinded treatment phase, patients
were offered the opportunity to participate in an open-label extension phase. Data from this extension
phase is not addressed in this report.
Patients who met inclusion criteria were randomly assigned to either Humatrope therapy or placebo after an
initial evaluation of baseline hormonal status and 6 months of baseline measurements to establish growth
velocity. Randomization was stratified by gender and Bayley-Pinneau predicted adult height into six strata:
predicted adult height <158.5 cm, 158.5 to 166.0 cm, and >166.0 cm for males; and <143.6 cm, 143.6 to
154.0 cm, and >154.0 cm for females. Patients were seen every 6 months to measure height until their
growth rates slowed to less than 1.5 cm (0.6 inches) per year (calculated over a 12-month interval).
Patients who completed the study were asked to return for final height measurement a year after protocol
completion. Patients who discontinued the study prior to protocol completion were asked to return for final
height measurement after their height velocity, measured locally, had fallen below 1.5 cm/y .
Number of Patients:
Planned: 80 Total.
Randomized: 71 Total; Humatrope: 29 Male, 9 Female, 38 Total; Placebo: 26 Male, 7 Female, 33 Total.
Final Height Population: 33 Total; Humatrope: 22; Placebo: 11.
Completed Protocol: 25 Total; Humatrope: 16; Placebo: 9.
Diagnosis and Main Criteria for Inclusion: Males and females (females had a normal karyotype)
between the chronological ages of 9 and 15 years (females), and 10 and 16 years (males), with documented
peak growth hormone (GH) response >7 ng/mL in standard GH stimulation tests, who had heights or
Bayley-Pinneau predictions of adult height that were at least 2.5 standard deviations (SDs) below the mean
CT Registry ID#843
Page 2
(within last 12 months prior to Visit 1), were included in the study. In addition, the patients had
proportionate stature, Tanner stage I or II breast or genital development at the start of the 6-month
pretreatment period, unfused carpal and phalangeal epiphyses by bone age x-ray (bone age ≤11 years in
girls; bone age ≤13 years in boys), and normal concentrations of circulating thyroxine. An informed
consent document was obtained from the parent and/or legal guardian, and an assent form was obtained
from the patient.
Humatrope: 0.074 mg/kg, given three times per week (0.222 mg/kg/wk) by subcutaneous injection.
Vials of lyophilized Humatrope, 5 mg.
Patients were to receive study drug per protocol until height velocity fell below 1.5 cm/y. However, a
number of patients discontinued the study prior to achieving this height velocity endpoint. There was no
statistically significant between-treatment group difference for the average time on study drug in either the
Safety Population (p=.359) or Final Height Population (p=.370).
Humatrope:
Mean: 3.7 ± 1.9 years (Safety Population, n=37).
Mean: 4.6 ± 1.6 years (Final Height Population, n=22).
Placebo:
Mean: 3.3 ± 1.6 years (Safety Population, n=31).
Mean: 4.1 ± 1.7 years (Final Height Population, n=11).
vials. The vials were reconstituted with diluent and administered by subcutaneous injection similar to
Humatrope.
Variables:
Efficacy: The primary efficacy measure was standing height. The primary efficacy variable was final
height standard deviation score (SDS). Final height SDS was the last height obtained after the height
velocity fell below 1.5 cm/y (either at protocol completion or at a poststudy follow-up visit), expressed as
the SDS that uses, as a reference standard, the height for an age- and gender-specific general population
(Kuczmarski et al. 2000).
A secondary variable, lower leg length, was evaluated in a subgroup of patients at Visits 1 through 4 and 6
to determine whether it would be predictive of long-term response to Humatrope treatment.
Safety: Data from patients who had received at least one dose of study drug were included in the Safety
Population analyses (n=68). Safety was assessed by analysis of serious adverse events (SAEs); nonserious,
clinically significant adverse events; and treatment-emergent adverse events (TEAEs).
CT Registry ID#843
Page 3
Evaluation Methods:
Data Sets Analyzed: The data analyses addressed four populations of study participants. Table 1
provides the number of patients in each data analysis population.
• Safety Population is defined as those patients who were randomized and received any study drug.
• Efficacy Evaluable Population is defined as those subjects who remained in the study until at least
Visit 5 (approximately 180 days postrandomization) and who had height data recorded at or
beyond that point.
• Final Height Population is defined as those Efficacy Evaluable subjects who had final height data
recorded.
• Protocol Completers are those subjects identified by the investigator as having completed the
protocol.
Table 1. Number of Patients in Data Analysis Populations
Population
Humatrope
Placebo
All Randomized Patients
38
33
Safety
37
31
Efficacy Evaluable
35
29
Final Height
22
11
Protocol Complete
16
9
Total
71
68
64
33
25
Statistical: The primary analysis was of final height SDS for the Final Height Population.
Between-group comparisons were performed using an analysis of covariance (ANCOVA) model,
incorporating the effects for treatment and baseline predicted height (BPH) SDS. The significance level for
this analysis was set at α=0.05 (two-sided).
The baseline comparability for continuous variables was assessed using a one-way analysis of variance
(ANOVA) with effect for treatment. For the categorical variables, baseline comparability between
treatments was assessed using Fisher’s exact test. Comparisons resulting in a p-value ≤.05 were considered
statistically significant.
CT Registry ID#843
Page 4
Summary
Disposition of Patient
Of the 71 randomized patients, 3 patients discontinued the study prior to receiving any
study drug (placebo, n=2 [protocol entry criteria not met]; Humatrope, n=1 [physician
decision]). The remaining 68 patients were included in the Safety Population (placebo,
n=31; Humatrope, n=37). Of the 68 patients in the Safety Population, 3 patients
discontinued without a height measurement at Visit 5 (placebo, n=1 [patient decision];
Humatrope, n=2 [1 adverse event, 1 patient decision]). One additional placebo patient
was excluded from the Efficacy Evaluable Population because they had received GH in
treatment unrelated to this study. The remaining 64 patients were included in the
Efficacy Evaluable Population (placebo, n=29; Humatrope, n=35). Analysis of this
population serves as the intent-to-treat analysis for this study. Twenty-five patients
formally completed the protocol (placebo, n=9; Humatrope, n=16) and were included in
the Protocol Complete Population.
The 25 patients in the Protocol Complete Population form the core of the Final Height
Population. In addition, 8 patients in the Efficacy Evaluable Population who had
discontinued the study prior to protocol completion and returned for a final height
measurement while still blinded to treatment assignment (placebo, n=2; Humatrope, n=6)
were included in the Final Height Population. Therefore, there were 33 patients in the
Final Height Population (placebo, n=11; Humatrope, n=22). In addition, 4 patients
returned for a final height measurement but were excluded from the Final Height
Population because they were not included in the Efficacy Evaluable Population for the
following reasons: did not receive study drug (placebo, n=1; Humatrope, n=1),
discontinued at Visit 1 (placebo, n=1), or received GH after discontinuing from the study
(placebo, n=1).
Table 2 provides the reasons for patients’ discontinuations from the study for all
randomized patients.
CT Registry ID#843
Table 2.
Page 5
Reasons for Study Discontinuation
Primary Reasons for Discontinuation
-----------------------------------Protocol completed
hGH
(N=38)
n (%)
--------16 (42.1)
Adverse event
1
Unable to contact patient (lost to
follow-up)
Protocol entry criteria not met
Sponsor's decision
3
Patient decision
Physician decision
*
(2.6)
Placebo
(N=33)
n (%)
--------9 (27.3)
1
Total
(N=71)
n (%)
--------25 (35.2)
p-Value*
--------.221
(3.0)
2
(2.8)
1.00
0
4 (12.1)
4
(5.6)
.042
0
2
2
(2.8)
.212
(6.1)
(7.9)
5 (15.2)
8 (11.3)
.459
17 (44.7)
12 (36.4)
29 (40.8)
.629
1
(2.6)
0
1
(1.4)
1.00
Frequencies are analyzed using a Fisher's Exact test.
Table 3 displays patient demographic and other baseline (Visit 1) characteristics for those
on whom a final height measurement was obtained (Final Height Population). There
were no statistically significant differences between the treatment groups at Visit 1 for
any of the variables analyzed.
CT Registry ID#843
Table 3.
Page 6
Demographic and Other Baseline (Visit 1) Characteristics
hGH
(N=22)
-----------
Placebo
(N=11)
-----------
Total
(N=33)
-----------
Age (yrs)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
22
12.49
12.23
1.61
10.02
15.12
11
12.90
12.54
1.06
11.49
15.15
33
12.63
12.41
1.44
10.02
15.15
.451**
Height (cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
22
132.82
132.64
7.95
119.38
149.13
11
134.88
135.92
6.74
120.29
143.32
33
133.51
133.67
7.52
119.38
149.13
.468**
Height SDS (NCHS)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
22
-2.69
-2.68
0.55
-3.90
-1.79
11
-2.75
-2.56
0.57
-3.75
-2.09
33
-2.71
-2.66
0.55
-3.90
-1.79
.770**
Bone Age (yrs)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
21
10.40
10.50
1.89
6.00
13.00
1
9
10.67
10.00
1.15
9.00
12.50
2
30
10.48
10.25
1.68
6.00
13.00
3
.695**
Predicted Height SDS (NCHS)
No. Patients
22
Mean
-2.08
Median
-2.06
Standard Dev.
0.69
Minimum
-3.60
Maximum
-0.78
Unspecified
0
10
-2.26
-1.95
0.80
-3.72
-1.34
1
32
-2.14
-2.04
0.72
-3.72
-0.78
1
.531**
Target Height SDS (NCHS)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
10
-1.32
-1.24
0.69
-2.37
-0.18
1
32
-1.18
-1.27
0.91
-2.80
1.87
1
.561**
Variable
------------------
22
-1.11
-1.28
1.00
-2.80
1.87
0
p-Value
-----------
(continued)
CT Registry ID#843
Table 3.
Page 7
Final Height Population (concluded)
hGH
Variable
(N=22)
------------------ ----------Lower Leg Measurement (mm)
No. Patients
8
Mean
355.89
Median
359.75
Standard Dev.
23.78
Minimum
322.23
Maximum
383.77
Unspecified
14
Placebo
(N=11)
-----------
Total
(N=33)
-----------
7
366.62
379.67
42.32
279.57
409.83
4
15
360.90
371.00
32.88
279.57
409.83
18
p-Value
----------.548**
Note:
Baseline bone age was assessed by a central reader and BPH was calculated using
bone age readings assessed by physicians at the NIH.
The number of patients
with each of these values may differ for the following reasons:
(1) BPH was assessed for only those patients who were in the study for >6 months.
(2) Some baseline bone age assessments from the central reader were missing, for
unknown reasons.
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
Efficacy
Primary Efficacy Objective
Height SDS at baseline was similar in the two treatment groups. By ANCOVA, the
patients who received Humatrope achieved a final height SDS of-1.81 ± 0.11 (least
squares mean [LSM] ± standard error of mean [SEM]), while those who received placebo
injections achieved a final height SDS of -2.32 ± 0.17, resulting in a mean Humatrope
effect on final height SDS of 0.51 ± 0.20 (p=.017). The Humatrope effect of 0.51 SDS
corresponds to a mean 3.7 cm difference between groups.
For each year of the study, the Humatrope-treated patient population had statistically
significantly greater mean height SDS than placebo-treated patients in the Efficacy
Evaluable Population (see Figure 1).
CT Registry ID#843
Page 8
P
0.58
0.02
<0.001
<0.001
0.002
0.02
Mean +/- 1 Std. Errs
-3.0
Height SDS
-2.5
-2.0
-1.5
-1.0
Hum
Pla
grp
H
P
H
P
H
P
H
P
H
P
H
P
nobs
35
29
34
26
31
26
26
23
18
13
11
6
mean
-2.74
-2.8
-2.4 -2.76
-2.06 -2.64
-1.8
-2.5
sd
0.46
0.52
0.49
0.58
0.56
0
0.63
1
0.52
0.65
2
3
Years on Study
-1.73 -2.44
0.62
0.5
4
-1.43 -2.32
0.71
0.55
5
Program: \\Eagle\Eagle.GRP\Programs._G\RMP\b9rs\gdch\HV2.ssc
Output: \\Eagle\Eagle.GRP\Programs._G\RMP\b9rs\Gdch\output\HTSDSEE
Figure 1.
Height standard deviation score by year on study.
By repeated measures analysis, the mean effect of Humatrope on height SDS at age
18 years was 0.69 ± 0.13 (p<.0001), which corresponds to an effect of 5.0 cm over
placebo. In addition, height gain across the duration of the study and the difference
between final height SDS and BPH SDS were statistically significantly greater for
Humatrope-treated patients than placebo-treated patients (see Table 4). Table 5 shows
the proportion of patients in the Final Height Population whose final height exceeded the
5th or 10th percentile of the standard growth curve (Kuczmarski et.al, 2000) for the US
population (Kuczmarski et al. 2000). There was a statistically significant difference in
the number of patients who achieved a final height above the 5th percentile between
treatment groups (p=.015) (40.9% of Humatrope-treated patients, 0% of placebo-treated
patients). Furthermore, a statistically significantly greater number of Humatrope-treated
patients gained at least 1 SDS in height from baseline to endpoint compared to
placebo-treated patients (50% versus 0%, respectively; p=.005, Fisher’s exact test).
Table 4.
Endpoint Characteristics
PARAMETER
HUMATROPE (n=22)
PLACEBO (n=11)
FHSDS – BPHSDS*
Final height SDS
Height gain (SDS)**
Height gain (cm)**
0.32
-1.77
0.93
28.30
-0.14
-2.34
0.42
22.58
(0.55)
(0.78)
(0.73)
(7.38)
(0.59)
(0.55)
(0.23)
(6.90)
EFFECT
P Value
0.46
0.57
0.51
5.71
0.043
0.039
0.034
0.040
Note: Data are expressed as mean(standard deviation).
Abbreviations: n = number of patients; SDS = standard deviation score; FHSDS = final height standard deviation score;
BPHSDS = baseline predicted height standard deviation score
•
n=10 for placebo, as one patient did not have a baseline predicted height due to missing bone age xray.
** Height gain is from start of treatment to final height.
CT Registry ID#843
Page 9
CT Registry ID#843
Table 5.
Variable
------------------
Page 10
Patients with Final Height Above 5th or 10th Percentile
hGH
(N=22)
-----------
Placebo
(N=11)
-----------
Total
(N=33)
-----------
Baseline Height > 5th Percentile?
No. Patients
22
11
No
22 (100)
11 (100)
33
33 (100)
Final Height > 5th Percentile?
No. Patients
22
No
13 (59.1)
Yes
9 (40.9)
33
24 (72.7)
9 (27.3)
11
11 (100)
0
Baseline Height > 10th Percentile?
No. Patients
22
11
No
22 (100)
11 (100)
33
33 (100)
Final Height > 10th Percentile?
No. Patients
22
No
16 (72.7)
Yes
6 (27.3)
33
27 (81.8)
6 (18.2)
11
11 (100)
0
p-Value
-----------
.015*
.077*
*Frequencies are analyzed using a Fishers-Exact test.
Secondary Efficacy Objective
In this study, there was no evidence that tibial growth velocity was a reliable predictor of
long-term growth in this subpopulation of patients. There was no statistically significant
effect, on final height minus BPH (cm), of either the difference between posttreatment
and pretreatment tibial growth velocity (p=.56) or the ratio of the two (p=.53).
Of the 181 samples analyzed for anti-Escherichia coli polypeptide antibodies, none were
positive. Additionally, no patient developed anti-GH antibodies.
Safety
Deaths, Serious Adverse Events and Discontinuations
Table 6 presents an overview of adverse events in the Safety Population. No patient
deaths were reported during this study. Seven SAEs were reported for 7 patients
(Humatrope, n=5; placebo, n=2). One Humatrope patient discontinued study
participation because of an adverse event (Hodgkin disease), which was considered
serious, unexpected, and possibly related. However, prior to entering the study, a chest
X-ray of this patient showed a widened mediastinum, characteristic of lymphoma.
Furthermore, at study entry, the patient had a borderline-high erythrocyte sedimentation
rate. At the time of diagnosis of Hodgkin disease (19 weeks after beginning Humatrope
therapy), clinic findings showed advanced disease. Although 1 placebo patient was listed
as a discontinuation due to an adverse event, the adverse event occurred after the patient
had discontinued from the study. The six remaining SAEs (Humatrope, n=4; placebo,
n=2) all involved hospitalization.
CT Registry ID#843
Table 6.
Page 11
Overview of Adverse Events
Safety Population
Number (%) of Patients
Humatrope
Placebo
Total
n=37
n=31
n=68
0 (0.0)
0 (0.0)
0 (0.0)
7 (10.3)
5 a (13.5)
2 (6.5)
1
0
1
6
2
4
1
0
1
1
1
0
1
0
1
2
0
2
1
1
0
1a (2.7)
1b (3.2)
2 (2.9)
1a (2.7)
0 (0.0)
1 (1.5)
15 (40.5)
10 (32.3)
25 (36.8)
36 (97.3)
30 (96.8)
66 (97.1)
Adverse Event
Death
Serious adverse event
Hodgkin disease
Hospitalization:
Alcohol ingestion
Injuries sustained in a motor vehicle accident
Injuries sustained in a fall
Fractured leg
Black widow spider bite
Discontinuation due to an adverse event
Serious, unexpected, possibly related adverse event
Nonserious clinically significant adverse event
Treatment-emergent adverse eventc
Abbreviations: n = number of patients in treatment group.
a Within three categories is noted a single event that was serious, possibly related to study drug, and
resulted in discontinuation.
b Although 1 placebo patient was listed as discontinuation due to an adverse event, the adverse event, in
fact, occurred after the patient had discontinued from the study. However, due to site error, the reason
for discontinuation was checked as an adverse event on the clinical report form (CRF).
c Patients with at least one TEAE.
Table 7 presents TEAEs by event classification term in order of decreasing frequency for
the Safety Population. TEAEs were reported for all but 1 patient in each of the treatment
groups. This finding is not unexpected in a pediatric population. There were no
statistically significant differences between treatment groups in the rate of occurrence of
reported TEAEs. The majority of these events represented common childhood
conditions, such as upper respiratory illnesses and accidental injuries.
There were no statistically significant differences in TEAEs by body system between
treatment groups. The body systems for which TEAEs were most frequently reported
were the respiratory system (84% of patients) and the digestive system (66% of patients).
Table 8 provides a summary of TEAEs that are of special interest due to concern that
development or worsening of some adverse events may potentially be related to GH
(nonserious, clinically significant adverse events) for the Safety Population. The
frequency and percentage of these TEAEs of special interest are summarized overall and
by treatment group.
There were no statistically significant differences between treatment groups for the Safety
Population for these events of special interest. The most commonly reported event in the
CT Registry ID#843
Page 12
Safety Population was scoliosis (generally of mild degree, reported as “trace scoliosis”).
There was no statistically significant difference between treatment groups in the reported
frequency of this event. Otitis media was reported for a greater number of patients in the
Humatrope group than in the placebo group; the difference was not statistically
significant. No occurrences of hyperglycemia or lymphedema were reported in either
treatment group.
As the incidence of above-range values and mean levels for glucose, insulin, and
hemoglobin A1c (HbA1c) were similar in both treatment groups, there was no evidence of
a GH effect on carbohydrate metabolism in this patient population. No patient developed
diabetes or impaired glucose tolerance. There was a statistically significant difference
between treatment groups for change in blood urea nitrogen across the study
(Humatrope=-0.33 mmol/L and placebo=0.28 mmol/L, p=.049) consistent with the
known anabolic effect of GH. As expected, Humatrope-treated patients had a statistically
significantly greater baseline-to-endpoint increase in mean serum Insulin-Like Growth
Factor I (IGF-I) concentration than placebo-treated patients (186.6 ± 123.5 versus
102.8 ± 105.2 ng/mL, respectively; p=.007); however, this was not statistically significant
when expressed as the change in IGF-I standard deviation score. There were no
statistically significant differences in blood chemistry, thyroid function, or lipid
concentrations between treatment groups. No patient found to be positive on screening
for anti-GH antibodies demonstrated a positive result when tested for anti-GH binding
capacity.
CT Registry ID#843
Table 7.
Page 13
Safety Population
Event Classification
--------------------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
RHINITIS
PHARYNGITIS
ACCIDENTAL INJURY
COUGH INCREASED
HEADACHE
FLU SYNDROME
FEVER
PAIN
INFECTION
ABDOMINAL PAIN
INJECTION SITE PAIN
VOMITING
RASH
DIARRHEA
EAR PAIN
LAB TEST ABNORMAL
ACNE
BACK PAIN
BONE DISORDER
LYMPHADENOPATHY
MYALGIA
SINUSITIS
ALBUMINURIA
CONTACT DERMATITIS
ALLERGIC REACTION
DYSPEPSIA
HEMATURIA
NAUSEA
NECK PAIN
TOOTH DISORDER
DIZZINESS
MALAISE
OTITIS MEDIA
REFRACTION DISORDER
CARDIOVASCULAR DISORDER
JOINT DISORDER
MIGRAINE
ARTHROSIS
ECCHYMOSIS
GASTROINTESTINAL DISORDER
SKIN DISCOLORATION
SURGICAL PROCEDURE
ANOREXIA
ARTHRALGIA
ASTHENIA
BILIRUBINEMIA
BRONCHITIS
FUNGAL DERMATITIS
INSOMNIA
PUSTULAR RASH
CHEST PAIN
DYSMENORRHEA
hGH
(N=37)
n (%)
--------36 (97.3)
1 (2.7)
28 (75.7)
21 (56.8)
19 (51.4)
20 (54.1)
19 (51.4)
20 (54.1)
14 (37.8)
17 (45.9)
18 (48.6)
13 (35.1)
12 (32.4)
8 (21.6)
8 (21.6)
8 (21.6)
10 (27.0)
9 (24.3)
9 (24.3)
10 (27.0)
9 (24.3)
9 (24.3)
9 (24.3)
7 (18.9)
6 (16.2)
3 (8.1)
5 (13.5)
3 (8.1)
3 (8.1)
5 (13.5)
6 (16.2)
7 (18.9)
2 (5.4)
4 (10.8)
6 (16.2)
4 (10.8)
5 (13.5)
3 (8.1)
5 (13.5)
4 (10.8)
1 (2.7)
5 (13.5)
2 (5.4)
5 (13.5)
3 (8.1)
4 (10.8)
3 (8.1)
3 (8.1)
3 (8.1)
4 (10.8)
2 (5.4)
3 (8.1)
2 (5.4)
3 (8.1)
Placebo
(N=31)
n (%)
--------30 (96.8)
1 (3.2)
24 (77.4)
18 (58.1)
19 (61.3)
17 (54.8)
16 (51.6)
11 (35.5)
15 (48.4)
12 (38.7)
9 (29.0)
10 (32.3)
7 (22.6)
9 (29.0)
8 (25.8)
7 (22.6)
5 (16.1)
5 (16.1)
4 (12.9)
3 (9.7)
4 (12.9)
4 (12.9)
4 (12.9)
6 (19.4)
4 (12.9)
7 (22.6)
4 (12.9)
6 (19.4)
6 (19.4)
4 (12.9)
3 (9.7)
2 (6.5)
6 (19.4)
4 (12.9)
2 (6.5)
4 (12.9)
2 (6.5)
4 (12.9)
2 (6.5)
2 (6.5)
5 (16.1)
1 (3.2)
4 (12.9)
1 (3.2)
2 (6.5)
1 (3.2)
2 (6.5)
2 (6.5)
2 (6.5)
1 (3.2)
3 (9.7)
2 (6.5)
2 (6.5)
1 (3.2)
Total
(N=68)
n (%)
--------66 (97.1)
2 (2.9)
52 (76.5)
39 (57.4)
38 (55.9)
37 (54.4)
35 (51.5)
31 (45.6)
29 (42.6)
29 (42.6)
27 (39.7)
23 (33.8)
19 (27.9)
17 (25.0)
16 (23.5)
15 (22.1)
15 (22.1)
14 (20.6)
13 (19.1)
13 (19.1)
13 (19.1)
13 (19.1)
13 (19.1)
13 (19.1)
10 (14.7)
10 (14.7)
9 (13.2)
9 (13.2)
9 (13.2)
9 (13.2)
9 (13.2)
9 (13.2)
8 (11.8)
8 (11.8)
8 (11.8)
8 (11.8)
7 (10.3)
7 (10.3)
7 (10.3)
6 (8.8)
6 (8.8)
6 (8.8)
6 (8.8)
6 (8.8)
5 (7.4)
5 (7.4)
5 (7.4)
5 (7.4)
5 (7.4)
5 (7.4)
5 (7.4)
5 (7.4)
4 (5.9)
4 (5.9)
p-Value*
--------1.00
1.00
1.00
1.00
.468
1.00
1.00
.148
.463
.626
.137
1.00
.425
.578
.777
1.00
.382
.550
.354
.120
.354
.354
.354
1.00
.745
.167
1.00
.282
.282
1.00
.494
.166
.129
1.00
.275
1.00
.442
.694
.442
.681
.085
.209
.400
.209
1.00
.366
1.00
1.00
1.00
.366
.653
1.00
1.00
.620
(continued)
CT Registry ID#843
Table 7.
Page 14
Safety Population (continued)
--------------------------------------EAR DISORDER
EPISTAXIS
EYE DISORDER
HORMONE LEVEL ALTERED
HYPERLIPEMIA
LEG CRAMPS
LIVER FUNCTION TESTS ABNORMAL
NAUSEA AND VOMITING
OTITIS EXTERNA
SEDIMENTATION RATE INCREASED
SKIN BENIGN NEOPLASM
SYNCOPE
TENDON DISORDER
URINE ABNORMALITY
AMBLYOPIA
CONSTIPATION
CREATINE PHOSPHOKINASE INCREASED
DYSPNEA
EOSINOPHILIA
GYNECOMASTIA
INJECTION SITE HEMORRHAGE
LYMPHOCYTOSIS
MONOCYTOSIS
SKIN NODULE
THINKING ABNORMAL
ABNORMAL VISION
ANXIETY
BLOOD DYSCRASIA
BONE PAIN
BREAST PAIN
CONJUNCTIVITIS
CONVULSION
CYST
DEPRESSION
DRY SKIN
EYE HEMORRHAGE
HEMORRHAGE
HYPERCHOLESTEREMIA
HYPESTHESIA
HYPOTHYROIDISM
INJECTION SITE INFLAMMATION
INJECTION SITE MASS
INJECTION SITE REACTION
LEUKOPENIA
MOUTH ULCERATION
NAIL DISORDER
NAUSEA VOMITING AND DIARRHEA
NECK RIGIDITY
PALLOR
RESPIRATORY DISORDER
SGOT INCREASED
SKIN HYPERTROPHY
SOMNOLENCE
hGH
(N=37)
n (%)
--------4 (10.8)
2 (5.4)
3 (8.1)
2 (5.4)
3 (8.1)
1 (2.7)
3 (8.1)
3 (8.1)
1 (2.7)
2 (5.4)
3 (8.1)
2 (5.4)
2 (5.4)
4 (10.8)
2 (5.4)
2 (5.4)
0
1 (2.7)
1 (2.7)
2 (5.4)
1 (2.7)
1 (2.7)
0
0
2 (5.4)
1 (2.7)
2 (5.4)
0
1 (2.7)
2 (5.4)
2 (5.4)
2 (5.4)
1 (2.7)
2 (5.4)
0
1 (2.7)
1 (2.7)
0
1 (2.7)
0
1 (2.7)
1 (2.7)
0
1 (2.7)
1 (2.7)
2 (5.4)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
Placebo
(N=31)
n (%)
--------0
2 (6.5)
1 (3.2)
2 (6.5)
1 (3.2)
3 (9.7)
1 (3.2)
1 (3.2)
3 (9.7)
2 (6.5)
1 (3.2)
2 (6.5)
2 (6.5)
0
1 (3.2)
1 (3.2)
3 (9.7)
2 (6.5)
2 (6.5)
1 (3.2)
2 (6.5)
2 (6.5)
3 (9.7)
3 (9.7)
1 (3.2)
1 (3.2)
0
2 (6.5)
1 (3.2)
0
0
0
1 (3.2)
0
2 (6.5)
1 (3.2)
1 (3.2)
2 (6.5)
1 (3.2)
2 (6.5)
1 (3.2)
1 (3.2)
2 (6.5)
1 (3.2)
1 (3.2)
0
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)
Total
(N=68)
n (%)
--------4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
4 (5.9)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
3 (4.4)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
p-Value*
--------.120
1.00
.620
1.00
.620
.324
.620
.620
.324
1.00
.620
1.00
1.00
.120
1.00
1.00
.090
.588
.588
1.00
.588
.588
.090
.090
1.00
1.00
.496
.204
1.00
.496
.496
.496
1.00
.496
.204
1.00
1.00
.204
1.00
.204
1.00
1.00
.204
1.00
1.00
.496
1.00
1.00
1.00
1.00
1.00
1.00
1.00
(continued)
CT Registry ID#843
Table 7.
Page 15
Safety Population (concluded)
--------------------------------------URINARY TRACT INFECTION
URTICARIA
VOICE ALTERATION
ALCOHOL INTOLERANCE
ANAPHYLACTOID REACTION
APHTHOUS STOMATITIS
BURSITIS
CEREBRAL HEMORRHAGE
DEHYDRATION
ECZEMA
ERYTHROCYTES ABNORMAL
EXFOLIATIVE DERMATITIS
EYE PAIN
FACE EDEMA
FLATULENCE
GAMMA GLUTAMYL TRANSPEPTIDASE INCREASED
GASTROENTERITIS
GINGIVITIS
GLYCOSURIA
HALITOSIS
HYPERKINESIA
HYPERTENSION
HYPERTHYROIDISM
HYPERTROPHY
IRON DEFICIENCY ANEMIA
JAUNDICE
LACTIC DEHYDROGENASE INCREASED
LEUKORRHEA
LYMPHOMA LIKE REACTION
MENSTRUAL DISORDER
METRORRHAGIA
NEOPLASM
OBESITY
PELVIC PAIN
PHOTOSENSITIVITY REACTION
PNEUMONIA
POLYCYTHEMIA
PROLACTIN INCREASED
PRURITUS
SLEEP DISORDER
SPEECH DISORDER
SPLENOMEGALY
THROMBOCYTOPENIA
TORTICOLLIS
TUBERCULOSIS REACTIVATED
TWITCHING
VAGINITIS
VENTRICULAR EXTRASYSTOLES
VISION ABNORMAL
VISUAL FIELD DEFECT
*
hGH
(N=37)
n (%)
--------1 (2.7)
0
1 (2.7)
1 (2.7)
1 (2.7)
0
1 (2.7)
1 (2.7)
1 (2.7)
0
1 (2.7)
1 (2.7)
1 (2.7)
0
0
1 (2.7)
1 (2.7)
0
1 (2.7)
1 (2.7)
0
1 (2.7)
0
1 (2.7)
0
1 (2.7)
0
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
0
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
0
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
0
0
0
0
0
Placebo
(N=31)
n (%)
--------1 (3.2)
2 (6.5)
1 (3.2)
0
0
1 (3.2)
0
0
0
1 (3.2)
0
0
0
1 (3.2)
1 (3.2)
0
0
1 (3.2)
0
0
1 (3.2)
0
1 (3.2)
0
1 (3.2)
0
1 (3.2)
0
0
0
0
1 (3.2)
0
0
0
0
0
0
1 (3.2)
0
0
0
0
0
0
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)
1 (3.2)
Total
(N=68)
n (%)
--------2 (2.9)
2 (2.9)
2 (2.9)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
p-Value*
--------1.00
.204
1.00
1.00
1.00
.456
1.00
1.00
1.00
.456
1.00
1.00
1.00
.456
.456
1.00
1.00
.456
1.00
1.00
.456
1.00
.456
1.00
.456
1.00
.456
1.00
1.00
1.00
1.00
.456
1.00
1.00
1.00
1.00
1.00
1.00
.456
1.00
1.00
1.00
1.00
1.00
1.00
.456
.456
.456
.456
.456
CT Registry ID#843
Table 8.
-----------------------PATIENTS WITH >= 1 TESS
SCOLIOSIS
OTITIS MEDIA
HYPERLIPIDEMIA
GYNECOMASTIA
HYPOTHYROIDISM
ACHING JOINTS
HIP PAIN
HYPERTENSION
*
Page 16
Nonserious Treatment-Emergent Adverse Events
Safety Population
hGH
(N=37)
n (%)
--------15 (40.5)
22 (59.5)
7 (18.9)
6 (16.2)
3 (8.1)
2 (5.4)
0
0
1 (2.7)
1 (2.7)
Placebo
(N=31)
n (%)
--------10 (32.3)
21 (67.7)
4 (12.9)
2 (6.5)
1 (3.2)
1 (3.2)
2 (6.5)
1 (3.2)
0
0
Total
(N=68)
n (%)
--------25 (36.8)
43 (63.2)
11 (16.2)
8 (11.8)
4 (5.9)
3 (4.4)
2 (2.9)
1 (1.5)
1 (1.5)
1 (1.5)
p-Value*
--------.615
.615
.742
.275
.620
1.00
.204
.456
1.00
1.00
Reference
Kuczmarski RJ, OgdenCL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, Mei Z,
Curtin LR, Roche AF, Johnson CL. 2000. CDC growth charts: United States. US
Department of Health and Human Services, Centers for Disease Control and
Prevention, National Center for Health Statistics 314:1-28.
CT Registry ID# 843
Page 1
Summary ID# 843
Clinical Study Summary: Study B9R-MC-GDCH
Extension Phase
Humatrope® in Non-Growth Hormone Deficient Children
with Short Stature
Date summary approved by Lilly: 05 January 2007
Brief Summary of Results
This study was the open-label extension phase (hereafter referred to as Extension period)
of Study B9R-MC-GDCH (GDCH; CT#843), a multicenter study conducted by the
National Institutes of Heath (NIH) in cooperation with Eli Lilly and Company between
January 1998 and February 2001. The core period (hereafter referred to as the Core
study) of study GDCH was a double-blind, randomized, parallel, placebo-controlled
clinical study that aimed to determine the effect of Humatrope (growth hormone [GH])
treatment on final height in pediatric patients with idiopathic short stature (ISS). The
primary objective of the study was to determine whether the final height of patients with
ISS who received GH (0.22 mg/kg/wk, administered in divided doses 3 times per week
[TIW]) would be greater than that of a placebo-treated group.
Study GDCH randomized 71 patients, the last of whom entered the trial in July 1999.
Based on recommendations received on 5 June 2000 from the NIH data and safety
monitoring board, the double-blind Core study was terminated in February 2001 and the
study continued thereafter as the open-label Extension period.
Somatropin
CT Registry ID# 843
Page 2
The following summarizes the general findings from the Extension period:
•
No treatment group differences in final height standard deviation scores
(SDS) and changes in height SDS were found between patients from the
PrevPlacebo (patients who received placebo injections during the Core
study) and PrevGH (patients who received GH injections during the Core
study) groups.
•
The mean changes in height SDS from baseline to the end of the
Extension period in patients from the PrevPlacebo group (0.48; n=6) were
lower than those from the PrevGH group (0.87; n=2).
•
Bone age SDS change from baseline to the end of the Extension period, as
expected, approached chronological age and was greater for patients from
the PrevPlacebo group (1.15; n=5) than from the PrevGH group (0.36;
n=1). This increased catch-up for the PrevPlacebo group occurred during
the core study. At the time of the extension, both groups had a similar
bone age/chronologic age ratio. Thereafter the change was 0.06 SDS, n=5
vs 0.13 SDS, n=1 respectively.
•
A total of 4 patients (67%) from the PrevPlacebo group and 2 patients
(40%) from the PrevGH group attained final height during the Extension
period.
•
Total cumulative exposure (Core study + Extension periods) for patients
in the PrevGH group (24-patient years) exceeds by more than two-fold the
exposure data for patients in the PrevPlacebo group (11-patient years) at
the end of the Extension period.
•
No deaths occurred during the Extension period.
•
The treatment-emergent adverse events (TEAEs) occurring in 2 or more
patients from the PrevPlacebo vs. PrevGH groups, respectively, included
pharyngolaryngeal pain and acne (each 33% vs. 20%); pyrexia, joint
sprain, scoliosis, nasal congestion, influenza, myalgia, blood creatine
phosphokinase increased, and dysmenorrhea (each 33% vs. 0%).
•
During the Extension period, 1 patient from the PrevGH group reported
serious adverse events (SAEs; abdominal pain and dysuria during the
same hospitalization).
•
During the Extension period, more patients in PrevPlacebo group (4 of 6
patients) had a nonserious but clinically significant adverse event (AE) as
compared to patients in the PrevGH (1 of 5 patients) treatment group. The
more commonly occurring nonserious clinically significant AEs in
patients from the PrevPlacebo group included scoliosis and myalgia
(each 33% as compared to 0%); the more commonly occurring nonserious
clinically significant AEs in patients from the PrevGH group included ear
infection and pain (each 20% as compared to 0%).
Somatropin
CT Registry ID# 843
•
Page 3
There was no measurable effect on the following: fasting insulin, the ratio
of fasting insulin to fasting glucose level, the quantitative insulin
sensitivity check index (QUICKI), hemoglobin A1c and adjusted
hemoglobin A1c, free T4, tri-iodothyronine, and triglycerides. Blood
thyroid-stimulating hormone (TSH) concentrations and aspartate
aminotransferase levels increased in 1 patient each (PrevPlacebo group)
and fasting glucose concentrations decreased in another patient
(PrevPlacebo group).
Somatropin
CT Registry ID# 843
Page 4
Title of Study: Humatrope® in Non-Growth Hormone Deficient Children with Short Stature
Investigators: This multicenter study included 3 principal investigators.
Study Centers: This study was conducted at 2 study centers in the US.
Length of Study: 13.1 years (Core study) + 4.9 years (Extension)
Date of first patient enrolled in Core study: 22 January 1988
Date of first patient enrolled in Extension period: 12 February 2001
Date of last patient completed in Extension period: 12 January 2006
Objectives:
Primary Objective:
•
To determine whether final height improved in children with idiopathic short stature (ISS) treated
chronically with Humatrope® (somatropin [rDNA origin] for injection, Lilly) to adult height.
Secondary Objectives:
•
To determine the clinical safety of Humatrope in these patients.
Study Design:
This study was the open-label extension phase (hereafter referred to as Extension period) of Study B9RMC-GDCH (GDCH), a multicenter study conducted by the National Institutes of Heath (NIH) in
cooperation with Eli Lilly and Company between January 1998 and February 2001. The core period
(hereafter referred to as the Core study) of study GDCH was a double-blind, randomized, parallel,
placebo-controlled clinical study that aimed to determine the effect of Humatrope (growth hormone [GH])
treatment on final height in pediatric patients with idiopathic short stature (ISS). The primary objective of
the study was to determine whether the final height of patients with ISS who received GH (0.22 mg/kg/wk,
administered in divided doses 3 times per week [TIW]) would be greater than that of a placebo-treated
group.
Study GDCH randomized 71 patients, the last of whom entered the trial in July 1999. Based on
recommendations received on 5 June 2000 from the NIH data and safety monitoring board, the
double-blind Core study was terminated in February 2001 and the study continued thereafter as the openlabel Extension period.
All active patients from the Core study were scheduled to return for a study visit to offer them the option to
be unblinded and, after obtaining informed consent, to enter the Extension period of the study. In addition,
all previous study participants (no longer active in the study) who were reachable and eligible were offered
the option of enrollment in the study Extension period.
Core Study (Double-Blind):
During this period, patients were randomized to placebo or GH. Patients participating in the double-blind
Core study were classified according to treatment group as follows for analysis:
• Placebo: Patients who received Placebo injections during the Core study.
• GH: Patients who received GH injections during the Core study.
(continued)
Somatropin
CT Registry ID# 843
Page 5
Study B9R-MC-GDCH (Continued)
Study Design: (Concluded)
Extension Period (Open-Label):
During this period, all patients from the Core study who entered the open-label Extension period received
GH. Patients were classified into two groups according to the original treatment group to which they were
randomized in the Core study:
• PrevPlacebo: Patients who received placebo injections during the Core study.
• PrevGH: Patients who received GH injections during the Core study.
Number of Patients:
Planned: 25 patients were eligible to enter the Extension period.
Entered: 11 patients enrolled; 6 of the 11 patients had received Placebo injections (PrevPlacebo) and 5
patients had received Humatrope (PrevGH) during the Core study. All patients received
Humatrope during the Extension period.
Completed: 6 patients; 4 from the PrevPlacebo group and 2 from the PrevGH group.
Diagnosis and Main Criteria for Inclusion:
Patients were considered eligible for participation in the Extension period if they fulfilled the following
criteria: for patients still receiving study drug, height velocity ≥1.5 cm/year measured over the prior
12-month period; for patients who had discontinued from the Core study, bone age ≤16 years for boys and
≤14 years for girls. Patients were not eligible to participate if they had any of the following: diabetes
mellitus; history, evidence or signs of active malignancy within five years prior to start of the Extension
period; active chronic infection (e.g., tuberculosis); any condition or medication that, in the opinion of the
investigator, might significantly increase the risk or decrease the efficacy of GH; pregnancy.
Humatrope® (somatropin [rDNA origin] for injection, Lilly) was used for both the Core study and
Extension period.
Core Study (Double-Blind):
There were 2 treatment groups in the Core study:
Group 1 received Humatrope (0.074 mg/kg) subcutaneously (SC) three times per week from entry to the
protocol. A maximum dose of 15 mg of study drug per week was not to be exceeded in any patient. Any
two doses were to be given on days separated by at least one non-treatment day. Group 2 received Placebo
for Humatrope SC.
Extension Period (Open-Label):
Humatrope was provided in the same form as in the Core study. Patients previously receiving placebo
(PrevPlacebo) were eligible to begin Humatrope. The dose of Humatrope and dosing procedure were
identical to that during the Core double-blind study.
Reference Therapy, Dose, and Mode of Administration:
Core Study (Double-Blind): Placebo for Humatrope SC three times per week.
Extension Period (Open-Label): No reference therapy was used in the Extension period (all 11 patients
received Humatrope).
(continued)
Somatropin
CT Registry ID# 843
Page 6
Duration of Treatment: The mean study drug exposure in the Extension period for patients in the
PrevPlacebo group (n=6) was 1.86 years vs. 1.07 years for patients in the PrevGH group (n=5). Patients
from the PrevPlacebo treatment group had lower average cumulative exposure to active drug (1.86 years)
as compared with patients from the PrevGH treatment group (4.80 years) who were on GH since
randomization.
Total cumulative exposure for GH group was the sum of GH exposure during the Core study and GH
exposure during the Extension period.
Variables:
Efficacy:
•
Final height standard deviation scores (SDS)
•
Height velocity
•
Patients attaining final height
Final height was defined by the protocol as the last observed height after the height velocity fell below
1.5 cm/year, determined over each 12-month interval. For patients who discontinued the study prior to
protocol completion, final height was defined as the height obtained at the final follow-up visit, at which
the investigator had determined that growth was nearly complete, based on height velocity and/or skeletal
maturation. All SDS-derived variables used the National Center for Health Statistics (NCHS) Stature-forAge standardization chart.
Safety:
•
Patient exposure
•
Adverse events (AEs)
•
Deaths
•
Vital signs and physical examinations
•
Clinical laboratory evaluations relevant to growth hormone treatment
Adverse events included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs),
clinically significant TEAEs, abnormal clinical laboratory evaluations (such as effects on insulin-like
growth factor-I, thyroid function, carbohydrate metabolism, and blood chemistry), and AEs that led to
discontinuations.
Evaluation Methods:
Statistical: The primary efficacy analysis was a comparison of final height SDS at the Extension period
endpoint for the treatment groups PrevPlacebo vs. PrevGH. The number of patients attaining final height
was expressed as numbers and percentages of patients who attained final height during the Extension
period. Final height was expressed in SD units relative to the general population of the same gender and
age. To determine that a subject had attained final height, height velocity was calculated after each
12-month time interval.
(continued)
Somatropin
CT Registry ID# 843
Page 7
Study B9R-MC-GDCH (Concluded)
Because of the differences in GH exposure between the two treatment regimens (i.e., GH throughout both
study periods vs. initial period of placebo followed by GH during the Extension period), 3 exploratory
analyses of final height SDS were performed using analysis of covariance (ANCOVA) models. Model 1
incorporated effects for treatment (two levels: PrevPlacebo and PrevGH), and baseline predicted height
standard deviation score (BPH-SDS) as a continuous variable; Model 2 included effects for treatment and
BPH-SDS as in model 1, with addition of duration of GH treatment (continuous variable); Model 3
included for treatment and BPH-SDS as in Model 1, with addition of age at initiation of GH treatment
(continuous variable). Because of the marked difference in duration of GH treatment between the two
Extension period treatment groups (PrevPlacebo and PrevGH), confidence intervals around the means for
the differences between treatment groups and significance testing for between-group differences in means
for these analyses (with α=0.05) were given for guidance only.
Height SDS by year on study was determined for individual patients in each of the treatment groups and
presented as mean ± standard error (SE) for each of the treatment groups.
Results:
Patient Background Characteristics
Table 1 summarizes baseline patient characteristics for the patients enrolled in the
Extension period.
No statistically significant differences between treatment groups in demographics and
baseline characteristics were found.
Patient Disposition
Table 2 summarizes the reasons for study discontinuation for patients enrolled in the
Extension period.
Of the 11 patients who gave informed consent to enter the open-label Extension period,
5 patients in the PrevGH group continued on Humatrope treatment and 6 patients in the
PrevPlacebo group began Humatrope treatment. A total of 6 patients completed the
Extension period (2 from the PrevGH group and 4 from the PrevPlacebo group).
Two of 6 (33%) patients from the PrevPlacebo group and 3 of 5 (60%) patients from the
PrevGH group discontinued based on patient decision.
Somatropin
Somatropin
Table 1.
Demographics and Other Baseline Characteristics
Arranged by Treatment Received during the Double-blind Period
All Subjects Enrolled in Extension Period
Study B9R-MC-GDCH
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Age (yrs)
No. Subjects
6
5
11
0.289*
Mean
10.96
12.05
11.45
Standard Dev.
0.744
2.259
1.626
Median
11.04
12.75
11.04
Minimum
10.12
9.20
9.20
Maximum
12.14
14.90
14.90
Gender
No. Subjects
Female
Male
6
3 ( 50.0)
3 ( 50.0)
5
2 ( 40.0)
3 ( 60.0)
11
5 ( 45.5)
6 ( 54.5)
1.000**
Origin
No. Subjects
6
5
11
1.000**
African Descent
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Asian
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Caucasian
5 ( 83.3)
5 (100.0)
10 ( 90.9)
Hispanic
1 ( 16.7)
0 ( 0.0)
1 ( 9.1)
Other
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 8
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Tanner Stage of Sexual Development
No. Subjects
6
5
11
0.455**
Stage 1
4 ( 66.7)
5 (100.0)
9 ( 81.8)
Stage 2
2 ( 33.3)
0 ( 0.0)
2 ( 18.2)
Stage 3
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Stage 4
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Stage 5
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Height (cm)
No. Subjects
6
5
11
0.204*
Mean
123.84
130.47
126.85
Standard Dev.
2.354
11.717
8.348
Median
123.59
132.42
123.76
Minimum
121.34
115.36
115.36
Maximum
127.21
146.28
146.28
Height SDS (NCHS)
No. Subjects
6
5
11
0.935*
Mean
-2.87
-2.90
-2.88
Standard Dev.
0.695
0.273
0.521
Median
-2.85
-2.85
-2.85
Minimum
-4.03
-3.21
-4.03
Maximum
-1.85
-2.59
-1.85
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 9
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Pre-treatment Height Velocity (cm/yr)
No. Subjects
6
5
11
0.813*
Mean
4.89
4.68
4.79
Standard Dev.
1.577
1.125
1.327
Median
5.54
4.30
4.35
Minimum
2.48
3.82
2.48
Maximum
6.24
6.66
6.66
Pre-treatment Height Velocity SDS
No. Subjects
6
5
11
0.579*
Mean
-0.77
-0.34
-0.57
Standard Dev.
1.230
1.254
1.199
Median
-0.14
-0.79
-0.48
Minimum
-2.46
-1.22
-2.46
Maximum
0.19
1.85
1.85
Weight (Kg)
No. Subjects
6
5
11
0.587*
Mean
26.88
28.40
27.57
Standard Dev.
2.119
6.242
4.296
Median
26.05
28.50
26.10
Minimum
24.60
22.30
22.30
Maximum
30.60
36.90
36.90
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 10
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Weight SDS
No. Subjects
6
5
11
0.107*
Mean
-1.77
-2.27
-2.00
Standard Dev.
0.543
0.348
0.516
Median
-1.86
-2.38
-1.96
Minimum
-2.51
-2.58
-2.58
Maximum
-0.85
-1.70
-0.85
Body Mass Index (Kg/m2)
No. Subjects
6
5
11
0.302*
Mean
17.57
16.51
17.09
Standard Dev.
1.900
1.154
1.628
Median
17.38
16.91
17.07
Minimum
15.20
14.62
14.62
Maximum
20.78
17.50
20.78
Body Mass Index SDS
No. Subjects
6
5
11
0.114*
Mean
-0.00
-0.77
-0.35
Standard Dev.
0.768
0.651
0.789
Median
-0.17
-1.01
-0.44
Minimum
-0.88
-1.40
-1.40
Maximum
1.35
0.23
1.35
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 11
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Bone Age (yrs)
No. Subjects
6
5
11
0.229*
Mean
9.28
10.47
9.82
Standard Dev.
1.089
1.927
1.570
Median
9.00
10.00
10.00
Minimum
7.83
7.83
7.83
Maximum
11.00
13.00
13.00
Bone Age - Chronological Age (yrs)
No. Subjects
6
5
11
0.915*
Mean
-1.68
-1.58
-1.64
Standard Dev.
1.409
1.465
1.361
Median
-2.17
-1.37
-2.14
Minimum
-3.21
-3.40
-3.40
Maximum
0.88
-0.02
0.88
Bone Age SDS
No. Subjects
6
5
11
0.967*
Mean
-1.65
-1.61
-1.63
Standard Dev.
1.411
1.383
1.327
Median
-1.97
-1.70
-1.82
Minimum
-3.10
-3.00
-3.10
Maximum
0.94
-0.02
0.94
__________________________________________________________________________________________________________________________________
(continued)
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Page 12
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Bone Age/Chronological Age Ratio
No. Subjects
6
5
11
0.758*
Mean
0.85
0.87
0.86
Standard Dev.
0.129
0.103
0.112
Median
0.81
0.85
0.82
Minimum
0.71
0.77
0.71
Maximum
1.09
1.00
1.09
Predicted Height (cm)
No. Subjects
6
5
11
0.685*
Mean
153.18
155.28
154.14
Standard Dev.
6.488
10.087
7.934
Median
154.94
153.62
154.87
Minimum
140.22
146.19
140.22
Maximum
158.22
170.09
170.09
Predicted Height SDS (NCHS)
No. Subjects
6
5
11
0.849*
Mean
-2.36
-2.26
-2.32
Standard Dev.
0.900
0.849
0.834
Median
-2.59
-2.58
-2.58
Minimum
-3.53
-3.07
-3.53
Maximum
-1.27
-0.85
-0.85
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 13
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Sitting Height (cm)
No. Subjects
6
5
11
0.397*
Mean
67.58
69.70
68.55
Standard Dev.
1.630
5.600
3.885
Median
68.26
70.56
68.54
Minimum
64.61
63.10
63.10
Maximum
68.91
76.51
76.51
Armspan (cm)
No. Subjects
6
5
11
0.317*
Mean
124.05
130.13
126.81
Standard Dev.
2.270
13.981
9.531
Median
124.67
130.30
124.67
Minimum
120.73
111.83
111.83
Maximum
126.43
148.83
148.83
Head Circumference (cm)
No. Subjects
6
5
11
0.307*
Mean
52.11
49.85
51.08
Standard Dev.
1.643
4.845
3.484
Median
52.22
50.83
51.77
Minimum
49.43
41.67
41.67
Maximum
53.87
54.20
54.20
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 14
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Frame Size
No. Subjects
6
5
11
Medium
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Small
6 (100.0)
5 (100.0)
11 (100.0)
Unspecified
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Habitus
No. Subjects
6
5
11
0.318**
Ectomorph
1 ( 16.7)
2 ( 40.0)
3 ( 27.3)
Endomorph
0 ( 0.0)
1 ( 20.0)
1 ( 9.1)
Mesomorph
5 ( 83.3)
2 ( 40.0)
7 ( 63.6)
Unspecified
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Mother's height (cm)
No. Subjects
5
5
10
0.227*
Mean
153.00
158.62
155.81
Standard Dev.
4.585
8.462
7.068
Median
152.40
160.02
154.30
Minimum
147.16
146.11
146.11
Maximum
160.02
168.76
168.76
__________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 15
Somatropin
Table 1.
__________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
Variable
N=6
N=5
N=11
P-values
__________________________________________________________________________________________________________________________________
Father's Height (cm)
No. Subjects
5
5
10
0.350*
Mean
164.27
169.56
166.91
Standard Dev.
6.400
10.058
8.422
Median
161.29
170.18
163.83
Minimum
159.24
156.06
156.06
Maximum
175.26
180.34
180.34
Target Height (cm)
No. Subjects
5
5
10
0.231*
Mean
157.33
165.39
161.36
Standard Dev.
8.410
11.054
10.187
Median
155.64
166.78
161.02
Minimum
150.34
148.26
148.26
Maximum
170.63
176.68
176.68
Target Height SDS (NCHS)
No. Subjects
5
5
10
0.224*
Mean
-1.63
-0.80
-1.21
Standard Dev.
0.631
1.243
1.025
Median
-1.97
-0.46
-1.53
Minimum
-2.26
-2.29
-2.29
Maximum
-0.77
0.56
0.56
__________________________________________________________________________________________________________________________________
PrevGH = Subjects who received growth hormone injections during the core and extension study, PrevPlacebo = Subjects who received
placebo injections during the core study and growth hormone during the extension study, Total = Combination of the two treatment
groups during the extension period.
NCHS = National Center for Health Statistics, SDS = standard deviation score.
Note: Bone age measurement was completed by central reader. However, baseline predicted height (BPH) was calculated according
to the Bayley-Pinneau method by using NIH readings.
* Means were analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM model = Treatment group.
** Frequencies were analyzed using Fisher's exact test.
CT Registry ID# 843
Page 16
Somatropin
Table 2.
Summary of Primary Reasons for Study Discontinuation
Study B9R-MC-GDCH
__________________________________________________________________________________________________________________________________
Core Double-blind Study
Extension Period
Placebo
GH
PrevPlacebo
PrevGH
Total
N=6
N=5
N=6
N=5
N=11
Primary Reason for Discontinuation
n (%)
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
Protocol completed
0 ( 0.0)
0 ( 0.0)
4 (66.7)
2 (40.0)
6 (54.5)
Adverse event
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Death
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Unable to contact patient
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Patient decision
1 (16.7)
3 (60.0)
2 (33.3)
3 (60.0)
5 (45.5)
Physician decision
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Protocol violation
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Sponsor's decision
5 (83.3)
2 (40.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
Lack of efficacy
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
__________________________________________________________________________________________________________________________________
GH = Subjects who received growth hormone injections during the core study, Placebo = Subjects who received placebo injections
during the core study, PrevGH = Subjects who received growth hormone injections during the core and extension study, PrevPlacebo =
Subjects who received placebo injections during the core study and growth hormone during the extension study, Total = Combination
of the two treatment groups during the extension period.
n = number of subjects with the specified reason, % = percentage of subjects in treatment group.
CT Registry ID# 843
Page 17
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Page 18
Primary Endpoint
The primary efficacy analysis was the comparison of final height standard deviation score
(SDS) at the Extension period endpoint of the PrevPlacebo vs. PrevGH treatment groups.
Final height was defined as the last observed height after the height velocity falls below
1.5 cm/year, determined over a 12-month interval. Height velocity at each study visit for
individual patients was determined, expressed as numbers and percentages of patients
who attained final height during the Extension period. Final height was expressed in SD
units relative to the general population of the same gender and age. To determine that a
subject had attained final height, height velocity was calculated after each 12-month time
interval. For patients who discontinued the study prior to protocol completion, final
height was defined as the height obtained at the final follow-up visit, at which the
investigator had determined that growth was near complete, based on height velocity
and/or skeletal maturation.
Height SDS by year on study was determined for individual patients in each of the
treatment groups and expressed as mean ± standard error (SE) for each of the treatment
groups. Table 3 summarizes final height SDS and change in height SDS based on
treatment received during the Core double-blind study. Because of the differences in GH
exposure between the two treatment regimens exploratory analyses of final height SDS
were performed using three ANCOVA models as described in the Evaluation Methods
section of the synopsis table.
No treatment group differences in final height SDS and changes in height SDS were
found between patients from the PrevPlacebo and PrevGH groups.
Somatropin
Somatropin
Table 3.
Final Height SDS and Change in Height SDS
All Subjects Enrolled in the Extension Period
Study B9R-MC-GDCH
___________________________________________________________________________________________________________________________________
Parameters
Treatment
_______________________________________________________________________
Group
Timepoint
n
Mean
SD
LSM
SE
95% CI
p-value*
____________________________________________________________________________________________________________________________________
PrevPlacebo
N=6
Core Baseline (Visit 1)
Extension Endpoint
Change from Core Baseline to Ext. End.
Change from Ext. Baseline to Ext. End.
4
4
4
4
-2.92
-2.39
0.53
0.23
0.892
0.871
0.256
0.237
PrevGH
N=5
Extension Endpoint
2
2
2
2
-2.90
-2.03
0.87
0.32
0.441
0.437
0.003
0.404
-2.45
0.441
-1.90
0.640
(PrevGH Ext. End.– PrevPlacebo Ext. End.)
0.36
0.55
0.805
(-2.01 - 3.12)
0.541
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 19
Somatropin
Table 3.
___________________________________________________________________________________________________________________________________
Parameters
Treatment
_______________________________________________________________________
Group
Timepoint
n
Mean
SD
LSM
SE
95% CI
p-value*
____________________________________________________________________________________________________________________________________
PrevPlacebo
N=6
Extension Endpoint
4
4
4
4
-2.92
-2.39
0.53
0.23
0.892
0.871
0.256
0.237
PrevGH
N=5
Extension Endpoint
2
2
2
2
-2.90
-2.03
0.87
0.32
0.441
0.437
0.003
0.404
-1.93
0.382
-2.94
0.647
0.36
-1.00
0.904
(-4.89 - 2.89)
0.383
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 20
Somatropin
Table 3.
___________________________________________________________________________________________________________________________________
Parameters
Treatment
_______________________________________________________________________
Group
Timepoint
n
Mean
SD
LSM
SE
95% CI
p-value*
____________________________________________________________________________________________________________________________________
PrevPlacebo
N=6
Extension Endpoint
4
4
4
4
-2.92
-2.39
0.53
0.23
0.892
0.871
0.256
0.237
PrevGH
N=5
Extension Endpoint
2
2
2
2
-2.90
-2.03
0.87
0.32
0.441
0.437
0.003
0.404
-2.08
0.442
-2.65
0.726
0.36
-0.57
0.998
(-4.87 - 3.72)
0.624
___________________________________________________________________________________________________________________________________
placebo injections during the core study and growth hormone during the extension study.
CI = confidence interval for the between-group difference, End. = endpoint, Ext. = extension, LSM = least square mean, n = total
number of subjects with the variable value at both baseline and endpoint, SD = standard deviation, SDS = standard deviation
score, SE = standard error.
* Given the small sample size and the marked differences in duration of growth hormone treatment received between the two groups,
the p-value is presented for guidance only. Exploratory analyses were performed based on the following ANCOVA model: Response
variable = Treatment group + Baseline predicted height standard deviation score + Duration of growth hormone treatment.
CT Registry ID# 843
Page 21
CT Registry ID# 843
Page 22
Other Efficacy Endpoints
Other efficacy endpoints included height SDS (Table 4), bone age SDS (Table 5), and the
number and percentage of patients who attained final height (Table 6).
Baseline (Visit 1) mean height SDSs were comparable for PrevPlacebo ( −2.87) and
PrevGH ( −2.90) treatment groups. The mean change in height SDS from baseline to the
end of the Extension period in patients from the PrevPlacebo group (0.48, n=6) was lower
than those from the PrevGH group (0.87, n=2).
Baseline (Visit 1) bone age SDS was -1.48 for the PrevPlacebo group as compared with
−1.61 for the PrevGH group. The mean changes in bone age SDS from baseline to the
end of the Extension period were greater for patients in the PrevPlacebo (1.15, n=5) than
from patients in the PrevGH group (0.36, n=1). Most of the change in bone age SDS for
the PrevPlacebo group occurred during the time from baseline to the first visit of the
extension phase (a positive change of 1.01 SDS) (Table 5). Baseline (Visit 1) mean bone
age was lower in the PrevPlacebo group compared with patients in the PrevGH treatment
group (9.28 years and 10.47 years, respectively) as was chronological age (10.96 years
and 12.05 years, respectively). (Table 1)
A total of 4 patients (67%) from the PrevPlacebo group and 2 patients (40%) from the
PrevGH group attained final height during the Extension period.
Somatropin
Somatropin
Table 4.
Height SDS
StudyB9R-MC-GDCH
___________________________________________________________________________________________________________________________________
Descriptive Statistics
Treatment
____________________________________________________________
Group
Timepoint
n
Mean
SD
Median
Minimum
Maximum
_____________________________________________________________________________________________________________________
PrevPlacebo
N=6
Core Endpoint
Extension Baseline (Visit 201)
Extension Endpoint
Change from:
Core Baseline to Core End.
Core Baseline to Visit 201
Core Baseline to Ext. End.
Visit 201 to Ext. End.
6
6
6
6
-2.87
-2.58
-2.57
-2.39
0.695
0.516
0.513
0.712
-2.85
-2.52
-2.47
-2.38
-4.03
-3.45
-3.46
-3.42
-1.85
-1.87
-1.90
-1.36
6
6
6
6
0.29
0.30
0.48
0.18
0.245
0.243
0.286
0.336
0.30
0.32
0.55
0.18
-0.03
-0.05
0.09
-0.35
0.58
0.58
0.81
0.54
PrevGH
N=5
5
-2.90
0.273
-2.85
-3.21
-2.59
Core Endpoint
5
-2.09
0.684
-2.33
-2.55
-0.88
2
-2.35
0.034
-2.35
-2.37
-2.32
Extension Endpoint
2
-2.03
0.437
-2.03
-2.33
-1.72
Change from:
5
0.81
0.627
0.76
0.28
1.82
5
1.04
0.802
0.84
0.26
2.35
2
0.87
0.003
0.87
0.87
0.87
2
0.32
0.404
0.32
0.04
0.61
___________________________________________________________________________________________________________________________________
CT Registry ID# 843
Page 23
Somatropin
Table 4.
Height SDS
StudyB9R-MC-GDCH (Concluded)
___________________________________________________________________________________________________________________________________
Treatment
____________________________________________________________
Group
Timepoint
n
Mean
SD
Median
Minimum
Maximum
_____________________________________________________________________________________________________________________
Total
N=11
Extension Endpoint
Change from:
11
8
8
-2.88
-2.51
-2.30
0.521
0.446
0.646
-2.85
-2.40
-2.22
-4.03
-3.46
-3.42
-1.85
-1.90
-1.36
8
0.22
0.329
0.18
-0.35
0.61
___________________________________________________________________________________________________________________________________
End. = endpoint, Ext. = extension, n = total number of subjects with the variable value at both baseline and endpoint,
SD = standard deviation.
Note: Core baseline is the most recent data collected prior to the first visit in the core study. Extension baseline (Visit 201)
refers to the extension first visit. Extension endpoint refers to the final visit in the extension period.
CT Registry ID# 843
Page 24
Somatropin
Table 5.
Bone Age SDS
Study B9R-MC-GDCH
___________________________________________________________________________________________________________________________________
Treatment
____________________________________________________________
Group
Timepoint
n
Mean
SD
Median
Minimum
Maximum
_____________________________________________________________________________________________________________________
PrevPlacebo
N=6
5
-1.48
1.503
-1.82
-3.10
0.94
Core Endpoint
5
-0.51
0.670
-0.06
-1.33
0.01
5
-0.53
0.687
-0.06
-1.33
0.01
Extension Endpoint
5
-0.47
0.605
-0.12
-1.16
0.02
Change from:
5
0.96
1.189
1.23
-0.93
2.08
6
1.01
1.071
1.26
-0.93
2.08
5
1.15
1.283
1.43
-1.05
2.15
5
0.06
0.114
0.07
-0.12
0.17
PrevGH
5
-1.61
1.383
-1.70
-3.00
-0.02
N=5
Core Endpoint
5
-1.38
0.889
-1.39
-2.67
-0.19
1
-0.19
-0.19
-0.19
-0.19
Extension Endpoint
1
-0.06
-0.06
-0.06
-0.06
Change from:
5
0.23
0.969
0.23
-1.13
1.61
5
0.29
1.016
0.26
-1.13
1.74
1
0.36
0.36
0.36
0.36
1
0.13
0.13
0.13
0.13
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 25
Somatropin
Table 5.
Bone Age SDS
___________________________________________________________________________________________________________________________________
Treatment
____________________________________________________________
Group
Timepoint
n
Mean
SD
Median
Minimum
Maximum
_____________________________________________________________________________________________________________________
Total
N=11
10
-1.54
1.364
-1.76
-3.10
0.94
6
-0.47
0.631
-0.12
-1.33
0.01
Extension Endpoint
6
-0.40
0.566
-0.09
-1.16
0.02
Change from:
6
0.07
0.106
0.10
-0.12
0.17
___________________________________________________________________________________________________________________________________
End. = endpoint, Ext. = extension, n = total number of subjects with the variable value at both baseline and endpoint,
Note: Core baseline is the most recent data collected prior to the first visit in the core study. Extension baseline (Visit 201)
refers to the extension first visit. If data were unavailable at Visit 201, data were carried forward from the last core
double-blind study visit. Extension endpoint refers to the final visit in the extension period.
CT Registry ID# 843
Page 26
Somatropin
Table 6.
Number/Percentage of Subjects Who Attained Final Height during the Extension Period
Study B9R-MC-GDCH
___________________________________________________________________________________________________________________________________
PrevPlacebo
PrevGH
Total
N=6
N=5
N=11
Variable
n (%)
n (%)
n (%)
__________________________________________________________________________________________________
Final Height Attained
No. Subjects
4
2
6
Female
3 ( 50.0)
1 ( 20.0)
4 ( 36.4)
Male
1 ( 16.7)
1 ( 20.0)
2 ( 18.2)
___________________________________________________________________________________________________________________________________
n = number of subjects with the specified gender, % = percentage of subjects in treatment group.
CT Registry ID# 843
Page 27
CT Registry ID# 843
Page 28
Other Efficacy Endpoints (Continued)
Figure 1 presents height velocity data during the Extension period for all patients enrolled
in the Extension period.
Because of limited data on height velocity no conclusions can be made with regard to
treatment group differences in height velocity observed during the Extension period.
Figure 2 presents height SDS data during the Core and Extension periods for individual
patients enrolled in the Extension period.
Although limited height SDS data precludes drawing conclusions about treatment group
differences, the change in height SDS of PrevGH patients, in general, show larger
increases in height SDS during the core phase and neither group demonstrated large
changes in height SDS during the extension phase. With the exception of one patient, all
others improved or maintained their height SDS during the extension phase.
Figure 3a presents mean height SDS±SE data during the Core period by year for all
Although the mean height SDSs during the Core period for PrevGH patients enrolled in
the Extension period were higher than that for PrevPlacebo patients, there were no
statistically significant differences over a 3.5-year study period.
Figure 3b presents mean height SDS±SE data by year during the Extension period for all
Although the mean height SDS during the Extension period for PrevGH patients enrolled
in the Extension period were consistently higher than that for PrevPlacebo patients on
study for up to 2 years (no statistically significant differences observed), the PrevPlacebo
(P) group was exposed to the active drug during the Extension period only whereas the
PrevGH (H) group was exposed to the active drug since randomization.
Somatropin
Somatropin
Note: Each line represents data from one patient. The patient represented by black circles in the PrevGH group did not have height
velocity data available during the Extension period.
Abbreviations: PrevGH = Subjects who received growth hormone injections during the Core period and Extension period;
PrevPlacebo = Subjects who received placebo injections during the Core period and growth hormone during the Extension period.
Figure 1.
CT Registry ID# 843
Height velocity during the extension period by year on study; all subjects enrolled in extension
period; Study B9R-MC-GDCH.
Page 29
Somatropin
Note: Each line represents data from one patient.
Abbreviations: PrevGH = Subjects who received growth hormone injections during the Core period and Extension period;
PrevPlacebo = Subjects who received placebo injections during the Core period and growth hormone during the Extension period;
SDS = standard deviation score.
Figure 2.
CT Registry ID# 843
Height SDS during the core study and extension period by year on study for subjects in the extension
period; all subjects enrolled in extension period; Study B9R-MC-GDCH.
Page 30
Somatropin
Note: At each time point, the p-value presented at the top of the figures was based on the two-sample t test. Summary statistics
were presented for every integer year only.
Abbreviations: PrevGH (H) = Subjects who received growth hormone injections during the Core period and Extension period;
PrevPlacebo (P) = Subjects who received placebo injections during the Core period and growth hormone during the Extension
period; SD=standard deviation; SDS=standard deviation score; SE=standard error
Figure 3a.
CT Registry ID# 843
Mean height SDS±SE by year on study for subjects in the extension period; all subjects enrolled in
extension period; Study B9R-MC-GDCH. (Continued)
Page 31
Somatropin
Note: At each time point, the p-value presented at the top of the figures was based on the two-sample t test. Summary statistics
were presented for every integer year only.
Abbreviations: PrevGH (H) = Subjects who received growth hormone injections during the Core period and Extension period;
PrevPlacebo (P) = Subjects who received placebo injections during the Core period and growth hormone during the Extension
period; SD = standard deviation; SDS = standard deviation score; SE = standard error.
Figure 3b.
CT Registry ID# 843
Mean height SDS±SE by year on study for subjects in the extension period; all subjects enrolled in
extension period; Study B9R-MC-GDCH. (Concluded)
Page 32
CT Registry ID# 843
Page 33
Safety
Table 7 presents study drug exposure in the Extension period: the mean exposure was
1.86 years for PrevPlacebo patients (n=6) vs. 1.07 years for PreGH patients (n=5). The
mean total cumulative exposure (during Core study + Extension periods) of patients
from the PrevGH (4.80 years) was more than two-fold that of patients from the
PrevPlacebo group (1.86 years).
The total cumulative exposure in terms of patient-years was 24 patient-years for patients
in the PrevGH group compared to 11 patient-years for patients in the PrevPlacebo at the
end of the Extension period.
There were no patient deaths during the Extension period.
Table 8 summarizes the incidence rates of treatment-emergent adverse events (TEAEs)
by preferred term. During the Core double-blind study, all patients subsequently enrolled
in the Extension period from both treatment groups experienced at least 1 TEAE and at
least 1 nonserious clinically significant AE (Table 10).
During the Extension period, 5 out of 6 (83%) patients from the PrevPlacebo treatment
group vs. 2 out of 5 (40%) patients from the PrevGH treatment group had at least
1 TEAE. The TEAEs occurring in more than 1 patient from the PrevPlacebo vs. PrevGH
patients, respectively, included pharyngolaryngeal pain and acne (each 33% vs. 20%);
pyrexia, joint sprain, scoliosis, nasal congestion, influenza, myalgia, blood creatine
phosphokinase increased, and dysmenorrhea (each 33% vs. 0%). However, the exposure
for the PrevPlacebo group (11 patient-years) exceeded by more than two-fold the
exposure for the PrevGH group (5 patient-years).
Table 9 summarizes the serious adverse events (SAEs) occurring in patients enrolled in
the Extension period. No SAEs were noted (in those patients enrolled in the Extension
period) during the Core (double-blind) period. During the Extension period, 1 patient
(from the PrevGH group) had SAEs (abdominal pain and dysuria) reported during the
same hospitalization. No patients discontinued the study due to an adverse event.
Table 10 summarizes the incidence rates of nonserious, clinically significant TEAEs by
preferred term. Nonserious clinically significant adverse events were prospectively
identified as potentially related to GH treatment. During the Extension period, more
patients in PrevPlacebo (4 of 6 patients) had a nonserious but clinically significant AE as
compared to patients in the PrevGH (1 of 5 patients) treatment group. The more common
nonserious clinically significant AEs occurring in 2 or more patients in the PrevPlacebo
group included scoliosis and myalgia (each 33% vs. 0%); the more commonly occurring
nonserious clinically significant AEs in patients from the PrevGH group included ear
infection and pain (each 20% vs. 0%).
No measurable effect was observed for the following: fasting insulin, ratio of fasting
insulin to fasting glucose, the quantitative insulin sensitivity check index (QUICKI),
Somatropin
CT Registry ID# 843
Page 34
hemoglobin A1c and adjusted hemoglobin A1c, free T4, tri-iodothyronine, and
triglycerides. Blood TSH concentrations and aspartate aminotransferase levels increased
in one patient each (PrevPlacebo group) and fasting glucose concentrations decreased in
another patient (PrevPlacebo group).
Somatropin
Somatropin
Table 7.
Study Drug Exposure
Study B9R-MC-GDCH
__________________________________________________________________________________________________________________________________
Extension Period
Cumulative
__________________________
__________________________
__________________________
Placebo
GH
PrevPlacebo
PrevGH
PrevPlacebo
PrevGH
Variable
N=6
N=5
N=6
N=5
N=6
N=5
__________________________________________________________________________________________________________________________________
Years on Study
No. Subjects
Mean
Median
Standard Dev.
Minimum
Maximum
Number of Injections Recorded
No. Subjects
Mean
Median
Standard Dev.
Minimum
Maximum
6
3.34
3.51
1.338
0.84
4.85
6
448.2
517.5
199.06
47.0
587.0
5
2.95
3.05
0.487
2.41
3.52
5
405.8
437.0
101.16
258.0
506.0
6
1.86
1.98
1.090
0.51
3.64
6
222.5
221.0
143.43
45.0
476.0
5
1.07
0.54
1.624
0.00
3.89
4
167.5
59.5
255.91
3.0
548.0
6
1.86
1.98
1.090
0.51
3.64
6
222.5
221.0
143.43
45.0
476.0
5
4.80
4.38
1.514
3.53
7.19
5
539.8
437.0
307.06
261.0
1054.0
___________________________________________________________________________________________________________________________________
Subjects who received placebo injections during the core study and growth hormone during the extension study.
Note: Cumulative exposure for placebo group = growth hormone exposure during the extension period. Cumulative exposure for growth
hormone group = sum of growth hormone exposure during the core double-blind study and growth hormone exposure during the extension
period.
CT Registry ID# 843
Page 35
Somatropin
Table 8.
Summary of Treatment-Emergent Adverse Events by Preferred Term
Study B9R-MC-GDCH
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
SUBJECTS WITH >= 1 TEAE
6 (100.00)
5 (100.00)
5 ( 83.33)
2 ( 40.00)
SUBJECTS WITH NO TEAE
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
3 ( 60.00)
NASOPHARYNGITIS
5 ( 83.33)
4 ( 80.00)
1 ( 16.67)
0 ( 0.00)
PHARYNGOLARYNGEAL PAIN
3 ( 50.00)
3 ( 60.00)
2 ( 33.33)
1 ( 20.00)
HEADACHE
5 ( 83.33)
3 ( 60.00)
1 ( 16.67)
0 ( 0.00)
COUGH
2 ( 33.33)
3 ( 60.00)
0 ( 0.00)
0 ( 0.00)
INJURY
1 ( 16.67)
3 ( 60.00)
0 ( 0.00)
0 ( 0.00)
PHARYNGITIS STREPTOCOCCAL
1 ( 16.67)
3 ( 60.00)
0 ( 0.00)
0 ( 0.00)
SINUSITIS
2 ( 33.33)
2 ( 40.00)
1 ( 16.67)
1 ( 20.00)
EAR PAIN
1 ( 16.67)
2 ( 40.00)
0 ( 0.00)
1 ( 20.00)
PYREXIA
2 ( 33.33)
2 ( 40.00)
2 ( 33.33)
0 ( 0.00)
ARTHRALGIA
2 ( 33.33)
2 ( 40.00)
1 ( 16.67)
0 ( 0.00)
BLOOD INSULIN INCREASED
2 ( 33.33)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
JOINT SPRAIN
1 ( 16.67)
2 ( 40.00)
2 ( 33.33)
0 ( 0.00)
PAIN IN EXTREMITY
1 ( 16.67)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
VISION BLURRED
1 ( 16.67)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
SCOLIOSIS
0 ( 0.00)
2 ( 40.00)
2 ( 33.33)
0 ( 0.00)
ENDODONTIC PROCEDURE
0 ( 0.00)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
HAND FRACTURE
0 ( 0.00)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
INJECTION SITE PAIN
0 ( 0.00)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
RHINITIS
0 ( 0.00)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
EAR INFECTION
2 ( 33.33)
1 ( 20.00)
0 ( 0.00)
1 ( 20.00)
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 36
Somatropin
Table 8.
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
BACK PAIN
0 ( 0.00)
1 ( 20.00)
1 ( 16.67)
1 ( 20.00)
ANKLE FRACTURE
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
1 ( 20.00)
DEPRESSION
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
1 ( 20.00)
NASAL CONGESTION
4 ( 66.67)
1 ( 20.00)
2 ( 33.33)
0 ( 0.00)
HAEMATURIA
3 ( 50.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
PROTEIN URINE PRESENT
3 ( 50.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
INFLUENZA
2 ( 33.33)
1 ( 20.00)
2 ( 33.33)
0 ( 0.00)
MUSCLE SPASMS
2 ( 33.33)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
WHITE BLOOD CELL COUNT DECREASED
2 ( 33.33)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
BLOOD THYROID STIMULATING HORMONE INCREASED
1 ( 16.67)
1 ( 20.00)
1 ( 16.67)
0 ( 0.00)
JOINT EFFUSION
1 ( 16.67)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
LACRIMATION INCREASED
1 ( 16.67)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
LYMPHADENOPATHY
1 ( 16.67)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
MULTIPLE ALLERGIES
1 ( 16.67)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
RED BLOOD CELL SEDIMENTATION RATE INCREASED
1 ( 16.67)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
MYALGIA
0 ( 0.00)
1 ( 20.00)
2 ( 33.33)
0 ( 0.00)
ASPARTATE AMINOTRANSFERASE INCREASED
0 ( 0.00)
1 ( 20.00)
1 ( 16.67)
0 ( 0.00)
SKIN EXFOLIATION
0 ( 0.00)
1 ( 20.00)
1 ( 16.67)
0 ( 0.00)
ANXIETY
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
BLOOD PRESSURE INCREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
BLOOD PROLACTIN INCREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
BLOOD TRIGLYCERIDES INCREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 37
Somatropin
Table 8.
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
CHEST INJURY
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
ENTEROBIASIS
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
HAEMOGLOBIN DECREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
IMPETIGO
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
JOINT DISLOCATION
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
JOINT INJURY
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
LIGAMENT INJURY
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
MUSCULOSKELETAL DISORDER
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
NECK PAIN
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
PHARYNGITIS
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
PLATELET COUNT DECREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
PROTEINURIA
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
RASH
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
SIALOADENITIS
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
TENDON DISORDER
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
TINEA INFECTION
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
TINEA PEDIS
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
TRACHEITIS
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
URINARY TRACT INFECTION
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
WART EXCISION
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
INSOMNIA
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
ACNE
0 ( 0.00)
0 ( 0.00)
2 ( 33.33)
1 ( 20.00)
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 38
Somatropin
Table 8.
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
ABDOMINAL PAIN
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
1 ( 20.00)
EPISTAXIS
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
1 ( 20.00)
ABNORMAL BEHAVIOUR
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
CONCUSSION
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
CYSTOSCOPY
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
DYSURIA
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
FACIAL BONES FRACTURE
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
JOINT CREPITATION
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
PAIN
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
REVERSAL OF SEDATION
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
SKIN LACERATION
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
TOOTH EXTRACTION
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
WRIST FRACTURE
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
MONOCYTE COUNT INCREASED
3 ( 50.00)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
VOMITING
3 ( 50.00)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
BRONCHITIS
2 ( 33.33)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
DIARRHOEA
2 ( 33.33)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
DIZZINESS
2 ( 33.33)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
FIBROUS CORTICAL DEFECT
2 ( 33.33)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
HYPERKERATOSIS
2 ( 33.33)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
LYMPHOCYTE COUNT INCREASED
2 ( 33.33)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
OTITIS EXTERNA
2 ( 33.33)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 39
Somatropin
Table 8.
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
ABDOMINAL PAIN UPPER
1 ( 16.67)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
MIGRAINE
1 ( 16.67)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
NAUSEA
1 ( 16.67)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
SINUS CONGESTION
1 ( 16.67)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
ABDOMINAL PAIN LOWER
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
ARTHROPOD BITE
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
BLOOD GLUCOSE DECREASED
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
BLOOD URINE PRESENT
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
BURNING SENSATION
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
DERMATITIS CONTACT
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
DRY SKIN
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
DYSPNOEA
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
ELECTRIC SHOCK
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
FIBROMA
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
FULL BLOOD COUNT ABNORMAL
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
GAMMA-GLUTAMYLTRANSFERASE DECREASED
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
GINGIVAL ULCERATION
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
INJECTION SITE IRRITATION
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
INJECTION SITE MASS
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
MOUTH HAEMORRHAGE
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
MYOPIA
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
ORCHIDOPEXY
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 40
Somatropin
Table 8.
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
PAIN TRAUMA ACTIVATED
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
RED BLOOD CELL SEDIMENTATION RATE ABNORMAL
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
RHINORRHOEA
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
SINUS HEADACHE
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
SKIN DISCOLOURATION
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
SNEEZING
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
TRI-IODOTHYRONINE INCREASED
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
URTICARIA
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
VAGINAL PAIN
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
VISUAL DISTURBANCE
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
VULVAR EROSION
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
BLOOD CREATINE PHOSPHOKINASE INCREASED
0 ( 0.00)
0 ( 0.00)
2 ( 33.33)
0 ( 0.00)
DYSMENORRHOEA
0 ( 0.00)
0 ( 0.00)
2 ( 33.33)
0 ( 0.00)
ASPIRATION BONE MARROW
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
ASTHMA EXERCISE INDUCED
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
BLOOD POTASSIUM INCREASED
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
BODY TINEA
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
CYST
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
DENTAL DISCOMFORT
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
DRY EYE
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
DUODENAL ULCER
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
DYSPEPSIA
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
___________________________________________________________________________________________________________________________________
(continued)
CT Registry ID# 843
Page 41
Somatropin
Table 8.
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
DYSPNOEA EXERTIONAL
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
EAR CANAL ABRASION
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
ENDOSCOPY
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
EPIGASTRIC DISCOMFORT
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
FAECAL OCCULT BLOOD POSITIVE
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
GASTROOESOPHAGEAL REFLUX DISEASE
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
HYPOGLYCAEMIA
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
LYMPHADENITIS
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
MENSTRUATION IRREGULAR
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
POST PROCEDURAL PAIN
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
PSORIASIS
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
RASH MACULO-PAPULAR
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
SEASONAL ALLERGY
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
SNORING
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
STOMACH DISCOMFORT
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
STOMATITIS
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
___________________________________________________________________________________________________________________________________
MedDRA Version: 8.0. MedDRA = Medical Dictionary for Regulatory Activities Terminology.
n = number of subjects with the specified event, TEAE = treatment-emergent adverse event, % = n/N.
CT Registry ID# 843
Page 42
Somatropin
Table 9.
Summary of Serious Adverse Events by Preferred Term
Study B9R-MC-GDCH
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
SUBJECTS WITH >= 1 SAE
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
SUBJECTS WITH NO SAE
6 (100.00)
5 (100.00)
6 (100.00)
4 ( 80.00)
ABDOMINAL PAIN
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
DYSURIA
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
___________________________________________________________________________________________________________________________________
n = number of subjects with the specified event, SAE = serious adverse event, % = n/N.
CT Registry ID# 843
Page 43
Somatropin
Table 10.
Summary of Nonserious, Clinically Significant Treatment-Emergent Adverse Events
Study B9R-MC-GDCH
___________________________________________________________________________________________________________________________________
Extension Period
_________________________________ _________________________________
Placebo
GH
PrevPlacebo
PrevGH
N=6
N=5
N=6
N=5
Preferred Term
n (%)
n (%)
n (%)
n (%)
__________________________________________________________________________________________________________________________________
SUBJECTS WITH >= 1 NCS TEAE
5 ( 83.33)
5 (100.00)
4 ( 66.67)
1 ( 20.00)
SUBJECTS WITH NO NCS TEAE
1 ( 16.67)
0 ( 0.00)
2 ( 33.33)
4 ( 80.00)
HEADACHE
5 ( 83.33)
3 ( 60.00)
1 ( 16.67)
0 ( 0.00)
ARTHRALGIA
2 ( 33.33)
2 ( 40.00)
1 ( 16.67)
0 ( 0.00)
PAIN IN EXTREMITY
1 ( 16.67)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
SCOLIOSIS
0 ( 0.00)
2 ( 40.00)
2 ( 33.33)
0 ( 0.00)
INJECTION SITE PAIN
0 ( 0.00)
2 ( 40.00)
0 ( 0.00)
0 ( 0.00)
EAR INFECTION
2 ( 33.33)
1 ( 20.00)
0 ( 0.00)
1 ( 20.00)
BLOOD THYROID STIMULATING HORMONE INCREASED
1 ( 16.67)
1 ( 20.00)
1 ( 16.67)
0 ( 0.00)
MYALGIA
0 ( 0.00)
1 ( 20.00)
2 ( 33.33)
0 ( 0.00)
BLOOD PRESSURE INCREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
BLOOD TRIGLYCERIDES INCREASED
0 ( 0.00)
1 ( 20.00)
0 ( 0.00)
0 ( 0.00)
PAIN
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
1 ( 20.00)
MIGRAINE
1 ( 16.67)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
BLOOD GLUCOSE DECREASED
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
INJECTION SITE IRRITATION
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
INJECTION SITE MASS
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
TRI-IODOTHYRONINE INCREASED
1 ( 16.67)
0 ( 0.00)
0 ( 0.00)
0 ( 0.00)
HYPOGLYCAEMIA
0 ( 0.00)
0 ( 0.00)
1 ( 16.67)
0 ( 0.00)
___________________________________________________________________________________________________________________________________
n = number of subjects with the specified event, NCS TEAE = nonserious, clinically significant treatment-emergent adverse event,
%= n/N.
CT Registry ID# 843
Page 44
CT Registry ID#0883
Page 1
Summary ID#0883
Clinical Study Summary: Study B9R-US-GDEO
The Effect of Chronic Somatropin Treatment on Bone
Mineral Density in Patients Diagnosed with Adult-Onset
Growth Hormone Deficiency
Date summary approved by Lilly: 30 August 2006
This was a Phase 4, double-blind, multicenter, parallel, placebo-controlled study designed
to test the hypothesis that after 24 months of treatment, patients with adult-onset growth
hormone (GH) deficiency who are treated with somatropin (Humatrope) will have a
greater bone mineral density (BMD) of the lumbar spine than those who were treated
with placebo.
•
There was a statistically significant increase in L2–L4 BMD in patients
treated with Humatrope at 24 months (p<.001) as compared to baseline, but
there was no corresponding increase seen in the placebo-treated patients. The
increases with Humatrope were statistically significantly different from those
seen in placebo-treated patients at 24 months (p=.037).
•
At the end of 24 months of treatment, there was a statistically significant
increase in L2–L4 bone mineral content (BMC) with Humatrope treatment
(p<.001) compared with placebo (p=.018).
•
Serum bone-specific alkaline phosphatase and urinary N-telopeptide-tocreatinine ratio increased statistically significantly (p=.03) from baseline to
24 months with Humatrope treatment. The increases for both markers in the
Humatrope-treated group were significantly greater (p=.012) than those in the
placebo-treated group only at Months 6 and 12.
•
Trunk fat mass decreased statistically from baseline (p<.05) with Humatrope
treatment, and this decrease was statistically different from placebo (p=.028).
Somatropin
CT Registry ID#0883
Page 2
•
There was no statistically significant difference in total hip BMD, total
thyroxine, free thyroxine, or urine creatinine between the Humatrope and
placebo groups at 24 months.
•
In Humatrope-treated patients, serum insulin-like growth factor-I (IGF-I)
concentrations and standard deviation scores (SDS) were increased above
baseline and compared with placebo at every visit (p<.001). The mean serum
IGF-I SDS in all Humatrope-treated subjects increased from -1.7 ± 0.9 at
baseline to 0.2 ± 1.4 at Month 24.
•
No statistically significant improvement in patients’ quality of life was
observed after 6 months of treatment with study drug compared with placebo.
•
Treatment-emergent adverse events (TEAEs) were reported in 94.1% of
patients treated with placebo and in 90.9% of patients treated with Humatrope.
Peripheral edema (24.2% versus 2.9%, p=.013) and paresthesias (12.1%
versus 0%, p=.053) were more common in the Humatrope group than in the
placebo group.
•
A total of 13 patients discontinued prematurely from the study. Of these, six
patients discontinued prematurely due to AEs (Humatrope: n=4; placebo:
n=2); the two patients in the placebo group discontinued due to serious
adverse events (SAEs; carcinoid tumor and transient ischemic attack), and the
four patients in the Humatrope group discontinued due to nonserious AEs.
There was no statistically significant difference in the number of patients
discontinuing due to AEs between the two treatment groups.
•
In the placebo and Humatrope-treated groups, 10 patients (29%), and
7 patients (21%), respectively, experienced at least one SAE.
•
There were no deaths reported during the study.
Somatropin
CT Registry ID#0883
Page 3
Title of Study: The Effect of Chronic Somatropin Treatment on Bone Mineral Density in Patients
Diagnosed with Adult-Onset Growth Hormone Deficiency
Investigator(s): This multicenter study included seven principal investigators.
Study Center(s): This study was conducted at seven study centers in one country.
Length of Study: 5.5 years
Date of first patient enrolled: 01 April 1998
Date of last patient completed: 21 October 2003
Objectives:
Primary:
• To test the hypothesis that after 24 months of treatment, patients with adult-onset growth hormone
(GH) deficiency who are treated with somatropin (Humatrope) will have a greater bone mineral
density (BMD) of the lumbar spine than those who are treated with placebo.
Secondary:
• To test the hypothesis that after 24 months of treatment, patients with adult-onset GH deficiency who
are treated with Humatrope will have a greater BMD in the hip than those who are treated with
placebo, and to correlate BMD changes with changes in total body composition.
• To test the hypothesis that patients with adult-onset GH deficiency who are treated with Humatrope
will demonstrate increased bone formation and decreased bone breakdown, as assessed by serum and
urinary markers, than those treated with placebo.
• To assess adverse events (AEs) associated with 24 months of Humatrope treatment in patients with
adult-onset GH deficiency.
• To collect data on a new health-related, quality-of-life questionnaire for GH deficiency.
Study Design: Phase 4, double-blind, multicenter, parallel, placebo-controlled study.
Number of Patients:
Planned: 36 active drug, 36 placebo
Randomized: 33 active drug, 34 placebo
Completed: 24 active drug, 30 placebo
Diagnosis and Main Criteria for Inclusion: Patients with adult-onset GH deficiency in association with
pituitary or hypothalamic disease for at least 24 months, and two additional pituitary hormone deficiencies
stably replaced for at least 1 year aged 21 years and older. Lumbar vertebral BMD scores did not exceed
3.0 standard deviations (SD) below the mean for young men and women, or if there was a history of
osteoporotic fractures or if the patient was over the age of 65 years, lumbar spine BMD did not exceed
2.5 SD below the mean for young men and women. Epiphyses were closed before enrollment.
Test Product, Dose, and Mode of Administration: Humatrope was titrated up from a starting dose of
2 µg/kg to a maximum of 12.5 µg/kg, given subcutaneously each day at a starting dose of 2 µg/kg/day for
1 month, followed by 4 µg/kg/day for 2 months, 8 µg/kg/day for 3 months, and finally 12 µg/kg/day for
18 months. Dose adjustments were made to maintain serum insulin-like growth factor-I (IGF-I)
concentrations within the age-adjusted normal range for each GH-treated patient, and simultaneously in a
placebo-treated patient, to maintain blinding.
Reference Therapy, Dose, and Mode of Administration: Placebo was titrated up to a maximum of
12.5 µg/kg given subcutaneously each day. In order to maintain blinding, dose adjustments were made to
placebo-treated patients when dose adjustments to GH-treated patients were required to maintain serum
IGF-I concentrations within the age-adjusted normal range.
Duration of Treatment: 24 months
Somatropin
CT Registry ID#0883
Page 4
Variables:
Efficacy: The primary efficacy evaluation focused on determining BMD of lumbar spine (L2–L4).
Secondary efficacy evaluation was designed to determine BMD of total hip and related sub-areas. A
secondary analysis of the L2–L4 BMD was conducted to describe the BMD profile, adjusted for baseline
BMD, for the study population over 24 months. Similar analyses were conducted for the following
secondary efficacy measures: lumbar spine BMC (L2–L4), BMD and BMC for total femur, BMD and
BMC for sub-areas of the femur (neck, trochanter, intertrochanter), trunk fat mass and lean mass, total body
fat mass (including head), total body lean mass (including head), IGF-I, IGF-I standard deviation score
(SDS), total thyroxine, free thyroxine, N-telopeptide-to-creatinine ratio, and serum bone-specific alkaline
phosphatase.
Safety: During the study, both nonserious and serious adverse events were collected at every visit for the
assessment of safety.
Health Outcomes: In an exploratory analysis, health outcomes were assessed by quality-of-life endpoints
for the first 6 months of treatment.
Evaluation Methods:
Statistical: All patients with at least one post-baseline measurement were included in the efficacy
analysis in accordance with an intent-to-treat principle. All patients randomized were included in the safety
analysis. The change in lumbar spine BMD (g/cm2) from baseline to end of treatment was analyzed using
two co-primary analyses:
1) analysis of covariance (ANCOVA) model with terms for randomization stratum (by baseline lumbar
spine T-score and gender), treatment, and baseline lumbar spine BMD value using the last observation
carried forward (LOCF) as specified by the protocol;
2) a mixed-model repeated measures (MMRM) with terms for randomization stratum (by baseline lumbar
spine BMD T-score and gender), treatment, visit, treatment-by-visit interaction, baseline lumbar spine
BMD value, and baseline BMD value-by-visit interaction. For the MMRM analyses, estimates for each
time point were based on all available data for each patient, even if the patient discontinued prior to
completion of the protocol. Within- and between-group changes from baseline in g/cm2 were analyzed.
Additional secondary analyses were performed to evaluate gender effects. Baseline-to-endpoint changes in
secondary efficacy measures were analyzed using ANCOVA with the baseline value for each efficacy
measure. Treatment comparisons were performed using least-squares means. In addition to age and
gender, analyses of the preceding primary measure were repeated using predefined baseline covariates.
The relationship of each important covariate to treatment effect was assessed with the treatment-bycovariate interaction.
The Nottingham Health Profile (NHP), Short Form 36 Health Survey (SF-36), and Fragen zur
Lebenszufriedenheit-Module (FLZM) questionnaires were used to assess quality of life in an exploratory
analysis.
Somatropin
CT Registry ID#0883
Page 5
Results:
Patient Demographics
Table 1, Table 2, and Table 3 display some of the baseline information for the evaluable
patients. The treatment groups were balanced (p>.05 for group comparisons) with
respect to age, ethnicity, height, weight, cause of growth hormone (GH) deficiency, types
of brain or pituitary tumors, years since diagnosis of disease, severity of GH deficiency
(serum insulin-like growth factor-I [IGF-I] and peak GH concentrations), presence of
secondary hormonal deficiencies, bone mineral density (BMD) and bone mineral content
(BMC) of the lumbar spine and total hip, total body BMC, lean body mass, biochemical
markers of bone turnover, and total thyroxine levels. However, body mass index (BMI),
trunk fat mass, and total body fat mass were significantly greater in the placebo group
than in the Humatrope group (p=.012, p=.024, and p=.025, respectively), while free
thyroxine was statistically significantly greater in the Humatrope group than in the
placebo group (p=.026).
Table 1.
Variable
Baseline Patient Characteristics
Placebo
(N=34)
49.08
hGH
(N=33)
50.62
Total
(N=67)
49.84
p-Value
Mean age (years)
.699*
Gender: [n (%)]
1.00**
Female
14 (41.2)
13 (39.4)
27 (40.3)
Male
20 (58.8)
20 (60.6)
40 (59.7)
Ethnicity: [n (%)]
1.00**
Caucasian
32 (94.1)
32 (97.0)
64 (95.5)
Other
2 (5.9)
1 (3.0)
3 (4.5)
Mean Height (cm)
168.52
172.17
170.32
.065*
Mean BMI (kg/m2)
30.73
27.65
29.21
.012*
Mean Weight (kg)
87.99
82.27
85.17
.057*
Abbreviations: BMI = body mass index; hGH = human growth hormone; N = total population size;
n = number per category.
* Means were analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM
model=investigator and treatment.
** Frequencies were analyzed using a Fisher exact test.
Somatropin
CT Registry ID#0883
Table 2.
Page 6
Baseline Disease Characteristics
Variable
Cause of GH Deficiency
Tumor/Adenoma
Idiopathic
Trauma-Sheehans
Other
Brain or Pituitary Tumor
Number of patientsa
Craniopharyngioma
Mass within sella turcica
Meningioma
Pinealoma
Pituitary Adenoma
Other
Pituitary Microadenoma/Macroadenoma
Number of patientsa
Macroadenoma
Microadenoma
Unknown
Pituitary Adenoma Functional/Non-functional
Number of patientsa
Functional
Non-functional
Functional Pituitary Adenoma Secretions
Number of patientsa
ACTH
FSH
GH
Prolactin
TSH
Prior Treatment for Pituitary Disease
Number of patientsa
CNS (non-pituitary) surgery
Other
Pituitary surgery
Radiotherapy
T-score for Lumbar Spine BMD (L2-L4)
<-2.5
≥-2.5
Secondary Hypothyroidism
No
Yes
Placebo
(N=34)
n (%)
hGH
(N=33)
n (%)
Total
(N=67)
n (%)
p-Value
.797*
26 (76.5)
1 (2.9)
1 (2.9)
6 (17.6)
27 (81.8)
1 (3.0)
2 (6.1)
3 (9.1)
53 (79.1)
2 (3.0)
3 (4.5)
9 (13.4)
.275*
30
7 (23.3)
0
2 (6.7)
0
20 (66.7)
1 (3.3)
29
4 (13.8)
1 (3.4)
0
1 (3.4)
23 (79.3)
0
59
11 (18.6)
1 (1.7)
2 (3.4)
1 (1.7)
43 (72.9)
1 (1.7)
.351*
20
19 (95.0)
1 (5.0)
0
23
18 (78.3)
4 (17.4)
1 (4.3)
43
37 (86.0)
5 (11.6)
1 (2.3)
1.00*
20
9 (45.0)
11 (55.0)
23
11 (47.8)
12 (52.2)
43
20 (46.5)
23 (53.5)
***
9
3 (33.3)
2 (22.2)
0
6 (66.7)
2 (22.2)
11
5 (45.5)
1 (9.1)
1 (9.1)
5 (45.5)
1 (9.1)
20
8 (40.0
3 (15.0)
1 (5.0)
11 (55.0)
3 (15.0)
***
28
3 (10.7)
2 (7.1)
24 (85.7)
17 (60.7)
1 (2.9)
33 (97.1)
29
1 (3.4)
3 (10.3)
24 (82.8)
17 (58.6)
0
33 (100)
57
4 (7.0)
5 (8.8)
48 (84.2)
34 (59.6)
1 (1.5)
66 (98.5)
.831**
1.00*
1.00*
1 (2.9)
33 (97.1)
1 (3.0)
32 (97.0)
2 (3.0)
65 (97.0)
(continued)
Somatropin
CT Registry ID#0883
Table 2.
Variable
Page 7
Baseline Disease Characteristics (concluded)
Placebo
(N=34)
n (%)
hGH
(N=33)
n (%)
Total
(N=67)
n (%)
p-Value
.673*
Secondary Hypogonadism
No
2 (5.9)
3 (9.1)
5 (7.5)
Yes
32 (94.1)
30 (90.9)
62 (92.5)
.734*
Secondary Hypoadrenalism
No
4 (11.8)
5 (15.2)
9 (13.4)
Yes
30 (88.2)
28 (84.8)
58 (86.6)
1.00*
Diabetes Insipidus
No
26 (76.5)
26 (78.8)
52 (77.6)
Yes
8 (23.5)
7 (21.2)
15 (22.4)
Abbreviations: ACTH = adrenocorticotropic hormone; BMD = bone mineral density; CNS = central
nervous system; FSH = follicle-stimulating hormone; GH = growth hormone; hGH = human growth
hormone; N = total population size; n = number per category; TSH = thyroid-stimulating hormone.
a Number of patients is specified only when it differs from the total number per group.
* Frequencies were analyzed using a Fisher exact test.
** Means were analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM
*** Statistical test was not performed.
Somatropin
CT Registry ID#0883
Table 3.
Page 8
Baseline Measurements
Variable
Years since Diagnosis
Mean
Total L2-L4 Lumbar Spine BMD (g/cm2)
Mean
Total Femur BMD (g/cm2)
Mean
Femoral Neck BMD (g/cm2)
Mean
Trochanter BMD (g/cm2)
Mean
Inter-trochanter BMD (g/cm2)
Mean
Total L2-L4 Lumbar Spine BMC (g)
Mean
Total Femur BMC (g)
Mean
Femoral Neck BMC (g)
Mean
Trochanter BMC (g)
Mean
Inter-trochanter BMC (g)
Mean
T-score for Lumbar Spine BMD (L2-L4)
Mean
T-score for Total Femur BMD
Mean
Trunk Fat (g)
Number of patientsa
Mean
Trunk Lean (g)
Number of patientsa
Mean
Total Body Fat Mass including Head (g)
Number of patientsa
Mean
Total Body Lean Mass including Head (g)
Number of patientsa
Mean
Total Body BMC Including Head (g)
Number of patientsa
Mean
Placebo
(N=34)
hGH
(N=33)
Total
(N=67)
p-Value
.088*
9.87
12.80
11.31
.833*
1.05
1.06
1.06
0.96
0.97
0.96
.998*
.967*
0.80
0.81
0.80
.729*
0.74
0.74
0.74
.730*
1.11
1.13
1.12
.144*
49.63
53.90
51.74
.372*
38.52
38.03
38.27
.890*
4.30
4.36
4.33
9.06
8.97
9.02
.480*
.340*
25.15
24.70
24.93
.831*
-0.47
-0.33
-0.40
.940*
-0.32
-0.28
-0.30
.024*
33
16685.38
31
13896.09
64
15334.32
33
26363.65
31
25478.77
64
25935.04
33
31344.81
31
26455.06
64
28976.34
.283*
.025*
.290*
33
52107.96
31
50412.26
64
51286.61
.929*
34
2437.63
32
2459.48
66
2448.23
(continued)
Somatropin
CT Registry ID#0883
Table 3.
Variable
Page 9
Baseline Measurements (concluded)
Placebo
(N=34)
hGH
(N=33)
Total
(N=67)
p-Value
.413*
IGF-I (ng/mL)
a
Number of patients
33
33
66
Mean
79.79
88.09
83.94
.196*
IGF-I SDS
Number of patientsa
33
33
66
Mean
-1.91
-1.65
-1.78
.627*
Peak GH Result (µg/L)
Number of patientsa
18
19
37
Mean
0.35
0.47
0.41
.385*
Thyroxine, Total (nmol/L)
Mean
117.04
120.51
118.75
.026*
Thyroxine, Free (pmol/L)
Mean
17.41
20.36
18.86
N-Telopeptide/Creatinine Ratio (nmol/mmol)
.298*
a
Number of patients
33
32
65
Mean
22.81
24.72
23.75
.644*
Urine Creatinine (mmol/L)
a
Number of patients
33
32
65
Mean
11.40
12.32
11.85
.372*
Bone-Specific Alkaline Phosphatase (µg/L)
a
Number of patients
33
33
66
Mean
10.10
9.31
9.70
Abbreviations: BMC = bone mineral content; BMD = bone mineral density; GH = growth hormone; hGH
= human growth hormone; IGF-I = insulin-like growth factor-I; N = total population size; SDS =
standard deviation score.
a Number of patients is specified only when it differs from the total number per group.
* Means were analyzed using a Type III Sum of Squares analysis of variance (ANOVA): PROC GLM
Patient Disposition
Out of 83 patients who underwent screening procedures for this study, 67 patients were
randomized in a double-blind fashion to receive either Humatrope (33 patients) or
placebo (34 patients). Fifty-four patients (30 placebo and 24 Humatrope) completed the
study (Figure 1). Thirteen patients (4 placebo, 9 Humatrope) discontinued prematurely
from the study. From the placebo arm, 1 patient discontinued for personal reasons,
1 patient discontinued due to protocol violation, and 2 patients discontinued due to
serious AEs. From the Humatrope arm, 2 patients discontinued for personal reasons,
1 discontinued due to protocol violation, 1 was lost to follow-up, 1 discontinued due to
perceived lack of efficacy, and 4 discontinued due to nonserious AEs. There were no
statistically significant differences in the reasons for discontinuation between the two
treatment groups.
Somatropin
CT Registry ID#0883
Page 10
N = 83
PATIENTS ENTERED
N = 67
PATIENTS RANDOMIZED
N = 33
Growth Hormone
N = 24
(72.7%)
COMPLETED
Growth Hormone
Figure 1.
N = 34
Placebo
N=9
WITHDRAWN
Reasons:
adverse event (4)
lack of efficacy, patient (1)
lost to follow-up (1)
personal conflict (2)
protocol violation (1)
N = 30
(88.2%)
COMPLETED
Growth Hormone
N = 16
SCREENING FAILURES
Reasons:
lost to follow-up (1)
entry criteria not met (10)
physician decision (1)
N=4
WITHDRAWN
Reasons:
adverse event (2)
protocol violation (1)
Patient disposition.
Primary Endpoint
Table 4 summarizes the change from baseline to Months 6, 12, 18, and 24 for L2–L4
BMD. Humatrope replacement for 24 months resulted in a statistically significant
increase from baseline in L2–L4 BMD (p<.001). In contrast, there was no change from
baseline with placebo treatment. The difference between treatments was statistically
significant (p=.037). A statistically significant interaction between treatment and gender
was observed (p=.009). Men treated with Humatrope showed a statistically significantly
greater increase in BMD than men treated with placebo (p<.001), but the change in
Humatrope-treated women was not significantly different from that in placebo-treated
women.
Somatropin
Somatropin
Table 4.
Change-from-baseline L2–L4 BMD to Visits 5, 6, 7, and 8
Mixed Model Repeated Measures Analysis
Variable
Therapy
n
------------------------ --------- ----
Change
from Baseline
----------------LSMean
StdErr
-------- --------
p-Values
----------------Within
Between
Group*1 Group*1
-------- --------
95% Confidence
Interval*2
--------------------
Visit 5 (6 Months)
Placebo
hGH
32
28
0.008
0.004
0.007
0.007
.280
.582
.716
( -0.02, 0.02)
Visit 6 (12 Months)
Placebo
hGH
32
27
0.004
0.017
0.007
0.008
.564
.031
.217
( -0.03, 0.01)
Visit 7 (18 Months)
Placebo
hGH
30
22
0.004
0.020
0.007
0.008
.568
.014
.127
( -0.04, 0.00)
Visit 8 (24 Months)
Placebo
hGH
29
24
0.013
0.035
0.007
0.008
.087
<0.001
.037
( -0.04, -0.00)
Abbreviations: BMD = bone mineral density; hGH = human growth hormone; LSMean = least squares mean; n = total number of patients in the treatment group
having non-missing data in both baseline and postbaseline periods; StdErr = standard error of the mean.
*1 Within Group p-values are from T-Tests for LSMean Change. Between Group p-values refer to between treatment contrast.
*2 95% Confidence Interval on Difference in least squares means.
CT Registry ID#0883
Page 11
CT Registry ID#0883
Page 12
Secondary Efficacy Measures
Table 5 summarizes the changes from baseline to 24 months for secondary efficacy
variables.
L2–L4 BMC increased statistically significantly in the Humatrope-treated patients at
24 months (p<.001) and the increase at Month 24 was significantly different from
placebo (p=.018).
Statistically significant increases from baseline occurred in both Humatrope-treated
(Months 12, 18, and 24) and placebo-treated patients (Months 12 and 24) for total hip
BMD (p<.05), and for total hip BMC (p<.05) but the Humatrope treatment effect did
not differ statistically from placebo at any visit.
Femoral neck BMD and BMC. Statistically significant increases from baseline
occurred in the placebo-treated patients at Months 12, 18, and 24 (p<.05), but there were
no statistically significant changes from baseline in the Humatrope-treated patients. The
Humatrope treatment effect did not differ statistically from placebo at any visit.
Trochanter BMD. Statistically significant increases from baseline occurred in both
Humatrope-treated (Months 12, 18, and 24) and placebo-treated patients (Months 18 and
24; p<.05), but the Humatrope treatment effect did not differ statistically from placebo at
any visit.
Trochanter BMC. A statistically significant increase from baseline occurred in the
Humatrope-treated patients at Month 24 (p=.032), but there were no statistically
significant changes from baseline in the placebo-treated patients. The Humatrope
treatment effect did not differ statistically from placebo at any visit.
Intertrochanter BMD. Statistically significant increases from baseline occurred in the
Humatrope-treated patients at Months 18 and 24 (p<.01), but there were no statistically
treatment effect did not differ statistically from placebo at any visit.
Intertrochanter BMC. Statistically significant increases from baseline occurred in both
Humatrope-treated (Months 12, 18, and 24) and placebo-treated patients (Months 12, 18,
and 24; p<.05), but the Humatrope treatment effect did not differ statistically from
placebo at any visit.
Trunk fat mass. Statistically significant decreases from baseline occurred in the
Humatrope-treated patients at Months 12 and 24 (p<.05), but there were no statistically
treatment effect was significant at both Months 12 and 24 compared with placebo
(p<.03).
Trunk lean mass. Statistically significant increases from baseline occurred in both
Humatrope-treated (Months 12 and 24; p<.003) and placebo-treated patients (Months 12
Somatropin
CT Registry ID#0883
Page 13
and 24; p<.04), but the Humatrope treatment effect did not differ statistically from
placebo at either visit.
There were no statistically significant changes from baseline in either the Humatrope- or
placebo-treated patients with respect to total body fat mass and total body lean mass.
No statistically significant differences between the two treatment groups were observed.
In Humatrope-treated patients, serum IGF-I concentrations and standard deviation
scores (SDS) were increased above baseline and compared with placebo at every visit
(p<.001). The mean serum IGF-I SDS in all Humatrope-treated subjects increased from
-1.7 ± 0.9 at baseline to 0.2 ± 1.4 at Month 24.
Serum bone-specific alkaline phosphatase and urinary N-telopeptide-to-creatinine
ratio both increased significantly from baseline to 24 months with Humatrope treatment
(p≤.03). The increases for both markers in the Humatrope-treated group were
significantly greater than those in the placebo-treated group at Months 6 and 12 (p≤.012).
Somatropin
CT Registry ID#0883
Table 5.
Variable
L2-L4 BMC (g)
L2-L4 Area (cm2)
Femur BMD (g/cm2)
Femur BMC (g)
Femur Area (cm2)
Neck BMD (g/cm2)
Trochanter BMD
Intertrochanter BMD
(g/cm2)
Neck BMC (g)
Trochanter BMC (g)
Intertrochanter BMC (g)
Trunk Fat (g)
Trunk Lean (g)
Total Body Fat (g)
Total Body Lean (g)
IGF-I (ng/mL)
Page 14
Change from Baseline to 24 Months (2 Years) for Secondary
Efficacy Variables
Mixed Model Repeated Measures Analysis
Placebo
n
LSMean ± StdErr
29 0.54 ± 0.50
29 0.10 ± 0.27
28 0.02 ± 0.01
28 1.23 ± 0.34
28 0.60 ± 0.24
28 0.01 ± 0.01
28 0.01 ± 0.01
28 0.01 ± 0.01
hGH
n
LSMean ± StdErr
24 2.30 ± 0.53
24 0.63±.0.38
24 0.02 ± 0.01
24 1.45 ± 0.54
24 0.36 ± 0.38
24 0.01 ± 0.01
24 0.02 ± 0.01
24 0.03 ± 0.01
28
28
28
26
26
26
26
29
24
24
24
23
23
23
23
24
0.06 ± 0.03
-0.03 ± 0.14
1.13 ± 0.30
223.46 ± 346.59
1072.32 ± 426.57
207.94 ± 597.75
2040.30 ± 735.47
-10.12 ± 4.05
0.06 ± 0.04
0.33 ± 0.15
1.07 ± 0.45
-996.86 ± 382.00
1525.66 ± 475.66
-1158.37 ± 660.15
3160.25 ± 743.87
85.03 ± 12.47
p-Value (95% CI)
.018 (-3.19, -0.31)
.262 (-1.47, 0.41)
.501 (-0.03, 0.01)
.726 (-1.47, 1.03)
.600 (-0.65, 1.12)
.672 (-0.01, 0.02)
.530 (-0.02, 0.01)
.185 (-0.05, 0.01)
.881 (-0.09, 0.11)
.081 (-0.77, 0.05)
.905 (-1.00, 1.13)
.021 (192, 2249)
.477 (-1715, 808)
.133 (-426, 3159)
.477 (-14376, 12136)
<0.001 (-121.03,69.27)
<0.001 (-2.30, -1.13)
.218 (-4.76, 20.73)
.849 (-2.83, 3.44)
.258 (-19.26, 5.33)
IGF-I SDS
29 -0.14 ± 0.08
24 1.58 ± 0.27
Total T4 (nmol/L)
29 -4.61 ± 4.35
23 -12.59 ± 4.85
Free T4 (pmol/L)
29 -2.73 ± 1.05
23 -3.03 ± 1.17
N-Telo/Creatinine
28 5.62 ± 2.63
23 12.59 ± 5.48
(nmol/mmol)
BS Alkaline Phos (µg/L)
29 1.65 ± 0.69
24 3.13 ± 0.76
.152 (-3.51, 0.56)
Urine Creatinine (mmol/L) 29 -0.58 ± 1.13
23 1.15 ± 1.26
.304 (-5.03, 1.58)
Abbreviations: BMC = bone mineral content; BMD = bone mineral density; BS = bone-specific; IGF-I =
insulin-like growth factor-I; hGH = human growth hormone; LSMean = least squares mean; n = total
number of patients in the treatment group having non-missing data in both baseline and postbaseline
periods; N-Telo = N-telopeptide; SDS = standard deviation score; StdErr = standard error of the mean;
T4 = throxine.
Somatropin
CT Registry ID#0883
Page 15
Safety
Adverse Events
Table 6 contains an overview of adverse events reported during this study.
Table 6.
Number and Percentage of Patients
Placebo
hGH
(N=34)
(N=33)
Adverse Eventa
n (%)
n (%)
Serious adverse events
10 (29)
7 (21)
Discontinuations due to an adverse event
2 (6)
4 (12)
Treatment-emergent adverse events
32 (94)
30 (91)
Abbreviations: hGH = human growth hormone; N = total population size; n = sample size.
a Patients may be counted in more than one category.
Treatment-emergent adverse events (TEAEs) were reported in 32 out of 34 patients
(94.1%) treated with placebo and in 30 out of 33 patients (90.9%) treated with
Humatrope. Table 7 summarizes TEAEs reported in this study. Treatment-emergent
peripheral edema was reported statistically significantly more frequently in Humatropetreated patients compared with placebo-treated patients (24.2% and 2.9%, respectively;
p=.013). Paresthesias were reported in 12.1% of Humatrope-treated and in none of the
placebo-treated patients (p=.053). Fatigue was reported in 17.6% of placebo-treated and
in none of the Humatrope-treated patients (p=.025). There were no other statistically
significant differences for treatment-emergent adverse events between the two treatment
groups.
Table 8 provides a summary of the AEs leading to patient discontinuation from the
clinical study. Six patients (9%) discontinued from the study due to AEs; two patients in
the placebo group discontinued due to serious AEs (carcinoid tumor and transient
ischemic attack), and four patients in the Humatrope group discontinued due to
nonserious AEs (12%). There was no statistically significant difference in the number of
patients discontinuing due to AEs between the two treatment groups.
Deaths
There were no deaths reported during the study.
In the placebo group, 10 of the 34 (29%) randomized patients experienced at least one
SAE, while in the Humatrope-treated group, 7 of the 33 (21%) randomized patients
experienced at least one SAE (Table 9). There was no statistically significant difference
in the number of SAEs experienced between the two treatment groups.
Somatropin
CT Registry ID#0883
Table 7.
Preferred Term
Page 16
Treatment-Emergent Adverse Events (Preferred Term)
Occurring in ≥5% of Patients
Ordered by System Organ Class
Comparison of Treatment Groups
Placebo
hGH
Total
(N=34)
(N=33)
(N=67)
n (%)
n (%)
n (%)
Musculoskeletal and connective tissue disorders
Arthralgia
5 (14.7)
8 (24.2)
13 (19.4)
Pain in extremity
5 (14.7)
7 (21.2)
12 (17.9)
Myalgia
3 (8.8)
3 (9.1)
6 (9.0)
Back pain
2 (5.9)
2 (6.1)
4 (6.0)
Neck pain
1 (2.9)
3 (9.1)
4 (6.0)
General disorders and administration site conditions
Oedema peripheral
1 (2.9)
8 (24.2)
9 (13.4)
Injection site bruising
5 (14.7)
1 (3.0)
6 (9.0)
Unexpected therapeutic drug effect
2 (5.9)
3 (9.1)
5 (7.5)
Asthenia
3 (8.8)
1 (3.0)
4 (6.0)
Energy increased
2 (5.9)
2 (6.1)
4 (6.0)
Infections and infestations
Nasopharyngitis
5 (14.7)
4 (12.1)
9 (13.4)
Upper respiratory tract infection
2 (5.9)
3 (9.1)
5 (7.5)
Bronchitis
2 (5.9)
2 (6.1)
4 (6.0)
Influenza
2 (5.9)
2 (6.1)
4 (6.0)
Sinusitis
3 (8.8)
1 (3.0)
4 (6.0)
Nervous system disorders
Headache
6 (17.6)
2 (6.1)
8 (11.9)
Dizziness
4 (11.8)
3 (9.1)
7 (10.4)
Hypoaesthesia
2 (5.9)
2 (6.1)
4 (6.0)
Paraesthesia
0
4 (12.1)
4 (6.0)
Gastrointestinal disorders
Diarrhoea
4 (11.8)
2 (6.1)
6 (9.0)
Vomiting
2 (5.9)
3 (9.1)
5 (7.5)
Psychiatric disorders
Depression
2 (5.9)
3 (9.1)
5 (7.5)
Respiratory, thoracic, and mediastinal disorders
Pharyngolaryngeal pain
3 (8.8)
2 (6.1)
5 (7.5)
Somatropin
p-Value
.369
.539
1.00
1.00
.356
.013
.197
.673
.614
1.00
1.00
.673
1.00
1.00
.614
.259
1.00
1.00
.053
.673
.673
.673
1.00
CT Registry ID#0883
Table 8.
Page 17
Adverse Events Leading to Discontinuation
Incidence by Decreasing Frequency within the Drug
Treatment Group
Preferred Term
--------------------------------------PATIENTS DISCONTINUED
Carcinoid tumour
Diabetes mellitus non-insulin-dependent
Dizziness
Joint swelling
Transient ischaemic attack
Vomiting
Placebo
(N=34)
n (%)
--------2 (5.9)
1 (2.9)
0
0
0
1 (2.9)
0
hGH
(N=33)
n (%)
--------4 (12.1)
0
1 (3.0)
1 (3.0)
1 (3.0)
0
1 (3.0)
Total
(N=67)
n (%)
--------6 (9.0)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
p-Value*
--------.427
1.00
.493
.493
.493
1.00
.493
* Frequencies are analyzed using a Fisher exact test.
Somatropin
CT Registry ID#0883
Table 9.
Page 18
Serious Adverse Events by System Organ Class and
Preferred Term
Comparison of Treatment Groups
System Organ Class
Preferred Term
Overall
Cardiac disorders
Patient with ≥1 event
Angina pectoris
Arteriospasm coronary
Tachycardia
Vision blurred
Dysphagia
Pancreatitis
Asthenia
Chest discomfort
Chest pain
Fatigue
Rigors
Cholelithiasis
Anaphylactic reaction
Diverticulitis
Gastroenteritis
Urinary tract infections
Hip Fracture
Wrist Fracture
Muscle spasms
Eye disorders
General disorders and
administration site
conditions
Hepatobiliary disorders
Immune system disorders
Injury, poisoning and
procedural complications
Musculoskeletal and
connective tissue disorders
Neoplasms benign,
Malignant and unspecified
(including cysts and
polyps)
Basal cell carcinoma
Adenoma benign
Carcinoid tumor
Prostate cancer
Squamous cell
carcinoma of skin
Dizziness
Hypoaesthesia
Syncope vasovagal
Transient ischemic
attack
Gynaecomastia
Placebo
(N=34)
n (%)
10 (29.4)
1 (2.9)
1 (2.9)
0
1 (2.9)
0
1 (2.9)
1 (2.9)
0
0
1 (2.9)
1 (2.9)
1 (2.9)
0
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
0
hGH
(N=33)
n (%)
7 (21.2)
0
0
1 (3.0)
0
1 (3.0)
0
0
1 (3.0)
1 (3.0)
0
0
0
1 (3.0)
0
0
0
0
0
1 (3.0)
Total
(N=67)
n (%)
17 (25.4)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (2.9)
1 (2.9)
1 (2.9)
0
1 (2.9)
1 (3.0)
0
0
1 (3.0)
0
2 (3.0)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
0
0
0
0
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
p-Value*
.576
0
1 (3.0)
1 (1.5)
Reproductive system and
breast disorders
Angioplasty
1 (2.9)
0
1 (1.5)
Surgical and medical
procedures
* Frequencies are calculated using a Fisher exact test.
Somatropin
CT Registry ID#0883
Page 19
Health Outcomes
Collection of data on a new, health-related, quality-of-life questionnaire
A secondary objective of the protocol was to collect data on a new health-related,
quality-of-life questionnaire, the Fragen zur Lebenszufriedenheit-Module (FLZM)
questionnaire. Results obtained with the FLZM were assessed relative to those obtained
with the Nottingham Health Profile (NHP) and Short Form 36 Health Survey (SF-36).
Baseline scores for the FLZM were statistically significantly lower in the placebo group
than in the Humatrope group, indicating lower quality of life in the placebo group. This
was not the case for the NHP and SF-36 questionnaires: there was no statistically
significant difference between the Humatrope group and the placebo group at baseline for
either of these questionnaires. None of the three questionnaires detected any statistically
significant difference between the Humatrope and placebo groups after 6 months of
treatment.
Somatropin
CT Registry ID#2704
Page 1
Summary ID# 2704
Clinical Study Summary: Study B9R-MC-GDFN
Efficacy and Safety of Somatropin Treatment in
Pediatric Subjects with SHOX Disorder and SHOXDeficient Turner Syndrome
Date summary approved by Lilly: 30 November 2006
This was a multicenter, multinational, randomized, open-label, 3-arm, untreated-control
study in prepubertal patients with short stature homeobox-containing gene (SHOX)
deficiency and in prepuberetal patients with Turner syndrome. The primary objective of
this study was to test the hypothesis that the mean first-year height velocity of patients
with SHOX deficiency who received approximately 1 year of treatment with Humatrope
was significantly greater than the mean first-year height velocity of patients with SHOX
deficiency who did not receive Humatrope. This hypothesis was tested by comparing
Humatrope-treated versus untreated patients with SHOX deficiency. A secondary
objective was to compare the effect of Humatrope treatment in patients with SHOX
deficiency to patients with Turner syndrome.
•
The mean first-year endpoint height velocity in the Humatrope-treated patients
with SHOX deficiency (8.68 cm/y) was statistically significantly greater (p<.001)
compared with untreated patients with SHOX deficiency (5.15 cm/y).
•
The effect on height velocity was also observed across other growth-response
parameters, such as change from baseline in height velocity, increase in height
velocity standard deviation score (SDS), change from baseline in height velocity
SDS, and change in height SDS.
Somatropin
CT Registry ID#2704
Page 2
•
Second-year endpoint height velocity in Humatrope-treated patients with SHOX
deficiency continued to exceed the normal range for age and was statistically
significantly greater compared with untreated controls.
•
After 2 years, 41% (11 patients) of the Humatrope-treated patients with SHOX
deficiency and 4.2% (1 patient) of the untreated patients had achieved a height in
the normal range (height SDS >-2); this difference was statistically significant
(p=.003).
•
Excluding a single patient in each group who was in the normal height range at
baseline, none of the untreated patients achieved normal height at the end of
2 years, whereas 10 patients in the treated group achieved normal height at the
end of 2 years.
•
This study also compared patients with SHOX deficiency to patients with Turner
syndrome, a group with similar etiology of short stature. Patients with SHOX
deficiency and patients with Turner syndrome responded almost identically to
Humatrope treatment. The increase in height SDS over 2 years among patients
with SHOX deficiency closely paralleled those with Turner syndrome.
•
There were no deaths or discontinuations due to adverse events in this study.
Somatropin
CT Registry ID#2704
Page 3
Title of Study: Efficacy and Safety of Somatropin Treatment in Pediatric Subjects with SHOX Disorder
and SHOX-Deficient Turner Syndrome
Length of Study: 49 Months
Date of first patient visit (Visit 1): 13 June 2000
Date last patient completed Extension Part A: 09 July 2004
Objectives: The primary objective of this study was to test the hypothesis that the mean first-year height
velocity of patients with short stature homeobox containing gene (SHOX) deficiency who received
approximately 1 year of treatment with Humatrope was significantly greater than the mean first-year height
velocity of patients with SHOX deficiency who did not receive Humatrope.
The secondary objectives for Extension Part A were as follows:
• To test the hypothesis that mean first-year height velocity of patients with SHOX deficiency who
received approximately 1 year of Humatrope treatment was not less than the mean first-year height
velocity of patients with Turner syndrome who received approximately 1 year Humatrope
treatment. This hypothesis was tested using noninferiority analysis.
• To test the hypothesis that the mean second-year height velocity of patients with SHOX deficiency
who received approximately 2 years of treatment with Humatrope was significantly greater than
the mean second-year height velocity of patients with SHOX deficiency who did not receive
Humatrope.
• To determine height velocity of patients with SHOX deficiency and Turner syndrome during the
extension phase of the study.
• To monitor safety during the treatment and extension periods of the study.
Study Design: A multicenter, multinational, randomized, open-label, 3-arm, untreated-control study in
prepubertal patients with SHOX deficiency and in prepubertal patients with Turner syndrome. This study
was divided into periods: Screening, Acute Treatment Period, Extension Part A (patients continued in their
previously assigned treatment group), and Extension Part B (all patients were given the option to receive
Humatrope treatment). This clinical trial summary presents data through Extension A (see Figure 1).
Number of Patients:
Planned: 75 (25 per arm)
Randomized/Entered: 78 patients (27 Humatrope-treated patients with SHOX deficiency; 25 untreated
patients with SHOX deficiency; 26 Humatrope-treated patients with Turner syndrome.
Completed Extension Part A: 77 patients (27 Humatrope-treated patients with SHOX deficiency; 24
untreated patients with SHOX deficiency; 26 Humatrope-treated patients with Turner syndrome.
Prepubertal pediatric patients (>3 years of age) with SHOX deficiency, or Turner syndrome.
For patients with SHOX deficiency, bone age <10 years for boys and <8 years for girls. For girls with
Turner syndrome, bone age <9 years.
Height below the third percentile or height below the 10th percentile and height velocity below the 25th
percentile, for an appropriate age-and-sex-matched ‘normal’ reference population based upon local
standards.
Patients with known growth hormone (GH) deficiency were not eligible for enrollment.
Test Product, Dose, and Mode of Administration: Humatrope 0.05 mg/kg/day, given as a single daily
subcutaneous injection.
Reference Treatment, Dose, and Mode of Administration: Untreated control
Duration of Treatment: 2 years
Somatropin
CT Registry ID#2704
Page 4
Variables:
Efficacy: Standing height and height velocity.
Safety: Adverse events (AEs), standard laboratory evaluations, and vital signs.
Evaluation Methods:
Statistical: The primary analysis was to compare the first-year endpoint height velocity for Humatropetreated and untreated patients with SHOX deficiency. First-year endpoint height velocity was defined as
first-year endpoint height minus baseline height divided by the exact elapsed time in years (365.25 days per
year was assumed throughout). Between-group comparisons were performed using an analysis of
covariance (ANCOVA) model incorporating treatment group (treated or untreated patients with analysis of
SHOX deficiency), Leri-Weill syndrome (present or absent), sex, baseline age, as variables. The primary
comparison was between least squares (LS) means from this model. Additional analyses using the same
model included: first-year endpoint height velocity in the Per Protocol Population and height velocity at
Month 3 (Visit 2) and Month 6 (Visit 3).
Secondary analyses included comparisons of first- and second-year endpoint height velocity between
Humatrope-treated patients with SHOX deficiency and patients with Turner syndrome, using noninferiority
testing. Additional secondary analyses of the change from baseline to endpoint were performed for
different populations on the following variables: height, height SDS, height velocity SDS, bone age, and
bone age SDS.
If the response variable was a change from baseline, p-values from both t-test and signed rank test were
presented with null hypothesis being whether the mean change was equal to zero.
Sample size was calculated to detect a mean difference in the first-year endpoint height velocity of 2 cm/y
between Humatrope-treated and untreated patients with SHOX deficiency, assuming a standard deviation
(SD) of height velocity in each group of 2 cm/y. Assuming that 20 patients would complete each arm, this
would yield approximately 89% power for a 2-sided 0.05-level test.
Safety was evaluated through analysis of AEs, standard laboratory evaluations, and vital signs.
Somatropin
CT Registry ID#2704
Screening
Page 5
Acute Therapy Period
Extension, Part A
Extension, Part B
SHOX deficiency
Nontreatment
All
patients
SHOX deficiency
0.05 mg/kg/day Humatrope
0.05 mg/kg/day
Humatrope
GeNeSIS
Turner syndrome
0.05 mg/kg/day Humatrope
1 year
3
mos
Visit Visit
1
0
3
mos
Visit
2
6
mos
Visit
3
6
mos
Visit
4
6
mos
Visit
101
3
mos
Visit
102
Randomize
SHOX-deficiency
patients
3
mos
Visit
201
Visits every 6 months until
either (1) patient reaches final
height or (2) the study is
closed on 1 October 2010.
Visit
202
Nontreatment pts
only
Abbreviations: GeNeSIS = : mos = months, SHOX = short stature homeoboxcontaining gene.
Figure 1.
Illustration of study design.
Table 1 shows the treatment sequences for this study.
Table 1.
Treatment Sequences
Visit 0
Visit 1
Visit 2
Visit 3
Visit 4
Visit 101
Visit 102
Visit 201
Visit 202 to last patient visit
Somatropin
Screening
Randomization
3 months ± 3 weeks after Visit 1
Every 6 months ± 4 weeks after Visit 102 either
(1) patient reaches final height or (2) the study is
closed on 01 Oct 2010
CT Registry ID#2704
Page 6
Results:
The groups were comparable for most demographic and other baseline characteristics.
Although not statistically significantly different across treatment groups, standing height
SDS was below the normal range (<-2 SDS) in the 3 treatment groups, indicating that on
average the patients were very short (see Table 2).
Table 2.
Somatropin
Patients in Modified Intent to Treat Population
CT Registry ID#2704
Table 2.
Page 7
Patients in Modified Intent to Treat Population (Concluded)
Bone age delay = bone age – chronological age.
Body Mass Index (BMI) (kg/m2) was calculated as weight (kg) divided by the square of height (m),
IQR = interquartile range, SD = standard deviation, SDS = standard deviation score, SEM = standard error
of the mean, TxSHOX = Treated patients with SHOX deficiency. UnTxSHOX = Untreated patients
with SHOX deficiency. Turner = Treated patients with Turner syndrome.
* The p-values for categorical variables were calculated using a Fisher’s exact test.
** The p-values for continuous variables were calculated using Type III Sum of Squares analysis of
variance (ANOVA) : PROC GLM model treatment group.
Patient Disposition
The study plan called for approximately 75 patients (25 per study group). Seventy-eight
patients were randomized and enrolled: 27 Humatrope-treated patients with SHOX
deficiency; 25 untreated patients with SHOX deficiency; and 26 Humatrope-treated
patients with Turner syndrome. All patients, with the exception of 1 untreated patient
with SHOX deficiency who discontinued from the study due to patient decision,
completed the Acute Treatment Period (see Table 3). All patients who completed the
Acute Treatment Period entered Extension Part A. No patient discontinued from the
study during Extension Part A.
Somatropin
CT Registry ID#2704
Table 3.
Page 8
Primary Reasons for Study Discontinuation during Acute
Treatment Period All Randomized Patients with SHOX
Deficiency and All Humatrope-Treated Patients with Turner
Syndrome
Primary Efficacy Measures
The primary objective of this study was to test the hypothesis that the mean first-year
height velocity of patients with SHOX deficiency who receive approximately 1 year of
therapy with Humatrope was statistically significantly greater than the mean first-year
height velocity of patients with SHOX deficiency who did not receive Humatrope.
For the primary efficacy analysis, the response to Humatrope treatment was statistically
significant (p<.001) compared with no treatment (see Table 4), as evidenced by a greater
mean first-year endpoint height velocity (8.68 cm/y) in the Humatrope-treated patients
with SHOX deficiency compared with untreated patients with SHOX deficiency
(5.15 cm/y).
Somatropin
CT Registry ID#2704
Table 4.
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Page 9
Height Velocity
Patients in Modified Intent-to-Treat Population with SHOX
Deficiency
CT Registry ID#2704
Page 10
Statistically significantly greater mean height velocity for Humatrope-treated patients
with SHOX deficiency compared with untreated patients with SHOX deficiency was also
noted at Months 6 (Visit 3), 12 (Visit 4), 24 (Visit 102), and at the second-year endpoint
(p<.001) (Table 4). The mean second-year change in height velocity from baseline in
SHOX patients treated with Humatrope (2.60 cm/yr was statistically significantly greater
when compared with the untreated patients with SHOX deficiency (0.45 cm/yr increase,
p<.001) (see Table 5).
Please note the number of patients with baseline height velocity available was smaller
than the number of patients with baseline height available due to the following reason: in
this study, height velocity was calculated based on measurements obtained at 12-month
intervals. If a pretreatment height measurement was reported and the elapsed time
between pretreatment height and baseline height was between 0.5 and 1.5 years, the
patient’s baseline height velocity was calculated as (baseline height minus pretreatment
height) / (elapsed time in years). For patients with data not meeting these criteria,
baseline height velocity could not be calculated; for example if pretreatment height was
not reported, or if the elapsed time between these measurements were less than 0.5 or
greater than 1.5 years, baseline height velocity was not calculated. Therefore, Table 5
reported the baseline height velocity only for patients in each treatment group who had
pretreatment height measurements and met the criteria for elapsed time. The same
argument also applies to Table 8 and Table 10.
Somatropin
CT Registry ID#2704
Table 5.
Somatropin
Page 11
Height Velocity Change from Baseline Patients
in Modified Intent-to-Treat Population with SHOX Deficiency
CT Registry ID#2704
Table 5.
Page 12
Height Velocity Change from Baseline
Deficiency (Concluded)
As shown in Table 6, the mean height velocity SDS for the second year in patients with
SHOX deficiency treated with Humatrope was statistically greater than for those patients
untreated with SHOX deficiency (2.31 versus -.44, p<.001). This translates to a
statistically greater increase in mean height velocity SDS for the second year in patients
with SHOX deficiency treated with Humatrope (3.58) than for the untreated SHOX
deficiency patients (.21, p<.001). The height velocity SDS remained below 0 for
untreated patients with SHOX deficiency throughout the study, indicating that they grew
at a slower rate than their age-matched peers.
Please note that the number of patients with baseline height velocity SDS available is
smaller than the number of patients with baseline height velocity available due to the
following reason: in this study, height velocity SDS was calculated with baseline height
velocity using Preece standards, only if the 2 height measurements were between 273 and
457 days apart, as the Preece standards were based on 2 height measurements nearly
1 year apart. Table 6 reports baseline height velocity SDS for patients meeting these
criteria for elapsed time. The same argument also applies to Table 9.
Somatropin
CT Registry ID#2704
Table 6.
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Page 13
Height Velocity Standard Deviation Score
Deficiency
CT Registry ID#2704
Table 6.
Page 14
Deficiency (Concluded)
At baseline, the proportion of patients with height below the reference range was similar
across the treatment groups. After 2 years, a statistically significantly greater proportion
of the Humatrope-treated patients with SHOX deficiency had a height above the 2.28th,
third, and fifth percentiles compared with untreated patients with SHOX deficiency.
Except for 1 patient, all of the untreated patients had a baseline height below the normal
range (<-2 SDS) and remained below the normal range during the study. In contrast, 10
Humatrope-treated patients who had subnormal height at baseline achieved height within
normal range within 2 years (Table 7).
Somatropin
CT Registry ID#2704
Table 7.
Page 15
Patients with Height Above Various Percentiles at the
Completion of Extension Part A
Deficiency
There were no statistically significant differences in Humatrope-treatment effect on mean
height velocity at any time point between patients with SHOX deficiency and patients
with Turner syndrome (see Table 8).
Somatropin
CT Registry ID#2704
Table 8.
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Page 16
Height Velocity
Humatrope-Treated Patients in Modified Intent-to-Treat
Population
CT Registry ID#2704
Page 17
As shown in Table 9, there were no statistically significant differences in Humatropetreatment effect on the mean height velocity SDS at any time point between patients with
SHOX deficiency and patients with Turner syndrome. Both Humatrope-treated patients
with SHOX deficiency and Humatrope-treated patients with Turner syndrome showed a
statistically significant increase in mean change in height velocity from baseline in height
velocity SDS for first-year and second-year endpoints.
Table 9.
Somatropin
Population
CT Registry ID#2704
Table 9.
Page 18
Population (Concluded)
There were no statistically significant between-group differences for patients with SHOX
deficiency and patients with Turner syndrome in Humatrope-treatment effect on the mean
change from baseline in height velocity at any time point as shown in Table 10.
Humatrope-treated patients with SHOX deficiency and Humatrope-treated patients with
Turner syndrome showed a statistically significant increase in mean height velocity from
baseline to first-year and second-year endpoints.
Somatropin
CT Registry ID#2704
Table 10.
Somatropin
Page 19
Height Velocity Change from Baseline
Population
CT Registry ID#2704
Page 20
Turner syndrome showed statistically significantly greater increase in mean height from
baseline to Month 6 (Visit 3), Month 12 (Visit 4), Month 24 (Visit 102), 1-year endpoint
and 2-year endpoint compared to untreated patients with SHOX deficiency (see Table
11).
Table 11.
Somatropin
Height Change from Baseline
Modified Intent-to-Treat Population
CT Registry ID#2704
Table 11.
Somatropin
Page 21
Modified Intent-to-Treat Population (Continued)
CT Registry ID#2704
Table 11.
Page 22
Modified Intent-to-Treat Population (Concluded)
Turner syndrome showed a statistically significantly greater mean height SDS compared
with untreated patients with SHOX deficiency at each time point (p<.001). There were
no statistically significant differences in mean height SDS between the Humatropetreated patients with SHOX deficiency and Humatrope-treated patients with Turner
syndrome (see Table 12).
Somatropin
CT Registry ID#2704
Table 12.
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Page 23
Height Standard Deviation Score at Various Time Points
CT Registry ID#2704
Table 12.
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Page 24
CT Registry ID#2704
Table 12.
Page 25
Abbreviations: CI = confidence interval; IQR = interquartile range; LS = least-squares; SD = standard
deviation; SDS = standard deviation score; SEM = standard error of the mean.
TxSHOX = treated patients with SHOX deficiency. UnTxSHOX = Untreated patients with SHOX
deficiency. Turner = Treated patients with Turner syndrome.
Type 3 sum of squares was used in the following ANCOVA models:
Baseline Resonse = (Treatment Group).
Postbaseline Response = (Treatment Group) = (Baseline Hight SDS).
1st Year endpoint is the last measurement obtained from patient during the Acute Treatment Period. 2nd
Year Endpoint is the last measurement obtained from patient during the Extension Part A.
Turner syndrome showed statistically significantly greater gain in mean height SDS from
baseline to Month 6 (Visit 3), Month 12 (Visit 4), first-year endpoint, Month 24
(Visit 102), and second-year endpoint compared with untreated patients with SHOX
deficiency. For Humatrope-treated patients with SHOX deficiency and Humatropetreated patients with Turner syndrome, the gain in mean height SDS from baseline was
statistically significant at each time point. There was no statistically significant
difference in gain in mean height SDS from baseline between the Humatrope-treated
patients with SHOX deficiency and Humatrope-treated patients with Turner syndrome
(Table 13).
Somatropin
CT Registry ID#2704
Table 13.
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Page 26
Height Standard Deviation Score Change from Baseline
CT Registry ID#2704
Table 13.
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Page 27
CT Registry ID#2704
Table 13.
Page 28
Safety
Safety analyses were performed for the Safety Population, which included all enrolled
patients with SHOX deficiency (n=52) or Turner syndrome (n=26) who had a
postbaseline visit. Safety analyses include all data through Extension Part A (see Table
14).
There were no deaths or discontinuations due to AEs in this study. Four serious adverse
events (SAEs) were reported for 3 Humatrope-treated patients with Turner syndrome. No
Humatrope-treated patient with SHOX experienced an SAE. Scoliosis, which was
permanently disabling, was experienced by 2 patients, 1 patient experienced a fall and a
clavicle fracture. None of the SAEs were considered to be possibly related to study drug,
and no patient discontinued due to an SAE.
Somatropin
CT Registry ID#2704
Table 14.
Page 29
Overview of Adverse Events – Safety Population
Abbreviations: GH = growth hormone; n = number of patients; NA = not applicable; SAE = serious
adverse event; TxSHOX = Humatrope-treated patients with SHOX deficiency; TEAE = treatmentemergent adverse event; Turner = Humatrope-treated patients with Turner syndrome; UnTxSHOX =
untreated patients with SHOX deficiency.
a Patients may be counted in more than 1 category.
b Refers to events that have been associated with GH exposure, although not necessarily in a causal
manner, and were specified in the protocol.
c As judged by the investigator.
Treatment-emergent adverse events (TEAEs) were defined as events that first occurred or
worsened in severity after the baseline visit. There were no statistically significant
between-group differences for Humatrope-treated patients with SHOX deficiency
compared with untreated patients with SHOX deficiency in the rate of occurrence of
reported TEAEs.
There were no statistically significant differences between Humatrope-treated patients
with SHOX deficiency and Humatrope-treated patients with Turner syndrome in the rate
of occurrence of reported TEAEs with the exception of 3 TEAEs (pyrexia, vomiting, and
oedema peripheral) that were reported at a significantly higher frequency for patients
with Turner syndrome (see Table 15).
Somatropin
CT Registry ID#2704
Table 15.
Page 30
Treatment-Emergent Adverse Events by Preferred Term
Humatrope-Treated Patients in Safety Population
p-Value*
Total
Turner
TxSHOX
(N=53)
(N=26)
(N=27)
n (%)
n (%)
n (%)
Pyrexia
6 (22.2)
15 (57.7)
21 (39.6)
0.012
Vomiting
3 (11.1)
10 (38.5)
13 (24.5)
0.028
Oedema peripheral
0 (0.0)
5 (19.2)
5 (9.4)
0.023
TxSHOX = Treated patients with SHOX deficiency. Turner = Treated patients with Turner
syndrome.
* The p-values were calculated using a Fisher’s exact test
Preferred Term
Table 16 presents TEAEs possibly related to study drug, as judged by the investigators,
for all Humatrope-treated patients in the Safety Population. There were no statistically
significant between-group differences for Humatrope-treated patients with SHOX
deficiency compared with Humatrope-treated patients with Turner syndrome in the rate
of occurrence of TEAEs that were judged to be possibly related to study drug.
Table 16.
Treatment-Emergent Adverse Events Possibly Related to
Study Drug
in Humatrope-Treated Patients in Safety Population
Clinical Laboratory Findings and Vital Signs
There were no statistically significant within-group changes in fasting glucose from
baseline to Month 12 (Visit 4) for Humatrope-treated and untreated patients with SHOX
deficiency or for Humatrope-treated patients with Turner Syndrome. There were no
statistically significant between-group differences for these treatment groups.
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CT Registry ID#2704
Page 31
Humatrope-treated patients with SHOX deficiency and patients with Turner syndrome
had a greater increase in insulin-like growth factor-1 (IGF-I) compared with untreated
patients
Mean baseline values for Thyroid-Stimulating Hormone (TSH) were similar across all
groups. From baseline to Month 12 (Visit 4), there were minimal changes and no
statistically significant differences between Humatrope-treated and untreated patients
with SHOX deficiency for mean change in TSH.
No Humatrope-treatment effect was observed for mean changes from baseline in heart
rate, systolic blood pressure, or diastolic blood pressure.
Somatropin
CT Registry ID#2889
Page 1
Summary ID# 2889
Clinical Study Summary: Study B9R-JE-K01A
Placebo-controlled double blind study of LY137998
[Somatropin (recombinant DNA origin)] in adults with
growth hormone deficiency
Date summary approved by Lilly: 12 April 2006
The primary objective of this placebo-controlled, double-blind study was to verify that at
24 weeks of therapy for adult growth hormone deficiency (GHD) subjects, a percent
change in LBM from the baseline value is significantly greater in the LY137998 group
than in the placebo group.
・ The improvement of Lean Body Mass (LBM) in the LY137998-group was
statistically significantly higher than that in the placebo-group (p<0.001).
・ The improvement of serum IGF-I concentration in the LY137998-group was
statistically significantly higher than that in the placebo-group (p<0.001).
・ There were no statistically significant changes between treatment groups in Quality of
Life (QOL).
・ The reliability and validity of the disease-specific QOL questionnaire (QLS) used in
the study could not be confirmed.
・ Oedema NOS and arthralgia frequently occurred as adverse drug reactions of
LY137998, which was expected for inevitable pharmacological effects of growth
hormone.
Somatropin
CT Registry ID#2889
Page 2
Title of Study: Placebo-controlled double blind study of LY137998 [Somatropin (recombinant DNA
origin)] in adults with growth hormone deficiency
th
Date of first subject enrolled: 12 July 2001
Date of last subject enrolled: 31st October 2002
Objectives:
Primary objective:
To verify that at 24 weeks of therapy for adult growth hormone deficiency (GHD) subjects, a percent
change in LBM from the baseline value was significantly greater in the LY137998 group than in the
placebo group.
Secondary objectives:
1) To clarify the safety profile of LY137998 in comparison with the placebo group
2) To verify that at 24 weeks of therapy the change in serum IGF-I level from the baseline value was
significantly greater than in the LY137998 group than in the placebo group
3) To compare the change in QOL at 24 weeks of therapy from the baseline between the LY137998
and placebo groups
4) To evaluate the reliability and validity of the disease-specific QOL questionnaire (QLS)
Study Design:
This was a multicenter, randomized, double-blind, parallel-group trial to compare the injection containing
LY137998 6 mg with the placebo injection (comparator). The subjects were assigned to either LY137998
or placebo group by randomly stratified minimization method.
Number of Subjects:
Planned:
For full analysis set, 58 subjects (29 each in the LY137998 and placebo groups) are targeted. Out of
them, childhood-onset subjects were 18 or older. Considering 15% of dropout until the start of
administration in these subjects, 68 subjects will be enrolled.
Randomized:
33 subjects in LY137998-group, 32 subjects in placebo-group among 69 subjects entered
Completed:
31 subjects in LY137998-group, 29 subjects in placebo-group
(1) Subjects who had experienced one of the following diseases in their childhood (under 18 years) or in
their adulthood (over 18 years) that could cause adult GHD:
1) Tumor in the pituitary or its adjacent area, which has been treated and completely cured (there
must be at least 2 years of interval between the completion of its treatment and the informed
consent to this trial.)
2) Trauma causing an injury to the pituitary or its adjacent area
3) Sheehan syndrome
4) Empty sella
5) Diagnosis of idiopathic or congenital GHD in childhood
(2) Subjects who had a maximum serum GH peak less than 3.0 ng/mL in a GH stimulation test
(3) Japanese males and females over 18 years and under 64 years
LY137998: The specified dose was administered subcutaneously in 6-7 divided doses: 0.021 mg/kg/week
for the first 4 weeks, then increased to 0.042 mg/kg/week for the next 8 weeks, then increased to 0.084
Somatropin
CT Registry ID#2889
Page 3
mg/kg/week for the remaining 12 weeks.
Reference Therapy, Dose, and Mode of Administration:
Placebo (amino acetic acid and mannitol): The same liquid volume as LY137998-group was administered
subcutaneously in 6-7 divided doses.
Duration of Treatment: 24 weeks
Variables:
Efficacy: Primary: Percentage change in LBM, determined by DEXA, from baseline to 24weeks.
Secondary: Change in IGF-I concentrations.
Safety: Frequencies and severities of treatment-emergent adverse events and adverse drug reactions.
Health Outcomes: Changes in QOL determined by MOS Short-Form 36-Item Health Survey (SF36) and
the reliability and validity of QLS questionnaire.
Evaluation Methods:
Statistical: Statistical analyses were conducted principally on the full analysis set. All tests of treatment
effects were conducted at a two-sided significance level of 5% unless otherwise stated. Two-sided 95%
confidence intervals were obtained. In order to ascertain the appropriateness of statistical methods, each
test was chosen based on the evaluation of the assumption of normality regarding the distributions of
efficacy variables and demographic characteristics.
For the efficacy analyses, all subjects were included in the allocated group, even if the study drug other
than allocated group was administered.
Results:
Data sets analyzed
Of the 65 randomized subjects, 64 subjects and 53 subjects were included in the Full
Analysis Set (FAS) and Per Protocol Set (PPS), respectively. One subject in the placebogroup was not included in the FAS since the subject was found to have not met all the
inclusion/exclusion criteria after enrollment in this study. Two subjects discontinued and
2 subjects with drug noncompliance in the LY137998-group, and 3 subjects discontinued
and 4 subjects with drug noncompliance in the placebo-group were not included in the
PPS.
Subjects Demographics
Demographic characteristics and baseline efficacy variables compiled using the FAS are
shown in Table 1.
There were no statistically significant differences in the primary subject demographic
characteristics including the allocation factors such as age, gender, onset, and in the
baseline efficacy variables, between the LY137998-group and the placebo-group.
Somatropin
CT Registry ID#2889
Table 1.
Page 4
Baseline Demographics
________________________________________________________________________________
LY137998
Placebo
p value*1
(N=33)
(N=31)
________________________________________________________________________________
Item
Age
Mean±SD
37.2±13.9
39.0±13.8
0.600
--------------------------------------------------------------------------------------------------------18~19
2 (6.1%)
1 (3.2%)
0.955
20~29
10 (30.3%)
9 (29.0%)
30~39
8 (24.2%)
8 (25.8%)
40~63
13 (39.4%)
13 (41.9%)
________________________________________________________________________________
Gender
Male
16 (48.5%)
15 (48.4%)
0.994
Female
17 (51.5%)
16 (51.6%)
________________________________________________________________________________
Onset
Adult Onset
14 (42.4%)
13 (41.9%)
0.968
Childhood Onset
19 (57.6%)
18 (58.1%)
_______________________________________________________________________________
Cause of GHD Idiopathic
6 (18.2%)
9 (29.0%)
0.749
Pituitary Adenoma
14 (42.4%)
9 (29.0%)
Therapy for adenoma
9 (27.3%)
10 (32.3%)
Sheehan's syndrome
2 (6.1%)
2 (6.5%)
Empty sella
1 (3.0%)
1 (3.2%)
Trauma
1 (3.0%)
0 (0.0%)
________________________________________________________________________________
Hormone Deficiency
Isolated
0 ( 0.0%)
1 (3.2%)
0.298
Multiple
33 (100.0%)
30 (96.8%)
________________________________________________________________________________
LBM (kg)
Mean±SD
40.52±9.70
38.99±10.19
0.413
________________________________________________________________________________
IGF-I (ng/mL)
Mean±SD
65±46
73±49
0.563
________________________________________________________________________________
IGF-ISDS
Mean±SD
-2.42±1.85
-2.03±1.58
0.643
________________________________________________________________________________
*1 Age, LBM, IGF-I: Wilcoxon Test, Categorical Item: Chi-Square Test
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CT Registry ID#2889
Page 5
Subject Disposition
The disposition of subjects is shown in Figure 1. The study was planned to be conducted
in 25 study centers. There were 23 study centers that entered a total of 69 subjects in this
study. Of those subjects, 1 subject who was judged ineligible at the screening test, 2
subjects who were judged ineligible at registration, and 1 subject who withdrew the
consent, 4 subjects in total, were excluded from the study. As a result, 65 subjects were
enrolled in the study: 33 and 32 subjects were randomized in the LY137998-group and
the placebo-group, respectively.
All randomized subjects received study drug: all the 65 subjects received either
LY137998 or placebo. In the LY137998-group, 31 subjects completed the study, and 2
subjects discontinued the study due to adverse events. In the placebo-group, 29 subjects
completed the study, and 3 subjects discontinued the study. Of the 3 subjects, 1 subject
each discontinued the study due to adverse event, investigator’s judgment, or difficulty in
continuous observation.
Subjects Acquired Informed Consent(69)
Subjects Excluded from Enrollment(4)*1
Subjects Enrolled(65)
Subjects Discontinued Before Administration(0)
Subjects Received Medication(65)
LY137998(33)
Subjects Completed(31)
Placebo(32)
Subjects Incompleted(2)*2
*1: Ineligible at screening(1), Ineligible at registration(2), Withdraw the consent(1)
*2: Subjects discontinued(2) <Adverse event(2)>
*3: Subjects discontinued(3) <Adverse event(1), Physician's judgement(1), Difficulty in continuous observation(1)>
Figure 1.
Subject disposition.
The reasons for discontinuation are summarized in Table 2 by group. No statistical
significance was observed in the discontinuation rate by reason and total discontinuation
rate between both groups (p>0.05). Two subjects in the LY137998-group and 1 subject
in the placebo-group discontinued due to adverse events.
Somatropin
CT Registry ID#2889
Table 2.
Page 6
Reasons for Discontinuation
__________________________________________________________________________
LY137998
Placebo
p value*2
(N=33)
(N=31)
__________________________________________________________________________
3 (9.7%)
0.590
Total
2 (6.1%)*1
---------------------------------------------------------------------------------------------------------------Adverse event
2 (6.1%)
1 (3.2%)
0.592
Difficulty in continuous observation
0 (0.0%)
1 (3.2%)
0.298
Physician's judgment
0 (0.0%)
1 (3.2%)
0.298
__________________________________________________________________________
*1 Number of Discontinued Subjects (Discontinuation Rate(%))
*2 Chi-square Test
Reason for Discontinuation
The LBM change from baseline to after administration of LY137998 and placebo is
shown in Table 3. The distribution of the LBM change rate is shown in Figure 2. The
percent change in LBM (mean ± SD) of LY137998-group was 4.7 ± 3.88%, showing
statistical significance (p<0.001). The percent change in LBM (mean ± SD) of placebogroup was -0.5 ± 4.10%, showing no statistical significance.
Table 3.
Summary of Lean Body Mass (LBM) Changes
______________________________________________________________________________________
Item
Treatment Visit
N
Mean SD
Max
Median Min p value*2
______________________________________________________________________________________
LBM (kg) LY137998
0w
33
40.52 9.702 59.80 38.18
28.43
24w
31
42.18 9.609 62.94 40.19
30.47
24w LOCF
32
41.94 9.546 62.94 38.91
30.47
*1
32
4.7
3.88
15.6
5.0
-2.4 <0.001
Change
_____________________________________________________________________________________
Placebo
0w
31
38.99 10.186 67.89 35.46
26.12
24w
29
38.27 9.717 65.55 34.24
26.94
24w LOCF
29
38.27 9.717 65.55 34.24
26.94
Change
29
-0.5
4.10
9.2
-0.7
-6.5 0.519
______________________________________________________________________________________
*1 % Change from 0w to 24w LOCF (Last observation carried forward)
*2 Paired-t Test
Somatropin
CT Registry ID#2889
Figure 2.
Page 7
Box-whisker-plot of percent change in lean body mass
(LBM).
The results of between-group comparison of the percent change in LBM are shown in
Table 4.
The percent change in LBM (mean ± SD) were 4.7 ± 3.88% in the LY137998-group and
-0.5 ± 4.10% in the placebo-group. The between-group differences were 5.2% in terms
of point-estimated value and 3.2 - 7.2% in terms of 95% confidence interval, indicating
the percent change in LBM was statistically significantly higher in the LY137998-group
than in the placebo-group (p<0.001).
Table 4.
Percent Changes in LBM (Comparison of Treatment Groups)
______________________________________________________________________________________
LY137998
Placebo
Difference (LY137998 - Placebo)
---------------------------------------------------------------------------------------------------------------------Mean±SD
Mean±SD
Point Estimate 95% C.I.
p value*2
Item*1
______________________________________________________________________________________
LBM(kg)
4.7±3.9
-0.5±4.1
5.2 (3.2~7.2)
<0.001
______________________________________________________________________________________
*1 Percent changes from 0w to 24w LOCF (Last observation carried forward)
*2 LBM: Student t Test
Somatropin
CT Registry ID#2889
Page 8
The changes of IGF-I from baseline to after administration of LY137998 and placebo are
shown in Table 5. The distributions of the changes of IGF-I are shown in Figure 3.
In the LY137998-group, the levels of IGF-I and IGF-I SDS increased after
administration. All changes were statistically significant (p<0.001). No statistically
significant change was observed in the distribution of IGF-I in the placebo-group
throughout the study period.
Somatropin
CT Registry ID#2889
Table 5.
Page 9
Summary of Changes of IGF-I
Item
Treatment
Visit
N
Mean
SD
Max
Median
Min
IGF-I
(ng/mL)
LY137998
0w
4w
8w
12w
24w
24w LOCF
Change *1
33
33
32
32
31
33
33
65
153
217
181
243
240
175
45.9
87.2
109.0
109.7
113.6
114.9
107.6
212
356
462
465
503
503
437
53
141
205
156
229
229
171
17
30
29
42
33
33
-1
<0.001
0w
4w
8w
12w
24w
24w LOCF
Change *1
31
30
28
29
29
31
31
73
69
70
67
63
65
-8
48.7
47.8
46.5
44.2
39.4
41.1
25.3
192
170
162
145
147
148
35
58
55
62
50
55
61
-4
11
11
13
11
9
9
-83
0.197
0w
4w
8w
12w
24w
24w LOCF
Change *1
33
33
32
32
31
33
33
-2.42
-0.58
0.40
-0.09
0.82
0.85
3.26
1.846
2.131
2.370
2.428
2.278
2.292
1.850
0.78
4.32
5.19
5.32
6.81
6.81
7.97
-2.47
-0.47
0.51
-0.23
0.98
0.98
3.54
-8.35
-7.04
-6.16
-6.36
-4.25
-4.25
-0.02
<0.001
0w
31 -2.03
4w
30 -2.13
8w
28 -2.05
12w
29 -2.16
24w
29 -2.26
24w LOCF 31 -2.21
Change *1 31 -0.18
*1 Change from 0w to 24w LOCF
*2 Wilcoxon Test
Abbreviation: LOCF = Last observation carried forward
1.580
1.659
1.588
1.575
1.443
1.435
0.607
0.47
0.80
0.44
0.46
-0.30
-0.30
0.83
-2.12
-2.11
-2.27
-2.37
-2.27
-2.27
-0.13
-4.81
-5.02
-5.15
-5.56
-4.92
-4.92
-1.71
0.194
Placebo
IGF-I SDS
LY137998
Placebo
Somatropin
pvalue*2
CT Registry ID#2889
Figure 3.
Page 10
Box-whisker-plot of changes in IGF-I and IGF-I SDS.
The shifts of IGF-I SDS in LY137998-group are summarized in Table 6. The majority of
subjects showed a shift from low values at baseline to normal range at 24w for both IGF-I
SDS. In addition, several subjects had high values at 24w.
Table 6.
Summary of IGF-I SDS Shift in LY137998-group
IGF-I SDS
> +1.96
Normal
< -1.96
0W
24 W
0
12
21
6
22
3
The results of between-group comparison of the changes of IGF-I and IGF-I SDS are
shown in Table 7. Each of the changes of IGF-I and IGF-I SDS was statistically
significantly larger in LY137998-group than in placebo-group (p<0.001).
Table 7.
Changes of IGF-I (Comparison of Treatment Groups)
LY137998
Placebo
Difference (LY137998 – Placebo)
Item *1
Mean ± SD
Mean ± SD
Point Estimate 95% CI
p-value*2
IGF-I (ng/mL)
175±108
-8±25
178 (131 ~ 224)
<0.001
IGF-I (SDS
3.26±1.85
-0.18±0.61
3.56 (2.76 ~ 4.11)
<0.001
*1 Change from 0w to 24w LOCF (Last observation carried forward)
*2 Wilcoxon Test
Change of LBM by subgroup
The percent changes in LBM by subgroup are summarized in Table 8. The mean of
percent change in LBM was 3.6% to 6.0% in LY137998-group, and -3.4% to 1.0% in
placebo-group. The mean of LBM change in LY137998-group was larger by 3% or over
than in placebo-group, for any subgroup.
Somatropin
CT Registry ID#2889
Table 8.
Page 11
Summary of Lean Body Mass (LBM) Changes by Subgroup
LBM (% change)
Onset
Gender
LY137998
Placebo
n
Mean
n
Male
4
4.2
4
AO
Female
9
6.0
8
Male + Female
13
5.5
12
Male
11
3.6
10
CO
Female
8
5.0
7
Male + Female
19
4.2
17
Abbreviations: AO = adult onset; CO = childhood onset; n = number of subjects in group.
Mean
-3.4
-1.3
-2.0
0.2
1.0
0.6
Change of IGF-I by subgroup
The changes of IGF-I SDS by subgroup are summarized in Table 9. The mean change of
IGF-I SDS was 2.59 to 4.56 in LY137998-group, and -0.98 to 0.02 in placebo-group.
IGF-I level significantly increased in LY137998-group, while almost no change was
observed in the placebo-group, for any subgroup.
Table 9.
Summary of IGF-I SDS Changes by Subgroup
IGF-I SDS change
Onset
Gender
LY137998
Placebo
n
Mean
n
Male
5
4.56
4
AO
Female
9
2.59
9
Male + Female
14
3.29
13
Male
11
2.75
11
CO
Female
8
3.93
7
Male + Female
19
3.24
18
Abbreviations: AO = adult onset; CO = childhood onset; n = number of subjects in group.
Somatropin
Mean
-0.98
-0.19
-0.43
-0.00
0.02
0.01
CT Registry ID#2889
Page 12
The shifts of IGF-I SDS in LY137998-group by subgroup were summarized in Table 10.
Upward shift was remarkable for any subgroup. The majority of adult onset (AO)
subjects were within normal range at 0W, while several subjects had high values at 24W.
The majority of childhood onset (CO) subjects was at low ranges at 0W, and was
elevated to within normal range at 24W.
Table 10.
Summary of IGF-I SDS Shift in LY137998-Group by
Subgroup
AO-Male
AO-Female
0W
24 W
0W
24 W
> + 1.96
0
4
0
2
Normal
4
0
6
6
< - 1.96
1
0
3
0
Abbreviations: AO = adult onset; CO = childhood onset
Somatropin
CO-Male
0W
24 W
0
0
2
10
9
1
CO-Female
0W
24 W
0
0
0
6
8
2
CT Registry ID#2889
Page 13
Safety
The summary of adverse events reported during this study is shown in Table 11. There
were no deaths of any subjects in both groups. Other serious adverse events were
observed in 1 subject in the LY137998-group and 1 subject in the placebo-group. Other
than serious adverse events, adverse events leading to discontinuation of the study and
adverse events leading to reduction of specified dose were observed in 1 subject (study
discontinuation) and 6 subjects (dose reduction) in the LY137998-group, and 1 subject
(study discontinuation) and 1 subject (dose reduction) in the placebo-group. In the
LY137998-group, 84.8% (28/33) of subjects experienced a total of 173 adverse events.
In the placebo-group, 83.9% (26/31) of subjects experienced a total of 170 adverse
events. The numbers of adverse drug reactions were 38 events in the LY137998-group
and 11 events in the placebo-group. Although the incidences of adverse events leading to
reduction of specified dose (18.2%) and adverse drug reactions (42.4%) were higher in
the LY137998-group than those in the placebo-group, no statistically significant
difference was observed between treatment groups.
Table 11.
Overview of Adverse Events Number and Percent of
Subjects
______________________________________________________________________________________
LY137998
Placebo
p value*2
(N=33)
(N=31)
______________________________________________________________________________________
Type of Adverse Event
Deaths
0
(0.0%)
0
(0.0%)
NA
1, 1
(3.0%)*1 4, 1
(3.2%)
0.964
Discontinuations due to an adverse event
1, 1
(3.0%)
1, 1
(3.2%)
0.964
Dose reductions due to an adverse event
6, 6
(18.2%) 1, 1
(3.2%)
0.055
Treatment-emergent Adverse Events
173, 28 (84.8%) 170, 26 (83.9%) 0.914
Adverse reactions
38, 14 (42.4%) 11, 7
(22.6%) 0.091
______________________________________________________________________________________
*1 Number of AEs, Number of Subjects with AE (Occurred Rate(%))
*2 Chi-Square Test
Death
There were no deaths during this study.
Other serious adverse events were observed in 2 subjects. In the LY137998-group, 1
event of cerebral infarction was reported. In the placebo-group, road traffic accident,
fractured pelvis NOS (not otherwise specified), contusion and injury NOS were reported
in 1 subject. All of these events were judged not related to the study drug.
Somatropin
CT Registry ID#2889
Page 14
Clinically Significant Adverse Events
Clinically significant adverse events, except for serious adverse events, in this study
means adverse events leading to discontinuation of the study and adverse events leading
to reduction of specified dose (including withdrawal of study drug).
In the LY137998-group, clinically significant adverse events were observed in 6 subjects.
The urticaria NOS (one subject) and gastroenteritis NOS (one subject) were judged not
related to the study drug. The arthralgia (two subjects), oedema NOS (one subject) and
musculoskeletal stiffness (one subject) were judged related to the study drug. In the
placebo-group, clinically significant adverse events were observed in 2 subjects. The
influenza (one subject) was judged not related to the study drug, and the pituitary tumor
benign NOS (one subject) was judged as unknown.
Adverse Events
Adverse events occurring in ≥5% of either treatment group (2 subjects or more) are
shown in Table 12. The most commonly observed adverse event in the LY137998-group
was nasopharyngitis (33.3%), followed by cough, rhinorrhoea, pyrexia (21.2% each),
arthralgia, headache, pharyngolaryngeal pain (18.2% each), and upper respiratory tract
inflammation (15.2%). The most commonly observed adverse event in the placebogroup was nasopharyngitis (54.8%), followed by pyrexia (38.7%), cough, rhinorrhoea,
(19.4% each), nausea, diarrhoea NOS, anorexia, pharyngolaryngeal pain (16.1% each),
arthralgia, headache, upper respiratory tract inflammation, and pruritus (12.9% each). In
the incidence of each adverse event, no statistically significant difference was observed
between groups.
The incidences of adverse events occurring in ≥5% in the LY137998-group were
calculated by MedDRA System Organ Class (SOC) as follows: 51.5% for respiratory,
thoracic and mediastinal disorders, 45.5% for general disorders and administration site
conditions, 39.4% for musculoskeletal and connective tissue disorders, 27.3% for nervous
system disorders, 27.3% for skin and subcutaneous tissue disorders, and 24.2% for
gastrointestinal disorders, in descending order of incidence. The incidences of adverse
events occurring in ≥ 5% in the placebo-group were calculated by SOC as follows: 71.0%
for respiratory, thoracic and mediastinal disorders, 51.6% for general disorders and
administration site conditions, 38.7 % for gastrointestinal disorders, 32.3% for skin and
subcutaneous tissue disorders, 19.4% for infections and infestations, and 19.4% for
nervous system disorders, in descending order of incidence. The incidences of adverse
events classified in musculoskeletal and connective tissue disorders in the LY137998group were statistically significantly higher than in the placebo-group (p = 0.016). In the
incidences of adverse events classified in other SOCs, no statistically significant
difference was observed between both treatment groups.
Somatropin
CT Registry ID#2889
Table 12.
Page 15
Treatment-Emergent Adverse Events Occurring in ≥5% of
Either Treatment Group
______________________________________________________________________________________
LY137998
Placebo
p value*2
(N=33)
(N=31)
______________________________________________________________________________________
MedDRA SOC, PT
19,8 (24.2%)*1 19,12 (38.7%) 0.212
Nausea
3,3 (9.1%)
5,5 (16.1%) 0.395
Constipation
3,3 (9.1%)
0,0
(0.0%) 0.086
Diarrhoea NOS
3,2 (6.1%)
5,5 (16.1%) 0.197
Vomiting NOS
1,1 (3.0%)
3,3
(9.7%) 0.272
-------------------------------------------------------------------------------------General disorders and
administration site conditions
26,15 (45.5%) 28,16 (51.6%) 0.622
Pyrexia
9,7 (21.2%) 12,12 (38.7%) 0.126
Oedema NOS
4,4 (12.1%)
2,2
(6.5%) 0.437
Malaise
3,3
(9.1%)
2,2
(6.5%) 0.694
Injection site pain
2,2
(6.1%)
2,2
(6.5%) 0.949
Injection site pruritus
2,2
(6.1%)
0,0
(0.0%) 0.164
Fatigue
1,1
(3.0%)
4,3
(9.7%) 0.272
-------------------------------------------------------------------------------------Immune system disorders
3,3 (9.1%)
0,0
(0.0%) 0.086
Seasonal allergy
3,3 (9.1%)
0,0
(0.0%) 0.086
-------------------------------------------------------------------------------------Infections and infestations
7,5 (15.2%)
6,6 (19.4%) 0.656
Tooth caries NOS
2,2 (6.1%)
0,0
(0.0%) 0.164
Influenza
0,0 (0.0%)
2,2
(6.5%) 0.138
-------------------------------------------------------------------------------------Investigations
7,5 (15.2%)
6,3
(9.7%) 0.508
Weight increased
2,2
(6.1%)
0,0
(0.0%) 0.164
-------------------------------------------------------------------------------------Metabolism and nutrition disorders
5,4 (12.1%)
5,5 (16.1%) 0.645
Appetite increased NOS
2,2
(6.1%)
0,0
(0.0%) 0.164
Anorexia
1,1
(3.0%)
5,5 (16.1%) 0.072
-------------------------------------------------------------------------------------Musculoskeletal and connective
tissue disorders
16,13 (39.4%)
7,4 (12.9%) 0.016
Arthralgia
7,6 (18.2%)
4,4 (12.9%) 0.561
Myalgia
2,2
(6.1%)
1,1
(3.2%) 0.592
Backpain
2,2
(6.1%)
0,0
(0.0%) 0.164
Pain in limb
2,2
(6.1%)
0,0
(0.0%) 0.164
-------------------------------------------------------------------------------------Nervous system disorders
14,9 (27.3%)
8,6 (19.4%) 0.455
Headache
7,6 (18.2%)
4,4 (12.9%) 0.561
Hypoaesthesia
3,3
(9.1%)
0,0
(0.0%) 0.086
-------------------------------------------------------------------------------------Respiratory, thoracic and mediastinal
disorders
56,17 (51.5%) 63,22 (71.0%) 0.111
Nasopharyngitis
18,11 (33.3%) 27,17 (54.8%) 0.083
Cough
9,7 (21.2%) 11,6 (19.4%) 0.854
Rhinorrhoea
8,7 (21.2%)
7,6 (19.4%) 0.854
8,6 (18.2%)
8,5 (16.1%) 0.828
Upper respiratory tract inflammation
8,5 (15.2%)
5,4 (12.9%) 0.796
-------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders
11,9 (27.3%) 13,10 (32.3%) 0.663
Rash NOS
3,3
(9.1%)
1,1
(3.2%) 0.333
Pruritus
1,1
(3.0%)
5,4 (12.9%) 0.141
Contusion
1,1
(3.0%)
3,3
(9.7%) 0.272
______________________________________________________________________________________
*2 Chi-Square Test
Somatropin
CT Registry ID#2889
Page 16
Adverse Drug Reactions
Adverse events and adverse drug reactions occurring in ≥5% of either treatment group (2
subjects or more) are shown in Table 13. The most commonly observed adverse drug
reaction in the LY137998-group was oedema NOS (12.1%), followed by arthralgia,
headache (9.1% each), weight increased, appetite increased NOS, myalgia, pain in limb,
hypoaesthesia (6.1% each), and 1 event of injection site pain. The most commonly
observed adverse drug reaction in the placebo-group was injection site pain (6.5%). The
incidences of other adverse drug reactions were 3.2% or lower (1 subject or less). In the
incidence of each adverse drug reaction, no statistically significant difference was
observed between groups.
The incidences of adverse drug reactions occurring in ≥5% in the LY137998-group were
calculated by SOC as follows: 27.3% for musculoskeletal and connective tissue
disorders, 18.2% for general disorders and administration site conditions, 12.1% for
investigations and 12.1% for nervous system disorders, in descending order of incidence.
The incidences of adverse drug reactions occurring in ≥ 5% in the placebo-group were
calculated by SOC as follows: 12.9% for general disorders and administration site
conditions. The incidences of adverse drug reactions classified in the other SOCs were
3.2% or lower (1 subject or less). The incidences of adverse drug reactions classified in
musculoskeletal and connective tissue disorders in the LY137998-group were
significantly higher than in the placebo-group (p = 0.008). Those events (number of
subjects) in the LY137998-group were arthralgia (3), myalgia (2), pain in limb (2),
peripheral swelling (1) and musculoskeletal stiffness (1). The incidences of adverse drug
reactions classified in investigations in the LY137998-group were statistically
significantly higher than in the placebo-group (p = 0.045). Those events in the
LY137998-group were weight increased (2), aspartate aminotransferase increased (1),
alanine aminotransferase increased (1), blood alkaline phosphatase NOS increased (1),
glucose urine present (1). In the incidences of adverse drug reactions classified in other
SOCs, no statistically significant difference was observed between treatment groups.
Somatropin
CT Registry ID#2889
Table 13.
Page 17
Adverse Drug Reactions Occurring in ≥5% of Either
Treatment Group
______________________________________________________________________________________
LY137998
Placebo
p value*2
(N=33)
(N=31)
______________________________________________________________________________________
MedDRA SOC, PT
General disorders and administration
site conditions
9,6 (18.2%)*1
4,4 (12.9%) 0.561
Oedema NOS
4,4 (12.1%)
1,1
(3.2%) 0.185
Injection site pain
1,1 (3.0%)
2,2
(6.5%) 0.518
-------------------------------------------------------------------------------------Investigations
6,4 (12.1%)
0,0
(0.0%) 0.045
Weight increased
2,2 (6.1%)
0,0
(0.0%) 0.164
3,3 (9.1%)
0,0
(0.0%) 0.086
2,2 (6.1%)
0,0
(0.0%) 0.164
-------------------------------------------------------------------------------------Musculoskeletal and connective
tissue disorders
9,9 (27.3%)
1,1 (3.2%)
0.008
Arthralgia
3,3 (9.1%)
1,1 (3.2%)
0.333
Myalgia
2,2 (6.1%)
0,0 (0.0%)
0.164
Pain in limb
2,2 (6.1%)
0,0 (0.0%)
0.164
-------------------------------------------------------------------------------------Nervous system disorders
5,4 (12.1%)
2,1 (3.2%)
0.185
Headache
3,3 (9.1%)
0,0 (0.0%)
0.086
Hypoaesthesia
2,2 (6.1%)
0,0 (0.0%)
0.164
______________________________________________________________________________________
*2 Chi-Square Test
Clinical Laboratory Test
The clinical laboratory test includes evaluation of laboratory test values, urinalysis and
blood pressure by group.
Statistically significant changes of laboratories in LY137998-group were summarized in
Table 14. Statistically significant changes of laboratories in placebo-group were
summarized in Table 15. The mean value was within the reference range for any of these
tests.
Somatropin
CT Registry ID#2889
Table 14.
Page 18
Statistically Significant Changes of Laboratories in
LY137998-Group
Reference
Range
10-40
5-45
220-430
104-338
16-73
3.7-5.5
150-219
8.0-20
4.1-5.0
2.5-4.5
0.8-1.7
Mean
Change
-10
-15
-40
51
-22
-0.1
-14
-2.0
0.1
0.7
-0.2
p-value*1
Intra-group
Inter-group
0.020
0.258
<0.001
0.066
<0.001
<0.001
<0.001
<0.001
<0.001
0.007
0.006
0.016
0.025
0.036
0.001
0.085
0.004
0.185
<0.001
<0.001
<0.001
0.058
Mean at
24 W LOCF
28
26
357
279
39
4.3
206
11.7
4.8
4.3
1.2
Test
AST(GOT)(U/L)
ALT(GPT)(U/L)
LDH(U/L)
Al-P(U/L)
γ-GTP(U/L)
Albumin(g/dL)
Total Cholesterol (mg/dL)
BUN(mg/dL)
Ca(mEq/L)
P(mg/dL)
FT4 (ng/dL)
*1 Wilcoxon test
Abbreviations: LOCF = Last observation carried forward, AST(GOT) = Aspartate aminotransferase
(Glutamate oxaloacetate transaminase), ALT(GPT) = Alanine aminotransferase (Glutamate pyruvate
transaminase), LDH = Lactate dehydrogenase, Al-P = Alkaline phosphatase, γ-GTP = Gamma-Glutamyl
transpeptidase, BUN = Blood urea nitrogen, Ca = Calcium, P = Phosphorus, FT4 = Free thyroxine
Table 15.
Statistically Significant Changes of Laboratories in Placebogroup
Reference
Range
0.8-1.3
-89
Mean
Change
0.1
5
p-value*1
Intra-group
Inter-group
0.002
0.004
0.014
0.189
Mean at
Test
24 W LOCF
Creatinine (mg/dL)
1.0
DBP (mmHg)
77
*1 Wilcoxon test
Abbreviations: LOCF = Last observation carried forward, DBP = Diastolic blood pressure
Health Outcomes
SF-36
The QOL (SF-36) changes from baseline to after administration of LY137998 or placebo
are shown in Table 16.
In the LY137998-group, none of the changes from baseline to endpoint were statistically
significant. In the placebo-group, none of the changes from baseline to endpoint were
Somatropin
CT Registry ID#2889
Table 16.
Page 19
Summary of QOL Score Changes (SF-36)
______________________________________________________________________________________
Item Treatment Visit
N
Mean SD
Max
Median Min
p value*2
______________________________________________________________________________________
PF
LY137998 -4w
32
87.3
15.40 100.0
92.5
40.0
0w
31
87.1
16.22 100.0
95.0
40.0
24w
30
89.0
16.26 100.0
95.0
40.0
24wLOCF 31
89.0
15.99 100.0
95.0
40.0
*1
30
2.0
9.16
30.0
0.0
-20.0 0.309
Change
_____________________________________________________________________________________
Placebo
-4w
31
85.3
17.98 100.0
95.0
15.0
0w
30
85.8
14.98 100.0
90.0
35.0
24w
29
88.7
11.52 100.0
95.0
60.0
24wLOCF
30
88.2
11.60 100.0
95.0
60.0
Change
29
2.1
12.38 60.0
0.0
-15.0 0.439
______________________________________________________________________________________
RP
LY137998 -4w
33
83.3
22.68 100.0
93.8
25.0
0w
33
79.7
24.01 100.0
87.5
0.0
24w
31
78.8
26.65 100.0
87.5
0.0
24wLOCF 32
79.3
26.35 100.0
90.6
0.0
Change
32
0.0
20.88 50.0
0.0
-50.0 1.000
______________________________________________________________________________________
Placebo
-4w
31
82.7
24.30 100.0
93.8
25.0
0w
31
83.3
23.41 100.0
87.5
18.8
24w
29
79.2
24.70 100.0
87.5
12.5
24wLOCF 30
76.6
28.26 100.0
87.5
0.0
Change
30
-6.1
27.44 47.9
0.0
-100.0 0.294
______________________________________________________________________________________
BP
LY137998 -4w
33
78.2
21.46 100.0
84.0
41.0
0w
33
77.7
23.92 100.0
84.0
32.0
24w
31
74.9
23.59 100.0
74.0
22.0
24wLOCF 32
73.9
23.92 100.0
73.0
22.0
Change
32
-3.1
22.22 59.0
0.0
-58.0 0.342
______________________________________________________________________________________
Placebo
-4w
31
72.0
25.78 100.0
72.0
31.0
0w
31
79.5
20.91 100.0
84.0
41.0
24w
29
78.9
22.09 100.0
84.0
31.0
24wLOCF 30
76.3
26.05 100.0
84.0
0.0
Change
30
-3.4
25.22 58.0
0.0
-72.0 0.543
______________________________________________________________________________________
(continued)
*2 Wilcoxon Test
Abbreviations: PF = Physical Functioning, RP = Role-Physical, BP = Bodily Pain, GH = General Health,
VT = Vitality, SF = Social Functioning, RE = Role-Emotional, MH = Mental Health
Somatropin
CT Registry ID#2889
Table 16.
Page 20
Summary of QOL Score Changes (SF-36) (continued)
______________________________________________________________________________________
N
Mean SD
Max
Median Min
p value*2
______________________________________________________________________________________
GH
LY137998 -4w
32
54.0
21.26 100.0
51.0
15.0
0w
33
56.4
21.63 92.0
55.0
20.0
24w
31
58.3
21.12 92.0
57.0
10.0
24wLOCF 32
57.9
20.87 92.0
57.0
10.0
Change
32
1.2
10.25 32.0
0.0
-20.0 0.769
______________________________________________________________________________________
Placebo -4w
31
51.9
18.89 97.0
52.0
15.0
0w
30
52.6
18.71 87.0
52.0
15.0
24w
29
57.0
17.21 97.0
57.0
22.0
24wLOCF
30
57.2
16.93 97.0
57.0
22.0
Change
29
3.1
12.61 35.0
0.0
-22.0 0.306
______________________________________________________________________________________
VT
LY137998 -4w
32
56.3
21.36 87.5
59.4
0.0
0w
33
57.2
23.86 93.8
56.3
6.3
24w
31
59.1
19.29 87.5
56.3
6.3
24wLOCF 32
58.8
19.04 87.5
56.3
6.3
32
1.6
19.44 50.0
0.0
-25.0 0.843
Change*1
______________________________________________________________________________________
Placebo
-4w
31
48.8
21.56 87.5
43.8
0.0
0w
30
51.2
18.80 87.5
50.0
12.5
24w
29
53.0
21.50 100.0
56.3
18.8
24wLOCF 30
52.5
21.31 100.0
53.1
18.8
Change
29
0.7
15.64 37.5
0.0
-37.5 0.683
______________________________________________________________________________________
SF
LY137998 -4w
33
82.6
26.32 100.0 100.0
12.5
0w
33
81.4
22.56 100.0 100.0
25.0
24w
31
86.7
17.95 100.0 100.0
50.0
24wLOCF 32
85.9
18.17 100.0 100.0
50.0
Change
32
5.1
23.73 75.0
0.0 -25.0 0.419
______________________________________________________________________________________
Placebo
-4w
31
81.9
25.38 100.0 100.0
25.0
0w
31
85.5
18.85 100.0 100.0
50.0
24w
29
83.6
20.35 100.0 100.0
37.5
24wLOCF 30
84.2
20.22 100.0 100.0
37.5
Change
30
-0.8
19.95 37.5
0.0 -37.5 0.901
______________________________________________________________________________________
(continued)
*2 Wilcoxon Test
Somatropin
CT Registry ID#2889
Table 16.
Page 21
Summary of QOL Score Changes (SF-36) (concluded)
______________________________________________________________________________________
N
Mean SD
Max
Median Min
p value*2
______________________________________________________________________________________
RE
LY137998 -4w
33
79.8
27.17 100.0
91.7
0.0
0w
32
77.3
23.31 100.0
83.3
0.0
24w
31
80.1
24.60 100.0
83.3
0.0
24wLOCF 32
80.2
24.20 100.0
83.3
0.0
Change
32
2.9
18.77 50.0
0.0
-50.0 0.419
______________________________________________________________________________________
Placebo
-4w
31
79.3
27.54 100.0
91.7
0.0
0w
31
82.3
25.62 100.0
91.7
0.0
24w
29
78.4
25.44 100.0
91.7
16.7
24wLOCF 30
76.7
26.84 100.0
91.7
16.7
Change
30
-5.0
33.66 100.0
0.0
-83.3 0.447
______________________________________________________________________________________
MH
LY137998 -4w
32
69.5
18.33 95.0
70.0
30.0
0w
33
68.8
19.77 100.0
70.0
5.0
24w
31
72.7
16.58 95.0
75.0
15.0
24wLOCF 32
71.6
17.62 95.0
72.5
15.0
Change
32
2.8
17.04 50.0
0.0
-35.0 0.501
______________________________________________________________________________________
Placebo -4w
31
68.3
17.14 100.0
70.0
35.0
0w
30
70.8
13.33 90.0
75.0
45.0
24w
29
68.7
18.20 100.0
70.0
20.0
24wLOCF
30
67.7
18.63 100.0
67.5
20.0
Change
29
-3.9
18.94 30.0
0.0
-50.0 0.387
______________________________________________________________________________________
*2 Wilcoxon Test
The results of between-group comparison of the QOL (SF-36) changes by Wilcoxon test
are shown in Table17. There was no statistically significant difference between groups
for any of the SF-36 subscales.
Somatropin
CT Registry ID#2889
Table17.
Page 22
Changes of QOL (SF-36) Comparison of Treatment Groups
______________________________________________________________________________________
LY137998
Placebo
Difference(LY137998-Placebo)
---------------------------------------------------------------Subscale*1
Mean±SD
Mean±SD
Point Estimate 95% C.I. p value*2
______________________________________________________________________________________
PF:Physical Functioning
2.0± 9.2
2.1±12.4
0.0 (-5.0~0.0)
0.675
RP:Role-Physical
0.0±20.9 -6.1±27.4
0.0 (0.0~6.3)
0.410
BP:Bodily Pain
-3.1±22.2 -3.4±25.2
0.0 (-11.0~5.0)
0.618
GH:General Health
1.2±10.2
3.1±12.6
0.0 (-5.8~5.0)
0.605
VT:Vitality
1.6±19.4
0.7±15.6
0.0 (-12.5~6.3)
0.754
SF:Social Functioning
5.1±23.7 -0.8±19.9
0.0 (0.0~12.5)
0.597
RE:Role-Emotional
2.9±18.8 -5.0±33.7
8.3 (0.0~16.7)
0.238
MH:Mental Health
2.8±17.0 -3.9±18.9
5.0 (-5.0~15.0)
0.323
______________________________________________________________________________________
*1 Change from 0w to 24wLOCF (Last observation carried forward)
*2 Wilcoxon Test
QLS (Appropriateness of QLS Questionnaire)
The reliability and validity of QLS questionnaire was estimated by psychometric
evaluation methods, which included the comparison with previous QOL survey results of
Caucasian population. The reliability of three modules, QLS-A, QLS-G, and QLS-H is
examined in terms of internal consistency (homogeneity) with item selectivity (partwhole correlation) and Cronbach’s alpha, and test-retest reliability. Scale validity of
QLS-H was examined in terms of sensitivity to change and correlation with SF-36.
Those results were compared with the results of the international version of QLS. All
scales demonstrated satisfactory selectivity values and high Cronbach's alphas for the
total scores reflecting good internal consistency and homogeneity of the questionnaire.
The test-retest reliability was lower than the international version and sensitivity to
change of QLS-H could not be proven. The correlation coefficients with eight SF-36
scales were acceptable with the exception of social functioning.
The reliability and validity of the questionnaire used in the study could not be confirmed.
Somatropin
CT Registry ID#5123
Page 1
Summary ID# 5123
Clinical Study Summary: Study B9R- IT-GDFT
The Genetics and Neuroendocrinology in Children with
GHD: A Part of GeNeSIS
Date summary approved by Lilly: 28 August 2006
This was a pilot study conducted in one European country in preparation of participation
in an international more comprehensive study (GeNeSIS) for the characterization of
genetic defects associated with hypopituitarism and the development of an accurate
growth prediction model. The GeNeSIS study analysis at the 2004 datalock incorporates
data belonging to this study.
Title of Study: The Genetics and Neuroendocrinology in children with GHD: A part of GeNeSIS
Study Center(s): This study was conducted at 19 study centers in 1 country.
Length of Study: 1 year
Date of first subject visit: 12 September 2001
Date of last subject visit: 01 September 2003
Objectives: Primary objectives:
•
To characterize gene defects associated with hypopituitarism, growth disorder or
short stature. [DNA analysis study]
• To develop accurate growth prediction models using clinical data (auxologic
parameters, bone age) and biochemical data (insulin-like growth factor-I [IGF-I] and
insulin-like growth factor binding protein-3 [IGFBP-3], urinary bone markers)
[Growth prediction study].
To collect any adverse event, whether or not considered drug-related
Humatrope
CT Registry ID#5123
Page 2
Study Design: open-label, multicenter, national study. It was a part of GeNeSIS - The Genetics and
Neuroendocrinology of Short Stature International Study - which is an open-label, multicenter,
multinational, observational study, established as a post-marketing research program. It collects
information on the clinical management of patients with short-stature, growth disorder or disorders of
hypothalamic-pituitary function according to standard pediatric endocrinology practice, as documented by
the attending endocrinologist.
DNA Analysis Study: Patients, who fulfilled inclusion criteria, were eligible to enter B9R-IT-GDFT, in
the DNA analysis study. Once a patient was enrolled in this study, a blood sample for genetic analysis was
taken at baseline and sent to the central lab for analysis.
Growth Prediction Study: Patients who meet inclusion criteria and who have not yet received any growth
hormone (GH) therapy were eligible to participate in the growth prediction study. Once a patient was
enrolled in this study, a blood sample for evaluation of IGFs was taken at baseline. After one month of GH
therapy a sample of urine for bone markers evaluation was also taken and sent to the central lab for
analysis.
Discussion of Design and Control
This was an open-label, multicenter, national study for a total treatment period of 12 months (52 weeks)
involving about 60 GHD pre-pubertal patients who at enrolment received Humatrope therapy administered
from Visit 1 at the currently approved dosage for pediatric GHD (0.025-0.035 mg/Kg/day).
All subjects, regardless of which study they were enrolled in (DNA and Growth prediction), underwent
baseline anthropometric measurements and collection of blood sample for measurement of IGF-I, IGF-BP3
and blood chemistry and hematology for safety (if not available previously).
At Visit 1, after giving informed consent, physical examination of patients to determine the diagnosis was
performed according to the Schedule of Events, and blood sample was collected for thyroid function test
(performed in a Local Laboratory), DNA analysis (only subjects enrolled in this study) (a central
laboratory), IGF-I and IGF-BP3 (a central laboratory). A hand-wrist x-ray was performed to determine
bone age.
In addition, the subjects enrolled in Growth Prediction Study were given a urine collection kit and
instructions to collect urine at home approximately 1 month after the start of somatropin therapy.
One month (+ 1 week) after Visit 1, an interim history was collected including any adverse event, clinical
evaluation, Humatrope® therapy information.
At this visit, the patient brought his/her 24 hour urine collection for central laboratory to determine
deoxypiridinoline crosslinks, galactosylhydroxylysine and glucosylgalctosylhydroxylysine.
At Visit 2, after 3 months (+ 3 weeks) of GH treatment, an interim history was collected including any
adverse event, clinical evaluation, Humatrope® therapy information.
At Visit 3, after 6 months (+ 4 weeks), a blood sample was collected for IGF-I, IGF-BP3 performed in a
different Central Lab. Clinical evaluation including any adverse event and Humatrope® therapy
information was collected.
At Visit 4, after 12 months (+ 4 weeks), a blood sample was collected for IGF-I, IGF-BP3 performed in a
different Central Lab. A hand-wrist x-ray was performed to determine bone age. Clinical evaluation
including any adverse event and Humatrope® therapy information was collected.
Number of Subjects:
Planned: 60.
Entered: 36.
Completed: 32.
Humatrope
CT Registry ID#5123
Page 3
Main Criteria for Inclusion
DNA Analysis Study:
• Fulfillment of criteria defined in the scoring system
• They have never received any growth hormone therapy
• GHD defined as:
- peak response of GH under any pharmacological stimulation <10 ng/ml except for the combined
GHRH + pyridostigmine (or arginine) test (peak <20 ng/ml). GH secretion has to be assessed at the
moment of diagnosis and, in any case, not prior than two years before the enrollment in this study
- normal response to provocative tests but low spontaneous nocturnal GH secretion (<3 ng/ml) knows as
as “ neurosecretory dysfunction”.
• Pubertal clinical stage.
• Provision of informed consent.
Family members of patients who participate in the DNA analysis study may also participate in this study by
providing blood samples for DNA analysis (after having provided an appropriate informed consent).
Growth prediction study:
• They have never received any growth hormone therapy.
• Height SDS < -3 according to Tanner references (Tanner JM and Whitehouse RH, 1976)
at the moment of diagnosis.
• GHD defined as peak response of GH under any pharmacological stimulation <10 ng/ml
except for the combined GHRH + pyridostigmine (or arginine ) test (peak <20 ng/ml).
GH secretion has to be assessed at the moment of diagnosis and, in any case, not prior
than two years before the enrollment in this study
• Pubertal clinical stage defined as:
Female: Breast Tanner score less than 1
Male: Gonad Tanner score less than 2
Provision of informed consent.
Study Drug, Dose, and Mode of Administration: Humatrope therapy administered from Visit 1 at the
currently approved dosage for pediatric GHD (0.025-0.035 mg/Kg/day) to 1 year.
Comparator, Dose, and Mode of Administration: Not applicable (this is a non-comparative study)
Duration of Treatment: 1 year
Humatrope Frequency: daily
Humatrope
CT Registry ID#5123
Page 4
Variables: Safety:
•
•
•
Date of birth, sex, visit date
Diagnosis
Specific medical conditions, significant historical diagnoses, growth promoting
medications prior to study entry
• Medications
• Pre-existing conditions (data collected on “Pre-existing Conditions and Adverse Events”
running record)
• Humatrope therapy: dose at entry into the study (dose per injection, unit, number of
injections per week), date of first dose of growth hormone after entry into the study
• Adverse events
The frequency and percentage of adverse events for patients receiving Humatrope therapy were
summarized in multiple ways including by body system and by underlying disorders. Serious adverse
events were listed in detail for each individual patient. Detailed summaries of neoplastic disease recurrence
were also presented.
Efficacy: The following efficacy issues were explored: height and annualized height velocity. The
participating physicians were contacted if the following data are not provided:
• Date of birth, sex, visit date
• Diagnosis
• GH testing results
• Measurements (length or height)
• Humatrope therapy (for Humatrope-treated patients): prescribed dose at entry into the
study (dose per injection, unit, number of injections per week)
• Patients who, at the end of B9R-IT-GDFT, will be entered into GeNeSIS, will be
followed-up to the final height attainment (when their height velocity has dropped below
2 cm/year)
Gene defects: The following efficacy issues were explored: height and annualized height velocity. The
participating physicians were contacted if the following data are not provided:
• Date of birth, sex, visit date
• Diagnosis
• GH testing results
• Measurements (length or height)
• Humatrope therapy (for Humatrope-treated patients): prescribed dose at entry into the
study (dose per injection, unit, number of injections per week)
• Patients who, at the end of B9R-IT-GDFT, will be entered into GeNeSIS, will be
followed-up to the final height attainment (when their height velocity has dropped below
2 cm/year)
Bioanalytical: Not applicable
Pharmacokinetic/Pharmacodynamic: Not applicable
Health Outcomes: Not applicable
Evaluation Methods: Statistical: Patients entered in the study were included in any given analysis only if
they have the necessary data available for the analysis in question.
Student’s t-test was used for the comparison of means from two variables when more variables or unpaired
test were performed. Analysis of variance (ANOVA) was used.
Growth Prediction was performed after 3 months of treatment as follows: baseline data (height, weight,
bone age, pubertal stage, IGF-1 and IGFBP-3), urinary bone turnover markers (deoxypiridinoline
crosslinks, galactosylhydroxylysine and glucosylgalctosylhydroxylysine) after 4 weeks, and height, IGF-1
and IGFBP-3 after 3 months were collected and was calculated using a mathematical algorhytm. The
results were expressed as 1st year height velocity (HV) using the formulae 1-year HV(cm)=3.543(2.337xBA)-(0.010xIGF-I)+(0.100xDPD)+(0.299x3month HV).
Humatrope
CT Registry ID#5123
Page 5
Results:
The last patient was entered into treatment on 31 July 2002, instead of the planned date of
30 September 2001 because of the very low rate of enrollment of patients.
Completers’ demographics at baseline are summarized in Table 1.
Humatrope
CT Registry ID#5123
Table 1.
Page 6
Summary of Baseline Patient Demographics
-ANOVA p-values-
Group N Mean SD Median
Q1
Q3
Min
Max
Raw
Ranked
Age at diagnosis
All
32
5.09 3.73
4.73
1.90
7.57
0.03
14.67
Female
11
4.82 3.77
4.54
1.83
6.85
0.03
12.19
Male
21
5.23 3.79
4.92
2.00
7.67
0.06
14.67
0.775
0.727
0.516
0.482
0.523
0.395
0.790
0.717
0.783
0.840
0.811
0.862
Raw
Ranked
Baseline bone age GP SDS (BAGP-CA)/SD
All
Female
Male
27
-3.73 1.19
-3.61
-4.36
-2.80
-6.41
-1.63
9
-3.51 1.38
-3.41
-4.26
-2.42
-5.71
-1.63
18
-3.84 1.11
-3.66
-4.36
-3.04
-6.41
-2.46
Baseline bone age GP delay (BAGP-CA)
All
31
-2.31 1.06
-2.34
-2.89
-1.42
-4.63
-0.54
Female
11
-2.14 1.22
-1.65
-3.51
-1.05
-4.26
-0.86
Male
20
-2.40 0.98
-2.41
-2.86
-1.92
-4.63
-0.54
Baseline bone age Greulich-Pyle
All
31
3.12 2.88
2.72
0.85
4.41
-0.47
10.37
Female
11
2.93 2.92
2.03
0.85
3.91
-0.14
9.73
Male
20
3.22 2.93
2.91
1.07
4.90
-0.47
10.37
Baseline relative bone age GP (BAGP/CA)
All
31
0.42 0.37
0.52
0.34
0.67
-1.00
0.80
Female
11
0.44 0.31
0.55
0.27
0.62
-0.16
0.80
Male
20
0.40 0.40
0.47
0.35
0.68
-1.00
0.75
baseline age (yrs)
All
32
5.28 3.60
4.84
2.18
7.61
0.47
14.72
Female
11
5.07 3.61
4.63
2.21
7.02
0.82
12.21
Male
21
5.39 3.68
5.06
2.14
7.75
0.47
14.72
Group
N Mean
Median
Q1
Q3
Min
Max
Humatrope
SD
CT Registry ID#5123
Table 1.
Page 7
Summary of Baseline Patient Demographics (concluded)
Target height (cm)
All
32 165.50
8.32
167.33 158.38 171.25 149.65 181.50
Female
11 157.78
4.75
158.00 154.50 162.35 149.65 166.00
Male
21 169.55
6.79
170.40 167.50 172.50 150.50 181.50
<0.001
<0.001
0.791
0.954
target height sds
All
32
-0.88
0.85
-0.80
-1.27
-0.41
-3.48
0.75
Female
11
-0.83
0.73
-0.79
-1.33
-0.12
-2.08
0.44
Male
21
-0.91
0.93
-0.80
-1.20
-0.51
-3.48
0.75
Patient Disposition
Thirty-six patients entered in this open label, non-comparative study.
Thirty-two patients completed the study according to the study protocol; for 4 patients,
the required dose information at visit 1 and all subsequent visits were missing, and for
this reason, efficacy was not-evaluable. They were excluded from analysis (1 of these
patients dropped-out for SAE Pneumonia - Aortic valvular disease).
Disease characteristics are summarized in Table 2.
Humatrope
CT Registry ID#5123
Table 2.
Page 8
Disease Characteristics of Protocol Completers (N=32)
Diagnosis
Level 1
GHD
No (%)
Number of patients (%)
32 (100.0)
23 (71.9)
9 (28.1)
Level 2
Idiopathic
Organic
Level 4
Level 3
Classic
UNK
Abnormal pituitary development
UNK
Congenital
Level 4
Abnormal pituitary development
Level 5
1 (11.1)
8 (100)
Ectopic posterior pituitary
Pituitary aplasia/absence
Pituitary hypoplasia
UNK
UNK
23 (100)
23 (100)
8 (88.9)
4 (50)
1 (12.5)
3 (37.5)
24 (100)
The number of years on GH Treatment for all GHD patients is reported in Table 3.
Table 3.
Total Years on GH Therapy
Years
0-1
> 1-2
All
Humatrope
Number of Patients (%)
17 (53.1)
15 (46.9)
32 (100)
CT Registry ID#5123
Page 9
Tanner Stage values at baseline and endpoint are presented in Table 4.
Table 4.
Tanner Stages at Baseline and Endpoint
Tanner Stage at Baseline
Females
B1
n (%)
11 (100)
Males
Tanner Stage at Last Visit
Females
B1
B2
n (%)
9 (81.8)
2 (18.2)
Males
G1
G2
n (%)
19 (95)
1 (5)
G1
G2
Unknown
n (%)
16 (80)
1 (5)
3 (15)
Abbreviations: B = breast; G = gonad; n = number of patients.
Efficacy Measures Growth Prediction Model Results: For the females an HV of 12.98±
4.82 cm/year was predicted after three months of observation and at the first year the HV
was 13.05±3.91 cm/year; for the males an HV of 13.95±5.39 cm/year was predicted and
at the first year the HV was 12.93±5.02 cm/year.
Height, height SDS, weight, weight SDS IGF-I SDS, IGF-I/IGFB-3 ratio, statisticall
increased in all treatment groups and by age because pts. were going according with pts.
enrolled characteristics .
In the same manner, IGFB-3 SDS was statistically increased during the study in males
and total population (p<0,05) but not in females (P=0.106), maybe because of the small
sample size(N=7).
Humatrope
CT Registry ID#5123
Page 10
All results are summarized in the following pages (Table 5- Table 15):
Table 5.
Summary of Height Velocity (cm/year)
SUMMARY OF HEIGHT VELOCITY SDS
Group N Mean SD Median Q1
-ANOVA p-values-
Q3
Min Max
Raw
Ranked
Baseline height velocity
All
Female
Male
15
7.20 6.55
4.62
3.55
6.51
2.68 24.67
5
8.35 9.17
4.79
4.62
4.96
2.68 24.67
10
6.62 5.32
4.22
3.55
6.51
3.10 16.60
0.649
0.560
0.489
0.388
0.547
0.187
0.226
0.096
0.941
0.656
0.636
0.668
Change from 3 months to 1 Year
All
30
-0.76 2.75
-0.83 -2.49
1.66 -7.28
6.13
Female
10
-0.26 2.24
-0.57 -1.68
1.78 -4.28
2.62
Male
20
-1.01 2.99
-0.86 -2.81
0.27 -7.28
6.13
Change from baseline to 1 Year
All
Female
Male
15
5.15 6.07
6.86
2.68
9.49 -8.10 12.35
5
3.75 5.35
5.31
2.69
6.02 -4.79
10
5.85 6.55
7.27
6.50
9.91 -8.10 12.35
9.49
Change from baseline to 3 months
All
14
6.48 5.44
6.89
3.64
8.07 -4.31 16.66
Female
5
4.05 3.19
3.64
2.96
6.87 -0.51
Male
9
7.83 6.10
7.96
6.06 11.21 -4.31 16.66
7.29
First year height velocity (cm/yr)
All
32
12.97 4.60
11.91
9.93 14.59
6.46 26.86
Female
11
13.05 3.91
12.18 10.10 16.37
7.66 19.89
Male
21
12.93 5.02
11.51
9.93 13.63
6.46 26.86
Height velocity first 3 months of GH Rx
All
30
13.63 5.15
12.41 10.54 15.38
6.71 29.82
Female
10
12.98 4.82
12.22
9.56 15.38
7.92 24.16
Male
20
13.95 5.39
12.44 10.72 16.14
6.71 29.82
Humatrope
CT Registry ID#5123
Table 6.
Page 11
Summary of Height Velocity SDS
SUMMARY OF HEIGHT VELOCITY SDS
Q3
-ANOVA p-values-
Min Max
Raw
Ranked
Baseline height velocity SDS
All
12
-1.38 2.64
-2.05 -2.57 -1.20 -3.75
6.56
Female
4
-1.82 1.30
-1.31 -2.59 -1.05 -3.75 -0.92
Male
8
-1.16 3.18
-2.07 -2.57 -1.62 -3.28
0.701
0.523
0.647
0.331
0.610
0.545
6.56
Change from baseline to 1 Year
All
12
6.58 5.03
7.93
3.52
9.12 -5.66 14.25
Female
4
5.58 2.99
5.00
3.13
8.03
Male
8
7.09 5.92
8.39
5.77
9.89 -5.66 14.25
3.10
9.22
First year height velocity SDS
All
31
4.51 2.92
5.04
2.10
6.12 -0.68 12.16
Female
11
4.14 3.17
2.53
2.10
5.50 -0.68
Male
20
4.71 2.83
5.26
2.76
6.24 -0.20 12.16
Humatrope
9.93
CT Registry ID#5123
Page 12
Summary of BMI (kg/m2)
Table 7.
t-test signed
Group N Mean SD Median Q1 Q3 Min Max p-value p-value
Baseline
All
31
16.1 2.4
15.8 14.4 17.5 11.7
21.7
Female
11
15.3 2.2
15.8 13.5 17.3 11.7
18.5
Male
20
16.5 2.5
15.8 14.5 17.6 12.8
21.7
28
15.2 2.1
14.8 13.4 16.2 12.6
20.5
9
14.5 1.7
14.0 13.2 15.3 12.6
17.6
19
15.5 2.2
15.3 13.6 16.5 13.0
20.5
After 1 Year
All
Female
Male
Change from Baseline to 1 Year
All
Female
Male
27
-0.6 1.2
-0.7 -1.5
0.3
-3.3
1.8
0.012
0.014
9
-0.6 1.3
-0.5 -0.9 -0.1
-3.3
1.8
0.252
0.164
18
-0.7 1.2
-0.9 -1.8
-2.5
1.1
0.029
0.038
0.6
Model Effects Baseline After 1 Year Change
ANOVA Comparison (Raw Data)
GENDER
0.190
0.259
0.792
ANOVA Comparison (Ranked Data)
GENDER
Humatrope
0.340
0.276
0.652
CT Registry ID#5123
Table 8.
Page 13
Summary of BMI SDS
Q3
t-test signed
Min Max p-value p-value
Baseline
All
Female
Male
26
-0.43 1.57
-0.26 -1.51
0.68 -4.86
1.92
9
-1.08 1.94
-1.51 -1.60
0.46 -4.86
1.40
17
-0.08 1.26
0.06 -0.91
0.68 -2.95
1.92
23
-0.93 1.30
-0.38 -2.19
0.17 -3.06
1.31
7
-1.30 1.38
-2.03 -2.56 -0.10 -2.62
0.80
16
-0.77 1.28
-0.19 -1.87
0.18 -3.06
1.31
After 1 Year
All
Female
Male
All
Female
Male
22
-0.30 1.06
-0.27 -0.91
0.18 -2.47
2.67
0.205
0.163
7
0.07 1.23
0.03 -0.85
0.09 -1.02
2.67
0.880
0.938
15
-0.47 0.97
-0.44 -1.23
0.28 -2.47
0.97
0.083
0.151
GENDER
0.125
0.381
0.276
GENDER
Humatrope
0.212
0.398
0.708
CT Registry ID#5123
Table 9.
Page 14
Summary of Height
t-test signed
Q3 Min Max p-value p-value
Baseline
All
31
94.0 20.9
92.3 77.0 110.0 56.5 142.4
Female
11
90.3 19.5
87.8 70.5 103.2 64.5 129.4
Male
20
96.1 21.9
93.8 82.1 112.9 56.5 142.4
28
103.4 19.1
102.5 87.2 116.6 74.5 151.7
9
98.2 13.9
101.7 86.0 108.3 77.8 118.0
19
105.8 21.1
103.0 88.4 122.6 74.5 151.7
After 1 Year
All
Female
Male
All
Female
Male
27
11.6
3.5
10.7
9.3
13.3
6.2
22.0
<0.001
<0.001
9
11.9
3.4
12.6
9.8
13.3
6.3
16.3
<0.001
0.004
18
11.4
3.6
10.2
9.3
12.8
6.2
22.0
<0.001
<0.001
GENDER
0.471
0.332
0.702
GENDER
Humatrope
0.300
0.373
0.482
CT Registry ID#5123
Table 10.
Page 15
Summary of Height SDS
Q3
t-test signed
Baseline
All
Female
Male
26
-3.24 0.94
-3.12 -3.74 -2.74 -5.58 -1.21
9
-3.76 1.04
-3.70 -4.36 -3.15 -5.58 -1.99
17
-2.96 0.77
-3.01 -3.48 -2.36 -4.30 -1.21
23
-2.20 0.98
-1.84 -3.22 -1.33 -3.68 -0.86
7
-2.56 1.18
-2.98 -3.48 -0.94 -3.57 -0.86
16
-2.04 0.87
-1.83 -2.77 -1.38 -3.68 -0.92
After 1 Year
All
Female
Male
All
Female
Male
22
1.02 0.56
0.92
0.69
1.20
0.17
2.46
<0.001
<0.001
7
1.25 0.76
1.05
0.88
2.01
0.17
2.46
0.005
0.016
15
0.92 0.43
0.91
0.62
1.13
0.29
1.70
<0.001
<0.001
GENDER
0.035
0.244
0.194
GENDER
Humatrope
0.035
0.328
0.254
CT Registry ID#5123
Table 11.
Page 16
Summary of Weight (kg)
t-test signed
Baseline
All
31
15.0 8.1
13.0 10.1 16.6
4.6
44.1
Female
11
12.7 5.2
12.5
9.0 14.4
5.8
25.3
Male
20
16.3 9.1
14.0 11.3 19.3
4.6
44.1
28
17.1 8.5
15.5 11.8 18.8
7.6
45.4
9
14.1 3.4
14.8 13.0 16.8
8.5
18.3
19
18.6 9.9
16.0 11.0 23.4
7.6
45.4
After 1 Year
All
Female
Male
All
Female
Male
27
2.9 1.4
2.9
2.0
3.8
0.5
6.5
<0.001
<0.001
9
2.8 1.3
2.8
2.4
3.5
0.8
4.9
<0.001
0.004
18
3.0 1.5
3.0
2.0
3.8
0.5
6.5
<0.001
<0.001
GENDER
0.242
0.197
0.804
GENDER
Humatrope
0.246
0.360
0.901
CT Registry ID#5123
Table 12.
Page 17
Summary of Weight SDS
t-test signed
Baseline
All
Female
Male
26
-2.9 2.0
-2.5 -3.8 -1.6
-9.7
0.2
9
-4.0 2.4
-3.6 -4.3 -2.1
-9.7
-1.8
17
-2.3 1.5
-2.1 -3.7 -1.3
-4.6
0.2
23
-2.2 1.4
-2.3 -3.2 -0.8
-4.7
0.2
7
-2.9 1.7
-3.2 -4.4 -0.8
-4.7
-0.2
16
-1.9 1.2
-2.2 -2.8 -0.9
-4.1
0.2
After 1 Year
All
Female
Male
All
Female
Male
22
0.9 1.2
0.8 -0.1
1.3
-0.7
5.0
0.002
<0.001
7
1.5 1.7
1.0
0.7
2.0
-0.3
5.0
0.060
0.031
15
0.6 0.7
0.6 -0.1
1.2
-0.7
1.5
0.008
0.018
GENDER
0.035
0.144
0.076
GENDER
Humatrope
0.070
0.127
0.175
CT Registry ID#5123
Table 13.
Page 18
Summary of IGF-I SDS
Q3
t-test signed
Baseline
All
30
-2.67 2.37
-2.34 -3.62 -1.24 -7.88
0.67
Female
11
-2.23 2.48
-1.92 -2.60
0.25 -7.66
0.67
Male
19
-2.93 2.34
-2.86 -4.00 -1.24 -7.88
0.36
28
-0.72 1.80
-0.91 -1.69
0.77 -4.04
2.51
9
0.03 1.74
0.25 -1.16
0.87 -2.65
2.51
19
-1.08 1.76
-1.25 -2.37
0.66 -4.04
2.40
After 1 Year
All
Female
Male
All
Female
Male
26
2.25 2.09
2.22
1.02
3.35 -1.13
6.26
<0.001
<0.001
9
2.60 1.88
2.03
1.11
2.76
0.76
6.26
0.003
0.004
17
2.07 2.23
2.37
0.17
3.35 -1.13
5.26
0.001
0.002
GENDER
0.444
0.131
0.544
GENDER
Humatrope
0.300
0.181
0.774
CT Registry ID#5123
Table 14.
Page 19
Summary of IGFB-3 SDS
Q3
t-test signed
Baseline
All
Female
Male
25
-1.21 2.11
-0.57 -3.27 -0.14 -5.25
2.11
9
-1.12 2.24
-0.57 -3.34
0.07 -4.47
1.90
16
-1.26 2.10
-0.71 -2.91 -0.16 -5.25
2.11
After 1 Year
All
Female
Male
27
0.25 1.72
0.17 -0.74
1.81 -3.25
2.79
9
0.27 1.88
0.17 -1.64
1.96 -1.95
2.79
18
0.24 1.69
0.23 -0.72
1.63 -3.25
2.52
All
Female
Male
21
1.67 2.01
1.84
0.33
2.71 -1.72
6.27
0.001
<0.001
7
1.59 2.20
1.29
0.33
4.09 -1.72
4.64
0.106
0.109
14
1.71 1.99
2.35
0.01
2.71 -1.32
6.27
0.007
0.007
GENDER
0.878
0.961
0.900
GENDER
Humatrope
0.869
0.881
0.829
CT Registry ID#5123
Table 15.
Page 20
Summary of IGF-I/IGFB-3 Ratio
t-test signed
Q3
Baseline
All
Female
Male
25
31.90 18.10
26.99 21.94 39.53
4.39 78.69
9
38.89 24.78
31.66 23.25 50.84
6.49 78.69
16
27.96 12.27
26.66 20.31 36.72
4.39 48.48
27
44.02 19.90
40.89 25.95 60.59
6.39 92.76
9
50.77 16.95
51.89 36.32 64.98 25.95 74.21
18
40.65 20.84
39.50 24.49 53.43
After 1 Year
All
Female
Male
6.39 92.76
All
Female
Male
21
18.23 18.06
20.10 -0.82 26.92 -6.06 58.85
<0.001
<0.001
7
25.09 17.78
33.32
8.06 37.76 -1.88 45.40
0.010
0.031
14
14.79 17.83
18.94 -1.21 22.63 -6.06 58.85
0.008
0.017
GENDER
0.151
0.220
0.227
GENDER
0.318
0.169
0.213
Safety
Adverse events that occurred during the study are reported in the following tables (Table
16 - Table 23).
Gene Defects
At the time of the study conduction, no gene defects were discovered searching for
mutations related to genes investigated
Humatrope
CT Registry ID#5123
Table 16.
Page 21
Summary of Serious Adverse Events on GH Treated
MedDRA Preferred Te All
rm
Patients
32
5
(15.63%)
Any
1 (3.13%)
Vomiting
1 (3.13%)
Any
2 (6.25%)
Pharyngitis
1 (3.13%)
Pneumonia
1 (3.13%)
Any
1 (3.13%)
MedDRA SOC Term
Number of patients
Patients with >=1 SAE
Injury, poisoning and procedural
complications
Head injury
Any
Hypoglycaemia
Metabolism and nutrition disorders
Table 17.
Summary of Treatment Emergent Adverse Events (TEAEs)
All
Patient has >=1 AE recorded
(Y/N)
N
Y
Humatrope
1 (3.13%)
2 (6.25%)
2 (6.25%)
n
3
2
1
1
2
1
%
100.
0
34.4
65.6
CT Registry ID#5123
Table 18.
Summary of TEAEs by System Organ Class
MedDRA SOC Term
Blood and lymphatic system disorders
Eye disorders
General disorders and administration site
conditions
Page 22
MedDRA Preferred Te
rm
Any
Anaemia
Any
Conjunctivitis
Any
Diarrhoea
Vomiting
Any
All
Patients
1 (3.13%)
1 (3.13%)
1 (3.13%)
1 (3.13%)
2 (6.25%)
1 (3.13%)
1 (3.13%)
2 (6.25%)
Pyrexia
Any
2 (6.25%)
16
(50.00%)
5 (15.63%)
1 (3.13%)
3 (9.38%)
3 (9.38%)
2 (6.25%)
1 (3.13%)
2 (6.25%)
1 (3.13%)
1 (3.13%)
5 (15.63%)
1 (3.13%)
2 (6.25%)
1 (3.13%)
1 (3.13%)
3 (9.38%)
2 (6.25%)
1 (3.13%)
1 (3.13%)
1 (3.13%)
1 (3.13%)
1 (3.13%)
1 (3.13%)
1 (3.13%)
(continued)
Bronchitis
Bronchopneumonia
Ear infection
Gastroenteritis
Influenza
Nasopharyngitis
Pharyngitis
Pneumonia
Tonsillitis
Varicella
Wound infection
Injury, poisoning and procedural complications Any
Head injury
Multiple fractures
Any
Hypoglycaemia
Iron deficiency
Any
Dizziness
Any
Vomiting psychogenic
Respiratory, thoracic and mediastinal disorders Any
Cough
Humatrope
CT Registry ID#5123
Table 18.
Summary of TEAEs by System Organ Class (concluded)
MedDRA SOC Term
Skin and subcutaneous tissue disorders
Table 19.
All
Patients
2 (6.25%)
1 (3.13%)
1 (3.13%)
All
Patients
32
2(
6.25%)
Summary of Treatment-Emergent Specific Medical
Conditions (SMC)
Number of patients
Patients with >=1 SMC (Recurrent otitis
media)
Humatrope
MedDRA Preferred Ter
m
Any
Skin lesion
Urticaria
Summary of Drug Related Treatment-Emergent Specific
Medical Conditions (SMC)
Number of patients
Patients with >=1drug related SMC (Intestinal
disturbances)
Table 20.
Page 23
All
Patients
32
1 (3.13%)
CT Registry ID#5123
Table 21.
Frequencies of TEAE and SMC in Patients by GH Dose
Group
Patient has >=1 AE recorded
(Y/N)
N
Y
Patients with >=1 SMC
N
Y
Patients with >=1 SMC drug
related
N
Y
Table 22.
Page 24
All
n %
GH doses are starting doses
(mg/Kg/wk)
< 0.15
0.15 - < 0.30 0.30 - < 0.45
n %
n
%
n
%
1
1
2
1
3
1
1
34.
4
65.
6
96.
9
3.1
0 0
100.
1 0
100.
1 0
0 0
3
0
2
93.
100.
8
1 0
9
6.3 0 0
0
4
44.4
7
31.8
5
55.6
15
68.2
8
1
88.9
11.1
22
0
100.0
0
100.0 20
0
2
90.9
9.1
Comparison of TEAEs between GH dosage groups
GH doses are starting doses (mg/Kg/wk)
< 0.15
0.15 - < 0.30 0.30 - < 0.45 All
Patient has >=1 AE recorded (
Y/N)
Yes
n
1
All
1
No
Humatrope
%
n
100. 5
0
100. 9
0
4
%
55.6
n
15
n
21
%
65.6
100.0 22
100.0 32
44.4
31.8
100.
0
34.4
7
%
68.2
11
Humatrope
Table 23.
Patient group
Therapy
Diagnosis
Naive
GH treated
Pituitary hypoplasia
Naive
GH treated
Pituitary aplasia
Naive
GH treated
Pituitary aplasia
Naive
GH treated
Classic
Naive
GH treated
Ectopic posterior
pitui
Naive
GH treated
Classic
Listing of Serious Adverse Events (SAE)
Age at SAE,
Age (y) at
Years since
GH Start, GH Rx start,
Years since
Gender,
History of GeNeSIS entry
neoplasia to SAE onset
5.8
6.2
Female
0.44
No
0.44
0.8
Male
No
0.8
Male
No
0.5
Male
No
3.9
Male
No
1.0
0.21
0.21
1.0
0.21
0.21
1.3
0.82
0.82
4.8
0.89
0.89
Actual term,
MedDRA SOC,
MedDRA Preferred Term
MINOR HEAD TRAUMA
Injury, poisoning and procedural
complications
Head injury
VOMITING
Vomiting
HYPOGLYCEMIA
Hypoglycaemia
ACUTE PHARYNGITIS
Pharyngitis
PNEUMONIA
Pneumonia
7.5
Male
No
8.2
0.71
0.71
KETOTIC HYPOGLYCAEMIA
Hypoglycaemia
CT Registry ID#5123
SAE duration
Severity,
Causal,
Relationship
1 Day
Severe
Not related
Seriousness,
Criteria,
Discontinuatio
n
due to AE
Yes
Hospitalization
No
1 Day
Moderate
Not related
1 Day
Moderate
Not related
7 Days
Mild
Not related
10 Days
Severe
Not related
Yes
Hospitalization
No
Yes
Hospitalization
No
Yes
Hospitalization
No
Yes
Hospitalization
No
3 Days
Moderate
Related
Yes
Hospitalization
No
Page 25
CT Registry ID#5123
Page 26
References
(1) Tanner JM, Whitehouse RH, 1976. Archives of Disease in childhood, Vol 51, p 170.
Humatrope
CT Registry ID#5300
Page 1
Summary ID# 5300
Long-term clinical study of LY137998
[somatropin (recombinant DNA origin)] in adults with
growth hormone deficiency
The objective of this multicenter non-controlled study was to investigate the safety of
LY137998 administered for 48 weeks in treatment for adult patients with growth
hormone deficiency (GHD), who had been enrolled in a preceding double-blind placebocontrolled comparative study (for results see CT#2889).
•
The mean dose of LY137998 for all subjects at Week 48 was 0.049
mg/kg/week.
•
86% of the subjects (49/57) had IGF-I concentration values within the
reference range at Week 48.
•
•
Serious adverse events were observed in 2 subjects in the LY/LYgroup (somatropin-/somatropin-treated group) and 1 subject in the
Placebo/LY-group (placebo-/somatropin-treated group).
•
One subject in the LY/LY-group discontinued the study. Adverse
events leading to dose reduction or withdrawal of investigational drug
were observed in 4 subjects in the LY/LY-group and 3 subjects in the
Placebo/LY-group.
•
Common adverse events included nasopharyngitis, pyrexia,
rhinorrhoea and cough, while the most common adverse drug reaction
was arthralgia in both treatment groups.
Somatropin
CT Registry ID#5300
Page 2
•
There was no increased incidence of adverse events or adverse drug
reactions in the LY/LY-group, who received LY137998 for a total of
72 weeks.
•
No subject was discontinued due to laboratory abnormalities.
•
Statistically significant changes in laboratory test parameters were
observed including the increase in Alkaline phosphatase (Al-P), the
increase in phosphorus (P) and the increase in HbA1c during the
present study, but the mean values for each treatment group remained
within the reference range throughout the study period.
•
The change of whole body lean body mass (LBM) was maintained in
the LY/LY-group during the present study, and the increase in whole
body LBM in the Placebo/LY-group was statistically significant
compared with that during the preceding study.
Title of Study:
Long-term clinical study of LY137998 [somatropin (recombinant DNA origin)] in adults with growth
hormone deficiency
Investigator(s): This multicenter study included 23 principal investigators
Study Center(s): This study was conducted at 23 study centers in one country
Date of first subject enrolled: 29 January 2002
Date of last subject completed: 9 October 2003
Objectives:
Primary objective:
The objective of this study was to investigate the safety of LY137998 administered for 48 weeks in
treatment for adult patients with growth hormone deficiency.
(1) Group given LY137998 in the preceding trial (LY/LY-group)
• To confirm that the change in LBM obtained in the preceding trial was maintained with continued
LY137998 therapy
• To confirm that the serum IGF-I concentration was maintained within the normal range with
continued LY137998 therapy
• To confirm that the improvement of QOL obtained in the preceding trial was maintained with
continued LY137998 therapy
(2) Group given placebo in the preceding trial (Placebo/LY-group)
• To compare the change in LBM in the present trial with that in the preceding trial
• To compare the change in serum IGF-I concentration in the present trial with that in the preceding
trial
• To compare the change in QOL in the present trial with that in the preceding trial
Study Design:
This was a multicenter non-controlled study to investigate the safety of an injection containing 6 mg of
LY137998 in adult patients with growth hormone deficiency, conducted following the preceding doubleblind placebo-controlled comparative study
Number of Subjects:
Planned: Not set particularly for this study that entered the subjects of the preceding study.
Enrolled: 31 subjects in LY/LY-group, 29 subjects in Placebo/LY-group among 60 subjects entered (ICD
obtained from 60 subjects)
Somatropin
CT Registry ID#5300
Page 3
Completed: 30 subjects in LY/LY-group, 27 subjects in Placebo/LY-group
Subjects who have completed 12 weeks’ therapy with LY137998 in the preceding trial, undergone tests and
observation at Week 12 in the preceding trial and have received necessary replacement therapy other than
GH in case that the pituitary hormone replacement therapy was needed. Subjects also needed to be judged
eligible for the transfer to the long-term treatment with LY137998 from the safety standpoint by the
investigator or sub investigator and submitted written consent document to participate in the long-term
extension trial
LY137998: An initial dose of 0.021 mg/kg/week was administered subcutaneously in 6-7 divided doses for
8 weeks. The subsequent doses were adjusted appropriately in the range of 0.021 to 0.084 mg/kg/week
based on the serum IGF-I concentration at previous visit.
Reference Therapy, Dose and Mode of Administration: None
Duration of Treatment: 48 weeks
Variables:
Efficacy: Primary: Percentage change in lean body mass, determined by DEXA.
Secondary: Change in serum IGF-I concentrations.
Safety: Frequencies and severities of treatment-emergent adverse events and adverse drug reactions.
Periodic analysis of treatment-emergent adverse events and adverse drug reactions.
Health Outcomes: Changes in quality of life determined by MOS Short-Form 36-Item Health Survey (SF36)
Evaluation Methods:
Statistical: Statistical analyses were conducted principally on the full analysis set. All tests of treatment
effects were conducted at a two-sided significance level of 5% unless otherwise stated. And two-sided
95% confidence intervals were obtained.
Results:
Data sets analyzed
Of the 60 enrolled subjects, 59 subjects and 49 subjects were included in the full analysis
set (FAS) and per protocol set (PPS), respectively. One subject in the Placebo/LY-group
was not included in the FAS since the subject was found to have not met all the inclusion
criteria after enrollment in this study. The following subjects were excluded from the
PPS: one discontinued subject, 2 subjects with treatment noncompliance and one subject
without available LBM observed values at Week 48 in the LY/LY-group (4 subjects in
total), and one discontinued subject, 4 subjects with treatment noncompliance and one
subject without available LBM observed values at Week 48 (6 subjects in total).
Subject Demographics
The primary subject demographics compiled using the FAS are shown in Table 1.
Somatropin
CT Registry ID#5300
Table 1.
Page 4
Overview of Subject Demographics
__________________________________________________________________________________
Item
LY/LY
Placebo/LY
(N=31)
(N=28)
__________________________________________________________________________________
Age
Mean±SD
36.2±13.3
39.6±13.7
------------------------------------------------------------------------------------------18 - 19
2(6.5%)
1(3.6%)
20 - 29
10(32.3%)
8(28.6%)
30 - 39
8(25.8%)
7(25.0%)
40 - 64
11(35.5%)
12(42.9%)
__________________________________________________________________________________
Gender
Male
15(48.4%)
14(50.0%)
Female
16(51.6%)
14(50.0%)
__________________________________________________________________________________
Onset
Adult Onset
12(38.7%)
11(39.3%)
Childhood Onset
19(61.3%)
17(60.7%)
__________________________________________________________________________________
Cause of GHD
Idiopathic
6(19.4%)
9(32.1%)
Pituitary Adenoma
13(41.9%)
7(25.0%)
Therapy for adenoma
9(29.0%)
9(32.1%)
Sheehan's syndrome
1(3.2%)
2(7.1%)
Empty sella
1(3.2%)
1(3.6%)
Trauma
1(3.2%)
0(0.0%)
__________________________________________________________________________________
Hormone Deficiency
Isolated
0(0.0%)
1(3.6%)
Multiple
31(100.0%)
27(96.4%)
__________________________________________________________________________________
Somatropin
CT Registry ID#5300
Page 5
Subject Disposition
The disposition of subjects is shown in Figure 1. The study was planned to be conducted
in 25 study centers. There were 23 study centers that entered a total of 60 subjects in this
study. All enrolled subjects received study treatment. In the LY/LY-group, 30 subjects
completed the study, and one subject discontinued the study due to an adverse event
(Craniopharyngioma). In the Placebo/LY-group, 27 subjects completed the study, one
subject discontinued the study due to the violation of enrollment criteria (the use of
prohibited concomitant medication before the start of the preceding study), and another
subject discontinued the study due to the difficulty in continuous observation (Lost of
Last Visit).
Subjects Acquired Informed Consent(60)
Subjects Excluded from Enrollment(0)
Subjects Enrolled(60)
Subjects Discontinued Before Administration(0)
Subjects Received Medication(60)
LY/LY(31)
Placebo/LY(29)
*1: Subjects discontinued(1)<Adverse event(1)>
*2: Subjects discontinued(2)<Violation of concomitant therapy(1), Difficulty in continuous observation(1)>
Figure 1.
Subject disposition
The reasons for discontinuation are summarized in Table 2 by treatment group. Two
subjects discontinued the study in total, which consisted of one subject in the LY/LYgroup discontinued due to an adverse event (Craniopharyngioma) and another subject in
the Placebo/LY-group discontinued due to the difficulty in continuous observation.
Somatropin
CT Registry ID#5300
Table 2.
Page 6
________________________________________________________________________________
Reason for
LY/LY
Placebo/LY
Total
Discontinuation
(N=31)
(N=28)
(N=59)
________________________________________________________________________________
1(3.6%)
2(3.4%)
1(3.2%)*1
-------------------------------------------------------Adverse event
1(3.2%)
0(0.0%)
1(1.7%)
0(0.0%)
1(3.6%)
1(1.7%)
________________________________________________________________________________
*1 Number of Discontinued Subjects (Discontinuation Rate (%))
Total
Somatropin
CT Registry ID#5300
Page 7
The LBM change during the study period is shown in Table 3 and Table 4. The
distribution of the LBM change rate is presented in Figure 2.
In the LY/LY-group, the mean LBM change rate after administration of LY137998 was
0.1% and 1.2% at 24W LOCF (Last observation carried forward) and 48W LOCF,
respectively. In the Placebo/LY-group, the mean LBM change rate was 3.4% and 4.5% at
24W LOCF and 48W LOCF, respectively. The mean LBM change rates in the present
study were statistically significantly higher compared with that during the placebotreatment period of the preceding study (p=0.009 at 24W LOCF, p=0.001 at 48W LOCF).
Table 3.
Item
LBM
(kg)
Treatment
LY/LY
Summary of LBM Changes
Visit
0w
24w
24w LOCF
48w
48w LOCF
24w %Change*1
48w %Change*2
N
31
28
31
29
31
31
31
Mean
42.18
42.76
42.38
43.16
42.81
0.1
1.2
SD
9.61
10.87
10.55
10.66
10.64
4.68
4.91
Max
62.94
64.00
64.00
66.35
66.35
14.1
12.3
Median
40.19
41.05
39.57
40.64
40.64
0.3
0.5
Min
30.47
28.90
28.90
30.32
28.90
-7.1
-6.5
95% CI
(34.84-48.47)
(33.83-50.90)
(34.96-47.61)
(34.79-49.88)
(34.79-47.47)
(-1.6-1.8)
(-0.6-3.0)
Placebo/LY
0w
28 38.60 9.73
65.55 35.84
26.94 (31.43-44.03)
24w
26 39.95 10.38 66.23 35.79
25.93 (32.26-45.85)
24w LOCF
28 39.89 10.01 66.23 36.43
25.93 (32.26-45.85)
48w
26 40.43 9.55
65.45 37.31
26.2
(33.39-45.52)
48w LOCF
28 40.16 9.47
65.45 37.31
26.2
(31.96-45.52)
24w %Change
28 3.4
4.79
13.8
3.3
-7.3
(1.6-5.3)
48w %Change
28 4.5
5.25
15.9
4.2
-4.3
(2.4-6.5)
*1 = % Change from 0w to 24w LOCF (Last observation carried forward)
*2 = % Change from 0w to 48w LOCF (Last observation carried forward)
95%CI: Confidence interval of the mean for % change; Confidence interval of the median for others.
Somatropin
CT Registry ID#5300
Table 4.
Item
Page 8
LBM Change Rate of P/LY-Group Comparison to Preceding
Study (K01A)
Visit
N
Mean
SD
Max
Median
LBM
(kg)
Min
95%CI
pvalue*1
0.436
pvalue*2
24w LOCF/ 28 -0.6
4.12 9.2
-1.1
-6.5 (-2.2-1.0)
K01A
24w LOCF/ 28 3.4
4.79 13.8 3.3
-7.3 (1.6-5.3) <0.001
0.009
K02A
48w LOCF/ 28 4.5
5.25 15.9 4.2
-4.3 (2.4-6.5) <0.001
0.001
K02A
*1 = Null hypothesis: % Change=0, Paired-t Test
*2 = Null hypothesis: % Change of K01A = % Change of K02A, Paired-t Test
95%CI = Confidence interval of the mean, Abbreviation: LOCF = Last observation carried forward
Figure 2.
Distribution of LBM changes.
The changes of IGF-I and IGF-I SDS during the study period are shown in Table 5.
In the LY/LY-group, the mean values of IGF-I SDS decreased by about 1.6, in Weeks 0 4 and stayed at low levels in Weeks 4 - 8 as all subjects were administrated LY137998 of
0.021 mg/kg/week during Weeks 0 - 8, and then gradually increased until Week 24 as the
dose of LY137998 was adjusted for each subject based on serum IGF-I concentration
after Week 8. The levels of IGF-I became stable in Weeks 24 - 48 with the mean values
ranging from 0.48 to 0.65. The mean values of IGF-I SDS were within the reference
range throughout the study period. The mean change in IGF-I SDS determined using
Somatropin
CT Registry ID#5300
Page 9
LOCF in Week 48 was -0.57. IGF-I SDS in Week 0 ranged from -4.25 to 6.81. IGF-I
SDS in Week 48 ranged from -1.81 to 2.82, and 90% of subjects (27/30) had values
within the reference range.
In the Placebo/LY-group, the mean values of IGF-I SDS increased by about 1.5, in
Weeks 0 - 4 and showed smaller increase in Weeks 4 - 8 as all subjects were
administrated LY137998 of 0.021 mg/kg/week during Weeks 0 - 8, and then gradually
increased during Weeks 8 - 24. Levels of IGF-I became stable in Weeks 24 - 48 with the
mean values of IGF-I SDS ranged from 0.32 to 0.67. The mean values of IGF-I SDS
were within the reference range in Weeks 4 as well as throughout the study period
afterwards. The mean changes in IGF-I SDS were 2.73 and 2.74 at 24W LOCF and 48W
LOCF, respectively. All of the changes in IGF-I and IGF-I SDS in the Placebo/LY-group
were statistically significant (p<0.001), and were statistically significantly larger than the
changes observed during the placebo-treatment period of the preceding study (p<0.001).
Somatropin
CT Registry ID#5300
Table 5.
Page 10
Summary of Changes of IGF-I
______________________________________________________________________________________
Item
Treatment
Visit
N
Mean
SD
Max
Median Min
95%C.I.
______________________________________________________________________________________
IGF-I
LY/LY
0w
31
243
113.6
503
229
33
(193-265)
(ng/mL)
4w
31
148
84.0
368
128
40
(99-156)
8w
31
147
89.2
417
123
46
(100-156)
12w
31
170
80.9
409
158
33
(124-194)
16w
30
184
73.7
297
182
57
(134-249)
20w
30
187
85.6
381
178
41
(133-247)
24w
29
217
71.4
347
198
112
(167-248)
36w
30
203
76.4
352
202
43
(141-262)
48w
30
206
77.4
367
203
80
(146-246)
48wLOCF
31
200
82.2
367
201
33
(146-227)
Change*1 31
-43
111.5
220
-77
-229
(-118-36)
______________________________________________________________________________________
Placebo/LY
0w
28
61
39.1
147
52
9
(29-79)
4w
28
133
82.0
332
103
27
(72-184)
8w
28
140
73.1
305
150
25
(84-182)
12w
28
169
85.6
326
166
48
(90-232)
16w
28
178
86.8
348
177
46
(113-231)
20w
28
181
79.3
341
185
24
(122-234)
24w
27
195
91.6
412
200
18
(151-236)
36w
28
213
90.1
377
229
24
(168-258)
48w
27
191
78.2
343
196
24
(148-244)
48wLOCF
28
191
76.8
343
197
24
(148-244)
Change
28
130
63.3
268
133
0
(84-172)
______________________________________________________________________________________
IGF-I
LY/LY
0w
31
0.82
2.278
6.81
0.98
-4.25
(0.01-1.32)
SDS
4w
31
-0.74
1.945
3.13
-0.93
-6.96
(-1.62-0.12)
8w
31
-0.73
2.041
3.90
-0.84
-6.32
(-1.25--0.10)
12w
31
-0.34
1.999
2.36
-0.13
-7.82
(-0.76-0.38)
16w
30
0.11
1.311
2.26
0.38
-3.45
(-0.37-0.92)
20w
30
0.18
1.555
2.98
0.24
-3.06
(-0.48-1.12)
24w
29
0.65
1.113
2.30
0.44
-1.20
(-0.27-1.48)
36w
30
0.48
1.295
3.23
0.63
-3.00
(-0.32-1.25)
48w
30
0.51
1.247
2.82
0.58
-1.81
(-0.12-1.28)
48wLOCF
31
0.24
1.935
2.82
0.55
-7.82
(-0.12-1.24)
Change
31
-0.57
1.749
2.80
-0.72
-4.45
(-1.45-0.75)
______________________________________________________________________________________
Placebo/LY
0w
28
-2.33
1.418
-0.30
-2.41
-4.92
(-3.53--1.05)
4w
28
-0.81
2.021
2.34
-1.21
-5.21
(-2.32-0.88)
8w
28
-0.59
1.809
3.65
-0.68
-3.96
(-1.63-0.72)
12w
28
-0.12
1.664
2.77
-0.16
-2.78
(-1.65-1.33)
16w
28
0.05
1.561
2.75
0.16
-2.71
(-0.72-1.16)
20w
28
0.07
1.461
2.04
0.55
-3.53
(-0.64-1.06)
24w
27
0.32
1.700
2.51
0.76
-3.81
(-0.11-1.27)
36w
28
0.67
1.647
2.68
0.98
-3.69
(0.10-1.83)
48w
27
0.38
1.667
4.23
0.60
-3.69
(-0.31-1.35)
48wLOCF
28
0.41
1.641
4.23
0.68
-3.69
(-0.31-1.35)
Change
28
2.74
1.341
5.67
2.71
0.00
(2.01-3.30)
______________________________________________________________________________________
95%C.I.: Confidence interval of the median
Somatropin
CT Registry ID#5300
Page 11
The distributions of IGF-I SDS at Week 0 and Week 48 were summarized in Table 6.
In the LY/LY-group, 71% (22/31) of subjects had the values within the reference range at
Week 0 for IGF-I SDS. At Week 48 in the LY/LY-group, 90% (27/30) of subjects had
the values within the reference range for IGF-I SDS. In the Placebo/LY-group, 61%
(17/28) of subjects had values below the reference range at Week 0 for IGF-I SDS.
However, at Week 48 in the Placebo/LY-group, 81% (22/27) of subjects had the values
within the reference range for IGF-I SDS.
Table 6.
Summary of IGF-I SDS Shift
________________________________________________________________
Treatment
SDS
IGF-I SDS
--------------------------------------0w
48w
________________________________________________________________
LY/LY
>+1.96
6
3
Normal
22
27
<-1.96
3
0
________________________________________________________________
Placebo/LY
>+1.96
0
3
Normal
11
22
<-1.96
17
2
________________________________________________________________
Efficacy (LBM and IGF-I) by Subgroup Analyses
Change of LBM by subgroup
The changes of LBM by subgroup were summarized in Table 7.
In the LY/LY-group, LBM increased in childhood onset (CO) subjects (both genders)
while it decreased in adult onset (AO) subjects (both genders) during the study period.
The mean change rate of each subgroup was -0.9% in AO male subjects, -2.3% in AO
female subjects, 4.6% in CO male subjects and 1.0% in CO female subjects. In the
Placebo/LY-group, LBM increased in any of the subgroups to a larger extent in AO
subjects. The mean change rate of each subgroup was 6.4% in AO female subjects, 5.4%
in AO male subjects, 5.3% in CO female subjects and 2.1% in CO male subjects, in
descending order.
Somatropin
CT Registry ID#5300
Table 7.
Page 12
LBM Change Rates by Subgroup
______________________________________________________________________________________
Onset
Gender
LY/LY
Placebo/LY
----------------------------------------------------------------------------------------N
Mean
N
Mean
______________________________________________________________________________________
AO
Male
4
-0.9
4
5.4
Female
8
-2.3
7
6.4
Male + Female
12
-1.9
11
6.1
______________________________________________________________________________________
CO
Male
11
4.6
10
2.1
Female
8
1.0
7
5.3
Male + Female
19
3.1
17
3.4
______________________________________________________________________________________
Change of IGF-I by subgroup
The changes of IGF-I SDS by subgroup were summarized in Table 8.
In the LY/LY-group, serum IGF-I concentration decreased in AO subjects as the dose of
LY137998 was adjusted for each subject based on serum IGF-I concentration, with the
larger degree of the decrease observed in AO male subjects (-2.07 as mean IGF-I SDS
change). Serum IGF-I concentration in CO subjects was stable. In the Placebo/LYgroup, serum IGF-I concentration increased in any of the subgroups, with the mean IGF-I
SDS changes having ranged from 2.42 to 2.95.
Table 8.
Summary of IGF-I SDS Changes by Subgroup
______________________________________________________________________________________
Onset
Gender
LY/LY
Placebo/LY
----------------------------------------------------------------------------------------N
Mean
N
Mean
______________________________________________________________________________________
AO
Male
4
-2.07
4
2.57
Female
8
-1.13
7
2.95
Male + Female
12
-1.44
11
2.81
______________________________________________________________________________________
CO
Male
11
0.27
10
2.88
Female
8
-0.43
7
2.42
Male + Female
19
-0.02
17
2.69
______________________________________________________________________________________
Somatropin
CT Registry ID#5300
Page 13
The distributions of IGF-I SDS by subgroup at Week 0 and Week 48 were summarized in
Table 9.
In the LY/LY-group, the shifts from values above the reference range to within the
reference range were observed in 2 AO male subjects and 1 AO female subject (3
subjects in total). The shifts from values below the reference range to within the reference
range were observed in 1 CO male subject and 1 CO female subject (2 subjects in total).
In the Placebo/LY-group, the shifts from values below the reference range to within the
reference range were observed in 3 AO female subjects, 6 CO male subjects and 5 CO
female subjects (14 subjects in total). The shifts from within the reference range to above
the reference range were observed in 2 AO male subjects and 1 AO female subject (3
subjects in total).
Table 9.
Summary of IGF-I SDS Shift by Subgroup
______________________________________________________________________________________
Treatment
SDS
AO-Male
AO-Female
CO-Male
CO-Female
----------------- ----------------- -------------------------------0w
48w
0w
48w
0w
48w
0w
48w
______________________________________________________________________________________
LY/LY
>+1.96 4
2
2
1
0
0
0
0
Normal 0
2
6
7
10
11
6
7
<-1.96 0
0
0
0
1
0
2
0
______________________________________________________________________________________
Placebo/LY
>+1.96 0
2
0
1
0
0
0
0
Normal 4
2
4
6
3
9
0
5
<-1.96 0
0
3
0
7
0
7
2
______________________________________________________________________________________
Somatropin
CT Registry ID#5300
Page 14
Safety
were no deaths of any subjects in either treatment group. Serious adverse events, other
than death, were observed in 1 subject in the Placebo/LY-group and 2 subjects in the
LY/LY-group. Of them, one subject in the LY/LY-group discontinued the study. No
adverse event other than serious ones led to discontinuation of the study. Adverse events
resulting in reduction of the prescribed dose occurred in 3 subjects in the Placebo/LYgroup and 4 subjects in the LY/LY-group. Also, dose reduction due to an adverse event
carried over from the preceding study occurred in one subject in the LY/LY-group. A
total of 214 and 266 adverse events were observed in 92.9% of subjects (26/28) in the
Placebo/LY-group and 96.8% of subjects (30/31) in the LY/LY-group, respectively. A
total of 27 and 31 adverse drug reactions were observed in 53.6% of subjects (15/28) in
the Placebo/LY-group and 48.4% of subjects (15/31) in the LY/LY-group, respectively.
In the LY/LY-group for a total of 72 weeks including the preceding study, there were no
deaths of any subjects. Serious adverse events other than death were observed in 2
subjects. No adverse event other than serious ones led to discontinuation of the study.
Adverse events resulting in reduction of the prescribed dose occurred in 9 subjects. A
total of 434 adverse events were observed in 100% of subjects (31/31). A total of 67
adverse drug reactions were observed in 64.5% of subjects (15/28).
Table 10.
Overview of Adverse Events Number and Percentage of
Subjects
______________________________________________________________________________________
K02A(48w)
K01A+K02A(72w)
-----------------------Placebo/LY
LY/LY
LY/LY
Adverse Event
(N=28)
(N=31)
(N=31)
______________________________________________________________________________________
Deaths
0
(0.0%)
0
(0.0%)
0
(0.0%)
1,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
Discontinuations due to
an adverse event
0,0 (0.0%)
0,0 (0.0%)
0,0 (0.0%)
Dose reductions due to
an adverse event
3,3 (10.7%)
4,4 (12.9%)
9,9 (29.0%)
Treatment-emergent Adverse Events
214,26 (92.9%) 266,30 (96.8%)
434,31 (100.0%)
Adverse reactions
27,15 (53.6%) 31,15 (48.4%)
67,20 (64.5%)
______________________________________________________________________________________
* Number of AEs, Number of Subjects with AE (Occurred Rate(%))
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CT Registry ID#5300
Page 15
Deaths
There were no deaths of any subjects during this study.
Other serious adverse events
Other serious adverse events were observed in 3 subjects. In the LY/LY-group, one
event each of vertigo and craniopharyngioma were reported. In the Placebo/LY-group,
one event of depression was reported.
The causal relationship of the vertigo and depression with administration of the
investigational drug was not considered by the investigator to be related. The causal
relationship of the craniopharyngioma was judged as unknown.
Clinically significant adverse events
Other significant adverse events in this study included adverse events leading to
discontinuation of the study and adverse events leading to reduction of specified dose
(including withdrawal of investigational drug).
Other significant adverse events were observed in 5 subjects in the LY/LY-group and in 3
subjects in the Placebo/LY-group. Of those 8 subjects, 2 subjects belonged to CO
subgroup and the other 6 subjects belonged to AO subgroup.
The causal relationship of the nasopharyngitis was not considered by the investigator to
be related. The causal relationship of the arthralgia, oedema peripheral, oedema NOS (not
otherwise specified) and musculoskeletal stiffness was related. The causal relationship of
the hypertension NOS and arthralgia was judged as unknown.
Adverse Events
Adverse events occurring in ≥5% (2 subjects or more) after the administration of
LY137998 are shown in Table 11. The most common adverse event in the Placebo/LYgroup was nasopharyngitis (39.3%), followed by cough (35.7%), pyrexia (28.6%),
rhinorrhoea (25.0%), arthralgia (21.4%) and headache (21.4%). The most common
adverse event in the LY/LY-group during the present study was nasopharyngitis (61.3%),
followed by pyrexia (38.7%), rhinorrhoea (32.3%), arthralgia (25.8%), headache
(25.8%), pharyngolaryngeal pain (19.4%) and cough (19.4%). The most common adverse
event in the LY/LY-group for a total of 72 weeks including the preceding study was
nasopharyngitis (74.2%), followed by pyrexia (48.4%), rhinorrhoea (45.2%), cough
(38.7%), arthralgia (35.5%), headache (32.3%), pharyngolaryngeal pain (32.3%), upper
respiratory tract inflammation (22.6%), malaise (22.6%).
Frequent adverse events in the Placebo/LY-group by MedDRA System Organ Class
(SOC) were “Respiratory, thoracic and mediastinal disorders” (71.4%), “General
disorders and administration site conditions” (64.3%), “Musculoskeletal and connective
tissue disorders” (39.3%) and “Gastrointestinal disorders” (39.3%) in descending order of
incidence. Frequent adverse events in the LY/LY-group during the present study by
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CT Registry ID#5300
Page 16
MedDRA SOC were “Respiratory, thoracic and mediastinal disorders” (74.2%),
“General disorders and administration site conditions” (51.6%), “Nervous system
disorders” (48.4%) and “Musculoskeletal and connective tissue disorders” (41.9%) in
descending order of incidence. Frequent adverse events in the LY/LY-group for a total of
72 weeks including the preceding study by MedDRA SOC were “Respiratory, thoracic
and mediastinal disorders” (83.9%), “General disorders and administration site
conditions” (80.6%), “Musculoskeletal and connective tissue disorders” (54.8%) and
“Nervous system disorders” (54.8%) in descending order of incidence.
Adverse events by subgroup
As for oedema NOS, arthralgia and “musculoskeletal and connective tissue disorders”,
each incidence in AO subjects was higher than that in CO subjects in the LY137998group of the preceding study. In the present study, oedema NOS was observed only in
Placebo/LY-group (AO: 9.1%, CO: 5.9%). As for arthralgia, the incidence of arthralgia
was higher in AO subjects of the LY/LY-group (AO: 41.7%, CO: 15.8%), while that was
higher in CO subjects of the Placebo/LY-group (AO: 9.1%, CO: 29.4%). The incidence
of “musculoskeletal and connective tissue disorders” was higher in AO subjects of the
LY/LY-group (AO: 66.7%, CO: 26.8%), while that was higher in CO subjects of the
Placebo/LY-group (AO: 36.4%, CO: 41.2%).
Somatropin
CT Registry ID#5300
Table 11.
Page 17
Treatment-Emergent Adverse Events Occurring in ≥5%
______________________________________________________________________________________
K02A(48w)
K01A+K02A(72w)
MedDRA SOC, PT
----------------------------------------Placebo/LY
LY/LY
LY/LY
(N=28)
(N=31)
(N=31)
______________________________________________________________________________________
Eye disorders
9,7 (25.0%)
5,4 (12.9%)
10,6 (19.4%)
Conjunctivitis
1,1 (3.6%)
1,1 (3.2%)
2,2 (6.5%)
Asthenopia
2,2 (7.1%)
0,0 (0.0%)
0,0 (0.0%)
--------------------------------------------------------------------------------------Gastrointestinal disorders
23,11 (39.3%) 22,11 (35.5%)
40,14 (45.2%)
Vomiting NOS
5,4 (14.3%)
3,3 (9.7%)
4,4 (12.9%)
Diarrhoea NOS
6,4 (14.3%)
3,2 (6.5%)
6,4 (12.9%)
Nausea
1,1 (3.6%)
2,2 (6.5%)
5,5 (16.1%)
Abdominal discomfort
0,0 (0.0%)
2,2 (6.5%)
3,3 (9.7%)
Abdominal pain NOS
0,0 (0.0%)
2,2 (6.5%)
3,3 (9.7%)
Dyspepsia
0,0 (0.0%)
2,2 (6.5%)
3,3 (9.7%)
Gastroenteritis NOS
1,1 (3.6%)
2,1 (3.2%)
3,2 (6.5%)
Abdominal pain upper
4,3 (10.7%)
1,1 (3.2%)
2,2 (6.5%)
Constipation
2,2 (7.1%)
1,1 (3.2%)
3,3 (9.7%)
--------------------------------------------------------------------------------------General disorders and
administration site conditions
29,18 (64.3%) 34,16 (51.6%)
59,25 (80.6%)
Pyrexia
13,8 (28.6%)
13,12 (38.7%)
22,15 (48.4%)
Malaise
2,2 (7.1%)
6,4 (12.9%)
9,7 (22.6%)
Fall
0,0 (0.0%)
4,3 (9.7%)
4,3 (9.7%)
Rigors
0,0 (0.0%)
2,2 (6.5%)
2,2 (6.5%)
Chest pain
1,1 (3.6%)
2,1 (3.2%)
3,2 (6.5%)
Fatigue
3,3 (10.7%)
1,1 (3.2%)
2,2 (6.5%)
Oedema peripheral
3,3 (10.7%)
1,1 (3.2%)
1,1 (3.2%)
Injection site pain
1,1 (3.6%)
1,1 (3.2%)
3,2 (6.5%)
Feeling cold
0,0 (0.0%)
1,1 (3.2%)
2,2 (6.5%)
Oedema NOS
3,2 (7.1%)
0,0 (0.0%)
3,3 (9.7%)
Injection site pruritus
0,0 (0.0%)
0,0 (0.0%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Hepatobiliary disorders
1,1 (3.6%)
2,2 (6.5%)
3,3 (9.7%)
Hepatic function abnormal NOS 0,0 (0.0%)
2,2 (6.5%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Immune system disorders
2,2 (7.1%)
2,2 (6.5%)
5,4 (12.9%)
Seasonal allergy
2,2 (7.1%)
2,2 (6.5%)
5,4 (12.9%)
--------------------------------------------------------------------------------------Infections and infestations
7,7 (25.0%)
5,5 (16.1%)
12,8 (25.8%)
Tooth caries NOS
0,0 (0.0%)
2,2 (6.5%)
4,4 (12.9%)
Vaginal candidiasis
2,2 (7.1%)
0,0 (0.0%)
0,0 (0.0%)
--------------------------------------------------------------------------------------Injury, poisoning and procedural
complications
3,3 (10.7%)
8,6 (19.4%)
9,6 (19.4%)
Joint sprain
1,1 (3.6%)
3,3 (9.7%)
3,3 (9.7%)
--------------------------------------------------------------------------------------Investigations
9,4 (14.3%)
13,8 (25.8%)
20,12 (38.7%)
Sputum increased
4,3 (10.7%)
3,3 (9.7%)
4,4 (12.9%)
White blood cell count
increased
0,0 (0.0%)
2,2 (6.5%)
2,2 (6.5%)
Weight increased
0,0 (0.0%)
0,0 (0.0%)
2,2 (6.5%)
0,0 (0.0%)
5,4 (12.9%)
10,8 (25.8%)
Anorexia
0,0 (0.0%)
3,3 (9.7%)
4,4 (12.9%)
0,0 (0.0%)
0,0 (0.0%)
2,2 (6.5%)
---------------------------------------------------------------------------------------
(continued)
Somatropin
CT Registry ID#5300
Table 11.
Page 18
Treatment-Emergent Adverse Events Occurring in ≥5%
(concluded)
______________________________________________________________________________________
K02A(48w)
K01A+K02A(72w)
MedDRA SOC, PT
----------------------------------------Placebo/LY
LY/LY
LY/LY
(N=28)
(N=31)
(N=31)
______________________________________________________________________________________
Musculoskeletal and connective
tissue disorders
23,11 (39.3%) 23,13 (41.9%)
38,17 (54.8%)
Arthralgia
8,6 (21.4%)
10,8 (25.8%)
16,11 (35.5%)
Back pain
6,4 (14.3%)
4,4 (12.9%)
6,5 (16.1%)
Peripheral swelling
0,0 (0.0%)
3,3 (9.7%)
4,3 (9.7%)
Myalgia
1,1 (3.6%)
2,2 (6.5%)
4,4 (12.9%)
Musculoskeletal stiffness
2,2 (7.1%)
1,1 (3.2%)
2,2 (6.5%)
Muscle stiffness
1,1 (3.6%)
1,1 (3.2%)
2,2 (6.5%)
Pain in limb
1,1 (3.6%)
1,1 (3.2%)
3,2 (6.5%)
--------------------------------------------------------------------------------------Nervous system disorders
16,8 (28.6%)
35,15 (48.4%)
48,17 (54.8%)
Headache
12,6 (21.4%)
22,8 (25.8%)
29,10 (32.3%)
Dizziness
1,1 (3.6%)
7,5 (16.1%)
8,5 (16.1%)
Hypoaesthesia
2,2 (7.1%)
3,2 (6.5%)
6,5 (16.1%)
Somnolence
0,0 (0.0%)
1,1 (3.2%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Psychiatric disorders
2,2 (7.1%)
2,2 (6.5%)
2,2 (6.5%)
Insomnia
1,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Respiratory, thoracic and
mediastinal disorders
72,20 (71.4%) 82,23 (74.2%)
138,26 (83.9%)
Nasopharyngitis
22,11 (39.3%) 36,19 (61.3%)
54,23 (74.2%)
Rhinorrhoea
10,7 (25.0%)
16,10 (32.3%)
24,14 (45.2%)
6,4 (14.3%)
8,6 (19.4%)
16,10 (32.3%)
Cough
15,10 (35.7%)
7,6 (19.4%)
16,12 (38.7%)
Upper respiratory tract
inflammation
5,3 (10.7%)
6,3 (9.7%)
14,7 (22.6%)
Sneezing
1,1 (3.6%)
3,3 (9.7%)
3,3 (9.7%)
Pharyngitis
6,3 (10.7%)
2,2 (6.5%)
2,2 (6.5%)
Hyperventilation
0,0 (0.0%)
1,1 (3.2%)
2,2 (6.5%)
Laryngeal pain
0,0 (0.0%)
1,1 (3.2%)
2,2 (6.5%)
Rhinitis NOS
3,2 (7.1%)
0,0 (0.0%)
0,0 (0.0%)
--------------------------------------------------------------------------------------Skin and subcutaneous tissue
disorders
10,7 (25.0%)
15,8 (25.8%)
25,14 (45.2%)
Rash NOS
1,1 (3.6%)
4,2 (6.5%)
7,4 (12.9%)
Contusion
1,1 (3.6%)
3,2 (6.5%)
3,2 (6.5%)
Pruritus
3,3 (10.7%)
2,2 (6.5%)
3,3 (9.7%)
Eczema
2,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
Urticaria NOS
0,0 (0.0%)
1,1 (3.2%)
3,2 (6.5%)
--------------------------------------------------------------------------------------Vascular disorders
1,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
Hypertension NOS
1,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
______________________________________________________________________________________
Adverse drug reactions occurring in ≥5% (2 subjects or more) after the administration of
LY137998 are shown in Table 12. Adverse drug reactions occurring in ≥ 5% in the
Placebo/LY-group included arthralgia (10.7%), oedema peripheral (7.1%) and oedema
NOS (7.1%). Adverse drug reactions occurring in ≥ 5% in the LY/LY-group during the
present study included arthralgia (12.9%), back pain (9.7%), peripheral swelling (9.7%),
hypoaesthesia (6.5%), insomnia (6.5%) and hypertension NOS (6.5%). During the total
Somatropin
CT Registry ID#5300
Page 19
treatment period of Week 0-72 in the LY/LY-group, adverse drug reaction occurring in ≥
5% were arthralgia (19.4%), hypoaesthesia (12.9%), oedema NOS (9.7%), back pain
(9.7%), peripheral swelling (9.7%), headache (9.7%), weight increased (6.5%), appetite
increased NOS (6.5%), musculoskeletal stiffness (6.5%), pain in limb (6.5%), myalgia
(6.5%) insomnia (6.5%) and hypertension NOS (6.5%). The most common adverse drug
reactions were arthralgia in the both treatment groups during the present study.
Adverse drug reactions occurring in ≥ 5% in the Placebo/LY-group by MedDRA SOC
were “General disorders and administration site conditions” (21.4%), “Musculoskeletal
and connective tissue disorders” (17.9%) and “Nervous system disorders” (10.7%) in
descending order of incidence. Adverse events occurring in ≥ 5% in the LY/LY-group
during the present study by MedDRA SOC were “Musculoskeletal and connective tissue
disorders” (25.8%) and “General disorders and administration site conditions” (9.7%) in
descending order of incidence. Adverse events occurring in ≥ 5% in the LY/LY-group for
a total of 72 weeks including the preceding study by MedDRA SOC were
“Musculoskeletal and connective tissue disorders” (38.7%), “General disorders and
administration site conditions” (22.6%) and “Nervous system disorders” (19.4%) in
descending order of incidence.
Adverse Drug Reactions by subgroup
As for oedema NOS and “musculoskeletal and connective tissue disorders”, each
incidence in AO was higher than that in CO subjects in the LY137998-group of the
preceding study. In the present study, oedema NOS was observed only in Placebo/LYgroup (AO: 9.1%, CO: 5.9%). The incidence of “musculoskeletal and connective tissue
disorders” was higher in AO subjects of the LY/LY-group (AO: 33.3%, CO: 21.1%),
while there was little difference of incidence between AO subjects and CO subjects of the
Placebo/LY-group (AO: 18.2%, CO: 17.6%).
Somatropin
CT Registry ID#5300
Table 12.
Page 20
Adverse Drug Reactions Occurring in ≥5%
______________________________________________________________________________________
K02A(48w)
K01A+K02A(72w)
---------------------------------------Placebo/LY
LY/LY
LY/LY
(N=28)
(N=31)
(N=31)
______________________________________________________________________________________
MedDRA SOC, PT
General disorders and administration
site conditions
8,6 (21.4%)
3,3 (9.7%)
11,7 (22.6%)
Oedema peripheral
2,2 (7.1%)
1,1 (3.2%)
1,1 (3.2%)
Oedema NOS
3,2 (7.1%)
0,0 (0.0%)
3,3 (9.7%)
--------------------------------------------------------------------------------------Investigations
2,1 (3.6%)
2,1 (3.2%)
8,4 (12.9%)
Weight increased
0,0 (0.0%)
0,0 (0.0%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Metabolism and nutrition disorders
0,0 (0.0%)
1,1 (3.2%)
4,4 (12.9%)
0,0 (0.0%)
0,0 (0.0%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Musculoskeletal and connective
tissue disorders
7,5 (17.9%)
13,8 (25.8%)
21,12 (38.7%)
Arthralgia
4,3 (10.7%)
5,4 (12.9%)
7,6 (19.4%)
Back pain
0,0 (0.0%)
3,3 (9.7%)
3,3 (9.7%)
Peripheral swelling
0,0 (0.0%)
3,3 (9.7%)
4,3 (9.7%)
Musculoskeletal stiffness
1,1 (3.6%)
1,1 (3.2%)
2,2 (6.5%)
Pain in limb
0,0 (0.0%)
1,1 (3.2%)
3,2 (6.5%)
Myalgia
1,1 (3.6%)
0,0 (0.0%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Nervous system disorders
3,3 (10.7%)
3,2 (6.5%)
8,6 (19.4%)
Hypoaesthesia
1,1 (3.6%)
3,2 (6.5%)
5,4 (12.9%)
Headache
1,1 (3.6%)
0,0 (0.0%)
3,3 (9.7%)
--------------------------------------------------------------------------------------Psychiatric disorders
0,0 (0.0%)
2,2 (6.5%)
2,2 (6.5%)
Insomnia
0,0 (0.0%)
2,2 (6.5%)
2,2 (6.5%)
--------------------------------------------------------------------------------------Vascular disorders
1,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
Hypertension NOS
1,1 (3.6%)
2,2 (6.5%)
2,2 (6.5%)
______________________________________________________________________________________
* Number of ADRs, Number of Subjects with ADR (Occurred Rate(%))
Periodic Analysis of Adverse Events
The time courses of adverse event-experienced subjects and overall adverse events for
each 4 weeks after administration of LY137998 are presented in Figs. 3 and 4. In the
LY/LY-group, the numbers of subjects with adverse events (the number of events)
ranged 10 - 15 subjects (18 - 39 events) during the preceding study and 9 - 17 subjects
(16 - 31 events) during the present study. In the Placebo/LY-group, the numbers of
subjects with adverse events (the number of events) ranged 6 - 14 subjects (10 - 26
events).
Somatropin
CT Registry ID#5300
Page 21
Figure 3.
Time-course of adverse events experienced subjects.
Figure 4.
Time-course of overall adverse events.
The time courses of adverse drug reactions-experienced subjects and overall adverse drug
reactions for each 4 weeks after administration of LY137998 are presented in Figs. 5 and
6. In the LY/LY-group, the numbers of subjects with adverse drug reactions (the number
of events) ranged 1 - 7 subjects (2 - 14 events) during the preceding study and 1 - 4
subjects (1 - 5 events) during the present study. In the LY/LY-group, the incidence of
adverse drug reactions didn’t show a peak during the present study while it showed a
peak at an early period (Week 4-8) in the preceding study that contained the followings:
In the Placebo/LY-group, the numbers of subjects with adverse drug reactions (the
number of events) ranged 0 - 3 subjects (0 - 6 events) during the present study and didn’t
show a peak after administration of LY137998.
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Page 22
Figure 5.
Time-course of adverse drug reactions experienced
subjects.
Figure 6.
Time-course of overall adverse drug reactions.
For the LY/LY-group, statistically significant changes in laboratory test values from
baseline after LY137998 administration for 72 weeks including the preceding study are
shown in Table 13. For the Placebo/LY-group, statistically significant changes in
laboratory test values from baseline after LY137998 administration for 48 weeks during
the present study are shown in Table 14.
In the LY/LY-group, the changes in 11 laboratory test parameters were statistically
significant. For all of the 11 laboratory test parameters, the mean values by 48 weeks
LOCF in the present study were within the respective reference ranges.
In the Placebo/LY-group, the changes in 11 laboratory test parameters and LDL/HDL
were statistically significant. For all of the 11 laboratory test parameters, the mean values
by 48 weeks LOCF in the present study were within the respective reference ranges.
Somatropin
CT Registry ID#5300
Table 13.
Page 23
Statistically Significant Changes of Laboratories in LY/LYGroup
______________________________________________________________________________________
Item
Normal Range
Mean
p value
Mean
(Change)
(within)
(48w LOCF)
______________________________________________________________________________________
RBC(x10000/uL)
376-577
-10
0.040
442
WBC(/uL)
3500-9700
-636
0.046
6404
AST(GOT)(U/L)
10-40
-9
0.016
29
ALT(GPT)(U/L)
5-45
-14
0.008
29
LDH(U/L)
220-430
-35
0.001
366
Al-P(U/L)
104-338
34
0.018
263
γ-GTP(U/L)
16-73
-22
<0.001
41
Albumin(g/dL)
3.7-5.5
-0.2
0.002
4.3
P(mg/dL)
2.5-4.5
0.5
<0.001
4.1
HbA1c(%)
4.3-5.8
0.2
<0.001
4.8
FT4(ng/dL)
0.8-1.7
-0.2
0.038
1.3
______________________________________________________________________________________
p value: Wilcoxon test
Abbreviations: LOCF = Last observation carried forward, RBC = Red blood cell, WBC = White blood cell,
AST(GOT) = Aspartate aminotransferase (Glutamate oxaloacetate transaminase), ALT(GPT) = Alanine
aminotransferase (Glutamate pyruvate transaminase), LDH = Lactate dehydrogenase, Al-P = Alkaline
phosphatase, γ-GTP = Gamma-Glutamyl transpeptidase, P = Phosphorus, HbA1c = Haemoglobin A1c,
FT4 = Free thyroxine
Table 14.
Statistically Significant Changes of Laboratories in
Placebo/LY-Group
______________________________________________________________________________________
Item
Normal Range
Mean
p value
Mean
(Change)
(within)
(48w LOCF)
______________________________________________________________________________________
Al-P(U/L)
104-338
29
0.002
245
γ -GTP(U/L)
16-73
-7
0.007
26
Total Protein(g/dL)
6.5-8.2
-0.2
0.049
7.0
Albumin(g/dL)
3.7-5.5
-0.2
0.002
4.3
Triglyceride(mg/dL)
50-149
-32
0.047
125
HDL(mg/dL)
41-90
4
0.004
61
LDL(mg/dL)
70-139
-11
0.032
116
LDL/HDL
-0.39
<0.001
2.26
BUN(mg/dL)
8.0-20.0
-1.6
0.016
12.4
Creatinine(mg/dL)
0.6-1.3
-0.1
<0.001
0.9
P(mg/dL)
2.5-4.5
0.5
0.002
4.1
HbA1c(%)
4.3-5.8
0.2
<0.001
4.7
______________________________________________________________________________________
p value: Wilcoxon test
Abbreviations: LOCF = Last observation carried forward, Al-P = Alkaline phosphatase, γ-GTP = GammaGlutamyl transpeptidase, HDL = High density lipoprotein cholesterol, LDL = Low density lipoprotein
cholesterol, LDL/HDL = High density lipoprotein cholesterol/ Low density lipoprotein cholesterol ratio,
BUN = Blood urea nitrogen, P = Phosphorus, HbA1c = Haemoglobin A1c
Somatropin
CT Registry ID#5300
Page 24
Health Outcomes (Quality of Life Evaluation)
SF-36
The QOL (SF-36) changes during the present study are shown in Table 15.
In the LY/LY-group at Week 24, the mean scores increased for 6 items and decreased for
2 items. At 48W LOCF, the mean scores increased for 5 items and decreased for 3 items.
Of the 6 items that the mean scores increased in Week 0 - 24, the mean scores of 5 items
further increased in Week 24 - 48 with the mean change of 5.0 points for “Rolephysical,” 3.0 point for “Vitality,” 1.6 points for “Role-emotional,” 0.7 points for
“General health” and 0.2 point for “Physical functioning” at 48W LOCF. The mean
score of “Mental health” increased in Week 0 - 24, and decreased in Week 24 - 48 with
the mean change of -3.7 points at 48W LOCF. The mean score of “Social functioning”
decreased in Week 0 - 24 and decreased even more in Week 24 - 48 with the mean
change of -8.1 points at 48W LOCF. The mean score of “Bodily pain” decreased in
Week 0 - 24 and further decreased in Week 24 - 48 with the mean change of -2.2 points
at 48W LOCF.
Somatropin
CT Registry ID#5300
Table 15.
Page 25
Summary of QOL (SF36) Changes
______________________________________________________________________________________
Item
Treatment
Visit
N
Mean
SD
Max
Median Min
95%C.I.
______________________________________________________________________________________
PF
LY/LY
0w
30
89.0
16.26
100.0
95.0
40.0
(90.0-95.0)
24w
29
89.3
20.43
100.0
95.0
5.0
(90.0-100.0)
48w
29
90.2
17.03
100.0
95.0
35.0
(90.0-100.0)
48w LOCF
31 89.2
17.66
100.0
95.0
35.0
(90.0-100.0)
Change*1
30
0.2
7.48
15.0
0.0
-25.0
(0.0-5.0)
______________________________________________________________________________________
Placebo/LY
0w
28
88.6
11.73
100.0
95.0
60.0
(85.0-95.0)
24w
27
88.6
12.11
100.0
95.0
50.0
(85.0-95.0)
48w
27
87.8
13.54
100.0
95.0
55.0
(85.0-95.0)
48w LOCF
28 87.9
13.29
100.0
95.0
55.0
(85.0-95.0)
Change
28
-0.8
8.17
10.0
0.0
-30.0
(0.0-0.0)
______________________________________________________________________________________
RP
LY/LY
0w
31
78.8
26.65
100.0
87.5
0.0
(68.8-100.0)
24w
29
82.1
28.33
100.0
93.8
0.0
(81.3-100.0)
48w
30
84.8
21.88
100.0
96.9
0.0
(75.0-100.0)
48w LOCF
31 83.9
22.11
100.0
93.8
0.0
(75.0-100.0)
Change
31
5.0
20.12
43.8
0.0
-37.5
(0.0-6.3)
______________________________________________________________________________________
Placebo/LY
0w
28
81.2
22.80
100.0
87.5
12.5
(66.7-100.0)
24w
27
83.1
20.93
100.0
93.8
31.3
(75.0-100.0)
48w
27
78.7
27.80
100.0
93.8
18.8
(62.5-100.0)
48w LOCF
28 79.5
27.58
100.0
93.8
18.8
(62.5-100.0)
Change
28
-1.7
16.90
43.8
0.0
-37.5
(-4.2-6.3)
______________________________________________________________________________________
BP
LY/LY
0w
31
74.9
23.59
100.0
74.0
22.0
(61.0-100.0)
24w
29
73.5
26.50
100.0
80.0
10.0
(62.0-100.0)
48w
30
72.8
22.51
100.0
74.0
22.0
(61.0-84.0)
48w LOCF
31 72.7
22.14
100.0
74.0
22.0
(62.0-84.0)
Change
31
-2.2
20.49
59.0
0.0
-38.0
(-11.0-0.0)
______________________________________________________________________________________
Placebo/LY
0w
28
78.2
22.11
100.0
84.0
31.0
(72.0-100.0)
24w
27
74.7
20.09
100.0
74.0
12.0
(62.0-84.0)
48w
27
72.8
24.92
100.0
72.0
22.0
(52.0-100.0)
48w LOCF
28 73.8
24.99
100.0
73.0
22.0
(52.0-100.0)
Change
28
-4.4
26.42
68.0
0.0
-68.0
(-18.0-11.0)
______________________________________________________________________________________
GH
LY/LY
0w
31
58.3
21.12
92.0
57.0
10.0
(52.0-72.0)
24w
28
59.5
23.43
82.0
67.0
5.0
(50.0-77.0)
48w
28
60.6
23.50
100.0
59.5
10.0
(47.0-80.0)
48w LOCF
31 59.0
22.98
100.0
57.0
10.0
(47.0-77.0)
Change
31
0.7
15.90
38.0
0.0
-32.0
(-5.0-8.0)
______________________________________________________________________________________
Placebo/LY
0w
28
57.6
17.20
97.0
57.0
22.0
(45.0-67.0)
24w
27
57.5
16.46
87.0
57.0
25.0
(47.0-72.0)
48w
27
57.4
19.85
100.0
55.0
25.0
(45.0-67.0)
48w LOCF
28 57.4
19.48
100.0
56.0
25.0
(45.0-67.0)
Change
28
-0.2
13.89
38.0
0.0
-35.0
(-5.0-7.0)
______________________________________________________________________________________
(continued)
95% C.I.: Confidence interval of the median
Somatropin
CT Registry ID#5300
Table 15.
Page 26
Summary of QOL (SF36) Changes (concluded)
______________________________________________________________________________________
Item
Treatment
Visit
N
Mean
SD
Max
Median Min
95%C.I.
______________________________________________________________________________________
VT
LY/LY
0w
31
59.1
19.29
87.5
56.3
6.3
(56.3-68.8)
24w
28
59.4
23.35
87.5
62.5
0.0
(50.0-75.0)
48w
28
62.3
21.88
93.8
68.8
6.3
(50.0-75.0)
48w LOCF
31 62.1
21.28
93.8
68.8
6.3
(50.0-75.0)
Change*1
31
3.0
14.51
25.0
0.0
-31.3
(-6.3-12.5)
______________________________________________________________________________________
Placebo/LY
0w
28
54.2
20.84
100.0
59.4
18.8
(37.5-68.8)
24w
27
53.5
17.10
81.3
56.3
12.5
(50.0-62.5)
48w
27
49.7
24.09
100.0
50.0
0.0
(37.5-62.5)
48w LOCF
28 49.7
23.64
100.0
50.0
0.0
(37.5-62.5)
Change
28
-4.5
19.59
31.3
-6.3
-37.5
(-12.5-0.0)
______________________________________________________________________________________
SF
LY/LY
0w
31
86.7
17.95
100.0
100.0
50.0
(75.0-100.0)
24w
29
86.2
21.22
100.0
100.0
37.5
(87.5-100.0)
48w
30
80.4
25.99
100.0
100.0
0.0
(75.0-100.0)
48w LOCF
31 78.6
27.42
100.0
100.0
0.0
(75.0-100.0)
Change
31
-8.1
25.53
37.5
0.0
-75.0
(-12.5-0.0)
______________________________________________________________________________________
Placebo/LY
0w
28
83.0
20.47
100.0
93.8
37.5
(62.5-100.0)
24w
27
82.4
22.80
100.0
100.0
25.0
(62.5-100.0)
48w
27
72.7
27.74
100.0
87.5
25.0
(62.5-100.0)
48w LOCF
28 73.2
27.37
100.0
87.5
25.0
(62.5-100.0)
Change
28
-9.8
25.31
25.0
0.0
-75.0
(-25.0-0.0)
______________________________________________________________________________________
RE
LY/LY
0w
31
80.1
24.60
100.0
83.3
0.0
(66.7-100.0)
24w
29
81.6
24.64
100.0
91.7
0.0
(75.0-100.0)
48w
30
82.8
25.89
100.0
100.0
0.0
(75.0-100.0)
48w LOCF
31 81.7
26.12
100.0
100.0
0.0
(75.0-100.0)
Change
31
1.6
23.41
50.0
0.0
-50.0
(0.0-0.0)
______________________________________________________________________________________
Placebo/LY
0w
28
80.4
23.70
100.0
91.7
16.7
(58.3-100.0)
24w
27
86.7
16.87
100.0
91.7
41.7
(75.0-100.0)
48w
26
77.9
27.28
100.0
83.3
0.0
(66.7-100.0)
48w LOCF
28 79.5
26.88
100.0
87.5
0.0
(66.7-100.0)
Change
28
-0.9
28.09
50.0
0.0
-83.3
(-8.3-8.3)
______________________________________________________________________________________
MH
LY/LY
0w
31
72.7
16.58
95.0
75.0
15.0
(65.0-80.0)
24w
28
72.9
21.71
100.0
77.5
25.0
(65.0-90.0)
48w
28
68.9
20.34
95.0
70.0
20.0
(60.0-85.0)
48w LOCF
31 69.0
20.59
100.0
70.0
20.0
(60.0-80.0)
Change
31
-3.7
18.71
45.0
0.0
-45.0
(-10.0-5.0)
______________________________________________________________________________________
Placebo/LY
0w
28
69.3
18.17
100.0
70.0
20.0
(60.0-81.3)
24w
27
69.4
13.96
90.0
70.0
40.0
(60.0-80.0)
48w
27
64.7
18.89
95.0
65.0
20.0
(55.0-75.0)
48w LOCF
28 64.2
18.75
95.0
63.8
20.0
(55.0-75.0)
Change
28
-5.1
19.68
40.0
-5.0
-56.3
(-10.0-5.0)
______________________________________________________________________________________
95% C.I.: Confidence interval of the median
Somatropin
CT Registry ID# 6018
Page 1
Summary ID# 6018
Extended Clinical Study of LY137998 [Somatropin
(Recombinant DNA Origin)] In Adults With Growth
Hormone Deficiency
The primary objective of this multicenter, non-controlled study was to investigate the
safety of LY137998 in the treatment of adult patients with growth hormone deficiency
(GHD) who completed the preceding 24-week double-blind, placebo-controlled
comparative study (Study K01A; CT#2889) and the 48-week long-term study (Study
K02A; CT#5300). The results of the current study are as follows:
•
The mean dose range of LY137998 was 0.048 to 0.050 mg/kg/week during the
treatment period.
•
Serum Insulin-like growth factor 1 (IGF-I) concentrations (mean IGF-I
standard deviation score [SDS] values) were maintained within the
reference range during this study, and the proportions of patients within
the reference range of IGF-I SDS were 88% (42/48) at Week 24 and 86%
(31/36) at the end of the study.
•
•
Serious adverse events were observed in 6 patients and one of them
discontinued the study.
•
Other than the serious adverse events, 2 patients experienced an adverse
event leading to discontinuation and 5 patients experienced those leading
to dose reduction (one patient was counted in both categories).
Somatropin
Page 2
•
Three other adverse events, which occurred in the preceding long-term
study, led to discontinuation of the study or dose reduction during this
study.
•
Common adverse events (treatment-emergent adverse events [TEAEs]
occurring in ≥5% of patients) included nasopharyngitis, pyrexia, cough,
diarrhoea not otherwise specified (NOS), headache, rhinorrhoea,
arthralgia, pharyngolaryngeal pain, and back pain while the most common
adverse drug reaction (occurring in ≥5% of patients) was arthralgia.
•
During this study period, the increase in glycosylated hemoglobin A1c
(HbA1c) was statistically significant. A total of 2 patients showed
abnormally high HbA1c values and the HbA1c values of most patients
were within the reference range throughout the study period.
•
No changes relevant to safety were observed in any other laboratory value.
•
The change of whole body lean body mass (LBM) was minimal (−0.2%)
during the 24-week administration of LY137998 in this study and the
improvement of LBM obtained by the end of the preceding study was
maintained.
Somatropin
Page 3
Title of Study: Extended Clinical Study of LY137998 [Somatropin (Recombinant DNA Origin)] In Adults
With Growth Hormone Deficiency
Study Center(s): This study was conducted at 23 study centers in one country. Five investigators either retired
or transferred patients.
Phase of Development: 3/4
Date of first patient enrolled: 03 February 2003
Date of last patient completed: 18 May 2006
Objectives:
Primary objective: To evaluate the safety of extended administration of LY137998 from the previous study
(CT#5300) in adult patients with growth hormone deficiency (GHD).
• To confirm that extended administration of LY137998 for 24 weeks maintains the changes in whole
body LBM achieved in the previous study
• To confirm that extended administration of LY137998 for 24 weeks maintains the serum IGF-I
concentrations in the normal range
• To confirm that extended administration of LY137998 for 24 weeks maintains improved quality of life
(QOL) achieved in the previous study
Study Design: This was a multicenter non-controlled study to investigate the safety of an injection containing 6
mg of LY137998 in adult patients with growth hormone deficiency, conducted following the preceding study
(CT#5300) for long-term safety evaluation. Patients visited every 24 weeks and continued the study by the end
of the entire study. Efficacy was evaluated 24 weeks after the start of this study.
Number of Patients:
Planned: N/A; based on number of patients from CT#5300
Enrolled: 51 patients (informed consent obtained from 51 patients)
Completed Week 24 visit: 48 patients
Completed study: 36 patients
Diagnosis and Main Criteria for Inclusion: Patients who had completed administration of LY137998 in the
previous trial (CT5300) and the Week 48 visit of that trial were entered. Patients also needed to be judged
eligible for the transfer to this study from the safety standpoint of the investigator or subinvestigator and submit
written consent document to participate in this study.
Somatropin
Page 4
Test Product, Dose, and Mode of Administration: LY137998 was administered subcutaneously, continuously
adjusted as needed, in the range of 0.021 to 0.084 mg/kg/week of Somatropin (recombinant DNA origin) in 6-7
divided doses. The dose for each patient was adjusted appropriately aiming at the serum IGF-I concentrations be
maintained in the range of ≥-1.96 SD and ≤+1.96 SD.
Duration of Treatment: Not set from any medical reasons. Maximum duration was 40 months at the
completion of this study.
Variables:
Efficacy: Primary: Percent change in lean body mass, determined by dual-energy x-ray absorptiometry
(DXA).
Secondary: Change in serum IGF-I concentrations.
Safety: Frequencies and severities of treatment-emergent adverse events (TEAEs) and adverse drug reactions.
Periodic analysis of TEAEs and adverse drug reactions.
(Adverse Event Terms: MedDRA[J] version 5.1 for display; MedDRA[J] version 4.0 for coding)
Health Outcomes: Changes in quality of life determined by the Medical Outcomes Study (MOS) Short-Form
36-Item Health Survey (SF-36.)
Evaluation Methods:
Statistical: Statistical analyses were conducted principally on the full analysis set. Two-sided 95% confidence
intervals were obtained and all exploratory tests of treatment effects were conducted at a two-sided significance
level of 5%.
Results:
Data Sets Analyzed
All 51 entered patients were enrolled and received study treatment (Full Analysis Set,
FAS).
The primary patient demographics compiled using the FAS are shown in Table 1. The
mean age of the 51 enrolled patients was 38.0 years old consisting of 16 patients aged 2029, 15 patients aged 30-39, and 20 patients aged 40 or over. As to gender and onset,
there were 24 males vs. 27 females and 20 adult onset (AO) patients vs. 31 childhood
onset (CO) patients. Major causes of growth hormone deficiency were tumor (17
patients), treatment for tumor (15 patients), and idiopathic or congenital (13 patients).
All patients except for one had a multiple deficiency of pituitary hormones. No relevant
differences were observed between the 27 patients in the LY/LY group and the 24
patients in the placebo/LY group of Study K02A (CT#5300).
Somatropin
Table 1.
Item
Page 5
Overview of Patient Demographics
LY/LY
(N=27)
Placebo/LY
(N=24)
Total
(N=51)
Age
Mean±SD
37.5±12.7
38.7±13.1
38.0±12.7
18-19
0 (0.0%)
0 (0.0%)
0 (0.0%)
20-29
10 (37.0%)
6 (25.0%)
16 (31.4%)
30-39
6 (22.2%)
9 (37.5%)
15 (29.4%)
40-65
11 (40.7%)
9 (37.5%)
20 (39.2%)
Gender
Male
13 (48.1%)
11 (45.8%)
24 (47.1%)
Female
14 (51.9%)
13 (54.2%)
27 (52.9%)
Onset
AO
11 (40.7%)
9 (37.5%)
20 (39.2%)
CO
16 (59.3%)
15 (62.5%)
31 (60.8%)
Cause of GHD
Idiopathic
5 (18.5%)
8 (33.3%)
13 (25.5%)
Pituitary Adenoma
11 (40.7%)
6 (25.0%)
17 (33.3%)
Therapy for adenoma
8 (29.6%)
7 (29.2%)
15 (29.4%)
Sheehan’s syndrome
1 (3.7%)
2 (8.3%)
3 (5.9%)
Empty sella
1 (3.7%)
1 (4.2%)
2 (3.9%)
Trauma
1 (3.7%)
0 (0.0%)
1 (2.0%)
Hormone Deficiency
Isolated
0 (0.0%)
1 (4.2%)
1 (2.0%)
Multiple
27 (100.0%)
23 (95.8%)
50 (98.0%)
Abbreviations: AO = adult onset; CO = childhood onset; GHD = growth hormone deficiency; LY =
LY137998; N = total number of patients; SD = standard deviation.
Patient Disposition
All of the 51 entered patients were enrolled and received study treatment. Of them, 48
patients completed the visit at Week 24 when interim analysis (final point for LBM and
QOL measurements) was done, and 36 patients completed the study.
The primary reasons for discontinuation are summarized in Table 2.
Table 2.
Reason for Discontinuation
N = 51
Total
15 (29.4%)a
Violation of concomitant medication
1 (2.0%)
Withdrawal of informed consent
9 (17.6%)
Adverse event
1 (2.0%)
Lack of efficacy
1 (2.0%)
1 (2.0%)
Physician’s judgment
2 (3.9%)
a Number of discontinued patients (discontinuation rate [%]).
Abbreviation: N = total number of patients.
Somatropin
Page 6
The LBM change between before and after 24-week administration of LY137998 in this
study is shown in Table 3. The mean LBM percent change was −0.2 and its 95%
confidence interval was −1.1% to 0.7%.
％
The analysis of LBM percent change in Table 3 excluded two patients with inappropriate
DXA-scan data and another patient with a LBM measure outside the visit window at
Week 0.
Table 3.
Summary of LBM Changes
Visit
N
Mean
SD
Max
Median
Min
95% CIa
0w
49
42.07
10.525
66.35
38.14
26.20
39.04 – 45.09
24w
46
41.84
10.690
67.07
37.24
25.00
38.66 – 45.01
24w LOCF
49
41.87
10.565
67.07
37.33
25.00
38.84 – 44.91
b
48
-0.2
3.13
6.5
-0.2
-9.3
-1.1 – 0.7
Change (%)
a 95% CI:CI of the mean for % change; CI of the median for others.
b % change from 0w to 24w LOCF.
Abbreviations: CI = confidence interval; LOCF = last observation carried forward; max = maximum; min =
minimum; N = number of patients; SD = standard deviation; w = week.
The changes of IGF-I SDS in this study are shown in Table 4 and the time course of IGFI SDS is shown in Figure 1. The mean values for IGF-I SDS were within the reference
range throughout the study period.
Table 4.
Summary of Changes of IGF-I SDS
Visit
N
Mean
SD
Max
Median
Min
95% CIa
0w
51
0.34
1.356
2.82
0.56
-3.69
0.08 – 1.08
24w
48
0.24
1.429
2.42
0.32
-4.67
0.00 – 0.78
48w
44
0.36
1.385
2.71
0.43
-3.71
-0.12 – 1.09
72w
41
0.26
1.493
3.73
0.36
-3.86
-0.34 – 0.88
96w
38
0.67
1.653
4.51
0.42
-3.53
-0.19 – 1.56
120w
37
0.42
1.175
3.08
0.41
-2.08
-0.32 – 1.04
144w
33
0.09
1.449
2.69
0.15
-3.38
-0.51 – 1.18
Study End
36
0.12
1.374
2.78
0.11
-3.06
-0.51 – 0.83
24w LOCF
51
0.23
1.492
2.42
0.34
-4.67
0.00 – 1.06
Overall LOCF
51
-0.20
1.649
2.78
-0.16
-3.21
-0.68 – 0.77
a CI of the median.
Abbreviations: CI = confidence interval; IGF-I = insulin-like growth factor-I; max = maximum; min =
minimum; N = number of patients; SD = standard deviation; SDS = standard deviation scores; w =
week.
Somatropin
Page 7
Abbreviations: IGF-I = insulin-like growth factor -1; N = number of patients;
SDS = standard deviation score; w = week.
Figure 1.
Time course of IGF-I SDS.
IGF-I SDS shift during the study is shown in Table 5. The proportions of patients within
the reference range of IGF-I SDS were 88% (42/48) at Week 24 and 86 (31/36) at the
end of the study.
％
Table 5.
Summary of IGF-I SDS Shift
0w
<-1.96
24w
-1.96 ~
+1.96<
+1.96
0
0
Total
<-1.96
Study End
-1.96 ~
+1.96<
+1.96
0
0
Total
<-1.96
2
2
1
1
-1.96 ~
0
41
3
44
3
30
1
34
+1.96
+1.96<
0
1
1
2
0
1
0
1
Total
2
42
4
48
4
31
1
36
Abbreviations: IGF-I = insulin-like growth factor-I; SDS = standard deviation scores; w = week.
Safety
were no deaths of any patients. Serious adverse events other than death were observed in
6 patients and one of them discontinued the study. Other than the serious adverse events,
2 patients experienced an adverse event leading to discontinuation and 5 patients
experienced those leading to dose reduction (one patient was counted in both categories).
A total of 865 adverse events were observed in 98.0% of patients (50/51). A total of 74
adverse drug reactions were observed in 47.1% of patients (24/51).
Somatropin
Table 6.
Page 8
Adverse Event
Na = 51
Deaths
0, 0 (0.0%)
9, 6 (11.8%)
2, 2 (3.9%)
Discontinuations due to an adverse eventb
7, 5 (9.8%)
Dose reductions due to an adverse eventb
865, 50 (98.0%)
Adverse reactions
74, 24 (47.1%)
a Number of adverse events (AEs), number of patients with AE (occurred rate [%]).
b Serious adverse events were excluded. Discontinuations and dose reductions were counted
independently.
Abbreviations: N = total number of patients.
Deaths
There were no deaths of any patients during this study.
Other Serious Adverse Events
Other serious adverse events were observed in 6 patients (9 events). None of these events
were life-threatening nor related to LY137998 according to the judgment of the
investigator.
Clinically Significant Adverse Events
Other significant adverse events in this study were defined as adverse events leading to
discontinuation of the study and adverse events leading to reduction of specified dose
(including withdrawal of investigational drug). Other than serious adverse events,
adverse events leading to discontinuation of the study occurred in 2 patients and those
leading to reduction of the specified dose occurred in 5 patients (one patient was counted
in both categories). Arthralgia (5 events in 4 patients) was the most common event
reported as other significant adverse events.
Three other adverse events, which occurred in the preceding study, led to discontinuation
of the study or dose reduction during this study. Two of them (arthralgia and
musculoskeletal stiffness) were related to LY137998 according to the judgment by the
investigator.
Adverse events occurring in ≥5% (3 patients or more) are shown in Table 7. The most
common adverse event was nasopharyngitis (70.6%), followed by pyrexia (39.2%),
cough (37.3%), diarrhoea NOS (29.4%), headache (29.4%), rhinorrhoea (29.4%),
arthralgia (25.5%), pharyngolaryngeal pain (25.5%) and back pain (23.5%).
Somatropin
Page 9
Frequent adverse events by MedDRA system organ class (SOC) in descending order of
incidence were “Respiratory, thoracic and mediastinal disorders” (82.4%),
“Gastrointestinal disorders” (68.6%), “General disorders and administration site
conditions” (56.9%) , “Skin and subcutaneous tissue disorders” (52.9%), and
“Musculoskeletal and connective tissue disorders” (47.1%).
Table 7.
Patients
MedDRA SOC, PT
Ear and labyrinth disorder
Tinnitus
Eye disorders
Eye pruritus
Conjunctivitis allergic
Diarrhoea NOS
Nausea
Abdominal pain upper
Vomiting NOS
Gastroenteritis NOS
Abdominal pain NOS
Gastritis NOS
Toothache
Gingivitis
Constipation
Stomatitis
General disorders and administration site conditions
Pyrexia
Malaise
Fall
Rigors
Fatigue
Immune system disorders
Seasonal allergy
Tooth caries NOS
Tinea pedis
Investigations
Sputum increased
Anorexia
N = 51
11, 8 (15.7%)
3, 3 (5.9%)
24, 13 (25.5%)
6, 5 (9.8%)
4, 4 (7.8%)
121, 35 (68.6%)
18, 15 (29.4%)
12, 10 (19.6%)
14, 8 (15.7%)
11, 8 (15.7%)
8, 7 (13.7%)
6, 6 (11.8%)
5, 5 (9.8%)
5, 4 (7.8%)
7, 3 (5.9%)
3, 3 (5.9%)
3, 3 (5.9%)
68, 29 (56.9%)
33, 20 (39.2%)
11, 8 (15.7%)
6, 5 (9.8%)
4, 4 (7.8%)
3, 3 (5.9%)
12, 9 (17.6%)
12, 9 (17.6%)
25, 20 (39.2%)
6, 5 (9.8%)
3, 3 (5.9%)
13, 8 (15.7%)
7, 5 (9.8%)
19, 11 (21.6%)
6, 6 (11.8%)
(continued)
Somatropin
Table 7.
Page 10
Patients (Concluded)
MedDRA SOC, PT
N = 51
72, 24 (47.1%)
Arthralgia
25, 13 (25.5%)
Back pain
20, 12 (23.5%)
Muscle stiffness
7, 6 (11.8%)
Pain in limb
4, 4 (7.8%)
Myalgia
4, 3 (5.9%)
67, 21 (41.2%)
Headache
43, 15 (29.4%)
Hypoaesthesia
8, 5 (9.8%)
Depressed level of consciousness
4, 3 (5.9%)
5, 5 (9.8%)
Insomnia
4, 4 (7.8%)
Respiratory, thoracic, and mediastinal disorders
318, 42 (82.4%)
Nasopharyngitis
131, 36 (70.6%)
Cough
32, 19 (37.3%)
Rhinorrhoea
35, 15 (29.4%)
27, 13 (25.5%)
Rhinitis allergic NOS
16, 11 (21.6%)
Sneezing
21, 7 (13.7%)
Upper respiratory tract inflammation
26, 6 (11.8%)
Bronchitis NOS
5, 4 (7.8%)
Nasal congestion
5, 4 (7.8%)
Epistaxis
4, 3 (5.9%)
Rhinitis NOS
3, 3 (5.9%)
Skin and subcutaneous tissue disorders
46, 27 (52.9%)
Eczema
8, 6 (11.8%)
Rash NOS
10, 5 (9.8%)
Contusion
4, 4 (7.8%)
Pruritus
3, 3 (5.9%)
Swelling face
3, 3 (5.9%)
Urticaria NOS
3, 3 (5.9%)
Surgical and medical procedures
14, 11 (21.6%)
Dental treatment NOS
4, 3 (5.9%)
Abbreviations: MedDRA =Medical Dictionary for Regulatory Activities ; N = total number of patients;
NOS = not otherwise specified; PT = preferred term; SOC = system organ class.
Somatropin
Page 11
The time courses of adverse event-experienced patients and overall adverse events for
each 4-week period after administration of LY137998 are presented in Figure 2 and
Figure 3. The numbers of patients with adverse events (the number of events) ranged
from 2 - 20 patients (3 - 44 events) during the entire study period, while there was a range
of 8 - 17 patients (11 - 29 events) for most of each 4-week period.
Abbreviations: AE = adverse event; N = number of patients; w = week.
Figure 2.
Time course of adverse event-experienced patients.
Abbreviations: AE = adverse event; N = number of patients; w = week.
Figure 3.
Time course of overall adverse events.
Adverse drug reactions occurring in ≥5% (3 patients or more) are shown in Table 8. This
included arthralgia (11.8%) and “Musculoskeletal and connective tissue disorders”
(21.6%) topped the incidence by MedDRA SOC.
Somatropin
Table 8.
Page 12
Adverse Drug Reactions Occurring in ≥5% of Patients
MedDRA SOC, PT
Na = 51
30, 11 (21.6%)
Arthralgia
16, 6 (11.8%)
a Number of ADRs, number of Patients with ADR (occurred rate[%])
Abbreviations: ADRS = adverse drug reactions; MedDRA =Medical Dictionary for Regulatory Activities ;
N = total number of patients; NOS = not otherwise specified; PT = preferred term; SOC = system organ
class.
The time courses of adverse drug reaction-experienced patients and overall adverse drug
reactions for each 4-week period after administration of LY137998 are presented in
Figure 4 and Figure 5. The numbers of patients with adverse drug reactions (the number
of events) were 5 patients (6 events) or fewer during the entire study period, while there
were approximately 2 patients (2 events) or fewer for most of each 4-week period.
Abbreviations: ADR = adverse drug reaction; N = number of patients; w = week.
Figure 4.
Time-course of adverse drug reaction-experienced patients.
Abbreviations: ADR = adverse drug reaction; N = number of patients; w = week.
Figure 5.
Somatropin
Time-course of overall adverse drug reactions.
Page 13
The change of glycosylated hemoglobin A1c (HbA1c) and its time-course during this study
are shown in Table 9 and Figure 6, respectively. The mean HbA1c values were 4.7% at
both Week 0 and Week 24, and there was no statistically significant change. The mean
HbA1c values were 4.9% at both Study End and Overall LOCF, and the change for
Overall LOCF (0.1%) was statistically significant (p<0.001).
A total of 2 patients showed abnormally high HbA1c values during the study period, while
HbA1c values of most patients were within the reference range throughout the study
period.
Table 9.
Summary of HbA1c Changes by Visit
Visit
N
Mean
SD
Max
Median
Min
p-valuec
0w
51
4.7
0.48
5.9
4.8
2.6
24w
48
4.7
0.48
5.8
4.8
2.9
48w
44
4.8
0.38
6.0
4.7
4.0
72w
41
4.7
0.37
5.7
4.7
3.9
96w
38
4.7
0.36
5.9
4.7
4.0
120w
37
4.8
0.38
5.9
4.8
4.0
144w
33
4.9
0.40
6.1
4.9
4.3
Study End
36
4.9
0.37
5.9
4.9
4.3
24w LOCF
51
4.7
0.47
5.8
4.8
2.9
Overall LOCF
51
4.9
0.47
6.0
4.9
2.9
51
-0.0
0.19
0.3
-0.1
-0.6
0.106
Change (24w)a
51
0.1
0.20
0.7
0.1
-0.2
<0.001
Change (overall)b
a Change from 0w to 24w LOCF.
b Change from 0w to Overall LOCF.
c Wilcoxon test.
Abbreviations: HbA1c = glycosylated hemoglobin A1c; LOCF = last observation carried forward; max =
maximum; min = minimum; N = number of patients; SD = standard deviation; w = week.
Abbreviations: HbA1c = glycosylated hemoglobin A1c; N = number of patients; w = week.
Figure 6.
Somatropin
Time-course of HbA1c.
Page 14
For other laboratory values and blood pressure, statistically significant changes from
Week 0 to Study End were observed in hemoglobin (increase), alkaline phosphatase
(ALP; decrease), γ-glutamyl transpeptidase (GTP; increase), total protein (increase),
albumin (increase), creatinine (increase) and free triiodothyronine (FT3; decrease).
However, the mean values of them were within the reference range at both Week 0 and
Study End. No changes relevant to safety were observed in any other laboratory value.
Health Outcomes (Quality of Life Evaluation)
SF-36
The changes of QOL (SF-36) between before and after 24-week administration of
LY137998 in this study are shown in Table 10. The mean scores increased in 3 items
including Bodily pain, Social functioning, and Role-emotional, and decreased in 5 items
including Physical functioning, Role-physical, General health, Vitality, and Mental
health. The mean changes were relatively small (−1.1 to 2.2 points) in 6 subscales other
than Social functioning (7.1 points) and Vitality (−4.4 points).
Somatropin
Table 10.
Page 15
Summary of QOL (SF-36) Changes
Visit
N
Mean
SD
Max
Median
Min
95% CIa
0w
50
89.4
15.27
100.0
95.0
35.0
90.0 – 95.0
24w
48
89.9
15.00
100.0
95.0
25.0
90.0 – 100.0
24w LOCF
51
88.4
16.20
100.0
95.0
25.0
90.0 – 100.0
50
-1.1
6.25
15.0
0.0
-15.0
0.0 – 0.0
Changeb
RP
0w
51
81.5
24.49
100.0
93.8
0.0
75.0 – 100.0
24w
48
82.4
22.32
100.0
93.8
25.0
81.3 – 100.0
24w LOCF
51
81.4
22.10
100.0
87.5
25.0
81.3 – 100.0
Change
51
-0.1
21.12
56.3
0.0
-75.0
0.0 – 0.0
BP
0w
51
70.9
23.47
100.0
72.0
22.0
62.0 – 84.0
24w
48
72.2
22.47
100.0
74.0
22.0
62.0 – 84.0
24w LOCF
51
71.9
22.52
100.0
74.0
22.0
61.0 – 84.0
Change
51
1.0
20.21
49.0
0.0
-48.0
0.0 – 1.0
GH
0w
49
59.6
22.26
100.0
57.0
10.0
47.0 – 72.0
24w
48
59.5
21.06
92.0
62.0
15.0
52.0 – 67.0
24w LOCF
51
58.6
20.92
92.0
62.0
15.0
50.0 – 67.0
Change
49
-0.2
12.29
35.0
0.0
-33.0
-3.0 – 5.0
VT
0w
49
57.0
22.95
100.0
62.5
0.0
50.0 – 68.8
24w
48
53.0
22.40
93.8
56.3
0.0
43.8 – 62.5
24w LOCF
51
52.2
22.70
93.8
56.3
0.0
43.8 – 62.5
Change
49
-4.4
16.86
43.8
-6.3
-43.8
-6.3 – 0.0
SF
0w
51
76.2
26.61
100.0
87.5
0.0
75.0 – 100.0
24w
48
84.6
19.68
100.0
93.8
37.5
87.5 – 100.0
24w LOCF
51
83.3
19.95
100.0
87.5
37.5
75.0 – 100.0
Change
51
7.1
18.41
75.0
0.0
-37.5
0.0 – 12.5
RE
0w
50
80.3
24.84
100.0
87.5
0.0
75.0 – 100.0
24w
48
81.9
21.83
100.0
91.7
25.0
83.3 – 100.0
24w LOCF
51
81.4
21.70
100.0
91.7
25.0
83.3 – 100.0
Change
50
2.2
15.41
33.3
0.0
-33.3
0.0 – 0.0
MH
0w
49
67.0
18.99
95.0
70.0
20.0
60.0 – 75.0
24w
48
67.7
17.86
100.0
70.0
15.0
60.0 – 75.0
24w LOCF
51
66.6
18.93
100.0
70.0
15.0
60.0 – 75.0
Change
49
-0.5
12.09
30.0
0.0
-30.0
-5.0 – 5.0
a C.I. of the median.
b Change from 0w to 24w LOCF.
Abbreviations: BP = Bodily Pain; CI = confidence interval; GH = General Health; LOCF = last
observation carried forward; max = maximum; MH = Mental Health; min = minimum; N = number of
patients; PF = Physical Functioning; RE = Role-Emotional; RP = Role-Physical; SD = standard
deviation; SF = Social Functioning; SF-36 = MOS Short-Form 36-Item Health Survey (MOS = Medical
Outcomes Study) ; VT = Vitality; w = week.
Item
PF
Somatropin
Page 1
Summary ID# 6581
Clinical Study Summary: Study B9R-EW-GDGB
12-Month and 24-Month Data
Optimization of Growth Hormone Treatment in
Short Children Born Small for Gestational Age
Based on a Growth Prediction Model: The OPTIMA Trial
Title of Study: Optimization of Growth Hormone Treatment in Short Children Born Small for Gestational
Age Based on a Growth Prediction Model: The OPTIMA Trial
Length of Study:
Date of first patient enrolled: 27 December 2002
Date of last patient completed 12 months of treatment: 12 June 2006
Date of last patient completed 24 months of treatment: 01 June 2007
Objectives:
Primary:
• To test the research hypothesis that GH (somatropin), given as an individually adjusted dose (IAD), is
non-inferior to a fixed high dose (FHD) regimen as measured by the change in height standard deviation
score (SDS) after 1 year of treatment. Dose adjustment after 3 months of treatment was based on a
growth prediction for the first 12 months using the “Cologne” growth prediction model.
Secondary:
• To compare absolute height velocity (HV) after 1 and 2 years of treatment in the 2 treatment arms,
including age, gender, pubertal development, and country as covariates.
• To investigate the change in height SDS from baseline to 1 and 2 years of treatment relative to midparental height SDS (= target height SDS).
• To compare the change in height SDS between both treatment arms from baseline to 24 months of
treatment.
• To compare the change in height SDS between both treatment arms from 12 to 24 months of treatment
• To investigate the association between change in height SDS during the second year of treatment and
change in height SDS during the first year of treatment.
• To compare the safety profiles of both treatment arms.
Somatropin
Page 2
Study Design: Randomized, open-label, multicenter Phase 3 study of outpatient GH treatment in children
with short stature born small for gestational age (SGA). The study was designed to demonstrate noninferiority of an individually adjusted GH dose (IAD) regimen versus a fixed high dose (FHD) regimen,
based on the change in height SDS after the first year of GH treatment as the primary outcome measure.
The study consisted of 8 visits and was divided into 4 periods: Screening, Treatment Period I (up to Month
3), Treatment Period II (up to Month 12, primary analysis), and Treatment Period III (second year of
treatment). Patients assigned to the FHD group received a fixed GH dose of 0.067 mg/kg body weight per
day during Study Periods I to III. Patients assigned to the IAD group started at a lower GH dose of
0.035 mg/kg per day for the initial 3 months. Individual dose adjustment occurred after 3 months, based on
the 1-year growth prediction using the “Cologne” growth prediction model, and after 12 months, based on
the actual change in height SDS after 1 year of treatment (see figure).
Figure 1. Study Design
1st year
Screening
Period I
2nd year
Period II
Period III
0.067mg/kg/day
HGH
HGH
0.067
mg/kg/day
0.067mg/kg/day
Fixed high dose
Screening
HGH
0.067mg/kg/day
(if ∆ height SDS < 0.75)
HGH
0.067mg/kg/day
0.067mg/kg/day if ∆ height SDS 1st yr < 0.75
0.035mg/kg/day
HGH
0.035mg/kg/day
(if ∆ height SDS > 0.75)
0.035mg/kg/day if ∆ height SDS 1st yr > 0.75
Individually adjusted dose
3 months
+/- 2w
< 6 months
V0
V1
Randomization
3 months
+/- 4w
V2
V3
6 months
+/- 4w
3 months
+/- 4w
V4/V101
V102
3 months
+/- 6w
V103
6 months
+/- 8w
V104
Growth prediction
Dose adjustment
Abbreviations: HGH = Humatrope, growth hormone of human origin,
SDS = standard deviation score, w = week, yr = year.
Number of Patients:
Planned: 185
Entered (signed informed consent): 200
Randomized: 194 (100 patients FHD, 94 patients IAD; 1 patient randomized to FHD had no study drug)
Completed 12 months of treatment: 175 (92 patients FHD, 83 patients IAD)
Completed 24 months of treatment: 164 (85 FHD, 79 IAD)
Per Protocol Set (first year) for primary analysis: 169 (89 patients FHD, 80 patients IAD)
Per Protocol Set (second year): 150 (78 patients FHD, 72 patients IAD)
Somatropin
Page 3
• Children born SGA, as defined by birth weight below the 10th percentile and/or birth length shorter than
2 standard deviations (SD) below the mean for gestational age, based on local standards
• Short stature, as defined by a height SDS ≤-3, based on local standards
• Chronological age ≥3 years
• Clinically prepubertal (girls: breast development Tanner Stage 1, boys: genital development Tanner
Stage 1)
• Bone age ≤9 years for girls and ≤10 years for boys
• Patients with known GH deficiency, chronic diseases, tumor activity, any growth affecting current or
previous treatment or any significant signs of dysproportion or underlying non-toxic, but proven or
assumed genetically based defined syndromal disease (as to the opinion of the investigator) were not
eligible for enrollment.
Test Product, Dose, and Mode of Administration: Humatrope® [somatropin, Lilly]; IAD regimen:
0.035 mg/kg per day up to Month 3, followed by 0.067 mg/kg per day up to Month 24 if the predicted
1-year change in height SDS was <0.75. If the predicted 1-year change in height SDS was ≥0.75, patients
continued on start dose of 0.035 mg/kg per day up to Month 12; if they remained below the predicted
growth response of a change in height SDS ≥0.75 at Month 12, their Humatrope dose was also increased to
0.067 mg/kg per day for the second year of treatment. Humatrope was given as a single daily subcutaneous
injection.
Reference Therapy, Dose, and Mode of Administration: Humatrope FHD regimen: 0.067 mg/kg per
day, given as a single daily subcutaneous injection.
Duration of Treatment: 24 months (primary analysis after 12 months)
Variables: Efficacy: Standing height and height SDS (primary outcome: 1-year change in height SDS),
height velocity (HV) and HV SDS, difference between height SDS and target height SDS.
Safety: Adverse events (AEs), solicited adverse events of specific interest, vital signs, pubertal
development, bone age, weight, body mass index (BMI), standard local laboratory data (including fasting
glucose, oral glucose tolerance test [OGTT], insulin, lipids, total T4 or free T4 and thyroid stimulating
hormone [TSH]), special laboratory data (central laboratory: IGF-I and IGFBP-3.
Evaluation Methods:
Statistical: The sample size was calculated to detect with 80% power that the 95% confidence interval (CI)
of the difference in ∆ height SDS between the 2 arms is completely above the non-inferiority margin of -0.5
SDS, assuming a treatment-group difference of -0.175 SDS and a common SD of 0.7. Assuming a 20%
drop-out rate, the required sample size was calculated to be 185 patients. Main analysis after the first
year of treatment: The primary analysis was to evaluate if the IAD regimen was non-inferior to the FHD
regimen in terms of the change in height SDS after the first year of treatment. The non-inferiority margin
for the difference in change of height SDS (IAD – FHD) was chosen at -0.5 SDS to reflect a lower limit of
a clinically relevant difference. Between-group analyses were performed using an analysis of covariance
(ANCOVA) model incorporating treatment group as fixed-factor effect and the baseline height SDS as a
covariate. The Per Protocol Population (first year) was used for the confirmatory analysis. It included all
patients who had no major protocol violation, who received the correct treatment as assigned to after
random allocation for at least 300 days during the whole treatment period, who did not miss more than
cumulative 2 weeks of treatment between start of Humatrope treatment and Visit 2 (3 months), who
completed standing height measurements at least at Visit 1, Visit 2, and Visit 4, and for whom all data
necessary for a growth prediction after 3 months were available.
Somatropin
Page 4
Secondary analyses: All secondary efficacy analyses after the first and second year of treatment are
presented for the Per Protocol Populations (first and second year). Secondary efficacy analyses included
between-group comparisons of (1) absolute HV after 1 and 2 years of treatment, using an ANCOVA model
corresponding to the primary analysis but including age, gender, and pubertal development as additional
factors; (2) change in height SDS from baseline to 24 months of treatment, change in height SDS from 12
to 24 months of treatment, and change in absolute HV after 1 and 2 years, all using the same ANCOVA
model as for the primary analysis; (3) 1- and 2-year change of the difference between child height SDS and
target height SDS, again using the same ANCOVA model as for the primary analysis. In addition, the
association between change in height SDS during the first and second year of treatment was evaluated
using regression analysis and an ANCOVA with the change in height SDS during the second year as
independent variable and the following factors/covariables as dependent variables: change in height SDS
during the first year, treatment group, and their interaction during the first year .
Only patients who at least attended Visit 4/101 (12 months) were included in the analysis after the second
year of treatment. The Per Protocol Population (second year) included only patients who were already in
the Per Protocol Population (first year), had no major protocol violations during the second year, did not
miss more than 65 cumulative days of GH treatment during the second year, and who completed standing
height measurement at Visit 104.
All safety analyses were based on the Safety Population (identical to the Full Analysis Set).
Summary:
A total of 193 patients (FHD group 99, IAD group 94 patients) received at least 1 dose of
Humatrope and were included in the Full Analysis Set (first year) and the Safety
Population. Of these, 175 patients (FHD 92, IAD 83) completed 12 months of treatment.
Baseline characteristics are summarized in Table 1.
Table 1.
Baseline Characteristics
Full Analysis Set, First Year (N=193)
FHD Group
IAD Group
(N=99)
(N=94)
Age (male / female) (years)
6.7 ± 2.5 / 6.7 ± 2.3
6.9 ± 2.5 / 6.8 ± 2.5
Male /female (%)
55.6 / 44.4
50.0 / 50.0
Gestational age (weeks)
36.8 ± 4.0
37.4 ± 3.0
Birth weight SDS
-2.11 ± 0.90
-2.17 ± 0.73
Birth length SDS
-2.81 ± 1.27
-2.79± 1.22
Standing height (cm)
103.5 ± 12.4
103.9 ± 12.3
Height SDS
-3.89 ± 0.64
-3.91 ± 0.67
HV (cm/year)
5.3 ± 1.6
5.3 ± 1.8
HV SDS
-1.45 ± 1.91
-1.47 ± 2.25
Height SDS – target height SDS
-2.17 ± 1.18
-2.17 ± 1.23
Absolute bone age delay (years)
-2.1 ± 1.1
-1.9 ± 1.2
Abbreviations: FHD = fixed high dose of Humatrope; HV = height velocity; IAD = individually adjusted
dose of Humatrope; N = number of patients with data available; SDS = standard deviation score.
Note: Data for continuous variables are presented as mean ± standard deviation.
Somatropin
Page 5
All patients were clinically prepubertal at baseline; 11 patients (5.7%) entered puberty
during the first treatment year (7 FHD, 4 IAD), 16 additional patients entered puberty
during the second year (8 FHD, 8 IAD).
Efficacy Analyses - First Year of Treatment
The confirmatory primary efficacy analysis was conducted on the Per Protocol
Population (first year), which included 169 patients (FHD 89, IAD 80), corresponding to
87.1% of all 194 randomized patients. In the IAD group, 38 patients had their dose
increased to 0.067 mg/kg per day after 3 months based on their growth prediction (Per
Protocol Population, first year). Forty-two patients remained on the initial Humatrope
dose of 0.035 mg/kg per day after growth prediction at Month 3. Table 2 summarizes
descriptive statistics for patients’ growth response after the first year of treatment.
Table 2.
Summary of Growth Response after 12 Months
Per Protocol Population, First Year (N=169)
Baseline
FHD
IAD
Group
Group
(N=89)
(N=80)
104.2 ± 12.3 103.8 ± 12.5
-3.88 ± 0.54 -3.84 ± 0.62
5.2 ± 1.5
5.4 ± 1.9
-2.15 ± 1.15 -2.12 ± 1.11
Month 12
FHD
IAD
Group
Group
(N=89)
(N=80)
114.6 ± 11.8 113.2 ± 12.5
-2.75 ± 0.65 -2.95 ± 0.68
10.3 ± 1.9
9.3 ± 1.5
-1.03 ± 1.15 -1.24 ± 1.11
Change from Baseline
FHD
IAD
Group
Group
(N=89)
(N=80)
+10.4 ± 1.9
+9.4 ± 1.5
+1.13 ±0.40 +0.89 ±0.34
+5.2 ± 2.4
+3.9 ± 2.7
+1.12 ±0.39 +0.89 ±0.35
Ht (cm)
Ht SDS
HV (cm/year)
Ht SDS –
target Ht SDS
Abbreviations: FHD = fixed high dose of Humatrope; Ht = height; HV = height velocity; IAD =
individually adjusted dose of Humatrope; N = number of patients with data available; SDS = standard
deviation score.
Note: Data are presented as mean ± standard deviation.
Table 3 summarizes the primary and secondary efficacy analyses after the first year of
treatment.
Table 3.
Treatment Group Comparisons after 12 Months
Per Protocol Population, First Year (N=169)
Difference between Treatment Groups (IAD minus FHD)
LS Mean
95% CI, LS Mean
p-Value (ANCOVA)
Change in Ht SDS
-0.24
-0.35 to -0.12
<.0001a
Absolute HV (cm/year)
-1.01
-1.49 to -0.53
<.0001b
Ht SDS – target Ht SDS
-0.23
-0.35 to -0.12
.0001c
individually adjusted dose of Humatrope; LS mean = least square mean; N = number of patients with
data available; SDS = standard deviation score.
a Covariate: baseline height SDS.
b Covariates/factors: baseline HV, age, sex, pubertal status at Visit 4
c Covariate: Ht SDS – target Ht SDS at baseline.
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In the primary statistical analysis, the change in height SDS after 1 year of Humatrope
treatment in the IAD group was shown to be non-inferior to the FHD group: The lower
limit of the 95% CI of the LS mean difference of the change in Ht SDS between
treatment groups (see Table 3) was above the predefined non-inferiority margin of -0.5.
The 95% CI for the difference in change in height SDS was narrow and completely
below zero, causing a statistically significant p-value of <.0001, although the actual
difference between treatment groups was small.
Efficacy Analyses - Second Year of Treatment
A total of 164 patients (85 FHD, 79 IAD) completed the entire 24-month period, and
150 patients (78 FHD, 72 IAD) were included in the Per Protocol Population (second
year). In the IAD group, 30 patients remained on the low Humatrope dose of
0.035 mg/kg per day during the second year of treatment, while 8 patients required a dose
increase to 0.067 mg/kg per day at Month 12 because their actual change in height SDS
at 12 months remained below the predicted ≥ 0.75 SDS (Per Protocol Population, second
year). Table 4 summarizes descriptive statistics for patients’ growth parameters after the
second year of treatment.
Table 4.
Growth Response after 24 Months
Per Protocol Population, Second Year (N=150)
Baseline
FHD
IAD
Group
Group
(N=78)
(N=72)
103.5±12.2
104.7±12.8
-3.90±0.55
-3.82±0.61
5.1±1.4
5.2±1.5
-2.12 ± 1.19 -2.06 ± 1.06
Month 12
FHD
IAD
Group
Group
(N=78)
(N=72)
113.8±11.6
114.1±12.7
-2.77±0.66
-2.91±0.67
10.3±1.9
9.3±1.5
-1.01 ± 1.17 -1.16 ± 1.07
Month 24
FHD
IAD
Group
Group
(N=78)
(N=72)
121.8±11.5
122.0±13.1
-2.22±0.74
-2.39±0.80
a
7.7±1.5a
7.9±1.3
-0.46±1.16
-0.63±1.12
Ht (cm)
Ht SDS
HV (cm/year)
Ht SDS –
target Ht SDS
a HV Month 24 = HV during second year of treatment
individually adjusted dose of Humatrope; N = number of patients with data available; SDS = standard
deviation score.
Note: Data are presented as mean ± standard deviation.
Table 5 summarizes secondary efficacy analyses after the second year of treatment.
Somatropin
Table 5.
Page 7
Treatment Group Comparisons after 24 Months
Per Protocol Population, Second Year (N=150)
Difference between Treatment Groups (IAD minus FHD)
LS Mean
95% CI, LS Mean
p-Value (ANCOVA)
Change in Ht SDS
Baseline to Month 24
-0.25
-0.42 to -0.08
<0.01a
Month 12 to Month 24
-0.02
-0.11 to +0.07
0.6507
Absolute HV (cm/year)
-0.58
-0.97 to -0.19
<0.01b
Ht SDS – target Ht SDS
-0.22
-0.39 to -0.06
<0.01c
individually adjusted dose of Humatrope; LS mean = least square mean; N = number of patients with
data available; SDS = standard deviation score.
a Covariate: baseline height SDS.
b Covariates/factors: baseline HV, age, sex, pubertal status at Visit 4
c Covariate: Difference Ht SDS - target Ht SDS at baseline.
The observed mean change in height SDS after the second year of Humatrope
treatment was +1.68 SDS in the FHD group and +1.43 SDS in the IAD group (Per
Protocol Population, second year). The lower limit of the CI of the treatment group
difference in change in height SDS (Table 5) was still above the predefined noninferiority margin of -0.5 SDS.
The association between the change in height SDS during the first versus second
treatment year was evaluated by regression analysis, separately for each treatment group
(Per Protocol Population, second year). The slopes of the regression line were 0.21
[95% CI 0.06 to 0.35] in the FHD group and 0.08 [95% CI -0.11 to 0.27] in the IAD
group, correlation coefficients (r) were 0.31 and 0.10, respectively. The difference in
slopes between the FHD and IAD group was not statistically significant (ANCOVA:
p=0.276).
Safety Data
No patient died during the study. Serious adverse events (SAEs) were reported for
8 patients (8.1%) in the FHD group and 9 patients (9.6%) in the IAD group (first and
second year combined). Of all SAEs, none in the FHD and 4 SAEs in 3 patients of the
IAD group were considered related to treatment by the investigator (1x epiphysiolysis
capitis femoris, serious due to hospitalization; 2x adenoidal hypertrophy; 1x tonsillar
hypertrophy). Discontinuations due to adverse events occurred in 3 patients of the
FHD group (2x related to treatment: impaired fasting glucose, mood altered; 1x not
related: pain in extremity), and 1 patient of the IAD group (not related to treatment: focal
glomerulosclerosis).
Overall, 63 of 99 FHD group patients (63.8%, 95% CI 58.0% to 76.1%) and 54 of 94
IAD group patients (57.4%; 95% CI 51.9% to 71.2%) experienced 1 or more treatmentemergent adverse event during the 2 years of treatment (TEAE; first and second year
combined). The most frequently reported TEAEs (≥5% of patients of either treatment
Somatropin
Page 8
group) during the first and second year of treatment were (first year [FHD 99, IAD 94
patients]: nasopharyngitis [FHD 10.1%, IAD 7.4%], pyrexia [FHD 3.0%, IAD 6.4%],
vomiting [FHD 3.0%, IAD 6.4%], headache [FHD 5.1%, IAD 3.2%], and tonsillitis
[FHD 5.1%, IAD 1.1%]; second year [FHD 91, IAD 84 patients]: nasopharyngitis
[FHD 6.6%, IAD 3.6%], bronchitis [FHD 2.2%, IAD 7.1%]).
In addition to the collection of spontaneously reported TEAEs, the investigators were
required to record, in a prospective and proactive manner, the occurrence of solicited
TEAEs of special interest potentially related to study drug: benign intracranial
hypertension, slipped capital femoral epiphysis, hypoglycemia, hyperglycemia,
hypothyroidism, edema, arthralgia, scoliosis, obesity, insulin resistance, hirsutism,
precocious pubarche, neoplastic disease, and increasing number or growth of naevi.
Table 6 summarizes the occurrence of these notable TEAEs of special interest during
Humatrope treatment. No events of benign intracranial hypertension, scoliosis, obesity,
precocious pubarche, or neoplastic disease were reported.
Table 6.
Notable Treatment-Emergent Adverse Events of Special
Interest During the First and Second Year of Treatment
Safety Population, First and Second Year Combined (N=193)
Number (%) of Patients [95% CI for Percentage]
FHD Group (N=99)
IAD Group (N=94)
Any notable TEAE
9 (9.1) [4.2-16.6]
11 (11.7) [6.0-20.0]
Glucose metabolism
Blood insulin increased
4 (4.0)
3 (3.2)
Hyperinsulinaemia
1 (1.1)
Glucose tolerance test abnormal
1 (1.1)
Impaired fasting glucose
1 (1.0)
Thyroid function
Blood TSH increased
1 (1.0)
Hypothyroidism
2 (2.0)
2 (2.1)
Other
Melanocytic naevus
2 (2.0)
Oedema
2 (2.1)
Arthralgia
1 (1.0)
Hirsutism
1 (1.1)
Epiphysiolysis
1 (1.1)
Abbreviations: CI = confidence interval; FHD = fixed high dose of Humatrope; IAD = individually
adjusted dose of Humatrope; N = total number of patients; TEAE = treatment-emergent adverse event;
TSH = thyroid stimulating hormone.
Dose reductions due to changes in IGF-I or IGFBP-3 levels were required in 8 patients of
the FHD and 2 patients in the IAD group. Otherwise, safety-relevant laboratory data
(IGF-I, IGFBP-3, fasting glucose, fasting insulin, OGTT, lipids) and bone age after the
first and second year of treatment did not reveal any clinically relevant differences in
safety signals between the IAD and FHD group.
Somatropin
CT Registry ID#Z007
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Summary ID#Z007
Clinical Study Summary: Studies B9R-EW-E003/4
Title of Study: Investigation of the Safety and Efficacy of Growth Hormone Replacement Therapy in
Adults with Growth Hormone Deficiency Arising in Adult Life
Study Center(s): This study was conducted at 7 study centers in 6 European countries.
Date first patient enrolled: February 1992
Date last patient enrolled: March 1993
Objectives:
Primary Objective: Determine the efficacy of Humatrope® (biosynthetic human growth hormone [hGH],
somatropin) in the treatment of patients with adult-onset growth hormone deficiency (GHD) with respect to
body composition, cholesterol and lipid parameters, and health-related quality of life.
Secondary Objective: Determine the efficacy and safety of long-term treatment of growth
hormone-deficient adults with Humatrope, and assess changes in insulin-like growth factor levels and bone
parameters. Safety assessments were made using measurements to evaluate the adequacy of glucose
homeostatic mechanisms, regular safety laboratory tests, and analysis of treatment-emergent adverse events
(TEAEs) to detect any side effects of treatment.
Study Design:
Studies B9R-EW-E003 (E003) and B9R-EW-E004 (E004) were similar, outpatient, randomized, parallel,
double-blind, and placebo-controlled studies involving patients with adult-onset GHD. Patients began a
single-blind placebo lead-in period for 1 month. Then patients were randomized to receive either
Humatrope or placebo for 6 months in a double-blind fashion, followed by 12 months of open-label growth
hormone (GH) therapy for all patients.
Number of Patients:
Planned: 100 patients total, 50 patients per study, with 25 patients per treatment group.
Enrolled: 102 patients (Study E003, N = 48) (Study E004, N = 54).
Randomized: 98 patients (Study E003, N = 48 total; Humatrope, N = 27; placebo, N = 21) (Study E004,
N = 50 total; Humatrope, N = 25; placebo, N = 25).
Completed: Ninety-three patients completed the double-blind treatment period; 84 patients completed the
entire 18-month treatment period.
Diagnosis and Main Criteria for Inclusion: Deficiency of GH present for at least 1 year, arising during
adult life from pituitary ablation or failure, demonstrated within the last 2 years by a negative response to
standard GH stimulations test (maximal peak less than 5 ng/mL)
Test Product, Dose, and Mode of Administration: Began with 6.25 µg/kg/day Humatrope (1 month),
then 12.5 µg/kg/day thereafter; 16 IU (5.92 mg) freeze-dried biosynthetic GH in vials reconstituted with
8 mL diluent. The maximum dose allowed was 0.5 mg/day during the first 4 weeks following
randomization and 1 mg/day thereafter. Patients whose body weight exceeded 80 kg were allowed to
exceed this dose provided they had no adverse effects. Humatrope was administered as a single
subcutaneous injection in the evening.
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Placebo (Placebo/hGH): 1-month placebo lead-in for all patients, followed by 6-month double-blind for
randomized patients, followed by 12-month open-label hGH for all patients.
Humatrope (hGH/hGH): 1-month placebo lead-in for all patients, followed by 6-month double-blind for
randomized patients, followed by 12-month open-label hGH for all patients.
vials reconstituted with 8 mL diluent and administered in a single subcutaneous injection in the evening.
Variables:
Efficacy:
Primary: Body composition (lean body mass, fat mass, and percent body fat) derived by bioelectrical
impedance measurement and skinfold thickness, and lipids (total cholesterol, high-density lipoprotein
[HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, very low-density lipoprotein [VLDL]
cholesterol).
Secondary: In a limited number of patients, the concentration of insulin-like growth factor-I (IGF-I) and
insulin-like growth factor binding protein-3 (IGFBP-3), and bone parameters (osteocalcin; urinary
pyridinoline and deoxypyridinoline) and apolipoproteins A-1 and B.
Safety: Adverse events, vital sign evaluation, oral glucose tolerance tests, thyroid hormone concentrations,
GH antibodies, and clinical laboratory tests.
Health Outcomes: Total health-related quality of life scores by the Nottingham Health Profile.
Evaluation Methods:
Statistical: Data were analyzed using analysis of variance (ANOVA) with terms for treatment, investigator,
and treatment-by-investigator interaction in the model. For the first 6 months after randomization, efficacy
was assessed by comparison of Humatrope treatment with placebo. For the remainder of the studies,
efficacy was assessed by comparison of baseline values with Humatrope treatment values at 6, 12, or
18 months of treatment.
Data from the individual studies were analyzed separately (as E003 and E004) and combined (as E003/4).
The analysis using the combined data is reported here as Studies B9R-EW-E003/4 (E003/4) with reference
to the individual study data where appropriate or when results differed.
Efficacy Measure, Health-Related Quality of Life: The Nottingham Health Profile, a generic questionnaire
designed to measure levels of health-related distress in a general population, has been used widely in
populations of GH-deficient adults and is validated in multiple languages. The questionnaire is limited by a
lack of sensitivity or a “floor effect” to minor changes over time. No disease-specific questionnaire for
GHD was available at the initiation of the study. For purposes of this analysis, nonparametric analysis was
used, and p-values less than or equal to 0.01 were considered statistically significant and a p-value between
.01 and .05 was considered marginally significant.
For all other data analyses, a p-value of ≤.05 was considered statistically significant and a p-value between
.05 and .1 was considered marginally significant and referred to as such in this report.
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Summary
Patient Disposition
Of the 102 patients enrolled, 98 patients were randomized at Visit 2 (48 into Study E003,
50 into Study E004) to receive either Humatrope for 18 months (Study E003, N = 27;
Study E004, N = 25; total, N = 52) or placebo for 6 months followed by Humatrope for
12 months (Study E003, N = 21; Study E004, N = 25; total, N = 46). The 4 remaining
patients, all in Study E004, were enrolled but not randomized due to sponsor’s decision
(2), did not meet entry criteria (1), or discontinued due to personal conflict (1). Of the
98 patients randomized, 93 patients (91.2%) completed the 6-month double-blind
treatment period (Visits 2 to 5), and 84 patients (82.4%) completed the entire 18-month
treatment period (Visits 2 to 10). Fourteen randomized patients discontinued the studies
early for the following reasons: adverse events (4), personal conflict (2), protocol interim
criteria not met (4), patient’s perception of lack of efficacy (2), sponsor’s decision (1),
and lost to follow-up (1).
Table 1 summarizes the results of selected demographic measurements at baseline. At
baseline, the study groups were similar with respect to the 3 primary outcome measures
(body composition, lipid parameters, and health-related quality of life) except for
Study E004, in which patients had a statistically significantly greater waist/hip ratio in the
Placebo/hGH group and tended to have more fat mass and percent body fat than those
randomized to the hGH/hGH group.
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Table 1.
Page 4
Demographic Summary of All Randomized Patients
The most commonly reported historical diagnoses are summarized in Table 2.
CT Registry ID#Z007
Table 2.
Page 5
Historical Diagnoses of All Randomized Patients
E003
n
Active Adenoma
9
Inactive Adenoma
13
Craniopharyngioma
10
Dysgerminoma, Pinealoma, Meningioma, Glioma,
Epidermoid Cyst
5
Post-Tubercular Condition, Histiocytosis
2
Trauma, Sheehan Syndrome, Empty Sella
7
Idiopathic, Hypothalamic Origin
2
Total
48
Abbreviations: n = number of patients with each diagnosis.
Study
E004
n
21
12
9
E003/4
n
30
25
19
1
0
2
5
50
6
2
9
7
98
Secondary Conditions
The large majority of patients had panhypopituitarism as a secondary condition to a
pituitary/hypothalamic tumor.
Efficacy: Combined Studies (Studies E003/4)
Primary Efficacy: Body Composition
Table 3 summarizes actual and baseline-to-endpoint statistics for lean body mass for each
study separately and combined. In the hGH/hGH treatment group there was a statistically
significant within- and between-group change from baseline in lean body mass in Study
E003 and the combined Studies E003/4 but not in Study E004. This therapeutic effect
persisted into the open-label period for the additional 12 months of study drug exposure.
Table 4 summarizes actual and baseline-to-endpoint statistics for fat mass for each study
separately and combined. In Study E003 and Studies E003/4 patients in the hGH/hGH
treatment group experienced a statistically significant decrease in fat mass from baseline
to endpoint (6 months, double blind). No statistically significant change in fat mass was
demonstrated in Study E004, except in the placeo/hGH treatment group 6 months after
receiving hGH (open-label). In Study E003 and Studies E003/4 patients in the hGH/hGH
treatment group showed a greater statistically significant decrease in fat mass at 6 months
(double blind) compared with patients in the placebo treatment group. It should be noted
that at baseline, the study groups were similar with the exception of Study E004, in which
patients had a statistically significantly greater waist/hip ratio (p = .032) in the
Placebo/hGH group than those randomized to the Humatrope group. Furthermore, in
Study E004 the mean and median dose received was numerically less than in Study E003,
while the number of patients who received ≥12 µg/kg/day was greater in Study E003.
Table 5 summarizes actual and baseline-to-endpoint statistics for lean body mass/fat mass
ratio for each study separately and combined. In each study separately and combined
CT Registry ID#Z007
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there was a greater statistically significant increase in lean body/fat mass ratio from
baseline to endpoint (6 months, double blind) in the hGH/hGH treatment group compared
to placebo/hGH that persisted into the open-label period. No statistically significant
change in percent body fat was seen in the placebo-controlled period of Study E004. The
Placebo/hGH group had a statistically significant decrease in percent body fat during the
12-month open-label treatment period.
Table 6 summarizes actual and baseline-to-endpoint changes in the sum of skinfolds (sum
of measurements of skinfold thickness at four anatomic sites). The sum of skinfolds
demonstrated that local fat was reduced during Humatrope treatment.
Measurement of body composition by labeled water was conducted, but due to poor
reliability of results and sample-collection difficulties, the results were not used.
Table 3.
Summary and Analysis of Lean Body Mass
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Table 4.
Summary and Analysis of Fat Mass
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Table 5.
Summary and Analysis of Lean Body Mass/Fat Mass Ratio
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Table 6.
Summary and Analysis of Sum of Skinfolds
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Primary Efficacy: Lipids
Approximately half of the patients had total cholesterol values exceeding 240 mg/dL and
HDL cholesterol values below 35 mg/dL at baseline. The combined data, summarized in
Table 7, showed a statistically significant decrease in mean serum concentrations of total
cholesterol, LDL cholesterol, and VLDL cholesterol, and a statistically significant
increase in mean HDL cholesterol in the Humatrope group at 6 months compared with
baseline. However, only the increase in the HDL/LDL ratio was statistically significant
for the between-group comparison of placebo and Humatrope at 6 months. The
between-group comparison for HDL cholesterol was marginally statistically significant.
Over time, the change in 12- and 18-month mean HDL cholesterol and HDL/LDL values
continued to significantly increase or normalize over previously low and abnormal
baseline values.
Table 7.
Summary of Baseline-to-Endpoint (6 Months)
Change in Total, HDL, LDL, and VLDL Cholesterol, HDL/LDL Cholesterol Ratio, and Triglycerides
Treatment Group
Efficacy Parameter
N
Baseline
Mean (SD)
hGH/hGH
Change from
Baseline
Mean (SD)
pValuea
N
Placebo/hGH
Baseline
Change from
Mean (SD)
Baseline
Mean (SD)
p-Valuea
pValueb
Study E003
21
234.52 (53.03)
-13.43 (37.76)
.044
20
248.60 (58.00)
-7.35 (30.83)
.265
.856
HDL-C (mg/dL)
21
26.86 (8.61)
8.33 (10.80)
.001
20
31.55 (9.53)
3.70 (9.54)
.078
.088
LDL-C (mg/dL)
21
172.52 (58.01)
-14.71 (39.53)
.009
20
181.80 (63.04)
-10.90 (35.30)
.156
.962
HDL/LDL-C ratio
21
0.17 (0.07)
0.07 (0.09)
.001
20
0.20 (0.09)
0.06 (0.10)
.036
.372
VLDL-C (mg/dL)
21
35.19 (19.49)
-7.10 (13.67)
.012
20
33.80 (16.03)
1.30 (17.12)
1.000
.456
Triglycerides (mg/dL)
21
181.52 (124.71)
-8.76 (67.01)
0.841
20 177.80 (111.68)
3.95 (62.71)
0.458
0.773
Study E004
25
240.64 (53.52)
-16.68 (47.15)
.118
23
242.44 (47.16)
0.43 (22.77)
.555
.088
HDL-C (mg/dL)
25
34.40 (12.80)
7.88 (9.59)
<.001
23
33.68 (11.13)
5.00 (4.88)
<.001
.303
LDL-C (mg/dL)
25
179.12 (57.01)
-17.68 (48.26)
.068
23
179.96 (52.05)
-1.70 (28.86)
.616
.078
HDL/LDL-C ratio
25
0.25 (0.25)
0.09 (0.14)
.002
23
0.21 (0.10)
0.03 (0.04)
.003
.020
VLDL-C (mg/dL)
25
27.00 (10.18)
-6.76 (11.00)
.004
23
28.88 (16.61)
-2.96 (19.38)
.148
.391
25
232.64 (293.25) -66.96 (266.03)
.285
23
181.24 (81.87)
-0.04 (47.55)
.895
.309
Studies E003/4
46
237.85 (52.68)
-15.20 (42.69)
.014
43
245.18 (51.72)
-3.19 (26.78)
.525
.283
HDL-C (mg/dL)
46
30.96 (11.61)
8.09 (10.04)
<.001
43
32.73 (10.39)
4.40(7.35)
<.001
.052
LDL-C (mg/dL)
46
176.11 (56.92)
-16.33 (44.03)
.003
43
180.78 (56.52)
-5.98 (31.96)
.191
.241
HDL/LDL-C ratio
46
0.21 (0.19)
0.08 (0.12)
<.001
43
0.20 (0.10)
0.04 (0.08)
<.001
.044
VLDL-C (mg/dL)
46
30.74 (15.53)
-6.91 (12.15)
<.001
43
31.07 (16.36)
-0.98 (18.28)
.319
.305
46
209.30 (231.17) -40.39 (201.49)
.323
43
179.71 (95.10)
1.81 (54.48)
.678
.431
Abbreviations: C=cholesterol; HDL = high density lipoprotein; hGH = Humatrope; LDL = low density lipoprotein; N = number of patients with measurements;
SD = standard deviation; VLDL = very low density lipoprotein.
a Within-group p-value for change from baseline.
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Primary Efficacy: Health-Related Quality of Life
The Hospital Anxiety and Depression scale was used at baseline to detect significant
mood disorders. There were no scores in the moderate-to-severe range, and the 6 patients
who scored above the normal range were within the 12- to 18-month prevalence range of
mood disorders for normal populations.
The Nottingham Health Profile was used to assess health-related quality of life in the
study population. The Nottingham Health Profile assesses 6 domains: Energy Level,
Emotional Reactions, Social Isolation, Sleep, Pain, and Physical Mobility. Patients with
adult-onset GHD at baseline experienced more distress than reference populations and as
much distress in this generic questionnaire as other diseases such as diabetes and breast
cancer, but not rheumatoid arthritis. Between-group comparisons for combined Studies
E003/4 demonstrated a statistically significant improvement (p<0.01), or decrease in
discomfort, in the areas of Social Isolation and Physical Mobility, which persisted
throughout treatment. There was a significant improvement long-term at 12 and
18 months for Energy Level, although no between-group differences could be detected
at 6 months.
Efficacy by Subgroup Analyses
Subgroup analyses were performed on the main efficacy variables (lean body mass,
percent body fat, total cholesterol, HDL cholesterol, and sum of skinfolds). The
subgroups were sex, age, and percent body fat. There were no statistically significant
differential treatment effects for the 6-month double-blind therapy period when sex or
age was considered. There were no statistically significant group differences for total
cholesterol, HDL cholesterol, or sum of skinfolds relative to percent-body-fat subgroups.
However, there were statistically significant group differences for percent body fat
(p=.001) and lean body mass (p<.001).
Secondary Efficacy Objective
Markers of Bone Metabolism
Surrogate markers (osteocalcin, urinary pyridinoline, and urinary deoxypyridinoline)
were tested to assess the effect of Humatrope on bone. The osteocalcin level was
statistically significantly different in the Humatrope-treated group (5.44 ± 5.30 ng/mL,
p<.001) compared with the placebo-treated group at 6 months and persisted over time
compared with baseline in the combined studies. Due to poor assay validity, urinary
pyridinoline, and urinary deoxypyridinoline values were not used.
Insulin-Like Growth Factor
Tables 8 and 9 summarize the baseline-to-endpoint (6 months and 18 months,
respectively) changes in IGF-I and IGFBP-3. A treatment effect on IGF-I and IGFBP-3
CT Registry ID#Z007
Page 14
was documented for the between- and within-group comparisons. The between-group
comparison showed that the Humatrope-treated group had a statistically significant
greater increase in IGF-I and IGFBP-3 compared with the placebo-treated group (p<.001)
during the double-blind therapy period (6 months). This effect persisted in the
hGH/hGH-treated group through the 12- and 18-month endpoints (p<.001).
Table 8.
Change in IGF-I and IGFBP-3
Treatment Group
Placebo/hGH
Baseline
Mean (SD)
Mean (SD)
Change
Efficacy
Parameter
Study E003
IGF-I (ng/mL)
IGFBP-3 (ng/mL)
21
21
67.76 (34.25)
2432.16 (940.82)
Study E004
IGF-I (ng/mL)
IGFBP-3 (ng/mL)
25
25
78.04 (44.65)
2510.64 (1052.56)
N
pValuea
N
Baseline
Mean (SD)
174.24 (111.01)
1174.26
(756.69)
<.001
<.001
21
21
68.10 (26.54)
2113.62 (844.54)
117.44 (86.46)
847.76
(1083.92)
<.001
.001
25
25
72.12 (35.81)
2488.20 (978.98)
Studies E003/4
IGF-I (ng/mL)
46
73.35 (40.14)
143.37 (101.40)
<.001
46
70.28 (31.64)
IGFBP-3 (ng/mL) 46
2474.81 (992.89)
996.82 (952.95)
<.001
46
2317.20 (929.37)
Abbreviations: hGH = human growth hormone (Humatrope); IGF-I = insulin-like growth factor I;
IGFBP-3 = insulin-like growth factor-binding protein 3; N = number of patients with measurements;
CT Registry ID#Z007
hGH/hGH
Mean (SD)
Change
pValuea
pValueb
-0.33 (18.70)
-0.52 (452.33)
.360
.880
<.001
<.001
4.92 (19.19)
-61.12 (634.99)
.215
.657
<.001
.001
2.52 (18.94)
-33.46 (554.00)
.590
.636
<.001
<.001
Page 15
Table 9.
Change in IGF-I and IGFBP-3
Efficacy Parameter
hGH/hGH Treatment Group
Baseline
N
Mean (SD)
Mean (SD)
Change
p-Valuea
Study E003
IGF-I (ng/mL)
67.76 (34.25)
21
184.71 (101.42)
<.001
IGFBP-3 (ng/mL)
2432.16 (940.82)
21
1293.36 (757.93)
<.001
Study E004
IGF-I (ng/mL)
78.04 (44.65)
25
133.96 (106.22)
<.001
IGFBP-3 (ng/mL)
2510.64 (1052.56)
25
704.79 (1162.53)
.007
Studies E003/4
IGF-I (ng/mL)
73.35 (40.14)
46
157.13 (106.03)
<.001
IGFBP-3 (ng/mL)
2474.81 (992.89)
46
973.49 (1031.49)
<.001
Abbreviations: hGH = human growth hormone (Humatrope); IGF-I = insulin-like growth factor I; IGFBP-3 = insulin-like growth factor-binding protein 3;
N = number of patients with measurements; SD = standard deviation.
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Apolipoprotein A-I and Apolipoprotein B
There was only a statistically significant within-treatment group change from baseline to
endpoint (12 months) for patients in the Placebo/hGH treatment group (9.35 mg/dL ±
13.70, p=.006) in Study E003 for apolipoprotein A-I.
There were several statistically significant changes from baseline for apolipoprotein B.
Patients treated in the hGH/hGH group in E003 showed within-treatment group changes
from baseline at 6 months(-20.52 mg/L ± 25.97, p=001), 12 months (-14.81 mg/L ±
26.86, p=.022), and at 18 months (- 14.10 ± 27.01 mg/L, p=.032). For the combined
studies, patients in the hGH/hGH treatment group showed a statistically significant
within-group decrease from baseline to endpoint at 6 months in apolipoprotein B (-15.26
mg/L ± 42.90, p=003). There were no other within or between-treatment group changes
from baseline. However, in Study E003 there was a statistically significant difference
between the two treatment groups with regard to the treatment effect observed during the
first 12 months of Humatrope treatment; the hGH/hGH treatment group had a 14.8 mg/L
decrease in apolipoprotein B compared to a 5.10 mg/L increase in the Placebo/hGH
treatment group (p=.017). In the combined studies, the hGH/hGH treatment group had a
6.72 mg/L decrease in apolipoprotein B compared to a 3.43 mg/L increase in the
Placebo/hGH treatment group (p=.034).
Efficacy by Individual Study (Study E003 and Study E004)
Separate analyses of the 2 studies showed differences between Studies E003 and E004.
While Study E003 efficacy parameters significantly improved compared with placebo,
this was not the case for several efficacy parameters in Study E004. There were no
statistically significant changes in fat mass, percentage body fat, or lean body mass in
Study E004, although the sum of skinfold thicknesses decreased significantly in
Study E004 as well as Study E003. Furthermore, while HDL cholesterol increased
compared with baseline during the first 6 months of each study, the changes in total
cholesterol and LDL cholesterol during the double-blind, placebo-controlled phase were
not significant in Study E004. This discrepancy between the 2 studies may be due to
dosage differences. In Study E003, most patients were given the full dose of
12.5 µg/kg/day, as outlined in the protocol. In Study E004, several investigators kept to a
maximum dose of 1 mg and also tended to reduce the dose due to initial therapy side
effects. As a result, patients in Study E004 were more likely to receive a dose less
than 12.5 µg/kg/day; thus, the overall dose of Humatrope was lower in Study E004 than
in Study E003.
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Safety
Deaths, Serious Adverse Events, and Discontinuations
Table 10 presents an overview of serious adverse events (SAEs) reported during these
studies. No patient deaths were reported. Fourteen SAEs were reported for 12 patients
during the first 18-month period, and 6 SAEs were reported for 6 patients during the
extension period of these studies. Ten patients required hospitalization.
Table 10.
Serious Adverse Events by Body System
and Treatment Period
Treatment
Group
Treatment
Period
Days on hGH
Therapya
hGH/hGH
Lead-in
0
hGH/hGH
hGH/hGH
Placebo/hGH
hGH/hGH
hGH/hGH
hGH/hGH
hGH/hGH
hGH
hGH
hGH
hGH
hGH
hGH
hGH
101
289
274
175
298
261
304
Lymphatic/Skin
Lymphedema, Skin Ulcer
Placebo/hGH
hGH
50
Nervous/Musculoskeletal
Tenosynovitis, Myalgia, Paresthesia
Tenosynovitis, Paresthesia
Placebo/hGH
Placebo/hGH
hGH
hGH
59
113
Respiratory
Rhinitis
Sinusitis
hGH/hGH
Placebo/hGH
Lead-in
hGH
0
351
Event
Body as a Whole
Dehydration, Fever, Electrolyte Abnormality,
Vomiting
Accidental Injury
Recurrence of Craniopharyngioma
Sepsis, Vomiting Fever, Hypotension
Surgical Procedure
Surgical Procedure
Addisonian Crisis, Hemorrhage, Hypokalemia
Syncope
Special Senses
Deafness, Tinnitus
hGH/hGH
hGH
Safety Reports Filed During the Extension Period
Recurrence of Pituitary Tumor
hGH/hGH
hGHb
Cellulitis
Placebo/hGH
hGHc
Surgical Procedure
hGH/hGH
hGHc
Cerebrovascular Accident
hGH/hGH
hGHc
Gastritis
Placebo/hGH
hGHc
Sinusitis
Placebo/hGH
hGHc
Abbreviations: hGH = human growth hormone (Humatrope); lead-in = placebo lead-in.
aNumber of days of Humatrope treatment prior to reporting the serious adverse event.
bDaily Humatrope treatment.
cHumatrope treatment on alternate days.
57
711
539
1066
834
464
381
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A total of 4 patients discontinued prior to completion of the studies due to hyperglycemia
(N = 1, 43 days on therapy), dyspnea (N = 1, 509 days of therapy), neoplasm (N = 1,
298 days of therapy), and arthralgia (N = 1, 320 days of therapy). All were receiving
Humatrope at the time of discontinuation.
Tables 11 and 12 summarize the percentage of patients reporting treatment-emergent
adverse events (TEAEs) with ≥5% overall incidence during the 6-month double-blind
therapy and the 18-month study period, respectively. The most frequent TEAEs during
the first 6 months of treatment for Humatrope-treated patients were edema, peripheral
edema, arthralgia, and myalgia. There was a statistically significant greater incidence of
edema and peripheral edema reported in Humatrope-treated patients than placebo-treated
patients during the first 6 months of therapy. There were no other statistically significant
TEAEs in the first 6 months. Over the 18-month course of the studies, edema, arthralgia,
paresthesia, pain, myalgia, and rhinitis were the most common TEAEs reported.
Table 13 shows those events that occurred in 5% or more of patients but were thought to
be unrelated to Humatrope therapy or that were a result of common illness.
Table 11.
Treatment-Emergent Adverse Events Occurring in 5% or
More of Patients During Double-Blind Therapy
p-valuesa
Placebo/hGH
hGH/hGH
0-6 months
0-6 months
(N=46)
(N=52)
Edema
9 (17.3%)
2 (4.3%)
0.043
Peripheral edema
6 (11.5%)
0 (0%)
0.017
Arthralgia
5 (9.6%)
1 (2.2%)
0.125
Myalgia
4 (7.7%)
2 (4.3%)
0.491
Headache
3 (5.8%)
2 (4.3%)
0.750
Back pain
3 (5.8%)
1 (2.2%)
0.369
Joint disorder
3 (5.8%)
0 (0%)
0.098
Abbreviation: hGH = human growth hormone (Humatrope).
aDifference in frequency for Humatrope versus placebo; Pearson chi-square test.
CT Registry ID#Z007
Table 12.
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Occurring in 5% or More of Patients
hGH/hGH
Placebo/hGH
Edema
21.2%
11.4%
Arthralgia
17.3%
13.6%
Paresthesia
17.3%
13.6%
Pain
13.5%
13.6%
Myalgia
13.5%
9.1%
Rhinitis
13.5%
11.4%
Peripheral edema
11.5%
18.2%
Back pain
9.6%
9.1%
Headache
7.7%
6.8%
Joint disorder
5.8%
2.3%
Table 13.
Adverse Events Unrelated to Treatment Occurring in 5% or
More of Patients
hGH/hGH
Placebo/hGH
Rhinitis
13.5%
11.4%
Hypertension
7.7%
4.5%
Surgical procedure
5.8%
2.3%
Flu syndrome
3.8%
6.8%
Vital Sign Evaluation
Patients in these studies had no statistically significant differences between treatment
groups at baseline or during the course of study for supine heart rate, supine diastolic
blood pressure, and systolic blood pressure.
The data from the clinical laboratory measurements were analyzed for categorical
distribution of results from baseline to endpoint, categorical distribution at endpoint, and
identification of patients with markedly abnormal laboratory results. During the 6-month
double-blind placebo-controlled study period, a statistically significant categorical shift in
treatment versus placebo was observed for serum glutamate-pyruvate transaminase
(SGPT), gamma glutamyl transferase (GGT), and inorganic phosphate. However, for
SGPT and GGT, the increase occurred in the placebo-treated group without any abnormal
clinical condition reported or related. For inorganic phosphate, the shift occurred in the
Humatrope-treated group, was without clinical relevance, and could be secondary to the
Humatrope effect on renal tubular function.
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Growth Hormone Antibody Formation
Two patients developed anti-growth hormone antibodies. For 1 patient (2 samples) with
specific growth hormone antibodies, binding capacity was ≤0.5 mg/L in each sample.
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Summary ID#Z009
Clinical Study Summary: Study B9R-EW-E001
Title of Study: The Efficacy and Safety of Biosynthetic Authentic Human Growth Hormone in Short
Prepubertal Children with Normal Growth Hormone Response to Standard Provocation Tests
Investigators: This multicenter study included 28 principal investigators.
Study Centers: This multinational study was conducted at 28 study centers in 10 countries.
Phase of Development:
Phase 3
Date first patient enrolled: March 1988
Date last patient completed: January 2001
Objectives:
Primary Objective: To evaluate if a higher dose (27 IU/m2 body surface area [BSA] per week
[0.37 mg/kg/wk]) of Humatrope® (LY137998, somatropin) administered over 2 years would result in a
greater increase in height velocity over pretreatment height velocity than a lower Humatrope dose
(18 IU/m2/wk [0.24 mg/kg/wk]).
• To assess whether increasing the Humatrope dose from 18 IU/m2/wk (0.24 mg/kg/wk) after the
first year to 27 IU/m2/wk (0.37 mg/kg/wk) during the second year would blunt the decrease in
height velocity that typically occurs after the first year of therapy,
• To assess whether the higher dose of Humatrope (27 IU/m2/wk [0.37 mg/kg/wk]) would result in
a greater final height compared to the lower dose (18 IU/m2/wk [0.24 mg/kg/wk]),
• To determine any difference in the rate of adverse events among the three different dosing
treatment groups (see Figure 1).
Study Design:
This was an open-label, randomized, dose-response study. The core study consisted of a screening phase,
followed by a randomized, open-label, 2-year dose-response phase. Patients who met study enrollment
criteria were randomized to one of three Humatrope treatment groups. During the first year of treatment,
patients in Dose 1 and 2 received 0.24 mg/kg/wk Humatrope while patients in Dose 3 received
0.37 mg/kg/wk Humatrope. At approximately 12 months (Visit 6), patients in Dose 2 were switched to
0.37 mg/kg/wk Humatrope while patients in Treatment Groups 1 and 3 remained at their initial dose.
Patients were evaluated every 3 months for height velocity and safety during this 2-year E001 core
dose-response phase of the study. The 2-year core study concluded at Visit 10.
All patients who completed the core study were eligible to receive Humatrope at the same dose they had
been receiving at Visit 10, then followed to final height in the E001 extension phase. During the
extension phase of the trial, patients’ height velocity, bone age data, and safety were collected annually.
An interim analysis was performed after 4 years of treatment. By 1996, a substantial number of patients
had concluded participation in the study and the global, multinational E001 extension phase was stopped.
Thereafter, four Lilly affiliates (France, Germany, Spain, and Netherlands) elected to continue the study
under local extensions, with the aim of obtaining as much final height data as possible.
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E001
Extension Phase/
Final Height
E001
Core Dose-Response Phase/
Height Velocity
Screening
Phase
Affiliate
Extension/
Final Height
0.37 mg/kg/wk
Dose 3
0.37 mg/kg/wk
Dose 2
0.24 mg/kg/wk
0.24 mg/kg/wk
Dose 1
Visit
Month
1
2
3
4
5
6
7
8
9
10
11a ………………………………….……..FH
-12 mo
to 0 days
0
3
6
9
12
15
18
21
24
36 a ………………………………….……..
Randomization/
Baseline
End of 2-year
core study
Abbreviation: FH = final height.
a Visit 11 procedures were repeated every 12 months until final height was
attained.
Figure 1. Study design.
Number of Patients:
Planned: 250
Entered: 261
Randomized: 239
Dose 1: Male: 49, Female: 29; Total: 78
Completed 2-Year Core Study (Visit 10): Dose 1: 70, Dose 2: 67, and Dose 3: 72.
Entered E001/Affiliate Extensions (Visit 11): Dose 1: 58, Dose 2: 58, and Dose 3: 57.
Attained Final Height On-Study or at Poststudy Follow-up: Dose 1: 17, Dose 2: 16, and Dose 3: 17.
Diagnosis and Main Criteria for Inclusion: Patients were included who had short stature (height at
least 2.0 standard deviations [SDs] below the mean for British standards), normal maximal plasma GH
peaks above 20 mU/L (10 ng/mL) in response to a standard stimulation test, a bone age less than 10 years
(females) or 12 years (males), normal thyroid function, chronological age 5 years or older, and prepubertal
status according to the criteria of Tanner (Marshall and Tanner, 1969; Marshall and Tanner, 1970).
Patients also had to have a height velocity below the 25th percentile for age below 10 years (females) or 12
years (males) and to have signed the informed consent document.
Humatrope was administered subcutaneously in divided doses given 6 days per week in the evening. The
average weekly-per-kilogram Humatrope doses in each of the treatment groups were as follows:
Dose 1: 0.24 mg/kg/wk;
Dose 2: 0.24 mg/kg/wk for 1 year, followed by 0.37 mg/kg/wk;
Dose 3: 0.37 mg/kg/wk.
Humatrope: 0.04 mg/kg/day, given six times per week (0.24 mg/kg/wk) by injection
Vials of lyophilized Humatrope, 1.48 mg.
Humatrope: 0.06 mg/kg/day, given six times per week (0.37 mg/kg/wk) by injection
Vials of lyophilized Humatrope, 1.48 mg.
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Duration of Treatment: The protocol consisted of a 2-year dose-response phase and an extension phase
with study drug to be continued until final height (defined as height velocity less than 2.0 cm/y).
All Randomized Patients (mean ± SD)
Dose 1: 4.69 ± 2.41 years (n=78)
Dose 2: 4.41 ± 2.38 years (n=78)
Dose 3: 4.50 ± 2.39 years (n=83)
Final Height Population (mean ± SD)
Dose 1: 6.09 ± 2.28 years (n=17)
Dose 2: 6.34 ± 2.19 years (n=16)
Dose 3: 6.97 ± 1.95 years (n=17)
Reference Therapy, Dose, and Mode of Administration: No reference therapy was used.
Variables:
Efficacy:
The primary efficacy analysis was the change in height velocity (cm/y) from pretreatment to 2-year
endpoint. Change in height velocity was the annualized treatment height velocity based on measurements
at the start of treatment and at Visit 10 (2 years of treatment) minus pretreatment height velocity. The
primary comparison was between Dose 1 and Dose 3.
Secondary efficacy variables were final height standard deviation score (SDS), final height minus baseline
height (centimeters and SDS), final height minus baseline predicted height (centimeters and SDS), and
final height minus target height (centimeters and SDS). Final height was considered to be the last height
measurement obtained after height velocity had slowed to less than 2.0 cm/y.
Safety: Safety endpoints were adverse events, vital signs (resting heart rate and systolic and diastolic
blood pressure), laboratory data (fasting blood glucose [FBG] and glycosylated hemoglobin), and
antibodies to hGH or Escherichia coli polypeptide.
Evaluation Methods:
Data Sets Analyzed: The data analyses addressed three populations of study participants. Table 1
provides a summary of the number of patients in each data analysis population.
• All Randomized Patients Population was defined as all patients who were randomized at Visit 2.
• 2-Year Height Velocity Population comprised all patients who had a height measurement at
Visit 10 (2 years) and was the primary efficacy analysis data set for this report.
• Final Height Population comprised patients for whom a final height measurement was obtained
after height velocity had fallen below 2.0 cm/y.
Table 1.
Number of Patients in Data Analysis Populations
Population
Dose 1
Dose 2
Dose 3
Total
2-Year Height Velocity
70
67
72
209
78
78
83
239
Final Height
17
16
17
50
Note: Dose 1 = 0.24 mg/kg/wk; Dose 2 = 0.24 mg/kg/wk for the first year, then 0.37 mg/kg/wk;
Dose 3 = 0.37 mg/kg/wk.
Statistical: The primary efficacy variable for this study was height velocity. The primary efficacy
analysis was the change in height velocity (cm/y) from pretreatment to 2-year endpoint (that is, height
velocity based on measurements at Visit 2 and Visit 10) for the 2-Year Height Velocity Population. The
primary comparison was between Dose 1 and Dose 3.
Safety: Fisher’s exact test was used in the analysis of adverse events.
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Summary
Disposition of Patients
Of the 261 patients screened for entry into this study, 22 patients either failed
inclusion/exclusion criteria at Visit 1, decided not to participate in the study, or were lost
to follow-up. The remaining 239 patients qualified for the study and were randomized
into one of three treatment groups at Visit 2 (Dose 1, n=78; Dose 2, n=78; Dose 3, n=83)
and comprised the All Randomized Patients Population. Of the 239 patients in the All
Randomized Patients Population, 30 patients discontinued between Visit 2 and Visit 10.
The 209 patients that remained at Visit 10 (Dose 1, n=70; Dose 2, n=67; Dose 3, n=72)
were included in the 2-Year Height Velocity Population. Fifty patients reached final
height and were included in the Final Height Population (Dose 1, n=17; Dose 2, n=16;
Dose 3, n=17). Of these 50 patients, 22 patients from the Netherlands had discontinued
the study prior to reaching final height and had subsequently been followed locally to
final height poststudy. Table 2 provides the reasons for patients’ discontinuations from
the study for all randomized patients.
Table 2.
Primary Reasons for Study Discontinuation
Primary Reasons for Discontinuation
-----------------------------------Protocol completed
Dose 1
(N=78)
n (%)
---------18 (23.1)
Dose 2
(N=78)
n (%)
---------11 (14.1)
Adverse event
2
(2.6)
0
Unable to contact patient (lost to
follow-up)
4
(5.1)
2
7
Sponsor's decision
6
Dose 3
(N=83)
n (%)
---------14 (16.9)
Total
(N=239)
n (%)
---------43 (18.0)
p-Value*
---------.322
1
(1.2)
3
(1.3)
.539
(2.6)
3
(3.6)
9
(3.8)
.772
(9.0)
9 (11.5)
8
(9.6)
24 (10.0)
.894
(7.7)
7
5
(6.0)
18
(7.5)
.786
91 (38.1)
.068
25 (10.5)
.748
Patient decision
22 (28.2)
Physician decision
10 (12.8)
(9.0)
31 (39.7)
38 (45.8)
7
(9.0)
8
(9.6)
1
(1.3)
2
(2.4)
3
(1.3)
.775
Unknown
0
Protocol Violation
6
(7.7)
6
(7.7)
2
(2.4)
14
(5.9)
.213
Lack of efficacy
3
(3.8)
4
(5.1)
2
(2.4)
9
(3.8)
.641
Dose 1=0.24 mg/kg/wk, Dose 2=0.24-0.37 mg/kg/wk, Dose 3=0.37 mg/kg/wk
Note: Report based on last available summary record for each patient.
* Frequencies are analyzed using a Fisher's Exact test.
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Table 3 displays patient demographic and other baseline (Visit 2) characteristics for those
patients who had a height measurement at Visit 10 (2-Year Height Velocity Population;
n=209). Treatment group comparisons were performed using an overall F-test for
numeric variables and the Fishers exact test for categorical variables. There were no
statistically significant differences in baseline age, gender, origin, weight, height, body
mass index, bone age, bone age to chronological age ratio, Tanner stage, predicted height,
pre-treatment height velocity, target height, or target height SDS.
There were statistically significant differences in baseline demographics among the
treatment groups in the All Randomized Patients and the 2-Year Height Velocity
Populations in the height SDS, predicted height SDS, and sitting height measures. To
assess the impact of baseline height SDS imbalance, the primary analysis was also
conducted with baseline height SDS as a covariate. As the results were similar to those
obtained without adding the covariate, the conclusions based upon the primary analysis
were not changed. There were no statistically significant differences among treatment
groups at baseline for any of the variables analyzed for the Final Height Population.
CT Registry ID#Z009
Table 3.
Variable
------------------
2-Year Height Velocity Population
Dose 1
(N=70)
------------
Dose 2
(N=67)
------------
Dose 3
(N=72)
------------
Total
(N=209)
------------
70
9.37
9.49
2.48
5.10
15.19
67
9.82
10.07
2.14
5.21
12.90
72
9.97
9.95
2.19
5.43
14.82
209
9.72
9.92
2.28
5.10
15.19
Age (yrs)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Gender
No. Patients
Female
Male
Origin
No. Patients
Asian
Caucasian
Page 7
p-Value
------------
.273**
70
25 (35.7)
45 (64.3)
67
24 (35.8)
43 (64.2)
72
21 (29.2)
51 (70.8)
209
70 (33.5)
139 (66.5)
.621*
70
0
70 (100)
67
2 (3.0)
65 (97.0)
72
0
72 (100)
209
2 (1.0)
207 (99.0)
.102*
Weight (kg)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
70
21.25
20.65
6.12
8.40
36.00
67
22.42
23.00
5.42
10.00
33.00
72
22.86
23.25
5.32
11.00
37.60
209
22.18
22.30
5.65
8.40
37.60
.217**
Height (cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
70
116.34
116.60
13.21
83.35
142.03
67
119.20
119.15
11.21
93.10
134.50
72
120.91
122.20
10.60
95.03
143.03
209
118.83
119.43
11.82
83.35
143.03
.067**
Height SDS
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
70
-3.41
-3.25
0.83
-7.13
-2.31
67
-3.21
-3.04
0.70
-5.44
-2.05
72
-3.02
-2.95
0.55
-5.50
-1.72
209
-3.21
-3.07
0.72
-7.13
-1.72
.004**
Body Mass Index (kg/m2)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
70
15.34
15.20
1.85
11.90
21.00
67
15.49
15.65
1.67
11.00
19.02
72
15.42
15.34
1.73
11.21
19.79
209
15.41
15.38
1.75
11.00
21.00
.877**
(continued)
CT Registry ID#Z009
Table 3.
Page 8
2-Year Height Velocity Population (continued)
Dose 1
(N=70)
------------
Dose 2
(N=67)
------------
Dose 3
(N=72)
------------
Total
(N=209)
------------
69
7.42
7.53
2.60
2.52
12.64
1
67
8.03
8.59
2.30
1.54
11.76
0
71
8.02
8.10
1.97
1.48
11.76
1
207
7.82
8.13
2.31
1.48
12.64
2
.210**
Bone Age/Chronological Age Ratio
No. Patients
69
Mean
0.81
Median
0.82
Standard Dev.
0.15
Minimum
0.47
Maximum
1.13
Unspecified
1
67
0.83
0.85
0.14
0.34
1.18
0
71
0.83
0.84
0.13
0.30
1.14
1
207
0.82
0.83
0.14
0.30
1.18
2
.567**
Variable
-----------------Bone Age (yrs)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
Tanner Stage of Sexual Development
No. Patients
70
Stage 1
69 (98.6)
Stage 2
1 (1.4)
Predicted Height (cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
Predicted Height SDS
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
67
67 (100)
0
72
71 (98.6)
1 (1.4)
209
207 (99.0)
2 (1.0)
p-Value
------------
1.00*
39
156.13
158.51
9.17
134.76
172.40
31
52
154.78
158.45
10.15
133.70
169.91
15
48
158.63
159.26
9.15
140.30
185.29
24
139
156.49
158.82
9.62
133.70
185.29
70
.130**
39
-2.76
-2.72
1.00
-5.07
-0.70
31
52
-2.87
-2.55
1.05
-5.32
-1.07
15
48
-2.34
-2.39
1.10
-4.13
1.24
24
139
-2.66
-2.56
1.07
-5.32
1.24
70
.034**
66
4.45
4.39
1.33
0.93
10.53
1
71
4.35
4.32
1.10
0.92
7.26
1
205
4.34
4.32
1.16
0.92
10.53
4
.534**
Pre-treatment Height Velocity (cm/yr)
No. Patients
68
Mean
4.23
Median
4.24
Standard Dev.
1.07
Minimum
1.66
Maximum
6.46
Unspecified
2
(continued)
CT Registry ID#Z009
Table 3.
Page 9
2-Year Height Velocity Population (concluded)
Variable
------------------
Dose 1
(N=70)
------------
Dose 2
(N=67)
------------
Dose 3
(N=72)
------------
Total
(N=209)
------------
Target Height (cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
68
163.88
165.60
8.13
143.00
179.00
2
64
165.57
166.32
8.28
147.10
189.50
3
72
165.91
167.50
8.05
143.20
186.00
0
204
165.13
166.55
8.16
143.00
189.50
5
.294**
68
-1.34
-1.28
0.90
-3.84
0.87
2
64
-1.09
-1.09
0.89
-2.96
1.87
3
72
-1.16
-1.23
0.87
-3.63
1.34
0
204
-1.20
-1.25
0.89
-3.84
1.87
5
.246**
Target Height SDS
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
p-Value
------------
Dose 1=0.24 mg/kg/wk, Dose 2=0.24-0.37 mg/kg/wk, Dose 3=0.37 mg/kg/wk
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
Efficacy
Primary Efficacy Analysis-Height Velocity
The primary efficacy analysis was the change in height velocity (cm/y) from pretreatment
to 2-year endpoint (that is, height velocity based on measurements at Visit 2 and Visit 10)
for the 2-Year Height Velocity Population. The primary comparison was between Dose 1
and Dose 3. Table 4 presents the effect of Humatrope on height velocity from
pretreatment to 2-year endpoint.
Patients who received 0.37 mg/kg/wk Humatrope (Dose 3) achieved a statistically
significantly greater pretreatment to 2-year endpoint change in height velocity than the
patients who received 0.24 mg/kg/wk Humatrope (Dose 1, p=.003) or 0.24 mg/kg/wk
Humatrope for the first year and 0.37 mg/kg/wk Humatrope thereafter (Dose 2, p=.001).
There was no statistically significant difference in height velocity change between Dose 1
and Dose 2 (p=.672).
CT Registry ID#Z009
Table 4.
Page 10
Height Velocity Changes from Pretreatment to 2-Year
Endpoint
Therapy
Baseline
Endpoint
Change
--------------------------------------------------------------------------
Dose 1
N
Mean
Std
Median
Min
Max
68
4.23
1.07
4.24
1.66
6.46
68
7.49
1.21
7.39
5.43
10.18
68
3.27
1.32
3.32
-0.07
6.05
Dose 2
N
Mean
Std
Median
Min
Max
66
4.45
1.33
4.39
0.93
10.53
66
7.61
1.47
7.63
4.67
11.28
66
3.16
1.53
3.02
0.45
7.74
Dose 3
N
Mean
Std
Median
Min
Max
71
4.35
1.10
4.32
0.92
7.26
71
8.39
1.32
8.38
5.79
11.27
71
4.04
1.66
3.95
0.20
7.25
Model
Baseline
Endpoint
Change
----------------------------------------------------------------------------
Main
ANOVA
Therapy
LS MEANS
Dose 1
Dose 2
Dose 3
p-value
Lsm(se)
Lsm(se)
Lsm(se)
.534
<.001
.001
4.23(0.14)
4.45(0.14)
4.35(0.14)
7.49(0.16)
7.61(0.16)
8.39(0.16)
3.27(0.18)
3.16(0.19)
4.04(0.18)
DIFFERENCES
Dose 3 minus Dose 1 Diff(se)
p-value
0.12(0.20)
.534
0.90(0.23)
<.001
0.78(0.26)
.003
p-value
-0.10(0.20)
.608
0.78(0.23)
.001
0.89(0.26)
.001
p-value
0.23(0.20)
.264
0.11(0.23)
.619
-0.11(0.26)
.672
Abbreviations: LOCF = last observation carried forward, Base Pred Ht SDS = baseline
predicted height standard deviation score,Lsm = least squares mean, Se = standard error,
Diff = difference.
Note: Dose 1 = 0.24 mg/kg/wk, Dose 2 = 0.24-0.37 mg/kg/wk, Dose 3 = 0.37 mg/kg/wk.
Technical Note: Baseline = LOCF to Visit 2 HV24. Endpoint = Visit 10 HV24.
CT Registry ID#Z009
Page 11
Secondary Efficacy Analyses
Height Velocity in 2-Year Height Velocity Population
Tables 5 and 6 present the analysis of variance (ANOVA) of the height velocity changes
from pretreatment to the end of the first year (Visit 6) and from the first year to the
second year, respectively, in the 2-Year Height Velocity Population. During the first year
of treatment, the increase in height velocity over pretreatment in Dose 3 was significantly
greater than Dose 1 and Dose 2: p=.005 and p<.001, respectively. There was no
statistically significant difference in height velocity change between Dose 1 and Dose 2
(p=.238). From the first year to the second year in the 2-Year Height Velocity
Population, there was a decrease in height velocity in the second year compared to the
first year in all three treatment groups. However, in the Dose 2 group, in which the hGH
dose was increased from 0.24 mg/kg/wk to 0.37 mg/kg/wk at the end of the first year,
height velocity decline was significantly smaller than in the Dose 3 (p=.005) or
Dose 1 (p=.032) groups. There was no statistically significant difference in height
velocity decline between Dose 1 and Dose 3 (p=.518). This finding indicates that
increasing the hGH dose at the end of the first year is associated with a lesser degree of
deceleration in height velocity in the second year of treatment.
Table 5.
Height Velocity Changes from Pretreatment to First Year
Therapy
Baseline
Endpoint
Change
-------------------------------------------------------------------------Dose 1
N
Mean
Std
Median
Min
Max
67
4.19
1.04
4.24
1.66
6.30
67
8.21
1.48
8.20
5.06
11.30
67
4.02
1.66
3.89
-0.00
8.08
Dose 2
N
Mean
Std
Median
Min
Max
65
4.45
1.34
4.37
0.93
10.53
65
8.10
1.69
8.04
5.15
13.02
65
3.66
1.76
3.34
0.27
10.02
Dose 3
N
Mean
Std
Median
Min
Max
71
4.35
1.10
4.32
0.92
7.26
71
9.23
1.63
8.88
6.31
14.16
71
4.88
1.87
4.63
0.62
10.36
(continued)
CT Registry ID#Z009
Page 12
Table 5.
Height Velocity Changes from Pretreatment to First Year
Model
Baseline
Endpoint
Change
--------------------------------------------------------------------------------------------Main
ANOVA
Therapy
p-value
.450
<.001
<.001
LS MEANS
Dose 1
Dose 2
Dose 3
Lsm(se)
Lsm(se)
Lsm(se)
4.19(0.14)
4.45(0.14)
4.35(0.14)
8.21(0.20)
8.10(0.20)
9.23(0.19)
4.02(0.22)
3.66(0.22)
4.88(0.21)
DIFFERENCES
p-value
0.16(0.20)
.430
1.02(0.27)
<.001
0.86(0.30)
.005
p-value
-0.10(0.20)
.628
1.13(0.28)
<.001
1.23(0.30)
<.001
p-value
0.25(0.20)
.212
-0.11(0.28)
.694
-0.36(0.31)
.238
Technical Note: Baseline = LOCF to Visit 2 HV12. Endpoint = Visit 6 HV12.
CT Registry ID#Z009
Page 13
Table 6.
Height Velocity Changes from First Year to Second Year
Therapy
Baseline
Endpoint
Change
-------------------------------------------------------------------------Dose 1
N
Mean
Std
Median
Min
Max
69
8.21
1.47
8.20
5.06
11.30
69
6.71
1.38
6.49
2.88
9.38
69
-1.50
1.63
-1.60
-6.26
2.54
Dose 2
N
Mean
Std
Median
Min
Max
66
8.08
1.69
7.99
5.15
13.02
66
7.17
1.60
7.24
3.86
10.61
66
-0.91
1.49
-0.74
-5.09
2.84
Dose 3
N
Mean
Std
Median
Min
Max
72
9.22
1.63
8.88
6.31
14.16
72
7.54
1.46
7.47
4.27
11.58
72
-1.67
1.63
-1.59
-7.49
2.85
(continued)
CT Registry ID#Z009
Page 14
Table 6.
Height Velocity Changes from First Year to Second Year
Model
Baseline
Endpoint
Change
--------------------------------------------------------------------------------------------Main
ANOVA
Therapy
p-value
<.001
.004
.015
LS MEANS
Dose 1
Dose 2
Dose 3
Lsm(se)
Lsm(se)
Lsm(se)
8.21(0.19)
8.08(0.20)
9.22(0.19)
6.71(0.18)
7.17(0.18)
7.54(0.17)
-1.50(0.19)
-0.91(0.20)
-1.67(0.19)
DIFFERENCES
p-value
1.01(0.27)
<.001
0.83(0.25)
.001
-0.17(0.27)
.518
p-value
1.14(0.27)
<.001
0.38(0.25)
.138
-0.76(0.27)
.005
p-value
-0.13(0.28)
.631
0.46(0.26)
.076
0.59(0.27)
.032
Technical Note: Baseline = Visit 6 HV12. Endpoint = Visit 10 HV12.
CT Registry ID#Z009
Page 15
CT Registry ID#Z009
Page 16
Endpoint and Final Height SDS
Table 7 provides the ANCOVA of endpoint height SDS for the 2-Year Height Velocity
Population, with baseline predicted height SDS as the covariate. A statistically
significant difference between Dose 3 and Dose 1 (p=.006) and between Dose 3 and
Dose 2 (p=.014) for endpoint height SDS of the 2-Year Height Velocity Population was
seen. When the ANCOVA was performed on the Final Height Population, Dose 3 had a
higher least squares mean (LSM) final height SDS than Dose 1 (0.45), but this difference
did not reach statistical significance (p=.086).
Dose 3 had a significantly higher height SDS at 18 years of age than Dose 1 (p=.012)
upon repeated measures analysis of height SDS in the 2-Year Height Velocity Population.
The treatment effect (0.44 SDS) in the repeated measures model is similar to the
difference in final height SDS between Dose 3 and Dose 1 (0.45 SDS) in the ANCOVA
for Final Height Population.
On the individual patient level, 14/17 (82.4%) patients in Dose 3 achieved final height
above the 5th percentile for Prader growth standards (Prader et al. 1989), compared to
8/17 (47.1%) patients in Dose 1.
Table 7.
Endpoint Height Standard Deviation Score,
Analysis of Covariance
Model
Endpoint
----------------------------------------------------------------Main
PARAMETER
Base Pred HT SDS
p-value
<.001
Therapy
p-value
.010
LS MEANS
Dose 1
Dose 2
Dose 3
Lsm(se)
Lsm(se)
Lsm(se)
-1.95(0.13)
-1.87(0.12)
-1.45(0.12)
DIFFERENCES
p-value
0.51(0.18)
.006
p-value
0.42(0.17)
.014
0.08(0.18)
p-value
.630
Abbreviations: LOCF = last observation carried forward, Base Pred Ht SDS = baseline
predicted height standard deviation score,Lsm = least squares mean, Se = standard error,
Diff = difference.
Technical Note: Baseline = HT_SDS LOCF to Visit 2. Endpoint = HT_SDS LOCF to Visit 103.
CT Registry ID#Z009
Page 17
Safety
Deaths, Serious Adverse Events, and Discontinuations Due to Adverse
Events
Table 8 provides an overview of the adverse events (serious and treatment-emergent) and
discontinuations seen during the study. Table 9 provides a summary of the serious
adverse events (SAEs) in the All Randomized Patients Population. There were no patient
deaths reported during this study. Thirty-eight SAEs were reported for 31 patients. Two
patients discontinued study participation because of SAEs which were deemed
unexpected and possibly related to study drug. An additional patient discontinued study
participation because of an adverse event that was deemed unexpected and possibly
related to study drug, but was not serious.
Treatment Emergent Adverse Events
Table 10 summarizes treatment-emergent adverse events (TEAEs) for All Randomized
Patients in order of decreasing frequency for the total patient group. Events were coded
using the Eli Lilly Event Classification Terms (ELECT) dictionary, which was in use at
the time of the study’s implementation.
The majority of these events represent common childhood conditions such as upper
respiratory illnesses and flu syndrome. Bronchitis, diarrhea, and anemia showed
statistically significant differences among treatment groups, but the differences were not
considered clinically relevant.
The body systems for which TEAEs were most frequently reported were body as a whole
(44% of patients), respiratory system (31% of patients), and digestive system (13% of
patients). There were statistically significant differences in the proportion of patients in
each treatment group who had at least one TEAE in the hemic and lymphatic system
(p=.033).
CT Registry ID#Z009
Table 8.
Page 18
Number and Percentage of Patients
Patients
n (%)
Dose 2
Dose 3
N=78
N=83
0 (0)
0 (0)
4 (5.1)
16 (19.3)
0 (0)
1 (1.2)
0 (0)
1 (1.2)
Dose 1
Total
Adverse Eventa
N=78
N=239
Death
0 (0)
0 (0)
11 (14.1)
31 (13.0)
Discontinuation due to an adverse event
2 (2.6)
3 (1.3)
Serious, unexpected, possibly related
1 (1.3)
2 (0.8)
adverse events
Nonserious adverse events
8 (10.3)
14 (17.9)
14 (16.9)
36 (15.1)
47 (60.3)
57 (73.1)
58 (69.9)
162 (67.8)
Abbreviations: N = number of patients in treatment group; n = number of patients who experienced at least
one adverse event.
a Patients may be counted in more than one category.
CT Registry ID#Z009
Table 9.
Page 19
Serious Adverse Event
Number of patients in treatment group
Number of patients for whom an event was reported
Total number of events
Dose 1
n (%)
78
11 (14.1)
12
Dose 2
n (%)
78
4 (5.1)
8
Dose 3
n (%)
83
16 (19.3)
18
Total
n (%)
239
31 (13.0)
38
Cancer
Intra-abdominal desmoplastic tumor
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Hospitalizations
Abdominal pain
2 (2.6)
0 (0.0)
0 (0.0)
2 (0.8)
Appendicitis
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Bronchitis
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Convulsion
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Dehydration
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Delayed puberty
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Epilepsy
0 (0.0)
0 (0.0
1 (1.2)
1 (0.4)
Enuresis
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Epiphysiolysis and surgical correction
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Fractures
0 (0.0)
0 (0.0)
3 (3.6)
3 (1.3)
Haematuria
0 (0.0)
1 (1.3)
0 (0.0)
1 (0.4)
Hematemesis
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Polymyositis
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Surgical procedures
Appendectomy
1 (1.3)
0 (0.0)
1 (1.2)
2 (0.8)
Cosmetic surgery
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Cyst removal
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Dental avulsion
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Insertion of transtympanic drain
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Nasal septum correction
1 (1.3)
0 (0.0)
0 (0.0)
1 (0.4)
Surgery NOS (toe arthalgia)
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Surgery NOS, Aortic valve stenosis
0 (0.0)
1 (1.3)
0 (0.0)
1 (0.4)
Surgery NOS, Esophageal atresia
0 (0.0)
1 (1.3)
0 (0.0)
1 (0.4)
Tonsillectomy/Adenoidectomy
2 (2.6)
1 (1.3)
2 (2.4)
5 (2.1)
Tularemia
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Other
Convulsions NOS
0 (0.0)
4 (5.1)
0 (0.0)
4 (1.7)
Overdose
Accidental overdose (non-therapeutic agent)
0 (0.0)
0 (0.0)
1 (1.2)
1 (0.4)
Abbreviations: n=number of patients for whom an event was reported, NOS = not otherwise specified.
CT Registry ID#Z009
Table 10.
Page 20
--------------------------PATIENTS WITH >= 1 TESS
INFECTION
PHARYNGITIS
FLU SYNDROME
RHINITIS
BRONCHITIS
ACCIDENTAL INJURY
GASTROENTERITIS
SURGICAL PROCEDURE
OTITIS MEDIA
ABDOMINAL PAIN
FEVER
SINUSITIS
ALLERGIC REACTION
PAIN
DIARRHEA
HEADACHE
URINARY TRACT INFECTION
ANEMIA
CONVULSION
COUGH INCREASED
ASTHENIA
BONE DISORDER
CONJUNCTIVITIS
ECZEMA
EOSINOPHILIA
HYPERLIPEMIA
MIGRAINE
VOMITING
ARTHRALGIA
ENTERITIS
HERPES SIMPLEX
LAB TEST ABNORMAL
OTITIS EXTERNA
PNEUMONIA
RASH
TOOTH DISORDER
ACNE
ALBUMINURIA
ANXIETY
ASTHMA
BACK PAIN
CYST
GASTROINTESTINAL DISORDER
HEMATURIA
HEMORRHAGE
HYPERCHOLESTEREMIA
HYPOTHYROIDISM
INJECTION SITE REACTION
JOINT DISORDER
MICROCYTIC ANEMIA
MYALGIA
Dose 1
(N=78)
n (%)
---------47 (60.3)
31 (39.7)
16 (20.5)
14 (17.9)
8 (10.3)
6 (7.7)
11 (14.1)
4 (5.1)
5 (6.4)
4 (5.1)
4 (5.1)
4 (5.1)
4 (5.1)
2 (2.6)
2 (2.6)
0
1 (1.3)
2 (2.6)
1 (1.3)
1 (1.3)
0
0
0
0
1 (1.3)
1 (1.3)
2 (2.6)
1 (1.3)
1 (1.3)
0
0
2 (2.6)
1 (1.3)
1 (1.3)
1 (1.3)
1 (1.3)
1 (1.3)
3 (3.8)
1 (1.3)
0
1 (1.3)
1 (1.3)
1 (1.3)
0
0
1 (1.3)
2 (2.6)
0
0
2 (2.6)
0
0
0
Dose 2
(N=78)
n (%)
---------57 (73.1)
21 (26.9)
12 (15.4)
8 (10.3)
9 (11.5)
10 (12.8)
7 (9.0)
2 (2.6)
4 (5.1)
3 (3.8)
4 (5.1)
4 (5.1)
3 (3.8)
2 (2.6)
1 (1.3)
4 (5.1)
5 (6.4)
3 (3.8)
2 (2.6)
4 (5.1)
3 (3.8)
3 (3.8)
2 (2.6)
2 (2.6)
0
1 (1.3)
2 (2.6)
0
2 (2.6)
3 (3.8)
1 (1.3)
1 (1.3)
1 (1.3)
0
1 (1.3)
2 (2.6)
1 (1.3)
0
0
2 (2.6)
0
0
0
1 (1.3)
0
1 (1.3)
0
2 (2.6)
1 (1.3)
0
2 (2.6)
2 (2.6)
1 (1.3)
Dose 3
(N=83)
n (%)
---------58 (69.9)
25 (30.1)
15 (18.1)
12 (14.5)
8 (9.6)
6 (7.2)
2 (2.4)
8 (9.6)
5 (6.0)
7 (8.4)
4 (4.8)
0
1 (1.2)
4 (4.8)
4 (4.8)
3 (3.6)
0
1 (1.2)
3 (3.6)
0
2 (2.4)
2 (2.4)
2 (2.4)
2 (2.4)
3 (3.6)
2 (2.4)
0
3 (3.6)
1 (1.2)
1 (1.2)
2 (2.4)
0
1 (1.2)
2 (2.4)
1 (1.2)
0
1 (1.2)
0
1 (1.2)
0
1 (1.2)
1 (1.2)
1 (1.2)
1 (1.2)
2 (2.4)
0
0
0
1 (1.2)
0
0
0
1 (1.2)
Total
(N=239)
n (%)
---------162 (67.8)
77 (32.2)
43 (18.0)
34 (14.2)
25 (10.5)
22 (9.2)
20 (8.4)
14 (5.9)
14 (5.9)
14 (5.9)
12 (5.0)
8 (3.3)
8 (3.3)
8 (3.3)
7 (2.9)
7 (2.9)
6 (2.5)
6 (2.5)
6 (2.5)
5 (2.1)
5 (2.1)
5 (2.1)
4 (1.7)
4 (1.7)
4 (1.7)
4 (1.7)
4 (1.7)
4 (1.7)
4 (1.7)
4 (1.7)
3 (1.3)
3 (1.3)
3 (1.3)
3 (1.3)
3 (1.3)
3 (1.3)
3 (1.3)
3 (1.3)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
2 (0.8)
p-Value*
---------.213
.213
.708
.395
.964
.426
.019
.174
1.00
.480
1.00
.084
.362
.737
.511
.133
.017
.530
.874
.047
.288
.288
.551
.551
.328
1.00
.396
.328
.844
.220
.775
.317
1.00
.775
1.00
.317
1.00
.068
1.00
.211
1.00
1.00
1.00
1.00
.331
.545
.211
.211
1.00
.211
.211
.211
1.00
(continued)
CT Registry ID#Z009
Table 10.
Page 21
All Randomized Patients (concluded)
--------------------------NAUSEA
URINARY INCONTINENCE
URTICARIA
ALOPECIA
ANOREXIA
BALANITIS
CARDIOVASCULAR DISORDER
CONSTIPATION
DEPRESSION
EAR DISORDER
EAR PAIN
ECCHYMOSIS
EMOTIONAL LABILITY
ENDOCRINE DISORDER
EYE DISORDER
FLATULENCE
GLUCOSE TOLERANCE DECREASED
GROWTH ACCELERATED
HAIR DISORDER
HEMATEMESIS
HEMOLYTIC ANEMIA
HYPERACUSIS
HYPERGLYCEMIA
HYPERURICEMIA
HYPOCHROMIC ANEMIA
INCREASED APPETITE
INJECTION SITE INFLAMMATION
INJECTION SITE PAIN
INSOMNIA
LARYNGITIS
LEUKOCYTOSIS
LEUKODERMA
LEUKOPENIA
LIPODYSTROPHY
LUNG DISORDER
LYMPHOCYTOSIS
MACULOPAPULAR RASH
MALAISE
MONILIASIS
MYOSITIS
NEOPLASM
OVERDOSE
PERIPHERAL EDEMA
PRURITUS
PSORIASIS
RECTAL DISORDER
SIALADENITIS
SKIN DISORDER
SYNCOPE
THROMBOCYTOPENIA
VAGINAL HEMORRHAGE
VAGINITIS
VENTRICULAR EXTRASYSTOLES
VISUAL FIELD DEFECT
Dose 1
(N=78)
n (%)
---------0
1 (1.3)
1 (1.3)
0
0
1 (1.3)
0
0
0
0
0
1 (1.3)
1 (1.3)
0
0
0
1 (1.3)
0
0
0
0
1 (1.3)
0
0
0
0
1 (1.3)
0
0
1 (1.3)
0
0
0
0
1 (1.3)
0
0
0
1 (1.3)
1 (1.3)
1 (1.3)
0
0
1 (1.3)
0
0
0
0
1 (1.3)
1 (1.3)
0
0
0
0
Dose 2
(N=78)
n (%)
---------2 (2.6)
0
1 (1.3)
1 (1.3)
1 (1.3)
0
0
0
0
1 (1.3)
1 (1.3)
0
0
1 (1.3)
0
0
0
1 (1.3)
0
0
0
0
0
0
1 (1.3)
0
0
1 (1.3)
0
0
1 (1.3)
1 (1.3)
1 (1.3)
0
0
1 (1.3)
0
1 (1.3)
0
0
0
0
1 (1.3)
0
1 (1.3)
0
1 (1.3)
0
0
0
0
0
0
0
Dose 3
(N=83)
n (%)
---------0
1 (1.2)
0
0
0
0
1 (1.2)
1 (1.2)
1 (1.2)
0
0
0
0
0
1 (1.2)
1 (1.2)
0
0
1 (1.2)
1 (1.2)
1 (1.2)
0
1 (1.2)
1 (1.2)
0
1 (1.2)
0
0
1 (1.2)
0
0
0
0
1 (1.2)
0
0
1 (1.2)
0
0
0
0
1 (1.2)
0
0
0
1 (1.2)
0
1 (1.2)
0
0
1 (1.2)
1 (1.2)
1 (1.2)
1 (1.2)
Total
(N=239)
n (%)
---------2 (0.8)
2 (0.8)
2 (0.8)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
p-Value*
---------.211
1.00
.545
.653
.653
.653
1.00
1.00
1.00
.653
.653
.653
.653
.653
1.00
1.00
.653
.653
1.00
1.00
1.00
.653
1.00
1.00
.653
1.00
.653
.653
1.00
.653
.653
.653
.653
1.00
.653
.653
1.00
.653
.653
.653
.653
1.00
.653
.653
.653
1.00
.653
1.00
.653
.653
1.00
1.00
1.00
1.00
Abbreviations: N = Total number of patients, n = Total number of patients for whom an
event was reported.
Dose 1 = 0.24 mg/kg/wk, Dose 2 = 0.24-0.37 mg/kg/wk, Dose 3 = 0.37 mg/kg/wk
CT Registry ID#Z009
Page 22
Laboratory Measurements
Table 11 presents a summary of the incidence of high (>7.0 mmol/L) or low
(<2.0 mmol/L) fasting plasma glucose values after baseline for All Randomized Patients.
There were no significant dose effects on the incidence of high or low fasting plasma
glucose values or on the mean fasting plasma glucose or glycosylated hemoglobin values.
Eight patients had fasting plasma glucose concentrations above the upper limit of the
reference range (7 mmol/L) on a single occasion after baseline. Since each patient had
only a single elevated fasting plasma glucose in the presence of normal glycosylated
hemoglobin, the elevations most likely reflect inadequate fasting status as occurs
commonly in pediatric study populations.
Vital Signs
There were no significant differences among treatment groups in mean change between
baseline and endpoint for all reported vital sign variables (pulse, systolic blood pressure,
and diastolic blood pressure).
Table 11.
Incidence of High or Low Fasting Plasma Glucose After Baseline
------------------------- p-Value *
Incidence
Group
----------
Dose 1(1)
(Total=75)
N
n
(%)
--------------
Dose 2(2)
(Total=78)
N
n
(%)
--------------
-------------------------
Dose 3(3)
(Total=80)
N
n
(%)
--------------
Overall
--------------
(1 )VS.(2 )
--------------
(1 )VS.(3 )
--------------
(2 )VS.(3 )
--------------
77
2
(2.6)
.539
.486
1.00
.497
77
4
(5.2)
.911
1.00
.682
1.00
77 71 (92.2)
.607
1.00
.496
.495
Lab Test: Fasting Glucose {mmol/L}
--LOW
72
1
(1.4)
76
0
HIGH
72
2
(2.8)
76
3
ALL NORMAL
72 69 (95.8)
(3.9)
76 73 (96.1)
Dose 1 = 0.24 mg/kg/wk, Dose 2 = 0.24-0.37 mg/kg/wk, Dose 3 = 0.37 mg/kg/wk
Note: Total = Total number of patients in the treatment group within the
requested time interval.
N = Total number of patients with the lab test.
n = Total number of patients within the specified range (e.g. HIGH).
Low = <2.0 mmol/L.
High = >7.0 mmol/L.
CT Registry ID#Z009
Page 23
CT Registry ID#Z009
Page 24
References
Marshall WA, Tanner JM. 1969. Variations in pattern of pubertal changes in girls. Arch
Dis Child 44:291-303.
Marshall WA, Tanner JM. 1970. Variations in the pattern of pubertal changes in boys.
Arch Dis Child 45:13-23.
Prader A, Largo RH, Molinari L, Issler C. 1989. Physical growth of Swiss children from
birth to 20 years of age. First Zurick Longitudinal study of growth and development.
Helv Paediatr Acta Suppl 52: 1-125.
CT Registry ID#Z019
Page 1
Summary ID#Z019
Clinical Study Summary: Study B9R-JE-6001
Title of Study: Evaluation of Growth Promoting Effect and Safety of Growth Hormone in Achondroplasia
Date of clinical study start: March 1993
Date of clinical study completion: June 1997
Objectives: The primary objective of the study was to assess the efficacy of 0.5 versus 1.0 IU/kg/wk of
somatropin in improving growth rates and height standard deviation scores (SDS) after 12, 24, and
36 months of treatment in achondroplasia. Secondary objectives included additional efficacy and safety
analyses.
Study Design: The present study was carried out as a multicenter, open-label study in patients divided into
2 dosage groups (0.5 and 1.0 IU/kg/wk). Patients were allocated to the 2 groups by the minimization
method to avoid group-related differences in the main background factors (chronological age, bone age,
and height SDS). Measurements were obtained before the start of treatment and after 1, 2, 3, 6, 9, 12, 15,
18, 21, 24, 27, 30, 33, and 36 months of treatment. If one or both of the following criteria were not met
after completion of one-year administration, the dose was increased from 0.5 IU to 1.0 IU for patients in the
0.5 IU Group, while growth hormone (GH) therapy was suspended for one year for patients in the
1.0 IU Group: a) growth rate in the one year of treatment was more than 4 cm/year, b) difference between
the growth rate in the year before treatment and that in the year of treatment was more than 1.0 cm.
Number of Patients:
A total of 46 patients were randomized in this study.
0.5 IU/kg/wk group: 22
1.0 IU/kg/wk group: 24
Diagnosis and Main Criteria for Inclusion: Patients were included if they had been diagnosed with
achondroplasia (with no history of GH therapy), had a height less than or equal to 2 standard deviations
below the standard value of persons of the same sex and age, had a chronological age of 4 to 10 years
(males) or 4 to 9 years (female) at the start of treatment, had not yet developed secondary sex
characteristics, had normal thyroid function, and had height data for 1 year prior to start of treatment.
Somatropin 0.5 IU/kg/wk, administered subcutaneously in 6 to 7 divided doses. (4 IU of recombinant
human GH per vial)
Somatropin 1.0 IU/kg/wk, administered subcutaneously in 6 to 7 divided doses. (4 IU of recombinant
human GH per vial)
Duration of Treatment: 3 years
Somatropin
CT Registry ID#Z019
Page 2
Variables:
Efficacy:
The growth rate (cm/y) and height SDS at the start of treatment and after 12, 24, and 36 months of
treatment were calculated from the height recorded 1 year before the start of treatment, and after 12, 24,
and 36 months of treatment. Additional efficacy measures were: body weight, distance between both
digital tips, length of both legs, sitting height, circumference of the head, chronological age and bone age.
Safety:
Safety was evaluated through the reporting of adverse events and laboratory tests (hematology,
biochemistry, endocrinology and antibody tests, and urinalysis).
Evaluation Methods:
Statistical: The significance of differences in the following parameters between before and after
treatment was determined by the paired t-test in each group and the significance of differences in the
following parameters between the two groups was determined by t-test. The level of significance was 5%
(two-sided test).
Parameters regarding Height:
• Growth rate (cm/y)
• Height SDS in the standard of normal children
• Height SDS in the standard of children with achondroplasia
Parameters regarding Bone Age:
• Bone age/height age in the standard of normal children
• Bone age/height age in the standard of children with achondroplasia
Other Parameters:
• Distance between both digital tips and the ratio of distance between both digital tips to height
• Leg length and the ratio of leg length to height
• Sitting height and the ratio of sitting height to height
• Head circumference and the ratio of head circumference to height
Drug safety was assessed in all 46 patients. Patients whose administration of drug was suspended (from
12 months to 24 months), whose dose was increased after 12 months (from 0.5 to 1.0 IU/kg/wk), who
showed poor compliance, or who dropped out were excluded from the efficacy analysis.
Summary:
Patient Disposition and Demographics:
Forty-six pediatric patients with achondroplasia were divided into two groups
(0.5 IU Group: 22 patients; 1.0 IU Group: 24 patients). Table 6001.1 lists demographic
data for these patients. Growth hormone deficiency (GHD) was detected in 2 patients in
the 0.5 IU Group and 5 patients in the 1.0 IU Group. Baseline characteristics were
similar between the two groups.
Somatropin
CT Registry ID#Z019
Table 6001.1.
Page 3
Demographic Data of Patients at the Start of Treatment
Number of Patients
Sex
Growth hormone secretion stimulating
test*
Male
Female
Normal
No. of Patients
0.5 IU Group 1.0 IU Group
22
24
11 (50.0%)
12 (50.0%)
11 (50.0%)
12 (50.0%)
20 (90.9%)
19 (79.2%)
Total
46
23 (50.0%)
23 (50.0%)
39 (84.8%)
Insufficient
2 (9.1%)
5 (20.8%)
7 (15.2%)
Chronologic age (years)
6.7±0.4
6.8±0.4
6.7±0.3
Bone age (years) 20 bones
5.5±0.4
5.6±0.5
5.5±0.3
Bone age (years) RUS
5.8±0.5
6.0±0.6
5.9±0.4
Height (cm)
92.4±1.8
93.1±2.
92.8±1.3
Height SDS (standard of normal children
-5.0±0.2
-5.1±0.2
-5.1±0.1
Height SDS (standard of children with
-0.2±0.2
-0.2±0.1
-0.2±0.1
achondroplasia
Body weight (kg)
18.3± 1.0
17.8±1.0
18.0±0.7
Obesity index (%)
34.9±3.8
29.3±3.4
31.9±2.6
Growth rate at the start of treatment
4.2±0.2
3.9±0.3
4.0±0.2
(cm/year)
Growth rate SDS in the standard of
-2.4±0.4
-2.7±0.4
-2.5±0.3
normal children
Abbreviations: RUS = Radius, ulnar, short bones; SDS = standard deviation score.
Note: Values are Mean±standard error (SE).
* GH secretion was classified as "insufficient" only when the peak value in at least 2 GH secretion
stimulating tests was ≤10 ng/ml.
Thirty-four patients (n=16, 0.5 IU Group; n=18, 1.0 IU Group) were evaluated for the
growth-promoting effect and utility. Twelve patients were excluded from the efficacy
evaluation: 4 patients whose growth hormone therapy was suspended after 12 months;
3 patients whose dose was increased after 12 months (from 0.5 to 1.0 IU/kg/wk);
3 patients who showed poor compliance or who dropped out; and 2 patients who violated
criteria for continuation of treatment.
Primary Efficacy Measures:
Results for the primary efficacy measures of growth rate (cm/y) and height SDS are
provided in Table 6001.2.
Somatropin
CT Registry ID#Z019
Table 6001.2.
Page 4
Efficacy Results
0.5 IU Group
Growth rate (cm/y)
0 months
12 months
24 months
4.0±0.2
5.9±0.2
4.7±0.2
36 months
Height SDS (standard of
normal children)
0 months
12 months
24 months
36 months
p-value
1.0 IU Group
p-value
(withingroup)
p-value
(between
groups)
<0.001
<0.05
3.8±0.3
6.9±0.2*
4.9±0.3*
<0.001
<0.05
3.8±0.2
NS
4.8±0.2*
< 0.05
<0.01
NS
(p=0.609)
<0.05
-4.98±0.30
-4.63±0.29
-4.51±0.30
-4.50±0.26
<0.01
<0.01
<0.001
-5.07±0.20
-4.47±0.20
-4.25±0.21
-4.30±0.23
<0.01
<0.01
<0.01
NS
NS
NS
Height SDS (standard of
patients with
achondroplasia)
0 months
-0.16±0.29
0.25±0.17
12 months
0.18±0.28
<0.01
0.33±0.17
<0.01
NS
24 months
0.24±0.28
<0.01
0.46±0.18
<0.01
NS
36 months
0.20±0.25
<0.001
0.44±0.21
<0.001
NS
Abbreviations: NS = Not significant; SDS = standard deviation score.
Note: Values are mean±standard error (SE)
* The growth rate at 12 and 36 months was significantly larger in the 1.0 IU Group than in the 0.5 IU
Group (p<0.01 and p<0.05, respectively).
Between the two groups, there was no statistically significant difference in the height
SDS (standard of patients with achondroplasia) recorded at 12, 24, or 36 months of
treatment.
Secondary Efficacy Measures:
In the 0.5 IU Group, the ratio of bone age to the height age relative to that of normal
children (referred to as BA/HA[normal]) showed no statistically significant changes
compared with that recorded at the start of treatment. In the 1.0 IU Group, the ratio
recorded at the start of treatment (1.78±0.09) decreased to 1.66±0.09 after 6 months of
treatment (p<0.001) and further decreased to 1.65±0.10 after 12 months of treatment
(p<0.05), but there were no statistically significant changes after 24 months of treatment.
In the 0.5 IU Group, the ratio of bone age to the height age relative to that of children
with achondroplasia (BA/HA[achondro]) recorded at the start of treatment was
0.89±0.04, and increased to 0.93±0.03 after 12 months of treatment, to 0.99±0.04 after
Somatropin
CT Registry ID#Z019
Page 5
24 months of treatment, and to 1.01±0.03 after 36 months of treatment; the increase was
statistically significant after 12, 24 and 36 months of treatment (p<0.05, p<0.01 and
p<0.05, respectively). In the 1.0 IU Group, compared with the value recorded at the start
of treatment (0.83±0.05), a statistically significant (p< 0.01) decrease was noted after
6 months (0.79±0.05) and a statistically significant (p<0.05) increase was noted after
24 months (0.89±0.04) of treatment. After 36 months of treatment, the change was not
When the two groups were compared, both the BA/HA (normal) and BA/HA (achondro)
were statistically significantly (p<0.05) smaller in the 1.0 IU Group after 36 months of
treatment.
Table 6001.3 lists the ratio of distance between both digital tips (arm span), leg length,
sitting height, and head circumference to height. The ratio of distance between both
digital tips, that of leg length, and that of sitting height to height showed no statistically
significant difference compared with the start of treatment in either group. The ratio of
head circumference to height at 36 months was statistically significantly decreased
compared with that of the start of treatment in both groups (p<0.001).
Somatropin
CT Registry ID#Z019
Table 6001.3.
Page 6
Ratio of Each Physical Parameter to Height
0.5IU Group
1.0IU Group
t-test
(0.5IU vs 1.0IU)
At the start of treatment
0.90±0.02(15)
0.92±0.01(17)
P=0.4058
Arm Span
At 12 months
0.91±0.01(14)
0.91±0.01(18)
P=0.8365
(Distance between
At 24 months
0.92±0.02(12)
0.91±0.01(17)
P=0.8062
both digital tips)
At 36 months
0.91±0.01(15)
0.91±0.01(15)
P=0.7111
Paired test (0M vs 12M)
P=0.3370
P=0.6684
P=0.3409
P=0.6692
P=0.3356
P=1.0000
0.39±0.01(15)
0.41±0.01(15)
P=0.0868
At 12 months
0.40±0.00(13)
0.41±0.01(17)
P=0.2139
Length of both
At 24 months
0.40±0.00(12)
0.41±0.01(16)
P=0.3966
lower legs
At 36 months
0.41±0.01(14)
0.41±0.01(15)
P=0.9614
P=0.3370
P=0.3343
P=0.3388
P=0.1648
P=0.1648
P=0.3370
0.68±0.01(14)
0.67±0.01(14)
P=0.6765
At 12 months
0.67±0.01(13)
0.67±0.01(15)
P=0.8900
At 24 months
0.68±0.01(12)
0.66±0.01(16)
P=0.3235
At 36 months
0.68±0.01(13)
0.66±0.01(12)
P=0.1560
P=0.1661
P=0.3356
P=0.1669
P=0.1654
P=1.0000
P=0.0811
0.58±0.01(13)
0.57±0.02(15)
P=0.8589
At 12 months
0.54±0.01(13)
0.57±0.01(18)
P=0.1276
Circumference
At 24 months
0.53±0.01(12)
0.53±0.02(15)
P=0.9367
of the head
At 36 months
0.51±0.01(13)
0.53±0.01(15)
P=0.2050
P=0.0172
P=0.1643
P=0.0162
P=0.0024
P=0.0007
P=0.0007
Sitting height
Note: Values are Means±SE (n), where SE = Standard Error and n = number of patients in analysis.
Somatropin
CT Registry ID#Z019
Page 7
Safety:
Table 6001.4 provides a summary of abnormal laboratory test findings. During the
treatment period, there were 47 incidents (21 patients) of abnormal laboratory findings
whose causal relationship with growth hormone could not be ruled out (positive or
indefinite): 5 patients in 0.5 IU, 13 patients in 1.0 IU, and 1 patient in 0.5 IU→1.0 IU, in
addition 2 patients suspended treatment and/or dropped out in 1.0 IU group.
The causal relationship was judged “positive” in 6 incidents (1 patient in 0.5 IU: positive
anti-hGH antibodies; 3 patients in 1.0 IU: increased triiodothyronine (T3), positive antihGH antibodies, and abnormal oral glucose tolerance test (OGTT); 1 patient in
0.5→1.0 IU: abnormal OGTT; 1 patient suspended treatment in 1.0 IU→0 IU: positive
anti-hGH antibodies), with 2 incidents out of the 6 showing no normalization (1 patient in
0.5→1.0 IU: abnormal OGTT; 1 suspended patient: positive anti-hGH antibodies). With
regard to abnormal OGTT, no follow-up testing was conducted because the patients
failed to visit the hospital after discontinuation of the growth hormone administration.
Regarding the patients who tested positive for anti-hGH antibodies, the investigators
judged it unnecessary to follow up with them because they showed no particular clinical
symptoms. The five positive anti-hGH antibody laboratory tests were judged to have a
“positive” or “indefinite” causal relationship with growth hormone administration. Three
of these patients subsequently tested negative for anti-hGH antibodies while continuing
to receive growth hormone. Although two patients continued to have a positive test for
anti-hGH antibodies, the investigator did not believe it was necessary to continue to
follow-up with the patients because the titer of the antibody was less than 100-fold
dilution.
Somatropin
Somatropin
Table 6001.4.
Abnormal Laboratory Tests
Dosage
0.5IU group
(Pts.)
(18)*
Relationship
Patients with Abnormal
Laboratory Test
Counts of Abnormal
Laboratory Test
RBC↓
WBC↑
WBC↓
Eosinophil↑
Neutrophil↑
Neutrophil↓
Lymphocyte↑
Lymphocyte↓
Monocyte↓
ATL
Plt↑
Hb↓
Ht↓
GOT↑
GPT↑
Al-p↑
BUN↑
BUN↓
Total Cholesterol↑
Cl↑
Ca↓
HbA1↑
T3↑
T4↑
Anti-hGH Antibody
Urinary Protein Positive
Urine Sugar Positive
Urinary Occult Blood
OGTT
1.0IU group
(21)
0.5IU→1.0IU group
(3)
Suspended/dropped out
patients in 1.0IU group
(3)
Positive or
Negative
Indefinite
Positive or
Indefinite
Negative
Positive or
Indefinite
Negative
Positive or
Indefinite
Negative
5(27.8%)
10(55.6%)
13(61.9%)
11(52.4%)
1(33.3%)
2(66.7%)
2(66.7%)
1(33.3%)
9
27
34
23
1
3
3
1
1
0
0
1
0
0
0
0
0
0
0
1
1
0
0
0
0
0
0
0
0
2
0
0
1
0
0
0
2
0
3
1
3
3
3
2
1
0
2
1
0
0
1
2
0
0
1
1
0
0
0
1
0
0
0
0
1
1
0
1
1
5
0
2
2
0
1
3
0
1
0
1
0
1
0
0
1
0
2
3
1
0
3
0
0
0
6
0
3
0
2
3
1
0
2
1
0
1
0
0
1
1
0
1
0
1
1
0
0
0
0
0
2
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
1
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
* One patient in the 0.5 IU group had treatment discontinued due to an adverse event unrelated to growth hormone treatment, and is not included in the group
total.
CT Registry ID#Z019
Page 8
CT Registry ID#Z019
Page 9
There were 53 adverse events reported from 28 patients during the growth hormone
treatment period. A causal relationship could not be ruled out in 11 incidents
(11 patients), but none of the events were considered positively related to growth
hormone administration. These 11 events were handled as adverse reactions
(Table 6001.5).
Table 6001.5.
Symptom
Number of Adverse Reactions (Subjective Symptoms and
Objective Findings)
0.5 IU
Group
1.0 IU
Group
5 IU→1.0 IU
Group
Suspended/
dropped out
patient in
1.0 IU group
N=3
0
0
0
0
0
0
0
0
0
0
0
Total
N=18*
N=21
N=3
aggravation of bowleg
0
2
0
2
glucose tolerance abnormal
1
0
0
1
hearing decreased
0
1
0
1
pain of the injection site
1
0
0
1
sudden weight increase
0
1
0
1
headache
1
0
0
1
venous angioma
1
0
0
1
epileptic seizure
1
0
0
1
progression of deformity of the joint
0
1
0
1
necrosis of the femoral head
0
1
0
1
Total
5
6
0
11
Abbreviation: N = Number of patients in the group.
* One patient in the 0.5 IU group had treatment discontinued due to an adverse event unrelated to growth
hormone treatment, and is not included in the group total.
There were 2 patients who had the preexisting condition of “bowleg” at baseline, whose
condition worsened during the growth hormone treatment period. In both cases, the
causal relationship with growth hormone was rated as “indefinite” because it was
impossible to completely rule out the possibility that the growth hormone exerted some
effects on bowleg. “Glucose tolerance abnormal,” which was noted in one patient, was
transient and resolved without treatment. Because it could not be clarified whether the
event was due to administration of hGH or attributable to some other cause, the causal
relationship with the growth hormone was rated as “indefinite.” The one patient in whom
“venous angioma” was reported showed no clinical symptoms or worsening of the
disease even after continuation of growth hormone administration. Although it was
suspected that the disease was congenital, the causal relationship was rated as
“indefinite” since the cause was unknown. In one patient, growth hormone treatment was
discontinued (after 1036 days of administration) and orthopedic treatment was given
because radiographic diagnosis indicated the possibility of “necrosis of the head of the
right femur.” In the one patient who reported “epileptic seizures”, the seizures
disappeared as a result of oral administration of an antiepileptic and the patient continued
receiving growth hormone. This patient had a history of febrile convulsions, but there
Somatropin
CT Registry ID#Z019
Page 10
were no other predispositions relating to epilepsy, and thus the causal relationship was
classified as “indefinite.”
Of the 42 events where the causal relationship with growth hormone was judged
“negative”, 3 incidents of “cerebral infarction”, “aggravation of obesity”, and
“atlantoaxial subluxation” were classified as severe. In the one patient in whom “cerebral
infarction” was reported, although stenosis of the internal carotid artery, which was
presumably the cause of the disease, was considered congenital, the causal relationship
with growth hormone was classified as “indefinite” and growth hormone treatment was
discontinued. In the one patient in whom “atlantoaxial subluxation” was reported, the
causal relationship was rated as “indefinite”, growth hormone was discontinued, and the
patient was hospitalized for treatment (extension and application of brace). However, a
specialist of atlantoaxial subluxation diagnosed that the disease was accidental and had
no causal relationship with growth hormone. Therefore, the causal relationship was
changed to “negative”, and growth hormone treatment was resumed with no recurrence
of the disease.
Somatropin

Humatrope - Lilly Clinical Trial Registry

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