Fucidin-H vs. Hydrocortisone in Atopic Dermatitis

Transcription

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website. It contains data and results regarding approved and non-approved uses. formulations or treatment
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CLINICAL STUDY REPORT
Fucidin-H vs. Hydrocortisone in Atopic
Dermatitis
A COMPARATIVE STUDY OF FUCIDIN-H CREAM
(fusidic acid 2°/o +hydrocortisone acetate 1°/o)
AND HYDROCORTISONE CREAM (hydrocortisone acetate 1°/o)
IN CHILDREN (4-17 yrs) WITH A FLARE-UP OF ATOPIC
DERMATITIS
A STUDY USING NON-INVASIVE BIOENGINEERING TECHNIQUES
A Singl e-centre, Prosp ective, Randomised, D ou bl e-blind, Controlle d, Right-left
Comparative Study
The clinical study re.p ort has J>e.en redacted using the follo'\'\-i ng principles: 'Where necessary, informa tionis anonymised to
protect tht privacy of stu dy subjects and nam ed persons associated with the trial as well as to retain commercial confidential
information.
Summary data are included but data on individual study subje cts,including data listings, are remove d. This rna y result in
page nwnbersnot being comecutiv ely numbered.
Access to anonymise d data on individual study subject rnay be obtained up on approval of are search proposal by the Patient
and Scientific Review Board.
Appendices to the clinical study report are omitted.
Further details and principles for anonymisationis av ailable in the document LEO PHAR1\1A PRINCIPLES FOR
Al.'lONThiiSATION OF CLINICAL TRIAL DATA
FUH9401 DK
Leo Pharmaceutical Products
Mathematical-Statistical Department
00116936
Final
13 August 2002
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COMPLIANCE WITH GOOD CLINICAL PRACTICE
This Study Report is designed to comply with the Good Clinical Practice (GCP)
standards issued by the International Conference on Harmonisation (ICH) (topic E 6
CPMP/ICH/135/95 and E 3 CPMP/ICH/137/95: "Structure and Content of Clinical Study
Reports").
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TABLE OF CONTENTS
1
2
3
4
5
6
6.1
6.2
6.3
7
7.1
7.2
7.3
8
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9
8.10
8.11
8.12
8.13
8.14
8.15
9
10
10.1
10.2
10.3
10.4
10.5
11
12
12.1
12.2
PAGE
TABLE OF CONTENTS .......................................................................................................... 3
CLINICAL STUDY REPORT APPROVAL .......................................................................... 5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... ................. 7
SYNOPSIS ............................................................................................................................... 11
REPORT AUTHORS .............................................................................................................. 19
INVESTIGATORS AND STUDY SITES ............................. ................................................. 21
COMPANY PERSONNEL .................................................................................................... 23
ETHICS .................................................................................................................................... 25
INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW
BOARD (IRB) ..................... .................................................................... ................................. 25
COMPLIANCE WITH ETHICAL RESPONSIBILITIES ................................................... 25
INSURANCE AND LIABILITY ........................................................................................... 26
INTRODUCTION AND RATIONALE. .............................................................................. 27
ATOPIC DERMATITIS ......................................................................................................... 27
FUSIDIC ACID .................... ................................................................................................... 29
PRESENT STUDY: RATIONALE ........................................................................................ 30
INVESTIGATIONAL PLAN ............. ................................................................................... 33
OBJECTIVES OF THE STUDY .............................................................................................33
STUDYDESIGN .....................................................................................................................33
PATIENTNUMBERS ............................................................................................................ 33
CRITERIAFORPATIENTSELECTION ............................................................................34
CRITERIA FOR EARLY WITHDRAWAL FROM THE STUDY .....................................37
TREATMENT ASSIGNMENT ............................................................................................. 38
BLINDING OF STUDY ......................................................................................................... 38
BREAKING OF THE BLINDING ........................................................................................ 38
INVESTIGATIONAL PRODUCTS ...................................................................................... 39
ADMINISTRATION OF STUDY MEDICATION ............................................................ .41
DRUG ACCOUNT ABILITY AND COMPLIANCE CHECKS ....................................... .41
CONCURRENT DRUG TREATMENT .............................................................................. .42
STUDY PROCEDURES .........................................................................................................43
CRITERIA FOR EFFICACY AND SAFETY ...................................................................... .47
ADVERSE EVENT REPORTING ......................................................................................... 49
QUALITY ASSURANCE ................................................. ,.................................................... 53
STATISTICAL A.NALYSIS .........................................................,......................................... 55
TRIAL POPULATIONS ....................................................................... ,................................ 55
BASELINE CHARACTERISTICS ............. .................... ...... .............. ................................... 55
EFFICACY ANALYSIS ..................................................................... ,.................................... 56
SAFETY ANALYSIS ....................... ,...................................................................................... 57
GENERAL PRINCIPLES ....................................................................................................... 58
CH ANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ......... 59
R.ESULTS ................................................................................................................................. 61
STUDY PERIOD ..................................................................................................................... 61
STUDY POPULATION ......................................................................................................... 61
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12.3 INTENTION-TO-TREAT (ITT) POPULATION ................................................................ 62
12.4 SAFETY POPULATION ....................................................................................................... 62
12.5 PER PROTOCOL POPULATION ....................................................................................... 63
12.6 PROTOCOL DEVIATIONS .................................................................................................. 63
12.7 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .............................. 63
12.8 EFFICACY RESULTS ............................................................................................................ 65
12.9 USE OF - AND COMPLIANCE WITH- PRESCRIBED STUDY MEDICATION ........ 99
12.10DURATION AND EXTENT OF EXPOSURE TO TREATMENT WITH STUDY
MEDICATION ............ .................................................................................. ....................... 100
12.11CONCOMITANT TREATMENT ...................................................................................... 100
12.12SAFETY EVALUATION ..................................................................................................... 100
13 DISCUSSION ........................................................................................................................ 103
14 CONCLUSION ..................................................................................................................... 105
15 REFERENCES ....................................................................................................................... 107
APPENDIX I:
Statistical Appendix
APPENDIX II:
Individual Subject Data
APPENDIX III:
Statistical Analysis Plan
APPENDIX IV:
The Study Protocol with Amendment
APPENDIXV:
Case Record Form Book
APPENDIX VI:
Informed Consent Form (sample)
APPENDIX VII:
Approval/ favourable opinion from IRBs/IECs
APPENDIX VIII:
List of Investigators and Subinvestigators
APPENDIX IX:
GCP Compliance including GCP Compliance Statement
and Audit Certificates
lat
L
E
0
GCPSOP 02
LEO PHARMACEUTICAL PRODUCTS
Department of Dermatological Research
CLINICAL STUDY REPORT APPROVAL FORM
STUDY CODE :
FUH 9401 OK
REPORT TITLE: Fucidin-H vs. Hydrocortisone in Atopic
Dermatitis
LEO 21-45
REPORT DATE (DDIMMIYY)
13/08/02
I confirm that I have read the Clinical Study Report and confirm that to the best of my knowledge it accurately
describes the conduct and results of the study.
APPROVAL BY HEAD OF DEPARTMENT OF DERMATOLOGICAL RESEARCH
Date
//
dd
PRINTED NAME
I t?/1 oc;
mm
yy
APPROVAL BY DIRECTOR OF RID
Date
2 'b I a 8 I 0
dd
PRINTED NAME
mm
Q._
yy
APPROVAL BY HEAD OF MATHEMATICAL-STATISTICAL DEPARTMENT, LEO OK
Date
PRINTED NAME
Distribution:
Original
~ Trial Master File
Copies
~ Study Report
!o
dd
1 o~ f)2._
mm
yy
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Adverse Event (AE)
Any untoward medical occurrence in a patient or
clinical
investigation
pharmaceutical
subject
product
and
administered
which
a
does not
necessarily have a causal relationship with this
treatment. An adverse event (AE) can therefore be
any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease
temporally associated with the use of a medicinal
(investigational) product, whether or not related to
the medicinal (investigational) product (see the ICH
Guideline for Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting).
Amendment (to the protocol)
See Protocol Amendment.
Audit
A systematic and independent examination of trial
related activities and documents to determine
whether the evaluated trial related activities were
conducted, and the data were recorded, analysed
and accurately reported according to the protocol,
sponsor's standard operating procedures (SOPs),
Good Oinical Practice (GCP), and applicable
regulatory requirement(s).
Baseline
Day 0, when treatment with study medication starts.
Case Report Form (CRF)
A printed, optical, or electronic document designed
to record all of the protocol required information to
be reported to the sponsor on each trial subject.
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The term is synonymous for Case Record Form.
Concurrent Medication
Any medication taken by a subject apart from the
investigational product(s).
Good Clinical Practice (GCP)
A standard for the design, conduct, performance,
monitoring,
auditing,
recording,
analysis,
and
reporting of clinical trials that provides assurance
that the data and reported results are credible and
accurate,
and
that
the
rights,
integrity,
and
confidentiality of trial subjects are protected.
Individual Treatment Code
A sealed letter/ envelope containing the direct
Envelope
information about a subject treatment/
investigational product.
Informed Consent
A process by which a subject voluntarily confirms his
or her willingness to participate in a particular trial,
after having been informed of all aspects of the trial
that are relevant to the subject's decision to
participate. Informed consent is documented by
means of a written, signed and dated informed
consent form.
Investigational Product
A pharmaceutical form of an active ingredient or
placebo being tested or used as reference in a clinical
trial, including a
product with a
marketing
authorisation when used or assembled (formulated
or packaged) in a way different from the approved
form, or when used for an unapproved indication, or
FUH9401DK
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Page 9 of108
when used to gain further information about an
approved use.
Investigator
A person responsible for the conduct of the clinical
trial at a trial site. If a trial is conducted by a team of
individuals at a trial site, the investigator is the
responsible leader of the team and may be called the
principal investigator. See also Subinvestigator.
Investigator Trial File
The collection of trial documents required by Leo
SOPs and ICH Guidelines to be on file at the
investigator site.
IRB/IEC
Institutional
Review
Board/Independent
Ethics
Committee.
Monitor
A person appointed by Leo to perform monitoring.
Monitoring
The act of overseeing the progress of a clinical trial,
and of ensuring that it is conducted, recorded, and
reported in accordance with the protocol, Standard
Operating Procedures (SOPs), Good Clinical Practice
(GCP), and the applicable regulatory requirement(s).
Principal Clinical Project
The person appointed by Leo to be Leo's main inter-
Co-ordinator (PCPC)
national representative responsible for all aspects of
a clinical trial.
Protocol
A document that describes the objective(s), design,
methodology,
statistical
considerations,
and
organisation of a trial. The protocol usually also
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gives the background and rationale for the triaC but
these could be provided in other protocol referenced
documents. Throughout the IOi GCP Guideline the
term protocol refers to protocol and protocol
amendments.
Protocol Amendment
A written description of a change(s) to or formal
clarification of a protocol.
Quality Assurance (QA)
All those planned and systematic actions that are
established to ensure that the trial is performed and
the data are generated documented (recorded), and
reported in compliance with Good Clinical Practice
(GCP) and the applicable regulatory requirement(s).
Randomisation
The process of assigning trial subjects to treatment or
control groups using an element of chance to
determine the assignments, in order to reduce bias.
Subinvestigator
Any individual member of the clinical trial team
designated and supervised by the investigator at a
trial site to perform critical trial-related procedures
and/ or to make important trial-related decisions
(e.g., associates, residents, research fellows). See also
Investigator.
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SYNOPSIS
Study code number
FUH 9401 DK Study
Study title
Fucidin-H vs. H ydrocortisone in Atopic Dermatitis.
Study Subtitle
A comparative study of Fucidin-H cream (fusidic acid 2% + hydrocortisone
acetate 1%) and Hydrocortisone cream (hydrocortisone acetate 1%) in children
(4 - 17 yrs) with a flare-up of atopic dermatitis. A study using non-invasive
bioengineering techniques.
Study objective
To compare the effect of Fucidin-H cream with that of Hyd rocortisone cream in
patients with a flare-up of atopic dermatitis with special emphasis on a) the
severity of disease measured by bioengineering techniques and b) the quantity
of Staph. aur. on the diseased skin.
Study design
A single-centre, prospective, randomised, double-blind, controlled, right-left
comparative study of Fucidin-H cream applied twice daily on one arm and
Hydrocortisone cream applied twice daily on the opposite arm for 14 days. The
patients were assessed at baseline (day 0), day 2, 4, 7, and 14.
Sample size
Twenty-four patients will be included in the study in order to be able to
demonstrate a clinically important difference between the two treatments in
respect of reduction in transepidermal water loss.
---
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-~-
-
- --
-
FUH9401DK
Eligibility criteria
Outpatients, 4-17 years of age, either sex with a diagnosis of atopic dermatitis
defined according to criteria proposed by Hanifin and Rajka. The disease must
be present on both arms and be in a stage of flare-up, lesions must be synunetric
with uniform eczema. Females of child bearing potential must have a negative
pregnancy test at visit 1 and must use an adequate method of contraception
throughout the study period. Excluded are patients with impetigo or cutaneous
herpes infection or widespread pruritic excoriation of the target lesions,
patients treated with: 1) systemic corticosteroid within 8 weeks prior to visit 1,
2) UV radiation within 1 week prior to visit 1, 3) topical corticorsteroids within
1 week prior to visit 1, and patients who concurrently are participating in any
other clinical study or who have previously been randomised in the present
study.
Patients are not permitted to receive any other treatment (topically or systemic)
that can affect the course of the disease. Treatment of pruritus with
antihistamine is allowed.
Parents/legal guardians and patients (when appropriate) will give their signed
information consent to join the study.
Study drugs
Fucidin-H
cream containing 20 mg/ g
hydrocortisone
acetate.
Hydrocortisone
fusidic
acid
cream
and 10 mg/ g
containing
of
10 mg/ g
hydrocortisone acetate. The drugs will be applied twice daily for 2 weeks
without occlusion to affected skin.
Primary response criterion
The two treatments will be compared with respect to reduction in Trans
Epidermal Water Loss (TEWL) from baseline (visit 1) to a) end of treatment and
b) each post-randomisation visit.
--
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Assessments
Non-invasive bioengineering measurements including TEWL, skin colour, skin
surface hydration, skin surface contour and skin thickening and oedema will be
done at baseline and at each post-randomisation visit. The severity of the atopic
dermatitis in the patient's target lesions will be assessed by investigator at
baseline (visit 1). Furthermore, the investigator will assess the overall response
to therapy at each post-randomisation visit.
At all visits a microbiological assessment will be done including quantitative
bacteriology. Adverse events will be elicited at all post-randomisation visits.
Schedule of study procedures:
Double-blind treatment
Visit
1
2
3
4
5
Day
0
2
4
7
14
Medical history
*
Randomisation
*
*
*
*
*
*
*
*
*
*
*
*
*
Transepidermal water loss
Additional non-invasive bioengineering
measurements:
Skin colour
Skin surface hydration
Skin surface contour
Skin thickening and oedema
Bacteriology
Investigator. Oinical Signs/ symptoms
*
*
*
*
*
Investigator: Overall efficacy assessment
Pregnancy test*
Collection of trial medication
* In female patients of child-bearing potential.
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Adverse events
Supply of trial medication
*
*
*
--- ---- - ---- -------------·-Page 14 of108
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Patient population
A total of 25 patients were recruited from a single Danish centre. Of these 24
were randomised to treatment with Fucidin-H on one arm and Hydrocortisone
on the other arm. All the 24 randomised patients were analysed for efficacy and
safety.
Sixteen females (66.7%) and 8 males (33.3%) were randomised in the study. The
mean age was 9.0 years (range 3 to 17).
The mean duration of the atopic dermatitis was 6.7 years (range 1 to 16).
Table 1 gives the investigator's assessment of the severity of clinical signs for
atopic dermatitis - for each arm separately.
Table 1:
Investi_gator's clinical assessment of randomised patients at baseline (visit 1)
Cl i nical s ign of atopic dermati tis
Severi ty
Fuc i d i n - H
<n=24l
Number of
pat: ienta
E:rythema score
Absent:
Slight i nvol v ement:
Moderat:e involvement
Sever e involvement
All pat:ients
Excoriation score
Absent:
Sl igh~ i nvol vement
Moderate involvement
severe involvement:
All patients
Lichenification score
Slight involvement
Moderate involvemen t
Severe involvement
All pat:ients
Scaling score
Absent
Slight inv olvement
Moderate involvemen t
Severe i nvolvement
All patients
Serious d i scharge
Absent
Slight involvement
Moderace inv olvement
All patients
0
10
12
2
24
6
6
11
1
24
5
15
4
24
l
13
10
0
24
Hydrocortisone
(n=24)
~
Number of
pat:ient:s
~
0
41.7
50 . 0
8.3
100.0
1
7
12
4
24
4 .2
29 . 2
50 . 0
16.7
1 00.0
25.0
25.0
45.8
4 .2
10 0.0
s
6
12
1
24
20.8
25 . 0
50.0
4 .2
100.0
~
37.5
11
4
45 .6
16 . 7
100.0
20 .8
62.5
16.7
100 . 0
24
4 .2
54.2
41.7
0
100 . 0
1
14
8
95.8
l
24
4 .2
58. 3
33.3
4.2
100.0
23
0
1
24
0
4 .2
100.0
23
1
0
24
1
5
16
4 .2
20.8
66 . 7
11
4.2
37 . 5
4 5. 8
3
24
100.0
95. 8
4. 2
0
100 . 0
Th i ckness score
Absent:
Slight i nvolvement
Moderate invol vement
Severe i nvolvement
All patien ts
2
8 .3
24
100.0
1
~
12.5
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Page 15 of108
Efficacy results
Non-invasive bioengineering measurements (including TEWL).
The two treatments were not statistically significantly different regarding any
bioengineering measurements of response, including the primary response
criterion, TEWL (Table 2).
Table 2:
Percentage change in non-invasive bioengineering parameters from baseline
to end o treatment (Intention-To-Treat o ulation)
Type of non - i nvasive
bioengineering
measurements
TEWL
Skin col our
Skin s u rface hydration
Skin t hickening
I nflammatory oedema
(R:zp 111 vertical)
Fucidi n - H
Hydrocor t i sone
(n• 24 )
(n• 24 )
Treatment compari son
(paired t-tes t )
Mean percent age
change
Mean percentage
change
-34.6
-25. 6
61 .4
- 8 .9
-12 . 5
- 31. 1
-23.6
47.3
· 12 .7
- 25 .0
-3.5
-2 .0
14 . 1
3 .8
9.3
( - 13.2 to 6.3)
( - 7.2 to 3.2)
( - 8. 9 t o 37 . 0)
( · 2 .o to 9.6)
( - 12 .7 to 31.4)
p
p
p
p
p
• 0.47
• 0.44
: 0.22
= 0 .1 9
• 0. 39
·1 2. 1
- 2.4
~9.8
( - 30 .9 t o 11.4) p
= 0 . 35
Differe nce
(95% Cil
P-va l ue
Table 2 contains the primary skin surface contour roughness parameter, RzorN
vertical. Twelve skin surface contour parameters were measured and analysed.
The results of the analyses are given in the main text of this report (Section
12.8). A total of 48 hypothesis tests regarding skin surface contour were
performed (change and percentage change, respectively, at visit 2 and at end of
treatment). Five of these resulted in P-values less than 0.05, but larger than 0.01.
These results might be type 1 errors in the significance tests. With any
reasonable adjustment for multiplicity no difference between the two
treatments reached statistical significance.
Bacteriology
Fucidin-H was statistically significantly (P = 0.031) superior to Hydrocortisone
with respect to eradication of pre-treatment pathog~ns.
Eight (89%) out of the 9 patients with pre-treatment pathogens at both sides had
their pre-treatment pathogens eradicated on the Fucidin-H side. Two (22%) out
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Page 16 of108
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of the 9 patients had their pre-treatment pathogens eradicated on the
Hydrocortisone side.
Investigator's overall assessment of efficacy
Seventeen (71 %) patients obtained 'marked improvement' or 'clearance' on the
Fucidin-H side according to the investigator's overall efficacy assessments.
Sixteen (67%) patients obtained 'marked improvement' or 'clearance' on the
Hydrocortisone side. The difference between the treatments was not statistically
significant (P = 1.00).
The distribution of the investigator's overall assessment of efficacy at each
treatment arm are given for each post randomisation visit in Table 3.
Table 3:
Investigator's overall assessment of efficacy at control visits (Intention-ToTreat population)
Via it
Invest i gatoris overal l
assessment
Number of
pat:.ient s
VISIT 2
Wor se
No change
Minimal i mpr ovement.
Moderate i mprove ment
Marked improvement
Compl e t ely cle ared
Total
VISIT 3
Worse
No chang e
Minimal improvement
Moderate i mprovemen t
Marked i mprovement
completely c leared
Total
VISIT 4
worse
Minimal improvement
Moderate i mprovemen t
Marked i mproveme nt
Compl etely cl ea red
Tot:.al
VIS IT 5 (END OP T~TMENT)
Worse
No change
Minimal i mprovement
Mode rate improvement
Marked improvement.
Complet:.ely c l eared
Total
Hydrocort:.iaone
(n: 24)
Fucidin-H
(n:24)
Number of
pat:.ients
t
0
3
7
5
8
1
24
0
12 .5
29.2
20.8
33.3
4.2
100 .0
0
1
4
12
1
19
0
5.3
5.3
21.1
63 .2
5 .3
100 . 0
0
2
0
0
9.1
1
22 . 7
50 . 0
18 .2
100 .0
12
4
22
l
5
ll
4
22
1
l
3
2
9
8
24
4 .2
4 .2
12.5
8. 3
37.5
33 . 3
100.0
0
0
8
6
9
1
24
0
0
1
7
10
1
19
5
2
1
1
4
10
6
24
%
0
0
33.3
25.0
37.5
4.2
100 . o
0
0
5.3
36.8
52.6
5 .3
100.0
0
4. 5
22 .7
54.5
18.2
100.0
8.3
4 .2
4 .2
16 .7
41. 7
25.0
100 . 0
FUH9401 DK
Page 17 of108
13 August 2002
Safety evaluation
A total of 5 patients reported mild adverse events.
Table 4:
Adverse events listed by system-organ class 1
System-organ clas~1
Pucidin-H
treated
arm only
(n• 24)
Number of
patients
Skin and appendages
disorders
Total number of adverse
events 2
Total number of
pat.ien t s
( %)
Hydrocortisone
trea t ed a.r m
only
(n• 24 )
Not armdependent
adverse
event
(no24)
All patients
(n=24)
Treatment
comparison
Number of
patients
Number of
patients
Number of
patients
(McNemar' s
test)
5
l
1
1
1 (4 . 2)
1
(4
. 2)
3
5
3 ( 12 . 5)
5
( 20 .8 )
p
= 1. 00
1 ) Cl assification according to the WHO Advers e Reaction Dictionary, 31. December 1 992 .
1) Dif fer ent adverse event s with i n t he same c lass and involving t he same patient have been counted
as one . A single patient could appear in mul tiple classes.
Conclusion
There was no statistically significant difference between Fucidin-H cream and
H ydrocortisone regarding the effect measured by bioengineering techniques.
with respect to eradication of pre-treatment pathogens.
Fucidin-H was not statistically significantly superior to H ydrocortisone
regarding the investigator's overall assessment of efficacyr
PagelS of108
FU1I'940.1,j)K
13 Augu;st 2002
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FUH9401 DK
3
13 August 2002
REPORT AUTHORS
M.Sc. Stat.
DK-2750 Ballerup
DENMARK
Page 19 of108
-
Page 20 of108
13 August 2002
---~------------------,
FUH9401DK
FUH9401 DK
4
13 August 2002
Page 21 of108
INVESTIGATORS AND STUDY SITES
PRINCIPAL CO-ORDINATING INVESTIGATOR
DEN MARK
SUBINVESTIGATORS: Investigator Site
DENMARK
MD, PhD
DENMARK
INVESTIGATOR: Dermatological bioengineering measurements
MD
Deparhnent of Dermatological Research
Industriparken 55
DK-2750 Ballerup
DENMARK
INVESTIGATOR: Bacteriology
Page22 of108
13 August 2002
FUH9401DK
FUH9401DK
5
13 August 2002
COMPANY PERSONNEL
PRINCIPAL CLINICAL PROJECT CO-ORDINATOR
MD
...............""' Department
DK-2750 Ballerup
DENMARK
STUDY CO-ORDINATOR
Ph.D. Bioi.
Department of Dermatological Research
DK-2750 Ballerup
DENMARK
DERMATOLOGICAL RESEARCH ACTIVITY
M.D., Ph.D., specialist in dermatology
of Dermatological Research
DK-2750 Ballerup
DENMARK
STATISTICIAN
M.Sc. Stat.
DK-2750 Ballerup
DENMARK
Page 23 of lOB
Page 24 of 108
13 August 2002
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I.
! i
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13 August 2002
6
ETHICS
6.1
INDEPENDENT ETHICS
COMMITTEE (IEC)
Page 25 of108
OR INSTITUTIONAL
REVIEW BOARD (IRB)
The protocol and amendments were submitted to the National Health
Authority and to the relevant Ethics Committee. Copies of approval/ favourable
opinion from IRB/IEC are given in Appendix VII.
6.2
COMPLIANCE WITH ETHICAL RESPONSIBILITIES
6.2.1
Ethical conduct of the study
The study was conducted to conform with the principles of the Declaration of
Helsinki as adopted by the 18th World Medical Assembly, 1964, and subsequent
amendments Tokyo, 1975, Venice, 1983 and Hong Kong 1989.
The protocol was approved by/ received favourable opinion from relevant
Institutional Review Boards (IRB/Independent Ethics Committees (IEC) prior
to inclusion to subjects.
The patient's/ parent's informed consent (in writing) to participate in the study
was obtained prior to enrolment in the study.
The study was approved/notified by the appropriate Regulatory Authority as
required.
The study was conducted in accordance with the principles of GCP.
6.2.2
Patient information and consent
All patients/ parents received written and verbal information concerning the
study. This information emphasised that participation in the study was
- - --- - - -·- · ·
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voluntary and that the patient could withdraw from the study at any time and
for any reason.
Consent was obtained prior to any study procedures carried out.
The above was also included specifically in the individual Investigator
Agreements signed by the investigators.
Sample Patient/Parent Consent Forms are presented in Appendix VI.
6.3
INSURANCE AND LIABILITY
The patients in the current study were covered by the product and general
liability insurance of Leo Pharmaceutical Products in the event of trial related
injury or death in accordance with applicable law and with the GPMP Note for
Guidance on Good Clinical Practise (CPMP/ICH/135/95) of 17 July 1996.
·•
------ FUH9401 DK
13 August 2002
7
INTRODUCTION AND RATIONALE
7.1
ATOPIC DERMATITIS
Page 27 of108
Atopic dermatitis (AD) is a chronically relapsing, pruritic inflammatory skin
disease with a characteristic cutaneous morphology and distribution occurring
in genetically predisposed individuals. A review of the literature showed that
before 1960 2-3% of children suffered from AD, in the 1960's some 4-8% was
recorded in several studies, and after 1970 most researchers found that 9-12%
developed AD during childhood (1). Thus, AD seems to increase in incidence,
maybe as a result of increased urbanisation. Many patients show up in
emergency departments with flare-up of the dermatitis (2). The genetic factors
result in an increased susceptibility to the atopic triad: asthma, hay fever, and
atopic dermatitis. Diagnostic criteria have been published to standardise the
diagnosis (3). The manifestation of cutaneous disease involves a complex
interrelationship between precipitating environmental factors and genetic
factors related to the immune response, to vascular reactivity, and to
neuroimmune or neurocutaneous responses. Such factors include microbial or
other cutaneous antigens, food antigens, psychological stress, and climatic
factors. Topical corticosteroids, in particular hydrocortisone, are the mainstay of
treatment for mild to moderate AD (eczema).
Among the microbial infections Staph. aur. is by far the most important flare
factor, but there is also increased risk of herpes simplex, warts and molluscum
contagiosum.
There is an extensive literature showing that patients with atopic dermatitis are
heavily colonised w ith Staphylococci (100%) in the acute lesions, and 91-93% in
chronic, lichenified lesions according to a review by Abeck and Ruzicka (4).
Quantitative studies analysing Staph. aur. have demonstrated a 100-1000 times
higher density of Staph. aur. in different types of lesional skin compared to non-
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lesional skin. The authors of the review conclude that the striking ecological
aspect of Staph. aur. colonisation has led to a concentration of scientific effort on
its possible pathogenic role in this disease. The quantity of Staph. aur. is
proportional to the severity of eczema and Phage group II accounts for 32% of
strains. Resistance to penicillin is present in 88% while resistance to fusidic acid
is uncorrunon, despite the use of the latter antibiotic for many years both
topically and systemically (5).
Several capsular antigens of Staph. aur. are known, and anti-Staph. aur. specific
IgE is increased in patients with AD although the exact significance of this
finding is not understood. IgE reactions may initiate the prurigo-scratch
excoriation sequence. Staph. aur. may also enhance the expression of the
receptor for IgE and the release of inflarrunatory mediators such as histamine.
Staph. aur. show an unusual adherence to corneocytes of patients with AD,
which may enhance both allergic and toxic effects elicited by Staphylococci. The
production of bacterial toxins is also suggested to be important for the
pathophysiology of AD.
Thus, different mechanisms may account for the aggravating role of Staph. aur.
in relation to AD, inflarrunation and the pruritic status. It also has to be
considered that these patients have a general abnormality or dysfunction of the
irrunune system with formation of interleukins, tumour necrosis factor and
other mediators of inflarrunation elicited at a relatively low threshold. This
constitutional background is not entirely understood. It may also involve
alterations at the receptor and gen expression levels. The very complex
mechanism outlined in this session of the rationale is based on a number of
recent reviews (6,7,8,9).
There is, however, despite the complexity and the different laboratory findings,
a general agreement with what is considered sound clinical knowledge; there is
in atopic dermatitis a spontaneous and constitutional tendency to inflarrunation
FUH9401 DK
13 August 2002
Page 29 oj108
and prurigo, elicited by a number of environmental factors at a low threshold.
There is a generally reduced resistance to microbes and infection. Colonisation
particularly with Staph. aur. is of pathogenetic significance during flare-up with
more advanced inflammation, prurigo and eczema, and occasionally manifest
impetigo. Staphylococci adhere especially to corneocytes of atopies, and they
may aggravate the skin inflammation through allergic and/ or toxic
mechanisms.
It has been shown that around 90% of eczematous lesions become colonised or
infected with Staph. aur. and/ or beta-haemolytic streptococcus (1). It has also
been found that the frequency of S. aureus in the normal skin of patients
presenting with atopic dermatitis is higher than in the normal skin of healthy
individuals (2).
The effect of Staph. aur. infection on atopic eczema may be more complex than
pyogenic infection alone. It has recently been demonstrated (3) that the majority
of Staph. aur. isolated from atopic eczema produces exotoxins with
"superantigenic properties 11, which if produced in sufficient quantities in
eczema would cause T-lymphocyte activation (4), cytokine release and mast cell
degranulation, thus exacerbating the eczema and resulting in serious discharge
and crusting (5). Another reason for considering antibiotic treatment is the
significant epidemiological hazards of superinfected eczema's, particularly in
the handling of food (6).
7.2
FUSIDIC ACID
7.2.1
Pharmacology
Fusidic acid (Fucidin) is a steroid-like antibiotic isolated from Fusidium
coccineum which penetrates human skin at a rate similar to glucocorticoids.
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Fucidin exhibits high in vitro and in vivo activity against Staph. aur. and is
effective against other skin pathogens such as streptococci and Bacteroides sp.
Despite many years of clinical use, resistance to fusidic acid amongst Staph. aur.
remains low. Hypersensitivity reactions in the form of skin rashes or mild
stinging and irritation on application, have been reported rarely.
7.2.2
Completed clinical studies using fusidic acid
Topical preparations of fusidic acid have been shown to be highly effective and
well-tolerated in the treatment of superficial skin sepsis (10). A fixed dose
combination of fusidic acid 2% with 1% hydrocortisone (Fusidin® H Ointment)
has also been found useful in the management of infected inflammatory
dermatoses. The application of a sodium fusidate and hydrocortisone
combination has also been used successfully in patients with infected dermatitis
(11,12). Fucidin-H cream was registered in Ireland and United Kingdom in 1985
and 1987, respectively.
7.3
PRESENT STUDY: RATIONALE
Concomitant
corticosteroid/ antibacterial
treatment
of
inflammatory
dermatoses has already been shown to be successful (12,13,14,15).
Studies are necessary to substantiate the clinical benefit of a fixed dose
combination such as Fucidin-H Cream by a direct comparison with
hydrocortisone alone.
The study is designed with emphasis on objective methods for evaluation of the
severity of dermatitis, since it is difficult to assess the severity of AD primarily
by clinical evaluations. Transepidermal water loss (TEWL) reflects the overall
damage of the cutaneous water barrier due to dermatitis, and TEWL is chosen
as the main effect parameter (15). Colour measurement (CIE system) and
FUH9401DK
ultrasound
13 August 2002
for quantification of redness and
respectively, will also be applied.
Page 31 of108
inflammatory oedema,
Page32 of108
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8
INVESTIGATIONAL PLAN
8.1
OBJECTIVES OF THE STUDY
Page 33 of108
• To compare the effect of Fucidin-H cream with that of Hydrocortisone cream
in patients with a flare-up of atopic dermatitis with special emphasise on: .
8.2
a)
the severity of the disease, measured by bioengineering techniques
b)
the quantity of Staph. aur. of the diseased skin
STUDY DESIGN
A single-centre, prospective, randomised, double-blind, controlled, right-left
comparative study of:
• Fucidin-H cream (fusidic acid 2% and hydrocortisone acetate 1 %) applied
twice daily
and
• Hydrocortisone cream (hydrocortisone acetate 1%) applied twice daily.
Patients were given double-blind treatment with Fucidin-H cream on one arm
and Hydrocortisone cream on the opposite arm for a period of 14 days.
The patients were assessed before start of treatment and after 2, 4, 7 and 14 days
of treatment.
8.3
PATIENT NUMBERS
The sample size calculation was based on the primary objective of the study: To
demonstrate a clinically important difference between Fucidin H cream and
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- -- - - - -- - FUH9401DK
Hydrocortisone cream regarding reduction in transepidermal water loss
(TEWL).
A total of 24 patients were to be included in order to detect a difference of 20%
in percentage change of TEWL between the two treated arms with a probability
o£80%.
The calculation assumed, based on published data (17), that the intra subject SO
ofTEWL w as 25% (range 17- 35%).
8.4
CRITERIA FOR PATIENT SELECTION
8.4.1
Inclusion criteria
8.4.1.1
A clinical diagnosis of atopic dermatitis defined according to the clinical
criteria proposed by Hanifin and Rajka (3):
1)
3 or more basic features:
i)
Pruritus
ii)
Typical morphology and distribution. Flexural lichenification or
linearity
iii)
Chronic or chronically relapsing dermatitis
iv)
Personal or family history of atopy (asthma, allergic rhinitis, atopic
dermatitis)
and
2)
3 or more minor features:
i)
Xerosis
ii)
Ichthyosis/ palmar hyperlinearity / keratosis pilaris
iii)
Immediate (type Ifskin test reactivity
iv)
Elevated serum IgE
13 August 2002
FUH9401 DK
Page 35 of108
v)
Early age of onset
vi)
Tendency towards cutaneous infections/impaired cell-mediated
immunity
vii) Tendency towards non-specific hand or foot dermatitis
viii) Nipple eczema
ix)
Cheilitis
x)
Recurrent conjunctivitis
xi)
Dennie-Morgan infraorbital fold
xii) Keratoconus
xiii) Anterior subcapsular cataracts
xiv) Orbital darkening
xv) Facial pallor/facial erythema
xvi) Pityriasis alba
xvii) Anterior neck folds
xviii) Itch when sweating
xix) Intolerance to wool and lipid solvents
xx) Perifollicular accentuation
xxi) Food intolerance
xxii) Course influenced by environmental/ emotional factors
xxiii) White dermographism/ delayed blanch
8.4.1.2
The patient's atopic dermatitis must be in a stage of worsening (flare-up) within
the 2 weeks prior to randomisation assessed by the investigator based on the
patient's medical history and the clinical picture.
8.4.1.3
Symmetric lesions of atopic dermatitis with uniform eczema (i.e. erythema,
thickness, lichenification, excoriation, scaling and serious discharge) on the
arms covering a total area of at least 15 cm2 on each arm (if necessary, as 2
smaller areas).
- - - - - - - - - · - - - - - - · - - - · - - · - - - - - - - - - - -- -- - -
Page 36 of108
13 August 2002
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8.4.1.4
Outpatients.
8.4.1.5
4 - 17 years of age.
8.4.1.6
Either sex.
8.4.1.7
Females of child-bearing potential must be using an adequate contraception.
8.4.1.8
Females of child-bearing potential must have a negative urine stix pregnancy
test.
8.4.1.9
Signed informed consent given by the patient (if appropriate) and a parent or
legal guardian at enrollment to the study (i.e. visit 1) following verbal and
written information about the study.
8.4.2
Exclusion criteria
8.4.2.1
Impetigo or cutaneous herpes infection of the target lesions where antibiotic
treatment is required.
8.4.2.2
Widespread pruritic excoriation's of the target lesions.
8.4.2.3
Treatment with a systemic corticosteroid within the 8-week period prior to
visit 1.
8.4.2.4
Treatment with UV-irradiation within the 1-week period prior to visit 1.
8.4.2.5
Treatment with topical corticosteroids on the arms within 1 week prior to
visit 1.
FUH9401 DK
8.4.2.6
13 August 2002
Page 37 of lOB
Treatment with any other medication (systemic or topical) that can affect the
course of the disease on the target regions during the study period
(antihistamine for pruritus is allowed).
8.4.2.7
Pregnancy, wish to become pregnant during the study period or breast-feeding.
8.4.2.8
Hypersensitivity to components of Fucidin-H or hydrocortisone acetate creams
(see Section 11).
8.4.2.9
Known or suspected of not being able to comply with a study protocol.
8.4.2.10
Concurrent participation in any other clinical stud y.
8.4.2.11
Previous randomisation in present study.
8.5
CRITERIA FOR EARLY WITHDRAWAL FROM THE STUDY
Patients could be withdrawn for any of the following:
8.5.1
Voluntary withdrawal
Patients were free to withdraw from the study at any time and for any reason.
8.5.2
Medical deterioration
The investigator was free to withdraw the patient at any time for medical
reasons.
8.5.3
Adverse Events
Any adverse event attributable to the study medication that the investigator
considered unacceptable to the patient.
Page 38 of108
8.5.4
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FUH9401DK
Exclusion criteria
Any exclusion criteria that became apparent during the course of the study.
8.6
TREATMENT ASSIGNMENT
At visit 1 patients found acceptable regarding all of the protocol's inclusion and
exclusion criteria, were randomised to receive double-blind treatment with
Fucidin-H cream (fusidic acid and hydrocortisone acetate) on one arm and
Hydrocortisone cream (hydrocortisone acetate) on the opposite arm. Patients
who met the criteria for entry were enrolled into the study in consecutive order
and assigned a code number in ascending order of recruitment.
8.7
BLINDING OF STUDY
Fucidin-H cream and Hydrocortisone cream were similar in appearance, smell
and texture. Therefore, it was not considered possible to differentiate one
treatment from the other solely by sensory evaluation.
Fucidin-H and Hydrocortisone creams were supplied in identical packaging.
The labels on the tubes contained no evidence of the identity of their contents.
8.8
BREAKING OF THE BLINDING
The investigator kept a copy of the treatment code for each individual patient in
a separate sealed envelope. The envelopes carried the randomisation code
number on the outside and information on the assigned medication inside.
The code was to be broken only in an emergency where drug identification was
necessary. In such an event, it was important that the date and the reason for
opening the envelope was noted in writing on the Conclusion Form in the Case
Record Form Book.
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13 August 2002
8.9
INVESTIGATIONAL PRODUCTS
8.9.1
Fucidin-H
Page 39 of108
Fucidin-H cream (produced and certified by Leo Pharmaceutical Products,
Denmark) containing 2% (20 mg/ g) of fusidic acid and 1% (10 mg/ g) of
hydrocortisone acetate in the following vehicle:
Butylhydroxyanisol
Cetanol
Glycerol
Liquid paraffin
Potassium sorbate
Tween60
White soft paraffin
Fucidin-H cream was be supplied in 30 g tubes.
One tube was provided at visit 1 and at visit 4, i.e. 1 tube per week's treatment.
8.9.2
Hydrocortisone
Hydrocortisone cream (produced and certified by Leo Pharmaceutical Products,
Denmark) containing 1% (10 mg/ g) of hydrocortisone acetate in the following
vehicle:
Butylhydroxyanisol
Cetanol
Glycerol
Liquid paraffin
Potassium sorbate
Tween60
White soft paraffin
13 August 2002
Page 40 of lOB
FUH9401DK
Hydrocortisone cream was supplied in 30 g tubes.
One tube was provided at visit 1 and at visit 4, i.e. 1 tube per week's treatment.
8.9.3
Storage of study medication
The study medication should be stored at room temperature, i.e. 15-25°C.
8.9.4
Packaging and labelling of study medication
Fucidin-H cream and Hydrocortisone cream were supplied in 30 g tubes for
dispensing by the investigator. The patient received one tube of 30 g of each of
the two study medications per week. The tubes were provided in boxes with
identical appearance (except for code numbers printed on the box). Each patient
had his/her own box of medication that contained supplies for the entire trial
period. Each box contained the tubes for dispensing at visits 1 and 4 packed in
separate plastic bags. Tubes to be used on the right arm had "Right" on the label
and the colour code was green. Tubes to be used on the left arm had "Left"
written on the label and the colour was red. Each visit bag contained the same
number of "Right" (green) and "Left" (red) tubes.
Labelling of boxes and tubes was in accordance to Danish laws/regulations and
contained the following information:
•
•
•
•
•
Study code number: FUH 9401 DK
•
Patient's initials
•
•
•
Randomisation code number
Clinical trial supplies
30 g of study cream
To be applied morning/ evening
For external use only
Doctor's name
Expiry date: _
/_
/_
FUH9401DK
8.10
13 August 2002
•
KEEP OUT OF REACH OF CHILDREN
•
Store at room temperature (i.e. 15-25°C)
•
Leo Pharmaceutical Products, DK-2750 Ballerup
Page 41 of108
ADMINISTRATION OF STUDY MEDICATION
The study medication was to applied to the arms only. Patients with atopic
dermatitis on other body areas could use hydrocortisone acetate cream if
needed (study medication was not to be used on areas other than the arms).
The patients were instructed to apply a thin layer of medication on the whole
arm (from the axial to the wrist) irrespective of the size of the lesion(s) and
lightly rub it in. Medication from tubes marked "Right" should be used on the
right arm, and tubes marked "Left11 should be used on the left arm. The patients
were told to wash their hands after each application to avoid inadvertent
spread of the study creams to other body areas.
The medication were applied \\rithout occlusion twice daily, i.e. in the morning
and in the evening mth approximately 12 hours intervals.
NOTE:
On days of control visits, there had to be an interval of at least 2
hours from application of the study creams to the non-invasive
bioengineering measurements (i.e. time of appointment).
8.11
DRUG ACCOUNTABniTY AND COMPLIANCE CHECKS
The investigator and his/her staff were fully responsible for maintaining
adequate control of the study medication and for documentation of all
transactions with them.
The study m edication was stored in a safe and secure place and proper
dispensing arrangements were made as follows:
- -- - -- --
Page42 of108
8.11.1
-
-
13 August 2002
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Sponsor - investigator inventory monitoring
All the study medication supplied by and returned to Leo Pharmaceutical
Products was fully documented by the trial monitor of Leo Pharmaceutical
Products with the help of the investigator.
8.11.2
Investigator - patient inventory monitoring
At visits 4 and 5 unused study medication was returned by the patient. An
inventory was kept of all supplies issued and returned by each patient enrolled
in the study. This inventory was available for inspection at monitoring visits
and was checked to ensure correct dispensing of study medication. All drug
supplies returned to Leo Pharmaceutical Products were reconciled with this
inventory. All tubes were weighed at Leo Pharmaceutical Products to
determine the amount of cream used.
8.11.3
Compliance
The patient was asked if he/ she had used the medication as prescribed. If not,
the reason for non-compliance was specified on the Case Record Form.
At visit 4 (day 7) and visit 5 (day 14), the patients were asked to return all the
dispensed tubes of study medication whether used or unused.
The returned tubes were collected and stored by the investigator for later
collection by the trial monitor (see Section 16).
8.12
CONCURRENT DRUG TREATMENT
Concurrent systemic medication (except for agents mentioned in Section 8.4.2)
for conditions other than atopic dermatitis could be continued throughout the
study, w ithout any change in dosage wherever possible. Usage of concurrent
medication was recorded in the Case Record Form. Antihistamine for treatment
of pruritus was allowed.
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Page 43 of108
13 August 2002
NOTE:
Concurrent topical treatment for atopic dermatitis on other body
areas than the arms should be hydrocortisone acetate. No other
active topical treatment was allowed. Indifferent moisturising creams
were allowed on body areas except on the arms.
8.13
STUDY PROCEDURES
The diagram summarises the study procedures:
Double-blind treatment
Visit
1
2
3
4
5
Day
0
2
4
7
14
Medical history
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Randomisation
Transepidermal water loss
Additional non-invasive bioengineering
measurements:
Skin colour
Bacteriology
Investigator: Clinical Signs/ symptoms
*
*
*
*
*
*
Investigator: Overall efficacy assessment
Pregnancy test*
*
Adverse events
Supply of trial medication
Collection of trial medication
*
*
* In female patients of child-bearing potential.
8.13.1
Medical history (visit 1 only)
At visit 1 the patient's suitability for the study was checked using the inclusion
and exclusion criteria. The patient's past history was taken and any concurrent
medication was recorded. Treatment with systemic corticosteroids was stopped
at least 8 weeks prior to the visit. Any topical treatment (except for bland
Page44 of108
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FUH9401DK
emollients) or UV-irradiation was stopped at least 1 week prior to visit 1.
Treatment with antihistamines was allowed and should be recorded in the Case
Record Form Book.
8.13.2
Selection of target lesions
Symmetric target lesion on the right and left arms for measuring the noninvasive bioengineering measurements were identified by the investigator at
visit 1. The area of each of the target lesions should be at least 15 cm2 (if
necessary, as 2 small areas). The target lesions should be the same during the
study. At visit 1, the investigator recorded the position of the target lesions on a
diagram of the arms in the Case Record Form Book.
8.13.3
Non-invasive bioengineering measurements
At each visit the investigator applied a number of relevant, non-invasive
measuring techniques for evaluation of disease activity and comparison of the
individual treatments. Reduction in transepidermal water loss was used as the
main response criterion. The same sites for respective measurements were used
throughout the study.
8.13.3.1
Transepidermal water loss (TEWL)
As an expression of the skin's barrier function, transepidermal water loss
(TEWL) was measured using an Evaporimeter EP-1 (Servo-Med, Kinna,
Sweden).
8.13.3.2
Skin colour
For measurement of (inflammatory) skin colour (redness) a Minolta Chroma
Meter (Minolta, Osaka, Japan) was used.
8.13.3.3
The hydration of the skin surface was measured using a Corneometer CM 820
(Courage-Khazaka, Cologne, Germany).
13 August 2002
FUH9401 DK
8.13.3.4
Page 45 of108
Any structural changes of the skin surface was assessed by taking replica of the
skin using SILFLO impression compound (FLEXICO Developments Limited).
8.13.3.5
Sectional pictures of skin structure and measurement of skin thickness and
inflammatory oedema were made by ultrasound scanning of the skin using
Dermascan-C (Cortex Technology, Hadsund, Denmark). The scanner was a
20 MHz skin scanner. Computerised image analysis of the hypoechogenic
subepidermal area was performed using the GIPS software.
For a detailed description of the specific procedures, see Appendix VI in the
Protocol.
8.13.4
Clinical assessments
8.13.4.1
Investigator's clinical assessment (visit 1)
At visit 1 the investigator assessed- for each arm, separately- the severity of
the following clinical signs:
a)
erythema
b)
thickness
c)
lichenification
d)
excoriation
e)
scaling
f) serious discharge
using a 4-point scale:
0 =absent
1 = slight involvement
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Page 46 of108
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2 = moderate involvement
3 = severe involvement
For each side the severity points were added to give the total clinical score.
Therefore, for each skin site the maximum total clinical score was 18.
8.13.4.2
lnvestigator•s overall assessment (visits 2 - 5)
At each post-randomisation visit the investigator made an assessment of the
overall response to therapy (for each arm separately) considering both the
extent and the degree of the disease (compared to baseline, i.e. visit 1) using a
6-point scale as follows:
0 = worse
1 = no change
2 = minimal improvement
3 = moderate improvement
4 = marked improvement
5 = completely cleared
8.13.5
Laboratory examinations
8.13.5.1
Pregnancy test
Urine stix.
8.13.5.2
Microbiological
i)
At all visits microbiological assessments were performed, see Appendix
VII in the Protocol.
NOTE:
Only Staph. aur. and beta-haemolytic streptococci were considered
as pathogens. S. epidermidis was regarded as a non-pathogenic skin
commensal.
FUH9401DK
ii)
13 August 2002
Page 47 of108
All isolates of Staph. aur. and beta-haemolytic streptococci were tested for
their in vitro susceptibility to fusidic acid, see Appendix VII in the
Protocol.
Strains of Staph. aur. were phage typed and stored.
iii)
Culture yields growth of 5 or less colonies, were regarded as negative.
NOTE:
Bacteriological results were not to be known by the investigators
during the trial. The results were released for data analysis at the end
of the study.
For specific procedures, see Appendix VII in the Protocol.
8.14
CRITERIA FOR EFFICACY AND SAFETY
The two treatments were compared according to the following:
8.14.1
Primary response criterion
Reduction in transepidermal water loss (TEWL) from baseline (visit 1) to a) end
of treatment and b) each post-randomisation visit.
8.14.2
Secondary response criteria
8.14.2.1
Change from baseline (visit 1) to:
a)
end of treatment
b)
each post-randomisation visit
of the following non-invasive bioengineering measurements:
I)
skin colour
Page48 of108
13 August 2002
II)
skin surface hydration
III)
skin surface contour
FUH9401DK
IV) skin thickening and oedema
8.14.2.2
Proportion of patients where the treatment had reduced the pre-treatment
pathogen (Staph. aur. and beta-haemolytic streptococci).
• Qualitative microbiological response were evaluated as follows:
Success: Eradication of pre-treatment pathogen (evaluation including phagetype) during treatment and on completion of treatment.
Failure: Presence of pre-treatment pathogen during treatment and/ or on
completion of treatment.
Unevaluable: Staph. aur. or beta-haemolytic streptococci not present at
baseline.
Only phage types present at baseline were considered.
• Quantitative microbiological response were evaluated as follows:
Reduction in Staph. aur. count from visit 1 to subsequent visits
Only phage types present at baseline were considered.
8.14.2.3
Proportion of patients obtaining "marked improvement" or . "clearance"
according to investigator's overall assessment at a) end of treatment and b) each
post-randomisation visit.
13 August 2002
FUH9401 DK
8.14.2.4
Any reported adverse events.
8.15
ADVERSE EVENT REPORTING
Page 49 o/108
At each post-randomisation visit the patient was asked a non-leading question
by the investigator: "Since I last saw you, have you had any problems while
using the treatment?" No specific symptoms were suggested.
If the answer was "NO", no further questions were asked. If the answer was
"YFS", the investigator recorded for left and right side, separately, the event's
nature, duration, severity, and suspected relationship to the use of study
medication.
In recording the patient's comments, the investigator should observe the
following definitions:
a) ADVERSE EVENT: any undesirable experience occurring to a subject
during a clinical trial, whether or not considered related to the
investigational product.
b) SERIOUS ADVERSE EVENT: an adverse experience that was fatal, life·threatening, disabling, or which resulted in hospitalisation or prolongation of
hospitalisation. In addition, congenital anomaly and occurrence of
malignancy were always considered serious adverse events.
c) UNEXPECTED ADVERSE EVENT: an experience not previously reported
(in nature, severity, or incidence) in the current Product Monograph, in the
general investigational plan or elsewhere.
NOTE:
Patient's remarks relating to the primary disease condition should
not, as a general rule, be included in the adverse event chart.
Page 50 of108
13 August 2002
FUH9401DK
It was important that the investigator also observed the patient for any skin
changes not reported by the patient, and recorded these changes.
Events either reported by the patient and/ or observed by the investigator, that
fell into any of the above definitions should be described in the following
manner:
1) The nature of the event was described in precise, standard medical
terminology (i.e. not necessarily the exact words used by the patient).
2) The duration of the event was described in terms of, e.g. the number of days
the event had been present since last visit.
3) The location of the event was described in precise, standard medical
terminology. For cutaneous adverse events it was specified whether the
reaction was lesional, perilesional (~ 2 em from the lesional border) or distant
(> 2 em from the lesional border).
4) The severity of the event was described in terms of:
a)
Mild signs and/ or symptoms that clear spontaneously without
specific therapy and do not recur despite continuation of the drug.
b)
Moderate signs and/ or symptoms which require specific therapy but
do not require discontinuation of the drug.
c)
Severe signs and/ or symptoms which require specific therapy and
discontinuation of the drug.
5)
The causal relationship of the event to use of the study medication was
described in terms of:
FUH9401DK
13 August 2002
a)
Page 51 of108
Unlikely: the adverse event
- does
not follow
a
reasonable
temporal
sequence
from
administration of the drug,
- could readily have been produced by the patient's clinical state,
environmental or toxic factor or other therapies administered to
the patient,
- does not follow a known response pattern to the suspected drug,
- does not reappear or worsen when the drug is re-administered.
b)
Possible: the adverse event
- follows a reasonable temporal sequence from administration of
the drug,
- could readily have been produced by the patient's clinical state,
environmental or toxic factor or other therapies administered to
the patient,
- disappears or decreases on cessation or reduction in dose,
- follows a known pattern or response to the suspected drug.
c)
Probable: the adverse event
- follows a temporal sequence from administration of the drug,
- could not be reasonably explained by the patient's clinical state,
environmental or toxic factors or other therapies administered to
the patient,
- disappears or decreases on cessation or reduction in dose,
- follows a known pattern or response to the suspected drug.
NOTE:
All adverse events should be followed-up to determine outcome of
the reaction. Details of follow-up care should be given (i.e. if
treatment was required, if hospitalisation was required, etc.).
Page 52 of108
8.15.1
13 August 2002
FUH9401DK
Reporting of serious and unexpected adverse events
Serious and unexpected adverse events should be reported immediately
(within 24 hours) to the local trial monitor mentioned on the inside front cover
of the Case Record Form Book or to the Company.
Within 5 working days an Adverse Event Report Form (see Appendix IV in the
Protocol) should be submitted to the Company accounting for the adverse
event(s). The information provided on the form should include a full
description of the clinical course, account for any concurrent drug therapy
given during the study period and, where possible, contain relevant
documentation (e.g. in case of death a copy of the post-mortem report). The
report should also include a statement from the investigator as to the possible
causal relationship between the adverse event and the study medication. If a
complete history was not available within 5 working days then the form should
be submitted and further details added as they became available.
If an investigator was in doubt whether to regard an adverse event as serious,
or unexpected, the event was serious or unexpected until the opposite was
proved.
In addition, Ethics Committees and National Regulatory Authorities should be
informed of the matter according to national/local rules and/ or regulations.
FUH9401DK
9
13 August 2002
Page 53 of108
QUALITY ASSURANCE
The trial protocol and the conduct of the trial as a whole were designed to
comply with the European Community Guidelines on Good Clinical Practice
(no. 3/3976/88, as of July 1991).
Any activity in relation to the trial could be subject to independent Internal
Audit.
This study was audited twice by the R&D, QA Department, Leo Pharmaceutical
Products, Ballerup, Denmark. The audit certificates are given in Appendix IX
together with the GCP compliance statement (Authentication Form).
FUH940lDK .
13 .August 2002
Page 54 of108
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~
· ,..:...
..
. ·~·.
...
;
• ..·
~.
,.'!. '
......
..
(
•'\;
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,... ,•1·.
-,
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.;
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.
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L
FUH9401DK
10
13 August 2002
Page 55 of108
STATISTICAL ANALYSIS
The statistical analysis was planned and described in the protocol (Appendix
III, section 23). A Statistical Analysis Plan was finalised before the study was
unblinded, but after blind review of the actual outcome of the data (Appendix
IV). The Statistical Analysis Plan gave a more technical and detailed elaboration
of some points in the statistical analysis described in the protocol. Additionally,
the document presented the analysis sets to be used for the statistical analysis.
10.1
TRIAL POPULATIONS
The analysis sets were determined from criteria given in the protocol:
All patients who entered the study were accounted for.
All patients who received treatment with the trial medication, provided any
data on efficacy, and complied with the major eligibility criteria, that is had a
flare-up of atopic dermatitis with symmetric lesions on the arms, were analysed
for efficacy.
All randomised patients who received treatment with trial medication and who
provided any information on safety were analysed for safety.
10.2
BASELINE CHARACTERISTICS
Demographics and other baseline characteristics, including baseline noninvasive bioengineering measurements were tabulated. Data on interval scale
were summarised by observed mean, standard deviation, minimum and
maximum. Distributions were presented for data on a nominal or ordinal scale.
13 August 2002
Page 56 of108
10.3
FUH9401 DK
EFFICACY ANALYSIS
The statistical analysis of efficacy was based on the defined response criteria.
10.3.1
Non-invasive bioengineering measurements (including TEWL)
The difference between the two treatments concerning changes from baseline to
end of treatment in non-invasive bioengineering measurements was assessed
by paired t-tests. Relations between changes and baseline values were
accounted for by analysis of absolute and percentage changes.
According
to
the
protocol the
repeated
non-invasive
bioengineering
measurements were analysed using an appropriate summary measure (Altman
DG. Practical statistics for medical research. London. Chapman and Hall1991;
426-33) determined by the actual outcome of the data before the code was
broken. Plots of individual patient response-time curves for right and left arm
separately were investigated at the blind review of the data. The general trend
was an early treatment effect, within the first 2 to 4 days, and no change during
the rest of the 2 weeks treatment (see, Appendix IV). It was, therefore, decided
to analyse the change from baseline to the first on-treatment visit after 2 days as
summary measure of the initial response. The initial response together with the
total response, measured as change from baseline to the end of treatment after 2
weeks (visit 5), gave a suitable description of the response-time curve. The
initial response was compared between the treatments by paired t-tests in the
same way as the total response.
Along with the statistical analysis of initial and total response the mean, SD,
minimum and maximum were tabulated by treatment and visit.
The individual patient response-time curves did not show any obvious
deviation from normality. The sensitivity of the results to the normality
assumption was addressed by comparison of the results of the paired t-tests
FUH9401DK
13 August 2002
Page 57 of108
with results of corresponding non-parametric Wilcoxon matched pairs tests.
The results were all robust regarding statistical analysis method. Details are
given in the Statistical Appendix, Appendix I.
10.3.2
Bacteriology
The difference between the two treatments concerning the proportion of
patients where the treatments had eradicated the pre-treatment pathogen was
analysed by McNemar's test. Additionally, the quantitative microbiological
response was tabulated by treatment and visit.
10.3.3
The distribution of the investigator's overall assessment of efficacy (6-point
scale) was tabulated by treatment for each post-randomisation visit. The
difference between the two treatments concerning the proportion of 'marked
improvement' or 'clearance' at visit 2 and at the of treatment, respectively, was
assessed by McNemar's test. The protocol only called for the end of treatment
comparison of the two treatments. The comparison of the visit 2 values was
decided at the blind review in analogy with the analysis of the bioengineering
measurements.
10.4
SAFETY ANALYSIS
Adverse events were tabulated and analysed according to the WHO System
Organ Class ('WHO Adverse Reaction Dictionary' ).
The difference between the two treatment arms with respect to the frequency of
adverse events was statistically assessed by McNemar's test.
The same adverse event recorded for a patient arm at different visits counted as
one event for that patient arm.
Page 58 of108
13 August 2002
FUH9401DK
The severity and estimated causaL relationship to study medication were
tabulated for the individual patients.
10.5
GENERAL PRINCIPLES
All tests and confidence intervals were two-sided and the 5% level of
significance was applied.
10.5.1
Handling of drop-outs and missing values
The handling of drop-outs and missing values was dealt with at the blind
review of the data:
There was no drop-out from the study. All the randornised patients attended
the last visit (visit 5). Five patients lost visit 3 but returned for visit 4 and 5. Two
patients lost visit 4 but returned for visit 5. The statistical comparison of the two
treatments was planned to be based on visit 2 values (initial response) and visit
5 values (end of treatment, total response). The comparison of the treatments
was, therefore, not affected by the lost visits (visit 3 and visit 4).
There were only few missing values besides the non-attended visits: The skin
surface hydration was missing at visit 1 (baseline) for a single patient. The skin
thickness was missing at visit 1 for two patients. The oedema was missing at
visit 1 for two patients, and a further patient only provided right arm oedema
data at visit 1 and left arm oedema data, only, at visit 2.
The TEWL data (primary response criterion), the skin colour (Minolta a* data)
and the skin surface contour (roughness parameters) were measured at all
attended visits.
The statistical hypothesis tests and the tabulation of descriptive statistics were
based on the available data.
FUH9401DK
11
13 August 2002
Page 59 of108
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED
ANALYSES
Protocol Amendment no. 1 dated 6 February, 1995 was implemented during the
study. This amendment lowered the age limit for inclusion in the study from 4
years to 2 years. The upper age limit of 17 years was maintained.
Page 60 o/108
13 August 2002
I· .,
FUH9401DK
FUH9401 DK
12
RESULTS
12.1
STUDY PERIOD
12.1.1
Study start
13 August 2002
Page 61 of108
The first patient was recruited for the study on 3 January 1995 and the last
patient was recruited on 5 March 1997.
12.1.2
Study completion
The last patient was recruited for the study on 5 March 1997 and completed the
study on 20 March 1997.
12.1.3
Duration of the study
The total duration of the study was 27 months.
12.1.4
Unblinding
The study was unblinded on 6 August 1998.
12.2
STUDY POPULATION
12.2.1
Disposition of study subjects
A total number of 25 patients were recruited from a single Danish centre. An
extra CRF book was started but a patient was never recruited (signing informed
consent) for this CRF book.
One patient was excluded before randomisation because of sun exposure
resulting in improved eczema condition.
All the 24 randomised patients attended the final study visit (visit 5) and
provided data on efficacy and safety.
The number of subjects who attended each visit is shown in Figure 1.
Page 62 oj108
13 August 2002
FUH9401DK
Figure 1: Disposition of study patients
Number of patients
Number of CRF books
started
1 Patien t was never recruited (CRF Recruited at visit 1
1 Exclusion criterion (CRF Randomised at visit 2
= Safety population
= Efficacy population
Attended visit 2
Attended visit 3
5 Lost visit 3 but returned for visit 4 and 5
Attended visit 4
2 Lost v isit 4 but returned for visit 5
Attended visit 5
Individual patient visit dates and withdrawal data appear from Appendix II,
Table II.1 and Table II.2.
12.3
INTENTION-TO-TREAT (fiT) POPULATION
The ITT sample for efficacy analysis consists of all the 24 randomised patients.
12.4
SAFETY POPULATION
The safety population consists of all the 24 randomised patients.
FUH9401 DK
12.5
13 August 2002
Page63 of108
PER PROTOCOL POPULATION
The per protocol population is identical to the ITT population and consists of 24
patients as described above
12.6
PROTOCOL DEVIATIONS
Some of the visits were missed (see Section 12.2.1): Five patients lost visit 3 but
returned for visit 4 and 5. Two patients lost visit 4 but returned for visit 5.
12.7
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Sixteen females (66.7%) and 8 males (33.3%) were randomised in the study. The
mean age of all patients randomised was 9.0 years (range 3 to 17). For data in
individual patients, see Appendix II, Table II.3.
12.7.1
History of atopic dermatitis
The mean duration of the atopic dermatitis was 6.7 years (range 1 to 16). For
data in individual patients, see Appendix II, Table Il.4.
12.7.2
Concomitant diagnoses
Two of the randomised patients (8.3%) suffered from other diseases in addition
to atopic dermatitis. See Appendix II, Table 11.5.
12.7.3
Concomitant drug treatment at baseline
Four of the randomised patients (16. 7%) used a total of 5 concomitant drugs at
baseline (visit 1).
For individual data on concomitant drug treatment, see Appendix II, Table 11.4.
13 August 2002
Page 64 of108
12.7.4
FUH9401DK
Severity of atopic dermatitis at baseline
Table 5 gives the investigator's assessment of the severity of clinical signs for
atopic dermatitis - for each arm separately.
Table 5:
Investi ator's clinical assessment o randomised atients at baseline (visit 1)
Clin ica l sign of atopic dermatitis
Severity
Fucid i n - H
(n=24 )
Number of
patienes
Erythema score
Absent
Slight i nvolvement
Severe involvement
All p a tients
Hydrocortisone
(n•24 )
%
0
10
12
0
41 . 7
2
24
8. 3
100 .0
Excori ation score
Absent
Slight i nvolvement
Moder a t e invol vement
Severe involvement
All patients
6
6
11
25 . 0
25.0
45 . 8
1
24
100.0
Liche nificat ion score
Slig ht i nvolvement
Sever e i nvolvement
All patients
5
15
Scaling score
J\bsent
Sl i g ht involvement
Severe i nvolvement
All patie nts
Serious discharge
J\bsent
S light involveme n t
Moderate i nvolvement
All patients
Thickness score
Absent
Slight i nvolvement
Moderate i nvolvement
Severe invol vement
All patients
so .o
4. 2
24
20.8
62.5
16 . 7
100 . 0
1
13
10
0
24
4 .2
54 . 2
41.7
0
100.0
23
4
Number of
patients
1
7
12
24
5
6
12
1
24
9
ll
4
24
4 .2
29.2
50.0
16 .7
100.0
20.8
25.0
50.0
4 .2
100.0
37.5
45.8
16.7
100.0
24
4.2
58.3
33.3
4.2
100.0
95. 8
0
23
95 . 8
1
4.2
4 .2
0
24
0
100.0
1
4.2
37.5
45 . 8
12.5
100.0
0
1
24
100.0
1
5
16
2
24
4. 2
20 . 8
66.7
8.3
100 . 0
1
14
8
1
%
9
ll
3
24
For each arm the six individual severity scores using the 4-point scale
(0 = absent, 1 =slight involvement, 2 = moderate involvement, 3 = severe
involvement) w ere summed to give the total clinical score. The mean total
clinical sign score was 8.2 (range 4 to 14) for the Fucidin-H arm and 8.0 (range 2
to 13) for the H ydrocortisone arm.
For data in individual patients, see Appendix II, Table II.6.
FUH9401DK
12.7.5
13 August 2002
Page 65 of108
Non-invasive bioengineering measurements at baseline
The baseline values of the non-invasive bioengineering measurements are given
in Section 12.8 EFFICACY RESULTS. The two treatment arms were well
matched at baseline.
12.7.6
Variability among study sites with respect to baseline patient characteristics
Not applicable.
12.8
EFFICACY RESULTS
12.8.1
Primary efficacy criterion (TEWL)
There was no difference between the treatments with respect to the primary
efficacy criterion: At end of treatment (2 weeks) the mean TEWL reduction was
34.6% with Fucidin-H compared to 31.1% with Hydrocortisone. The mean
difference of 3.5% points (95% confidence interval -6.3 to 13.2) was not
statistically significant (P = 0.47). The initial (2 days) mean TEWL reduction was
15.0% with Fucidin-H and 12.9% with Hydrocortisone. The mean difference of
2.0% points (95% confidence interval-8.5 to 12.6) was not statistically significant
(P = 0.69).
The mean TEWL at each treatment side and the mean difference between the
treatments are given for each visit in Table 6.
13 August 2002
Page 66 of1 08
Table 6:
FUH 9401DK
TEWL at baseline and at subse uent visits (Intention-To-Treat o u lation)
Visic
T EWL
VISIT 1 (BASELI NE)
Mean
SD
Minimum
Maximum
Numbe r
Fucidi n · H
Hydr cx:ortisone
Dif fer ence
( n=24)
( n • 24}
( n•2 4}
31.91
11 .11
10 .3
55.9
24
31.92
11.80
54. 9
24
- 0.01
7 . 38
-18. 0
11 . 8
24
26 . 46
12.18
10 . 1
65.8
24
26.53
1 0 .51
14. 0
50 . 3
24
- 0 . 07
7.20
-1 4. 3
15.5
24
20.11
5 . 26
9 .6
28.2
19
22.07
6 . 21
1 0 .7
33.9
19
- 1. 96
4 .4 8
- 11.2
8.2
19
20.37
8.04
7.0
37.9
22
21. 08
11 . 15
56.3
22
- 0 . 71
9 . 52
- 32.7
16 . 4
22
19 . 77
8 . 95
4 .1
3 6 .6
24
20 . 25
8 . 35
8.2
45.2
24
-0 .48
7.16
- 1 7.6
12.0
24
u .s
VISIT 2
Mean
SD
Minimum
Maximum
Number
VISIT 3
Mean
SD
Mi n imum
Maximum
Number
VIS IT 4
Mean
SD
Mini mum
Maximum
Number
VI S IT 5 (END OF
Mean
SD
Minimum
Ma ximum
Number
6. 5
TREATMENT)
The mean TEWL at each treatment side at baseline and at control visits during
double-blind treatment are shown in Figure 2.
Figure 2: TEWL (mean) at baseline (visit 1) and at subsequent visits during
treatment
13 August 2002
FUH9401 DK
Page 67 of108
The absolute change and the percentage change in TEWL from baseline to
subsequent control visits during double-blind treatment are given in Table 7
and8.
Table 7:
Change in TEWL from baseline to subsequent visits (Intention-To-Treat
population)
Visi t
Change in TEWL
Fucidin-H
(n=24)
Hydrocortisone
Dif f e rence
(n=24)
(n=24)
Treatment
comparison
(paired t - test:.)
VISIT 2
Mean
SD
Mi nimum
Maximum
Number
- 5 . 45
11.30
-31.8
18 . 3
24
- 5 .39
9.60
- 28.7
7. 7
24
-0 . 07
9.00
-14.4
1 8.5
24
- 11 . 88
10.62
-35. 4
7.3
19
- 9. 7 0
ll . 93
-28.9
9.7
19
- 2.18
6 . 75
-16 .7
12.3
19
-12 . 1 9
10 . 82
- 39. 1
9.1
22
-ll. 59
1 5.67
-35.3
33-1
22
-0 . 60
9.57
- 2 4. 0
14 . 0
22
- 12 . 15
1 0.68
· 36.7
14 . 2
- 11 . 67
11 .81
- 32.7
21 .9
24
-0 . 47
9.17
-18.1
20.3
24
p
= 0.97
p
= 0 .80
VISI T 3
Mean
SD
Mi nimum
Maximum
Number
VISIT 4
Mean
SD
Min imum
Maximum
Number
VISI T 5 (END OF TREATMENT)
Mean
SD
Mi nimum
Maximum
Number
Table 8:
24
Percentage change in TEWL from baseline to subsequent visits (IntentionTo-Treat population)
Visit
Percentage change
F\lcidin-H
Hydrocort isone
Difference
(n.c24)
(n• 24)
-14.99
26 . 7l
-6 5.2
48 . 7
24
-1 2 . 94
23.93
- 59 .6
27.9
24
-2 .05
25.09
- 42.6
53. 6
24
-30.78
26.32
-64 .1
- 23. 0 0
30.57
- 7.78
20.95
- 71 . 5
18.8
19
(n= 24)
in TEWL
Treatment
comparison
(pair ed t-te st)
VI SIT 2
Mean
SD
Mi nimum
Maximum
Numbe r
VISIT 3
Mean
SD
Minimum
Maximum
Number
so.o
-sa.o
19
41.. 9
19
- 33 .1 6
29 .14
- 69.9
6 2.4
- 26.85
5 2.60
· 75 . 4
14:2 . 3
22
22
-34. 58
35.81
- 7 5 .4
9 7.9
24
-31.11
34.40
- 70.7
94.4
24
p • 0 . 69
VISIT 4
Mean
SD
Minimum
Maxi mum
Number
VISIT 5 (END OF TREATMENT )
Mean
so
Mi n imum
Maximum
Number
-6.31
34 . 27
- 116.1
35 .1
22
-3.47
23 . 06
-48 . 9
5 7.4
24
p • 0. 47
13 August 2002
Page 68 of108
FUH9401DK
For TEWL data in individual patients, see Appendix II, Table Il.7.
12.8.2
Non-invasive bioengineering measurements
12.8.2.1
Skin colour
There was no difference between the treatments with respect to skin colour. At
end of treatment (2 weeks) the mean skin colour reduction was 25.6% with
Fucidin-H compared to 23.6% with Hydrocortisone. The mean difference of
2.0% points (95 % confidence interval-3.2 to 7.2) was not statistically significant
(P = 0.44). The initial (2 days) mean skin colour reduction was 18.5% with
Fucidin-H and 15.1% with Hydrocortisone. The mean difference of 3.3% points
(95% confidence interval -2.9 to 9.5) was not statistically significant (P = 0.28).
The mean skin colour at each treatment side and the mean difference between
the treatments are given for each visit in Table 9.
Skin colour (a* value) at baseline and at subsequent visits (Intention-ToTreat population)
Table 9:
Vi s i t
Sk in colou r
VISIT 1
(a • value)
Hydrocortisone
(ns 2 4 )
Di ff e rence
( n &24 )
(BAS ELI NE)
Mean
so
Minimum
Maximum
Number
VISIT 2
Mean
so
Minimum
Maximum
Number
VISIT 3
Mean
so
Min imum
Ma ximum
Number
VISIT 4
Mean
so
Min imum
Maximum
Numbe r
VI S IT 5 l END OF TREI>.TMENT)
Me an
so
Mi n imum
Ma ximum
Number
Fu cid in· H
(n• 24 )
1 2 .180
3 .15 4
7 . 51
21.16
24
1 2 . 372
3 . 625
6 . 77
22 .29
24
- 0 . 1 92
1. 53 3
· 2 . 90
3. 2 5
24
9 . 994
3 . 3 64
3 . 40
19 .15
24
1 0 . 4 56
3. 19 2
3. 72
18.71
24
- 0. 4 6 1
1 . 8 04
- 3 .44
4 .39
24
8 .936
2 .459
4 . 21
13 . 18
19
9 . 57 3
2 . 658
3 . 99
1 3.90
19
- 0.6 35
1.216
!L300
2.874
4.98
14. 45
22
9 . 275
3.280
3.92
1 5 .28
22
0.025
1 .4 4 2
- 3 . 27
3.03
22
8 . 8 7)
2. 8 22
4 . 91
1 5 .1 9
24
9 . 26 1
2. 7 51
5 .19
15 . 7 7
24
-0. 3 88
1. 3 71
- 3. 2 2
2 . 69
24
- 3 . 73
1 .86
19
13 August 2002
FUH9401DK
Page 69 of108
The absolute change and the percentage change in skin colour from baseline to ·
subsequent control visits during double-blind treahnent are given in Table 10
and 11.
Table 10: Chilnge in skin colour (a* value) from baseline to subsequent visits
(Intention-To-Treat population)
Visit.
Change i n ski n colour
(a• value)
VI SIT 2
Mean
so
Minimum
Maxi mum
Numbe r
Fucidin· H
Hydrocort.is one
Difference
<n=24)
(n• 24 )
(n=2 4)
- 2.186
l. 902
- 5.52
0.89
24
- 1 .91 7
1 .698
· 4 .97
1.09
24
- 0 . 270
1.886
- 3 . 51
4.59
24
- 3 . 414
2. 696
- 8 .56
0. 68
19
- 2 .981
2.509
• 8 . 65
0.74
19
- 0.433
l. 639
- 3.54
2.2 9
19
- 3 .041
2 . 713
- 7.64
0 .59
22
- 3 . 302
2 .216
-7. 3 3
0 . 86
22
0 . 26 1
1 . 741
- 3.30
3.09
22
-3 .307
3.189
- 11 .09
1.98
24
- 3.111
2.831
- 11.61
1. 3 0
24
- 0 . 1 96
1. 577
- 3. 72
2.80
24
Treatment
compar i son
(paired t ·t.es t.)
p -
0.49
p •
o. 55
VISIT 3
Mean
so
Minimum
Max imum
Number
VISIT 4
Mean
SD
Minimum
Maximum
Number
V I SIT 5 ( END OF TREATMENT )
Mean
so
Min imum
Naximum
Number
Table 11: Percentage chilnge in skin colour (a* value) from baseline to subsequent
visits (Intention-To-Treat population)
Visit
Percentage change in
sk i n colour (a• va l ue)
Fucidin -H
(n=24 )
Hydrocor tisone
Diff e rence
(n•24)
(n• 2 4)
Tr eatment
compar ison
(paired t- t est)
VISIT 2
Mean
SD
Minimum
f\1axi mum
Number
- 18 . 46
1 5.8 2
- 57.6
8 .1
24
· 15.14
1 3 .45
· 45.1
1 1.6
24
- 3.32
14 . 65
- 37 .1
32.2
24
· 26.3 1
17.97
- 52.0
5. 4
19
-22.6 7
1 4.62
· 44.1
5. 6
19
- 3.64
11.24
- 25.6
17 . 2
19
- 23 . 31
1 9 . 29
-57 . 3
4. 7
22
-26 .09
16.92
· 65.1
6 .5
22
2 . 78
12.51
-1 6.9
21.8
22
- 25 . 56
21.10
-54. 7
18. 4
24
· 23.5 7
1 6.67
·53.9
9.0
24
- 1 . 99
12.34
-3 3 .5
26.0
24
p
=
p
= 0 .44
0.28
VISIT 3
~lean
so
Minimum
~tax imum
Number
VISIT 4
tote a n
SD
Mi nimum
Maximum
Number
VISIT 5 (END Of TREATMENT)
Mean
so
Mini mum
Maxi mum
Number
13 August 2002
Page 70 of108
FUH9401DK
Individual patient skin colour data are given in Appendix II, Table 11.8.
12.8.2.2
There was no difference between the treatments with respect to skin surface
hydration. At end of treatment (2 weeks) the mean skin surface hydration
change was 61.4% increase with Fucidin-H compared to 47.3% with
H ydrocortisone. The mean difference of 14.1% points (95 % confidence interval
-8.9 to 37.0) was not statistically significant (P = 0.22). The initial (2 days) mean
skin surface hydration increase was 29.8% with Fucidin-H and 15.8% with
H ydrocortisone. The mean difference of 14.0% points (95% confidence interval
-1.9 to 29.9) was not statistically significant (P = 0.081).
The mean skin surface hydration at each treatment side and the mean difference
between the treatments are given for each visit in Table 12.
Table 12: Skin surface hydration at baseline and at subsequent visits (Intention-To-
Treat population)
Vi sit
VISIT ~ ( BASELINE)
Mean
SD
Minimum
Maximum
Number
VISIT 2
Mean
Fucidin-H
(n • 24)
44 .7
19 .9
18
102
23
Hydr ocor t i sone
(n~24)
44 . 7
18.6
23
~04
23
Di fference
(n - 24)
- o.o
9.4
-1 5
25
23
52 .3
16 .4
23
83
24
4 7.8
13 . 9
24
78
24
4 .5
11. 7
- 20
32
24
59.0
12 . 2
37
77
19
56 . 4
14 . 7
31
81
19
2 .6
8. 8
-20
6 1.5
11 . 5
37
86
22
64 . 9
13 . 0
43
93
22
-3 . 3
8.9
- 20
16
22
Min i mum
61. 7
15 .3
34
Max i mum
Number
24
60 . 6
16 . 6
29
90
24
1 .0
10 .3
- 21
20
24
so
Minimum
Maxi mum
Number
VISIT 3
Mean
so
Minimum
Maximum
Number
VI SIT 4
Mean
so
Minimum
Maximum
Number
VI SIT 5 (END OF TREATMENT)
Me an
so
9~
22
19
13 August 2002
FUH9401 DK
Page 71 of108
The absolute change and the percentage change in skin surface hydration from
baseline to subsequent control visits during double-blind treatment are given in
Table 13 and 14.
T able13: Change in skin surface hydration from baseline to subsequent visits
Visi t
Change in surface
hydration
VIS IT 2
Mean
SD
Minimum
Maximum
Number
VIS IT 3
Mean
SD
t-1inimum
MaXimum
Number
Fucidin· H
(n=24l
Hydrocortisone
(no24)
Difference
(n=24)
Treatment
compar ison
(paired t · t est)
7.9
16. 7
- 36
55
23
3 .4
14.3
-35
27
23
4 .4
11.0
- 15
28
23
p - 0.068
16.2
18 . 6
·26
45
18
11.6
17.1
-28
41
18
4.6
13 . 0
-20
25
18
15.2
20.8
· 39
44
21
19.5
16 . 3
·26
45
21
- 4.3
13 .5
· 25
31
21
17.3
19.5
· 28
56
23
15 .5
17.4
- 19
51
23
1. 8
11. 0
· 15
21
23
VI SI T 4
~tean
so
Minimum
Maximum
Number
VI SIT 5 ( END OF TREATMENT)
Mean
SD
Min imum
Maximum
Number
p
= 0. 4 5
Table 14: Percentage change in skin surface hydration from baseline to subsequent
Visit
Per centage c hange in
skin surface hydr ation
VISIT 2
Mean
SD
Minimum
Maxi mum
Number
VISIT 3
Mean
SD
Minimum
Maxi mum
Number
Pucidin- H
(n• 24 )
Hydr ocort i sone
(n•24)
Di fference
(n• 24 )
Treatme n t
comparison
(paired t · t est)
29.81
51.77
-35.0
192 . 9
23
15.79
35 . 65
· 36.3
108. 1
23
14.02
36 . 73
· 47 .o
121. 1
23
p . 0 . 0 81
62 62
70.50
· 25.2
250.0
18
37 . 93
48.39
-2 7 .2
164. 9
18
24.68
56 . u
· 46. 3
178 .9
18
54.21
62.52
- 37.9
201.5
21
58.55
49.20
· 25.2
14 7.1
21
44. 80
- 56.3
124.1
21
61.39
76.64
-43. 3
290.7
23
47.33
54 .61
-20.4
208.1
23
14.06
5 3.01
· 5 1 .6
192 . 8
23
VISIT 4
Mean
so
Mini mum
Maxi mum
Number
VISIT 5 \END 0!" TREATMENT)
Mean
SD
Minimum
Maximum
Number
· 4. 34
p • 0.2 2
Page 72 of108
13 August 2002
FUH9401DK
Individual patient skin surface hydration data are given in Appendix II, Table
II.9.
12.8.2.3
There was no difference between the treatments with respect to skin thickening.
At end of treatment (2 weeks) the mean skin thickening reduction was 8.9%
with Fucidin-H compared to 12.7% with Hydrocortisone. The mean difference
of -3.8% points (95% confidence interval -9.6 to 2.0) was not statistically
significant (P = 0.19). The initial (2 days) mean skin thickening reduction was
5.0% with Fucidin-H and 5.5% with Hydrocortisone. The mean difference of
-0.5% points (95% confidence interval-4.3 to 3.3) was not statistically significant
(P = 0.80).
The mean skin thickening at each treatment side and the mean difference
Table 15: Skin thickening (mm) at baseline and at subsequent visits (Intention-To Treat population)
Vi sit
Sk i n t hic ken i ng
( nun)
VISIT 1 (BASELINE)
Mean
Fucidin · H
(n• 24 )
Hyd rocortisone
(n • 24 )
Difference
(n-24)
Mini mum
Maximum
Number
1 .178
0.363
0.58
1 . 84
22
1 . 174
0 .284
0.70
1. 71
22
0 .004
0. 136
- 0.29
0 . 23
VISIT 2
Mean
SD
Minimum
Max imum
Nu mber
1 . 119
0 .332
0 . 62
1. 74
24
1.121
0.279
0.69
1 .68
24
- 0.002
0.098
- 0.17
0. 18
24
Maximum
Number
1. 020
0. 300
0.66
1. 66
19
1.045
0 .280
0.65
1 . 55
19
-0 . 025
0. 105
- 0.30
0. 14
VISIT 4
Mean
SD
Minimum
Max imum
Numbe r
1.067
0.297
0 .55
1. 7 5
22
1.060
0.25 5
0 .54
1. 4 8
22
0.007
0 . 100
- 0 .19
0.2 7
22
1.045
0.292
0.57
1.73
24
1 . 027
0.275
0.52
1.55
24
0.018
0.122
· 0. 24
0.34
24
so
VISIT 3
Mean
so
Mini mum
VISIT 5 (END OF TREATMENT)
Mean
so
Minimum
Maximum
Number
22
19
FUH9401 DK
13 August 2002
Page 73 of108
The absolute change and the percentage change in skin thickening from
Table 16 and 17.
Table 16: Change in skin thickening (mm) from baseline to subsequent visits
Vi s it
Change in ski n
thi ckeni ng
Fucidin- H
(ns24)
Hydrocortisone
Difference
( n=2 4)
( n=24 )
Treatment
compari son
(pa ired e-te s t )
VIS IT 2
• Mean
so
Minimum
Maximum
Numbe r
- 0. 065
0.08 9
- 0 . 35
0 .0 8
22
-0.066
0.097
- 0.35
- 0 . 1 40
0 . 1 70
- 0.63
0.15
17
- 0.122
0 .155
- 0.60
0.04
17
- 0.018
0. 133
- 0 . 14 8
0.154
- 0.6 5
0 . 17
20
- 0.156
0. 1 45
- 0.47
0 .07
20
0 .008
0 .129
- 0.23
0 . 32
20
- 0.132
0 . 190
-0.6 8
0 . .2 8
22
- 0.158
0. 1 97
- 0 . 67
0 . 24
22
0 .026
0. 15 4
- 0 .2 3
0 . 57
22
O.ll
22
0. 001
0.104
- 0. 1 8
0 .29
22
p
= 0.98
p
= 0. 44
VIS IT 3
Mean
so
Mini mum
Max imum
Number
-o. 34
0.27
17
VIS IT 4
Mean
so
Mi nimum
Maximum
Number
Mean
so
Min imum
Max imum
Number
Table 17: Percentage change in skin thickening (mm) from baseline to subsequent
Vis i t
Pe rcentage change in
s kin chickening
Fucidi n -H
<n=24 )
Hydrocorei sone
Di ff erence
(n • 2 4)
( n• 24 )
Tr eatment
c ompar ison
(paired t - t e st)
VISIT 2
Mean
so
Minimum
Maximum
Number
- 5. 03
7 . 65
-22 . 3
13 . 7
22
-5.49
7 . 45
-24.3
7 .7
:22
0. 46
8 .56
· 1 2.0
19 .6
22
- 9. 87
13 . 59
· 39 . 4
25. 9
17
- 9 . 77
1 0 .75
- 4 1. 3
3. 9
17
- 0 . 10
12 .13
-22 . 7
32 . 7
17
- 10 . 73
12. 86
· 40. 7
28.8
20
-12 . 51
11 . 15
- 32.5
7.8
20
1.78
9. 4 8
- 14 . 3
20.9
20
- 8.8 8
16. 67
-43 .0
4 9.0
22
- 1 2 .71
15 . 83
- 4 7. 4
27. 2
22
3 . 83
13 . 1 2
-12. 4
48.1
22
p
= 0.80
VIS IT 3
Mean
SD
Minimum
Maxi mum
Number
VISIT 4
Mean
so
Minimum
Maximum
Number
Mean
so
Mi nimum
Maximum
Number
p •
0. 19
13 August 2002
Page 74 of108
FUH9401 DK
There was no difference between the treatments with respect to inflammatory
oedema. At end of treatment (2 weeks) the mean inflammatory oedema
reduction was 12.5% with Fucidin-H compared to 25.0% with Hydrocortisone.
The mean difference of -9.3% points (95 % confidence interval-31.4 to 12.7) was
not statistically significant (P = 0.39). The initial (2 days) mean inflammatory
oedema reduction was 15.0% with Fucidin-H and 0.9% with Hydrocortisone.
The mean difference of 14.2% points (95% confidence interval -0.1 to 28.4) was
borderline statistically significant (P = 0.052) without adjustment for multiple
comparisons. Any kind of adjustment for multiple comparisons would deem
the difference not statistically significant.
The mean inflammatory oedema at each treatment side and the mean difference
Table 18: Inflammatory oedema at baseline and at subsequent visits (Intention-ToTreat population)
Visit:
I nf l ammatory oedema
VIS I T 1 ( BASELINE)
Mean
so
Minimum
Maximum
Number
VI SIT 2
Mean
so
Mi n i mum
Max imum
Number
Fucid i n · H
<n~24l
Hydrocorcison e
< n~2 4 }
Diffe r ence
( n;24}
3504 . 1
1756 .8
713
6 6 59
22
3 313. 6
151 7.8
943
7780
21
295.9
1463.3
- 2326
3 23 5
21
2918 . 2
1 5 8 2.1
369
656 8
23
2984 . 7
14 5 3.9
6 36
6443
24
-151. 6
952. 4
· 1536
2374
23
2033.9
1218 .8
405
4106
19
2314. 5
1066 . 1
2 97
502 8
19
- 280.6
872 . 6
- 18 24
153 9
19
1988.3
131 7.0
372
5 0 51
22
1879. 3
104 1.0
352
3872
22
2354 .5
1780 . 5
353
7286
24
22 58. 3
1 597 . 9
232
6777
24
VISIT 3
Me a n
so
Minimum
Maximum
Numbe r
VI S IT 4
Mean
so
Mi nimum
Maximum
Number
VI SIT 5 (END OF TREATMENT}
Mean
so
Min imum
Maximum
Number
109 . 0
947.9
- 1176
246 8
22 .
96 . 2
113 0.9
· 174 5
40 82
24
13 August 2002
FUH9401 DK
Page 75 of lOB
The absolute change and the percentage change in inflammatory oedema from
Table 19 and 20.
Tab le 19: Change in injlammaton; oedema from baseline to subsequent visits
Visit
Change i n i nflammatory
oedema
Fucidin- H
Hydrocortisone
Difference
(n• 24 )
(n • 24l
(ns24)
- 677 . 0
1 5 62 . 8
- 4070
3130
21
- 211.7
1298 . 2
-3687
2629
21
- 4 65.3
1226 . 5
- 3244
1432
21
· 1494 . 0
1758.2
-5897
660
17
- 1022 . 8
1188 . 8
· 4136
515
17
· 4 71 . 2
14 08 . 8
- 3569
1401
17
- 1500.1
175 4.5
-5771
1140
20
- 1295.0
1394.9
-426 1
1600
19
· 295.0
1 447.7
- 3519
1529
19
· 1031 . 0
2073 . 9
- 5793
3848
22
- 1013.1
1683 . 4
-3167
2 963
21
· 1 00 . 1
1338.4
- 341 8
2770
21
Treatment
compar ison
(paired t-test)
VI SI T 2
Mean
so
Minimum
Ma.x imum
Number
VISIT 3
Mean
SD
Mi nimum
Max imum
Number
p • 0.098
VISIT 4
Mean
so
Minimum
Maximum
Number
Mean
so
Minimum
Maximum
Number
., = 0 . 74
Table 20: Percentage change in inflammatory oedema from baseline to subsequent
Visit
Per centage change in
inflammatory oedema
Fucidin· H
Hydrocortisone
Difference
(n•24)
<n• 24l
(n=24)
- 15 . 0 4
3 6 .42
· 69 . 3
91.0
21
- 0 . 89
33 . 32
· 47. 4
68.9
21
- 1 4. 15
31.38
-78.8
39.8
21
- 29 . 29
4 2.66
-91 . 9
92 . 5
17
-26 . 30
27.92
-68.5
22.7
17
- 2 . 99
31.44
· 56.0
78 . 0
17
-31.86
42.78
- 91.3
66 . 0
20
- 36.39
38 . 07
· 85.5
70.4
19
2 . 00
30 . 3 7
- 48 . 5
71 .1
19
- 12 . 49
6 9 . 57
- 91.8
213.3
22
· 24.98
49 . 47
-90.3
7 7. 7
21
9.33
48 . 5 1
- 67.7
169 . 0
21
Treatment
comparison
(paired t - testl
VI SIT 2
Mean
so
Minimum
Maximum
Number
VISIT 3
Mean
so
Mini mum
Maximum
Number
VI SIT 4
Mean
SD
Min imum
Maximum
Number
p - 0 .052
Mean
SD
Minimum
Max.imum
Number
P
e
0.39
Page 76 of108
13 August 2002
FUH9401DK
Skin thickening and inflammatory oedema data are given for individual
patients in Appendix II, Table 11.10 and Table Il.l l.
12.8.2.4
Twelve skin surface contour roughness parameters were measured and
analysed: Ra,
R zDIN,
horizontal direction.
Rq,
Rt,
s-St, D - each measured in both vertical and
R zmN
was the main skin surface contour efficacy
parameter.
The two treatments were not statistically significantly different with respect to
response in skin surface contour:
At end of treatment (2 weeks) the mean change in
R zDIN
vertical was -12.1%
with Fucidin-H compared to -2.4% with Hydrocortisone. The mean difference
of -9.8% points (95% confidence interval -30.9 to 11.4) was not statistically
significant (P = 0.35). The initial (2 days) change in
RzDIN
was -5.6% with
Fucidin-H and -0.2% with Hydrocortisone. The mean difference of -5.3% points
(95% confidence interval-24.1 to 13.4) was not statistically significant (P = 0.56).
At end of treatment (2 weeks) the mean change in R zoiN horizontal was -13.8%
with Fucidin-H compared to -11.6% with Hydrocortisone. The mean difference
of -2.2% points (95% confidence inter val -15.4 to 10.9) was not statistically
significant (P = 0.73). The initial (2 days) chang·e in R zoiN was 4.3% with FucidinH and 1.5% with Hydrocortisone. The mean difference of 2.7% points (95 %
confidence interval-14.7 to 20.2) was not statistically significant (P = 0.75).
The results of the analyses of the skin surface contour roughness parameters are
given in Table 21 to Table 56. A total of 48 hypothesis tests have been
performed. Five of these resulted in P-values less than 0.05, but larger than 0.01:
Ra vertical, Rq vertical and Rt vertical showed larger reductions with Fucidin-H
than with Hydrocortisone. These results might be type 1 errors in the
13 August 2002
FUH9401DK
Page 77 of108
significance tests. With any reasonable adjustment for multiplicity no difference
between the two treatments reached statistical significance.
Tab le 21: Skin surface contour roughness parameter, Ra vertical, at baseline and at
subsequent visits (Intention-To-Treat population)
Vi ait
Sk in s urface contour
Puc idin-H
Hydrocortisone
Difference
(n: 24l
(n:24)
25.26
9 . 73
12. 3
48 . 6
24
21.26
1 0 . 76
10 . 9
59.4
24
4.01
8. 81
-10 . 8
20 . 1
24
2 1 .5 0
5. 84
12.6
3 9 .0
24
2 0 . 39
6 . 53
1 1 .7
35 . 0
24
1. 11
6 .58
- 1 3 .0
10 . 3
24
1 8 . 31
6.00
9.5
28. 5
19
1 7 50
5 . 09
10 . 2
26 . 8
19
0 . 80
5.8 0
- 12.5
13.3
19
1 6 .07
3.98
10 . 4
25.8
22
18 . 87
6.66
11. 1
37.5
22
- 2 .80
7 .17
- 21 . 9
9.4
22
1 8 . 08
7 .78
8.9
4 8 .2
24
19 . 74
6. 59
11 .0
32.9
24
- 1 . 66
7.20
- 17.8
17 . 3
24
(n:24 )
parameter R. vertical
VISIT l (BASELINE)
Mean
SD
Mini mum
Maximum
Number
VISIT 2
Mean
SD
Minimum
Max imum
Number
VI SIT 3
Mean
SD
Minimum
Maximum
Number
VIS IT 4
Mean
SD
Mi nimum
Ma x imum
Numbe r
VISIT 5 (SND OF TRSATMENT)
Mean
SD
Mi nimum
Max imum
Number
13 August 2002
Page 78 of108
FUH9401DK
Table 22: Change in skin surface contour roughness parameter, Ra vertical, from
baseline to subsequent visits (Intention-To-Treat population)
Vi sit
Change in s k in surface
contou r parameters
R. vertica l
VISI T 2
Mean
Fucidin-H
(n•24 )
Hydrocortisone
(n~24)
Difference
(n•24)
- 3.76
7.97
-2 4 .0
9.0
24
-0 . 87
10.20
-30.0
18 . 1
24
-2.90
10.76
-23. 7
20.4
24
-7.75
11 . 5 4
- 26.8
15.5
19
-4 .55
10.31
- 32 . 5
9.3
19
-3 . 20
11.97
- 22 . 5
1 2. 5
19
Mean
- 9.07
- 2 .64
-6.43
SD
Minimum
Maximum
Number
9 . 59
- 33 . 0
6.0
22
9.19
-23 . 6
8.9
22
9.62
-26.5
13 . 0
22
- 7 .19
10.53
- 28.8
7.6
24
- 1. 52
10.12
- 28.5
14 . 0
24
-5. 67
12 . 88
- 33.9
28.1
24
so
Minimum
Maximum
Number
VISIT 3
Mean
SD
Minimum
JJia x imum
Number
Treatment
c omparison
<pai red t- t e s t)
p
0.20
p -
0 . 0 42
VI SIT 4
Mean
SD
14inimum
Maximum
Number
Table 23: Percentage change in skin surface contour roughness parameter, Ra vertical,
from baseline to subsequent visits (Intention-To-Treat ~lation)
Visit
Percentag e chang e in skin
surface contour parameters
R. vertical
VISIT 2
t4ean
SD
Minimum
Maxi mum
Number
VI SIT 3
Mean
so
Minimu m
Maximum
Number
l'ucidin- H
Hydrocortisone
Difference
(n=24 )
(n•24)
(n=24)
- 6.40
33.63
-59.6
73.1
24
7 . 24
44.27
140.0
24
- 13.64
50.21
-163. 8
65.9
24
- 18.59
43.66
- 7l. 7
119. 2
19
- 9.97
36 . 21
- 54.8
72.6
19
- 8.61
45 .50
- 104.9
75.5
19
- 29.25
25.67
- 67 . 8
30.0
22
- 2 .47
34 . 40
-53.8
58.0
22
-26.78
35 . 09
- 82.4
44.1
22
- 20 . 48
34. 4 0
- 74 .9
49.3
24
3 . 37
41 .71
-5 5. 9
99.8
24
-23.85
47.07
- 133.2
47.1
24
-so .s
Treatment
compari son
(pa ire d t- t estl
p
= 0 . 20
VISIT 4
Mean
so
Minimum
Maximum
Number
VI SIT 5
(END OP TREAT11ENT )
Mean
so
Minimum
Maxi mum
Numbe r
p •
0 . 021
FUH9401 DK
Page 79 of108
13 August 2002
Table 24: Skin surface contour roughness parameter, Ra horizontal, at baseline and at
subse uent visits (Intention-To-Treat
Visit
ulation)
Fuci din -H
Hydr ocortisone
Differ ence
(n• 24)
(n•24 )
(n•24 )
23 . 35
10. 42
11.2
52.5
24
23 . 68
13.52
9.8
73 . 3
24
- 0 . 33
8.77
- 20 . 8
17 . 2
24
22.93
8.90
4 5.3
24
21.27
6 . 85
10.2
38.1
24
1.65
8.21
· 14 .3
20.3
1 9.02
8 . 01
6. 1
42.8
19
19 . 24
8 .4 8
?.9
46 . 4
19
-0.22
8.32
-1 7 . 8
21.0
19
19 . 87
6 . 87
11 . 3
4 4. 8
22
20.72
5.96
13 . 5
33.7
22
· 0 . 85
7.85
- 18 .1
21.6
22
19.95
8. 1 9
9 .4
41 . 0
24
20 . 32
7.61
8. 4
39 . 0
24
- 0.37
11.38
-24. 4
31.4
24
parameter R. horizontal
VISIT 1 (BASELINE)
Mean
SD
Min i mum
Maximum
Number
VI S IT 2
Mean
SD
Mini mum
Maximum
Number
13. 4
VIS IT 3
Mean
SD
Minimum
Maximum
Number
24
VISIT 4
Mea n
SD
Mini mum
Max imum
Number
VIS IT 5 (&ND OF TREATMENT)
Mean
SD
Minimum
Maximum
Numbe r
Table 25:Change in skin surface contour roughness parameter, Ra horizontal, at
baseline and at subsequent visits (Intention-To-Treat population)
Visit
Hydrocortisone
Difference
(n=24)
( n·24)
(n=24)
Number
-0.43
11.12
- 20.0
27.5
24
- 2.41
12 . 89
- 4 .2 .o
1 ·8 . 4
24
1. 98
12.36
- 21.0
29.7
24
VISIT 3
Mean
SD
Minimum
Maximum
Number
-4 . 64
10 .2 5
· 25.8
8.4
19
- 5.64
9.25
- 28.1
8.7
19
1 . 01
6.33
-13 . 4
11 . 1
19
- 4 . 08
10.57
-30 .4
l3 .4
22
- 2 . 83
11 . 60
- 41 . 0
6.9
22
- 1.25
9.56
- 1 5.9
14 .3
22
- 3 . 40
10.17
-26. 4
27 . 0
24
· 3.36
11.73
-4 3.3
12. 1
24
- 0.04
11.83
-22.0
30.0
24
Change in skin sur face
Fucidin-H
contour parameters
Treatment
comparison
(paired t - test)
R. horizonta l
VISIT 2
Mean
SD
Minimum
Maximum
VISIT 4
Mean
so
Min imum
Max imum
Number
Mean
SD
Minimum
Maxi mum
Number
p
0 . 44
p
= 0.99
13 August 2002
Page 80 of108
FUH9401DK
Table 26: Percentage change in skin surface contour roughness parameter, Ra
horizontal, from
pOE_ulation)
Vis i t
baseline to subsequent visits (Intention-To-Treat
Fucidi n- H
Percentage change in skin
surface contour paramet ers
R. horizonta l
Hydrocorti sone
Diffe r ence
(n:24 )
(n D24 )
<n• 24 )
10 . 95
54 .4 7
- 59 .5
1 92.2
24
2 . 62
44. 4 6
- 57 . 3
108. 8
24
6 . 13
57.84
- 109.2
1 09.0
24
- 1 0.08
37.7 8
- 76 . 3
47 . 9
19
- 16 . 53
24 . 18
- 51.9
4 1.3
19
6.45
33.51
- 41 .1
79 . 3
19
- 6 . 98
38.58
- 57.9
97 . 3
22
- 0.69
29.34
- 55 .9
52.5
22
- 6 . 28
44 . 71
- 75 . 3
109 .8
22
-4 .74
50. 4 7
- 6 1.8
192.6
24
- 6.30
31 . 04
-59.0
44.8
24
1. 56
56.03
- 80.3
216 .4
24
Treat ment
comparison
(paired t-test)
VIS I T 2
Mean
so
Min i mum
t-1ax i mum
Number
p
5
0 . 50
p
=
0.89
VISI T 3
Mean
so
Minimum
Maxi mum
Number
VISIT 4
r~ean
SD.
Mi n i mum
l-taxi mum
Number
Mean
so
Mini mum
Maximum
Number
Table 27: Skin surface contour roughness parameter,
R zDTN
vertical, at baseline and at
Vis it
Sk in s urface cont our
par ameter R.ot• vert ical
Fucidi n - H
Hydrocor tisone
Di ff e r ence
( n524 )
<n=24)
(n=24)
65.82
21 . 41
34 . 0
118 . 6
24
6 2. 6 4
28.98
3 4 .6
150.8
24
3.18
22 .82
- 4 5 .7
47 . 6
24
59 . 03
14 . 9 2
42 .7
103 . 9
24
56 . 66
15 . 33
30.3
91.6
24
2. 38
12.53
- 20 .2
22 . 0
24
51 .73
1 6 . 92
30.1
88 . 8
19
50.28
14 . 58
29 . 3
85 . 7
l9
1 . 45
1 3. 53
- 29 . 2
27.2
19
47.6 0
10.82
34 . 0
75 . 8
22
50.7 7
1 5.06
32 . 8
97.7
22
- 3 . 17
1 5.3 2
- 49.4
19 . 0
22
53 . 92
1 8 . 01
32.0
110 . 0
24
55 . 27
1 5 . 02
30 .4
90 . 5
24
- 1.35
16.85
- 51.8
24 . 3
24
VI SIT 1 (BASELI NE)
Mean
SD
Mi nimum
Maxi mum
Number
VISI T 2
Mean
SD
Mi nimum
Maximum
Number
VI S I T 3
Mean
so
Mi nimum
Maximum
Number
VISI T 4
Mean
SD
Mi ni mum
Maxi mum
Number
Mean
SP
Mi nimum
Maximum
Number
13 August 2002
FUH 9401 DK
Page 81 of108
Table 28: Change in skin surface contour roughness parameter,
R zDIN
vertical, from
Vis i t
Change i n skin surface
Fuc idin -H
(n=24)
Hydrocortisone
(n=24)
Difference
(n• 2 4)
contour parameters
R.,,. vertical
<paired t- t est)
VI S IT 2
Mean
so
Mi nimum
Maximum
Number
Treatment
compar ison
-o.ao
- 6.78
14 . 83
· 40 . 3
19 . 5
24
- 5.98
23.46
-64 .9
38.2
24
26.38
· 67.7
56.3
24
- 14 . 90
20.65
- 51.1
26.0
19
-13 .78
21.82
-65.2
18 .1
19
- 1 . 12
25.14
-49.1
41.4
19
- 1S.26
20.02
-64 . 2
10 . 2
22
- 12.37
21 . 53
- 67 . 5
17.9
22
-S .S9
21 . 68
- 49.4
52.5
22
-11 . 90
21.84
· 43. 8
26 . 8
24
· 7.37
25.28
· 73 .o
34 . 9
24
· 4.53
31.93
· 67.7
58 .5
24
P
= o.as
I?
= 0 . 49
VISIT 3
Mean
so
Mini mum
Maximum
Number
VI SIT 4
Mean
so
Mi nimum
Maxi mum
Number
Mean
SD
Minimum
Maximum
Number
Table 29: Percentage change in skin surface contour roughness parameter,
RzDIN
vertical, from baseline to subsequent visits (Intention-To-Treat population)
Vi sit
Per centage change in skin
R:olN
Fucidin-H
Hydrocortisone
Difference
(n• 24)
<n • 24)
(nc24)
·5.55
23 . 69
- 45.4
53.8
24
·0 .22
35.65
·52 . 0
106.3
24
- 5.33
44.36
-141.8
69.3
24
· 17 .03
30.94
·54 . 6
61.7
19
· 1 5. 42
24.35
· 4 7 .6
4-4.3
19
- 1.60
37 . 7 3
· 81.4
59.0
19
-22.53
23 .60
· 57 .0
22.7
22
-12.03
26.40
-5 0.3
48.0
22
- 10 .50
34.08
·93. 1
54 . 2
22
· 12 .11
33 . 27
·56.8
59 . 4
24
- 2.35
34.99
· 54.4
93.3
24
• 9. 76
50.02
- 140 . 4
6 1. 0
24
Treatment
comparison
(paired t - test)
vertical
VISIT 2
Mean
so
Minimum
Maximum
Number
I? .
0.56
VI SIT 3
Mean
so
Minimum
Maximum
Number
VIS IT 4
Mean
so
Minimum
Maximum
Number
Mean
so
Min imum
Maximum
Number
p
= 0.3 5
Page 82 of108
13 August 2002
FUH9401DK
Table 30: Skin surface contour roughness parameter,
horizontal, at baseline and
at subsequent visits (Intention-To-Treat population)
Vi sit
Fucidin - H
RzDIN
Hydrocortisone
Di fference
(na 24)
( n a 24 )
66. 03
34. 7 2
38.3
176.9
24
69 .28
45 . 52
32.8
240.9
24
-3.25
1 9.56
-64.0
29 .5
24
63.47
28 . 4 1
32 . 6
1 79 . 8
6 1 . 88
18.64
34.8
120.4
1 .59
20.02
- 33.6
59 . 3
24
24
24
53.74
1 9 .88
25.5
107 . 0
19
56.25
25.31
33 . 1
151.9
19
- 2 . 50
1 7.65
- 44.9
2 3 .9
19
54.88
1 3 . 00
37.3
86 .4
22
56 . 57
19 . 93
37.9
118 . 1
22
-3.69
16 . 82
- 34 . 0
34 . 9
22
52.52
22.38
34.8
141.1
24
54 . 50
1 7.37
27.0
107.7
24
- 1 . 98
20.13
- 36.5
36. 4
24
(n~24)
paramete r Rzon• horiz ontal
VISIT 1 (BASELINE)
Mean
so
Mini mum
Maximum
Number
VIS IT 2
Mean
SD
Minimum
Maximum
!>lumber
VI SIT 3
Mean
so
Minimum
Maximum
Number
VISIT 4
14ean
SD
Min imum
Maximum
Number
VISIT 5
Mean
(BND OF
TREATMENT)
so
Mi nimum
Max i mum
Number
Table 31: Change in skin surface contour roughness parameter,
horizontal, from
Vi si t
Fucidi n - H
Change in ski n surface
contour parameter s
(n • 24)
R zDIN
Hydrocortisone
Diffe rence
(n~24)
(n~24)
(pa i r ed t-test )
R"'"" hor izontal
VISIT 2
Mean
so
Mi nimum
Maximum
Number
VI SIT 3
Mean
so
Minimum
Maxi mum
Number
VISIT 4
Mean
so
Minimum
Maximum
Number
VIS IT 5 ( END
Mean
SD
Minimum
Maximum
Number
OF
Treatment
c omparison
- 2 . 55
24 .54
- 82.7
47 .4
24
- 7.40
35 .36
- 120.5
43.0
24
4.85
33.48
- 39 . 9
123.4
24
-14 . 25
33. 44
- 114 .6
27 .3
19
- 15.24
30 . 62
-107 . 5
9.3
19
0.99
18.19
-2 7.1
34.6
19
- 13.26
30.15
- 92.8
32 . 3
22
-11 . 12
34.64
-].2 2.8
22.1
22
- 2 . 14
21.80
-43 . ].
38.1
22
- 13.51
26 . 79
· 118 . 1
19 . 7
24
- 14. 78
34.50
-133 . 2
18 .9
24
1 . 28
27.19
- 36 .6
97. 4
24
p • 0. 49
TREATMENT)
p
~
0 . 82
FUH9401DK
Page 83 of108
13 August 2002
Table 32: Percentage change in skin surface contour roughness parameter,
R zDIN
1wrizontal, from baseline to subsequent visits (Intention-To-Treat
population)
Visit.
Percentage change i n s kin
Pucidin· H
Hydrocorti sone
Dif ference
(n=24 )
(n• 24)
(n=24 )
4.27
36.03
- 50.8
112 . 6
24
1.53
33.83
· 54. 8
8 1.7
24
2 . 74
41.29
- 88.0
69.4
24
-9.80
36 .97
- 70 . 3
65.0
19
- 12 . 94
19.37
· 59 . 8
1 9.6
19
3.14
33.46
-45.8
76.3
19
- 9 . 25
31.46
-5 6.7
5 9 .7
22
- 4.84
29 .40
- 5 1.0
46.6
22
· 4 .41
36.66
-80.2
80.3
22
-13. 80
25 . 70
-72 .4
34.4
24
· 11 . 59
27.34
- 55.3
36 . 8
24
-2. 21
31.14
· 63.8
46.1
24
surface contour paramecers
Rzoi N horizont.a l
VISIT 2
Mean
so
Mi nimum
Maximum
Number
Treatment
compa rison
(paired t.- test)
p .
0 . 75
VISIT 3
Mean
SD
Mi nimum
Maximum
Number
VISIT 4
Mean
so
Minimum
Maximum
Number
VIS IT 5 (END
Mean
SD
Minimum
OF
TREATMENT)
Maximum
Numbe r
p = 0.73
Table 33: Skin surface contour roughness parameter, Rq vertical, at baseline and at
Vi sit
Ski n surface contour
Hydrocort.isone
Difference
(n=24 )
(n=24)
(na 24 )
30 . 92
12 .1 2
15.8
63 . 1
24
26. 11
1 3.94
1 3.3
77.4
24
4.81
10.70
· 14 .3
23.8
24
26 . 25
7 . 19
15 . 8
47 .9
24
25. 0 5
7.68
14 .8
41.0
24
1.20
7 . 61
- 16 . 0
10 .9
24
22.44
7.40
11 .5
35.8
19
21.47
6.14
12 .6
33 . 4
19
0 . 97
7. 13
· 17 . 0
14 .8
19
19 .74
4.59
1 2.9
29.9
22
23.11
7 .92
-3. 37
8. 5 0
· 28.0
9.8
22
22 .34
9.25
11. 0
58.4
24
24 . 1 0
8.02
13.7
40 .8
24
Fucidin-H
pa rameter Rq vertical
VISIT 1 (BASELINE )
Mean
so
Min i mum
Maximum
Number
VISIT 2
Mean
SD
Minimum
Maxi mum
Number
VISIT 3
Mean
so
Minimum
Maximum
Number
VISIT 4
Mea.n
SD
Minimum
~taximum
Number
VIS IT 5 (END
Mean
SD
Mi nimum
Maximum
Number
OF
13 . 6
46.9
22
TREATMENT)
· 1. 75
8.54
-22 . 3
19 .7
24
FUH9401 DK
13 August 2002
Page 84 of108
Table 34: Change in skin surface contour roughness parameter, Rq vertical, from
Visit
Change in skin surface
Fuc i din- H
( n=24)
Hydrocortisone
(n•24)
Differenc e
(n=24)
Treatment
comparison
(pai red t - testl
contour parameters
Rq vertical
VISI T 2
- 4.67
l~ean
so
- 1.06
1 2.52
- 40.1
21 .3
24
- 3.61
12.52
- 29 . 3
24.9
24
-5.71
13. 12
-44.0
13.1
19
-3 . 81
14 .4 8
22
- 3.34
11 .24
- 30 .5
9 .6
22
- 7.77
11 .3 5
- 33.6
1 3.5
22
-8 . 58
12. 4 2
- 3 4. 6
10.2
24
- 2.01
1 2.70
- 38.7
16 .8
24
- 6.56
15.36
-41.8
3 4. 0
24
~ . 65
Mini mum
Maximum
Number
- 28 . 4
9 .2
24
p
= 0 . 17
VI SIT 3
-9. 51
1 4. 0 1
- 30 .6
1 9.1
l~ean
so
Mi nimum
Maximum
Number
1~
VISIT 4
Mean
SD
Mini mum
Maximum
Number
- 11. 1 0
1 2 . 14
- 44 . 2
5.4
VIS I T 5 (END OF TRBATMENT)
Mean
so
Mini mum
Maximum
Number
- 25.~
16 . 7
19
F • 0.048
Table 35: Percentage change in skin surface contour roughness parameter, Rq vertical,
from baseline to subsequent visits (Intention-To-Treat population)
Visit
Percent age change in aki n
surface c ontou r parameters
Rq vert i cal
VISIT 2
Mean
SD
Minimum
Maximum
Number
VISIT 3
Mean
so
Mi ni mum
Maximum
Number
VI SIT 4
Mean
so
Minimum
Maximum
Number
Mean
SD
Min imum
Maximum
Number
Fucidi n - H
(na24)
Hydrocortisone
<n- 24)
Difference
(n-24)
-7.13
31.06
- 59 . 5
57.1
24
7.60
42.24
- 51 .8
1 3 2.7
24
- 18 . 88
43.79
- 71.9
1 21 . 1
19
-~ . 79
- ~.0~
36.59
- 56.9
84 . 3
19
47.06
- 1 20.7
81 . 2
19
·28. 9 2
25 . 13
- 70 . 1
22.0
22
- 2.57
32.58
- 53 .6
53.9
22
-26.36
33.69
-87 . 4
38.2
22
- 19.85
33 . 66
- 74.2
44. 3
24
3.10
40 . 3 2
- 54.8
91. 5
24
·22.96
4 4. 60
- 121.8
42.6
24
- 14 .73
46. 39
- 160 . 0
54 . 0
24
.Treatment
comparison
(pa i red t- t est)
p
0 .13
p
= 0.019
13 August 2002
FUH9401DK
Page 85 of108
Table 36: Skin surface contour roughness parameter, R.q horizontal, at baseline and at
Visit
Fucid in - H
Skin sur face contour
Hydrocortisone
Dif ference
(n•24)
( n=24)
(ns24 )
28.56
12 .8 8
13 .6
67.8
2 <1
2 9.05
17.19
11.9
93.8
24
- 0.<19
10.23
-26.0
1 8 .9
24
28.03
11 . 07
15.9
54.1
24
26.20
8 .4 4
12 . 6
46 . 0
24
1.83
9.89
-17 . 8
25.2
24
23.36
9.55
7. 7
51.5
19
23 .6 7
10 . 78
10.1
59 . 8
19
1 0 . 02
- 23.8
24.7
19
24 .5 2
8.31
13.5
54.9
22
25 .4 5
7 . 24
16 . 0
40.0
22
- 0.93
9.49
- 19.7
27 .3
22
24 .22
9.82
11. 8
50.1
24
24 . 74
8 .99
10 .0
45.9
24
- 0.52
1 3 . 23
-2 8.2
34.9
24
parameter Rq horizontal
VISIT 1 (BASELINE)
Mean
so
Minimum
Maximum
Nu~ r
VISIT 2
Mean
so
Min imum
Maximum
Number
VI SIT 3
Mean
so
Mini mum
Maximum
Number
VISIT 4
Mean
so
Minimum
Ma.x i mum
Number
-o . 31
VISIT 5 (END OF TRSP.TMENT)
Mean
so
Minimum
Ma><imum
Number
Table 37: Change in skin surface contour roughness parameter, Rq horizontal, from
Visit
Change in skin surf ace
Fucidi n -H
Hydrocortisone
Difference
<n=24)
(n a 24l
(n• 24 )
- 0.5 3
13.56
- 24 .8
35.1
24
-2 .85
15.62
- 51.5
22. 2
24
2 .32
14.79
- 24 . 5
36.1
24
-5.68
12. 82
-31.9
10 . 4
19
- 6 . 86
11 . 33
-34 . 7
9.8
19
1.19
7.55
- 17.6
12.8
19
-4 . 84
12 . 99
- 38 . 9
19 . 3
22
-3 . 48
14.72
- 53 . 8
H.5
22
- 1 . 37
11 . 42
- 18. 4
17 . 0
22
- 4.34
11 . 8 7
-3 2 .8
29 . 3
24
- 4.3 2
1 4 . 68
-55. 8
14 .9
24
- 0.03
14.12
- 24 .0
38 .1
24
contour parameters
Treatment
comparison
(paired t - teet)
Rq horizontal
VIS IT 2
Mean
so
Minimum
Maximum
Number
VIS IT 3
Mean
so
Minimum
Maximum
Number
VI SIT 4
Mea.n
so
Minimum
Maximum
Number
VISI T 5 (END OF TRSP.TMENT )
Mean
so
Mi nimum
Ma><imum
Number
p
= 0.45
p • 0 .99
Page 86 of108
13 August 2002
FUH9401DK
Table 38: Percentage change in skin surface contour roughness parameter, Rq
horizontal, from baseline to subsequent visits (Intention-To-Treat
population)
Visit
Fuc i din -H
<n=24 )
Hydrocortisone
(n • 24)
Difference
<n• 24)
Treatment
compar ison
(paired e - test)
Rq horizontal
VISIT 2
Mean
SD
Minimum
Maxi mum
Numbe r
10 . 50
54 .5 3
-5 8.3
198 . 1
24
3.01
43.45
- 54 .9
112.2
24
7 . 49
56.90
- 110 . 8
104 .6
24
VI SIT 3
Mean
SD
Minimum
Maximum
Number
- 9.99
36 . 63
-76.6
54 . 2
19
- 16.33
23.04
- 51 . 9
38.5
19
6.34
31.66
- 41 . 1
71. 2
19
- 6.88
37.63
- 57.3
90.)
22
-0 .33
29.62
- 57 .3
57 .0
22
- 6.55
43 .28
- 82.8
100.6
22
-6 .19
4 5 . 85
- 58.3
166.6
24
- 6.50
30.87
- 59.5
48. 0
24
0. 31
52 . 34
- 78.1
190 . 1
24
p = 0 . 53
VIS IT 4
l~ean
SD
Minimum
Maximum
Number
Mean
SD
Minimum
Max imum
Number
p = 0.98
Table 39: Skin surface contour roughness parameter, Rt vertical, at baseline and at
Visic
Skin sur fac e contour
parameter R, vert i cal
VISIT 1 (BASELI NE)
Mean
SD
Minimum
Maximum
Number
VISI T 2
Mean
Fucidin - H
<n• 24)
Hydrocortisone
(n• 24)
Difference
<n=24 )
132.97
53.75
70 . 5
310.5
24
ll6. 93
66.96
65.4
368 . 5
24
16.04
45.05
- 58.5
90.6
24
113 . 76
33.40
4 . 63
32.11
- 56.1
74.2
24
Minimum
Maximum
Number
207.1
24
109 . 13
29.55
62 . 7
167 . 5
24
VIS IT 3
Mea n
SD
Mi nimum
Maximu m
Numbe r
99.48
32.22
53.4
162.5
19
94 . 03
26 .99
57.1
163.4
19
30 . 23
- 72 . 3
49.5
19
VI SIT 4
Mean
SD
Minimum
Maximum
Number
88.90
21.51
65 . 0
1 51. 6
22
1 01.96
33.70
60 .2
204 . 7
22
- 13.06
37.29
- 121.9
41.1
22
100.03
35 . 02
49 . 5
229.2
24
1.04 . 64
32 . 05
63.5
186.3
- 4 .6 2
35 .20
- 108 .2
57.5
24
24
so
VISIT 5 ( END OF TREATMENT)
Mean
SD
Mi n imum
Maximum
Number
77 .4
5 . 45
FUH9401 DK
13 August 2002
Page 87 of108
Table 40: Change in skin surface contour roughness parameter, Rt vertical, from
Vi si t
c ontour parameters
R, vert i cal
Fucidin-H
(n• 24)
Hydrocortisone
Di f ference
(ns24)
<n• 24)
Treatment
c ompari son
(paired t - test)
VISIT 2
Mean
so
Minimum
Max imum
Number
VISIT 3
Mean
SD
Mi nimum
Maximum
Number
- 19 .21
4 1 . 70
-103.4
43 .5
24
- 7 .80
55.75
-200.9
7 7.4
24
-11 . 4 1
49.58
-121 .5
97 . 6
24
- 38.60
5 7 . 48
- 148.1
92.0
19
-2 8.53
58 . 01
-2 0.5 .1
57 . 3
19
- 10 . 07
58 . 23
-102.2
69 . 1
19
- 44 .6 3
57. 14
- 227.7
20 . 3
22
- 16.73
51.43
- 16 3 . 8
4 7 .1
22
- 2 7 . 91
46.92
- 145.3
55 . 3
22
- 32 . 94
47. 7l
- 130. 6
5 1. 5
24
- 1 2 .29
59 . 52
- 19·6 . 8
7·4 .6
24
- 20 . 65
62.11
- 169. 4
115.5
24
p •
0.27
VISIT 4
Mean
so
Minimum
Maxi mum
Number
VISIT 5 (END OF TREATMJml')
Mean
so
Mini mum
Maximum
Numbe r
p
=
0 .12
Table 41: Percentage change in skin surface contour roughness parameter, Rt vertical,
Visit
Fucidin- H
Hydrocor~:isone
Difference
(n= 2 4 )
(n =24)
(n=24)
- 7 .73
28 . 00
- 56 . 1
44. 8
24
5 .84
38.73
- 5 4. 5
118. 3
24
- 13 . 57
42.02
-152 .0
33.9
24
- 18 . 12
43 .83
-65.6
130.5
19
- 1 2.63
3 3.57
- 55 . 7
83.8
19
- 5 .4 9
48.77
- 121 . 6
1 05.1
19
- 25 .86
26.66
-73 . 3
20.7
22
- 4.26
2 8.. 63
-56.5
5 2. 7
22
- 21.60
32.30
-9 0 . 6
45.2
22
- 17 . 60
30 . 77
-69 .1
49.8
24
1..61
38. . 6 2
- 54.7
- 1 9 . 21
43.2 9
- 120.4
41.6
24
s urface contour parameters
Re vert i ca l
VI SI T 2
Mean
so
Minimum
Maximum
Number
Treatment
compar ison
(pair ed t - test )
p
= 0. 1 3
p
= 0.040
VISIT 3
Mean
so
Mini mum
Maximum
Number
VISIT 4
Mean
so
Minimum
Maximum
Number
VISI T 5 (END OP TREATMENT)
Mean
so
Minimum
Maxi mum
Number
n .4
24
Page 88 o/108
13 August 2002
FUH9401DK
Table 42: Skin surface contour roughness parameter, Rt horizontal, at baseline and at
Visit
Fucidin- H
Skin surface c ontour
pa,r ameter Rt horizontal
VISIT 1 (BASELINE)
Mean
so
Mi nimum
Maxi mum
Number
Hydrocortisone
Dif f erence
(n• 24 )
(n-24)
(n=24)
12 2.80
56.02
64.6
316 . 6
24
128.28
78.72
51.0
435 . 1
24
- 5 . 47
42 . 29
- 118.5
68.7
24
120.53
47. 57
63 . 2
257 . 7
24
113.66
36 .95
63.7
220 . 0
24
6 . 87
38 . 93
-66 . 0
96 . 0
24
101.87
36 . 64
40.7
197.1
19
104.45
53.17
51.0
298 . 5
19
-2 . 58
41.98
- 125 .3
76 . 9
19
108.95
34.95
57.3
240.7
22
114 .81
39 .4 6
6 7.3
213 . 0
22
- 5 . 86
48 . 30
- 115.8
129 .0
22
103.58
43 . 31
58.1
258 . 0
24
107.44
37.88
42 . 7
187.3
24
- 3.86
49 .87
-106 . 0
111. 2
24
VI SIT 2
Mean
SD
Minimum
Maxi mum
Number
VISI T 3
Mean
so
Minimum
Maximum
Number
VISIT 4
Mean
so
Mini mum
Maximum
Number
Mean
so
Minimum
Maximum
Number
Table 43: Change in skin surface contour roughness parameter, Rt horizontal, from
Visit
Change in sk in surface
contour pa rameters
R. horizontal
Fuc i din-H
Differ ence
(n=24)
Hydrocortisone
(0= 24 )
-2.27
53. 03
- 111.5
150. 1
24
- l4 . 61
63 .9 0
- 215.1
85.2
24
12.35
57 . 55
- 93 .4
156.2
24
- 22. 90
53 . 67
- 143.5
50.3
19
-29 . 10
46.44
- 144.6
37 . 7
19
6 . 21
34 .09
- 63.7
74.6
19
- 17 . 76
55 .45
- 179 . 5
99 . 6
22
- 13.88
68 . 04
-253. 5
81.9
22
- 3.88
51.28
- 96 . 2
92 . 9
22
-1 9.23
4 2 .13
- 1 36 . 1
78.7
24
- 20.84
62 . 66
-247.8
60.9
24
1.61
57.65
-8 9 . 7
189.2
24
(n=24)
Treatment
compari son
(paired e - test)
VISIT 2
Mean
so
Mi nimum
Max imum
Number
VISIT 3
Mean
so
Minimum
Maximum
Number
VISIT 4
Mean
so
Mini mum
Maximum
Number
Mean
so
Minimum
Maximum
Number
p • 0.30
p = 0.89
13 August 2002
FUH9401 DK
Page 89 of108
Table 44: Percentage change in skin surface contour roughness parameter, Rt
Jwrizon tal, from baseline to subsequent visits (Intention-To-Treat
population)
Vis i t
R, hor izontal
VISIT 2
Mean
so
Minimum
Maximum
Number
Fucidin· H
Hydrocortisone
Difference
( n=24l
(n=24)
(n=24)
8 .17
48 . 7 5
·52 . 5
183.0
24
o .8 s
39 . 79
· 55 .4
1 05.6
24
7 .32
5 0 . 73
- 1 23 . 0
97.3
24
Treatment
comparison
(paired t· t est)
p - 0 . 49
VI SIT 3
Mean
so
- 8 . 94
- 15.84
6.90
35 .79
21.9 7
33. 7G
Mini mum
Maximum
·69 . 8
77 . 8
19
· 5 0. 1
36.5
19
· 41. 1
97.6
19
· 5.36
35 . 45
· 56 . 7
74 .a
22
o.85
33 . 95
· 5 8.3
78.8
22
- 6.21
4 5 .34
·92.6
92 . 6
22
· 9. 54
33.08
- 57 . 5
89 . 3
24
· 7 . 70
29.70
· 57 .0
50.1
24
· 1. 84
41 . 37
· 74.1
113 .s
24
Numbe r
VISIT 4
Mean
so
Min imum
Maximum
Number
Mean
so
Minimum
Maximum
Number
p
0.83
Table 45: Skin surface contour roughness parameter, s-St vertical, at baseline and at
Pucidin· H
Vis i t
Hydrocort i sone
Difference
(n-24)
(n•24)
(n• 24 )
159 . 05
50.90
89.4
285 . 9
24
1 60 . 4 5
71.47
78.9
361.6
24
·1.39
55 . 93
- 107.7
1 4 1.4
24
1 48.09
4 3.13
101. 9
291.9
24
142 . 32
4 1.43
74 . 6
263 . 6
24
5.77
4 0.83
- 60 .4
105. 4
24
138.77
44.08
84 . 4
216 . 4
19
134.56
37 . 52
80.2
198.7
19
4 . 21
31.97
- 84.6
48 . 3
19
126.12
32.72
78 .0
216.1
22
136.48
39.72
87 . 1
23 0. 8
22
-10 . 36
39.30
·92 . 2
54.2
22
137.08
42 . 4 4
81.8
237.7
24
1 43 . 67
36.75
86.3
218 . 6
24
· 6 . 59
5 0 . 73
·126. 7
89.4
24
par ameter s-St ve rtical
VISIT 1 (BASELINE)
Mean
so
Minimum
Maximum
Number
VISIT 2
Mean
so
Minimum
Maximum
Number
VISIT 3
Mean
so
Mini mum
Maximum
Number
VISIT 4
Mean
so
Minimum
Maximum
Number
VISIT 5
(END OF TREATMENT)
Mean
so
Minimum
Maximum
Number
Page 90 of108
13 August 2002
FUH9401DK
Table 46: Change in skin surface contour roughness parameter, s-St vertical, from
Visit.
Fuc idin- H
(n~24)
Hydrocortisone
(n=24 l
Difference
(nc24)
cont our parameters
Treatment
comparison
(paired t - tes t l
s - St vertical
VISIT 2
Mean
so
Minimum
Maximum
Nu mber
VISIT 3
Mean
so
Minimum
Max imum
Number
VISIT 4
Mean
so
Minimum
Maxi mum
Number
VI S IT 5 (END OF TREATMENT)
Mean
so
Mi nimum
Maxi mum
Number
- 10.96
40.36
- 83.8
62.7
24
- 18 .1 3
56.59
- 168 . 1
8 4 .7
24
7.17
70.25
- 168.5
204.8
24
- 2 1.69
42 . 85
- 98 . 9
63.2
19
-30 . 77
58.43
-178 . 8
40 .4
19
9.07
57 .77
- 121 .1
118.3
19
- 31. 86
5 0. 3 3
- 14 7. 0
48 . 8
22
- 23 . 13
58 . 36
- 1 82 .9
76.1
22
- 8 .74
52. 16
-89 .4
76.1
22
· 21. 9 7
46 . 49
- 113.3
84.3
24
- 16 .78
67 . 76
- 2 1 3.3
94. 9
24
- 5. 2 0
82.29
-181. 4
165. 1
24
p
0 . 62
p
= 0.76
Table 47: Percentage change in skin surface contour roughness parameter, s-St
vertical, from baseline to subsequent visits (Intention-To-Treat population)
Visit.
Pe r centage change i n skin
Pucidin - H
< n~24)
Hydrocorti sone
(n• 24)
Difference
(n=2 4 l
s - St vert i cal
VI SIT 2
Mean
so
Minimum
Maximum
Number
VISI T 3
Mean
so
Minimum
Maximu m
Number
V ISIT 4
Mean
so
Minimum
Maximum
Numbe r
VISIT 5 (SND OF TREATMENT)
Mean
so
Minimum
Maximum
Numbe r
Treatment
comparison
(pair ed t - test )
- 2 .45
26 . 44
-37. 9
67.9
24
- 2.62
34.55
- 47.8
101.7
24
0.17
42.90
- 13 9 .0
6 1.8
24
-9 . 81
26.76
- 43.9
50. 4
19
-12 .4 8
2 4.84
-49 . 4
27.4
19
2.67
3 2 .04
-67.0
62.6
19
-14. 47
29 .3 5
- 51.4
52 .8
22
- 5. 87
3 1.07
- 50.6
70. 4
22
- 8.60
38 . 64
- 95.5
52.3
22
- 8.97
30.98
- 54.8
91 .3
24
0 . 86
4 1.59
- 59 . 0
1 18. 8
24
- 9 . 83
53.09
-132 . 5
90 . 4
24
p = 0.98
p
= 0.37
13 August 2002
FUH9401DK
Page 91 of 108
Table 48: Skin surface contour roughness parameter, s-St horizontal, at baseline and
at subsequent visits (Intention-To-Treat population)
Vis i t
Fucidin- H
Hydrocortisone
Difference
(n= 24)
(n=24 )
(n-24)
1 53 . 8 3
8 6 . 31
80.8
446 . 8
24
1 66 .56
107 . 93
78 . 2
5 58. 7
24
- 12 . 73
41 .20
- 111. 8
62 . 4
24
1 5 2 .02
73 .28
78 . 3
45 9. 0
150.19
47 . 87
98.2
316.9
1.83
47.34
24
24
142.1
24
1 28 . 13
54.52
63 .9
287 . 5
19
132 . 04
66.14
8 5 .4
387 . 8
19
- 3.91
46. 87
-100. 3
78 . 2
19
125.59
32.84
81 . 7
223 . 3
22
144.42
59.17
85.3
306.3
22
- 18.83
4 5.75
- 1 49 .0
39 . 1
22
Min i mum
126.49
59.53
75 . 9
Maxi mum
37l.l
126 . 2 0
40.44
75.2
270 . 7
24
0 . 30
35.45
- 75.8
100. 5
24
parameter s - St hori zon t al
VISIT 1 (BASELI NE)
Mean
so
Minimum
Maximum
Numl:>er
VISIT 2
Mean
so
Minimum
Max imum
Number
- 77 . 3
VISIT 3
Mean
so
Minimum
Maximum
NulliDer
VISIT 4
Mean
SD
Minimum
Maximum
Number
VI S I T 5
(END OF TREATMENT)
Mean
so
Number
24
Table 49: Change in skin surface contour roughness parameter, s-St horizontal, from
Visi t
Change in skin su rface
Fucidi n-H
Hydrocortisone
Dif f erence
(n• 24)
( n a 24)
(na 24)
- 1.81
49.07
- 158.5
70.6
24
-16.37
81 .59
- 255. l
127 . o
24
1 4.56
72 .4 3
-9 8.3
253.9
24
-29.68
77.22
- 250.5
79.3
19
- 37 . 24
67 . 5 7
- 257 .1
12 . 2
19
7. 56
4 8 . 13
-77.3
120 .8
19
-3 2 .74
65. 33
- 223.5
61.3
22
-2 4 . 38
8 2 . 38
- 252 .4
1 06. 0
22
- 8 .3 5
55 .69
- 161. 3
96 . 7
22
- 2 7 . 34
57 .62
-24 8 . 6
27 .9
24
- 40.36
7 7 . 7l
- 288 . 0
36 .0
24
1 3.02
5 3.01
- 56 . 3
212.3
24
c o ntour parameters
Treatment
comparison
(paired t - teat)
s- S t horizontal
VISIT 2
Mean
so
Minimum
Maxi mum
Number
p .
0 .3 4
VISIT 3
Mean
so
Minimum
Maximum
Number
VIS I T 4
Mean
so
Mi nimum
Max i mum
Numbe r
VISIT 5
(END OF TREATMENT)
Mean
so
Minimum
Maximum
Number
p - 0.24
Page 92 of108
FUH9401 DK
13 August 2002
Table 50: Percentage change in skin surface contour roughness parameter, s-St
o ulation)
Vi sit
Per centage change in skin
s-St horizontal
VISIT 2
Mean
Fucidin"H
Hydrocortisone
Difference
(n= 24)
(n=24)
(n=24)
Minimum
Max i mum
Number
compari son
(paired t -test)
7.03
33. 5 2
SD
Treatment
70.3
24
3.67
38 . 98
· 58 . 9
115.7
24
3.36
43.54
· 114 . l
97 .5
24
- 6.87
39.08
·70 . 0
71. 5
19
- 14 . 30
18.80
· 59.4
14 .3
19
7 . 43
36 . 69
-49 .0
93.1
19
- 9.80
3 1. 18
-50.0
69.7
22
· 2 .59
38. 5 9
- 46 . 8
88.8
22
- 7.21
40 . 40
- 107.9
83 .8
22
·10.41
25.39
- 69.5
32.5
24
- 14. 18
24.99
- 57.3
3 2 .3
24
3.77
23 .80
-46.3
52.9
24
- 44.3
p
=
p
= 0.45
0 . 71
VISIT 3
Mean
SD
Minimum
Maximum
Numbe r
VISI T 4
Mean
SD
Minimum
Maximum
Numbe r
Mean
so
Mi nimum
Maximum
Number
Table 51: Skin surface contour roughness parameter, D vertical, at baseline and at
Visit
parameter D vertical
VIS I T 1 (BASEL INE)
Mean
so
Mi nimum
Max i mum
Number
Fucidin-H
Hydrocort i sone
Dif ference
(n s24)
( n = 24 )
(n• 24 )
3.22
1 .1 0
1 .3
5.3
24
3.86
1.22
1.7
6 .7
24
- 0 .64
1. 53
-3.0
3.3
24
3.32
1 .11
1 .7
5. 7
24
3.58
1 .37
1 .7
6 .7
· 0.26
1.16
-2.7
2.3
24
3 .65
1.38
1.7
6 .3
19
3 . 61
1. 53
1.3
7.3
19
0.04
3 . 86
1 . 83
1.0
7.0
22
3 . 54
1.46
1.7
6.3
22
0 . 32
1. 94
-3 .3
3 .7
22
3.96
1.69
1.0
7.0
24
3 . 75
1.37
2.0
7.3
24
0 . 21
1. 74
-2 .7
3.0
24
VI SIT 2
Mean
SD
Min imum
Max imum
Number
24
VISIT 3
Mean
so
Minimum
Maximum
Number
VISIT 4
Mean
SD
Minimum
Maximum
Numbe r
1. )1
-2.7
2.0
19
Mean
so
Minimum
Maximum
Number
13 August 2002
FUH9401DK
Page 93 of108
Table 52: Change in skin surface contour roughness parameter, D vertical, from
baseline to subs~q_uent visits (Intention-To-Treat IJOpulation)
Vis it
Fucidi n - H
Hydrocortisone
Difference
<n=24 )
(n• 24 l
(n•2 4 )
0- 10
1 .14
-1 . 7
2. 7
24
- 0.28
1 .42
- 2.7
2.3
24
o . 38
0 .38
1. 44
- 2.0
3.3
19
-o
39
1.59
-3.3
). 7
19
0 . 77
1 .8 3
- 3. 0
4 .0
19
0 . 67
2 .0 6
- 2. 7
5.0
22
- 0.20
2.01
- 3 .3
3.7
22
0 . 86
2 .8 5
- 3.7
5 .7
22
0 . 74
1 . 97
- 2.7
4 .0
24
-0.11
1 . 82
- 2 .7
3.3
24
0.85
2.49
- 4.3
4 .7
24
cont our pa rameters
D vertical
VISIT 2
Mean
so
Mi ni mum
Maximum
Number
VISIT 3
Me an
SD
Mini mum
Maximum
Number
VIS IT 4
Mean
so
Min imum
Maximum
Number
Tr eatment
comparison
(paired t - tes t)
p
= 0.29
1 .70
- 3 .0
3. 3
24
VISI T 5 (END OF TREATMENT}
Mean
SD
Minimum
Maxi mum
Number
p .
0. 11
Table 53: Percentage change in skin surface contour roughness parameter, D vertical,
Pucidin-H
Visit
Per centage change i n skin
surface contour parameter s
0 vertical
VISIT 2
Mean
SD
Minimum
Maximum
Number
VISI T 3
Me an
so
Min i mum
Maximum
Number
Hydrocortisone
Dif ference
(n=24 )
(n• 2 4)
( n=2 4)
10.88
45- 5 2
- 3 9 .9
133 . 5
24
-1 .16
40 .04
-57.2
66 .5
24
1 2.04
6 2. 0 1
- 9 1.5
149.8
24
2 0. 83
4 9. 17
- 54 . 5
1 11 . 0
19
- 6.66
41.11
-60 . 1
99 .7
19
27 . 5 0
59.58
- 87 . 2
123 . 0
19
3 5.89
8 7.64
- 72 . 8
2 50. 0
22
7.28
6 1 . 10
- 66.6
1 57.5
22
28.60
110.91
- 1 57 . 5
24 1.8
22
38.67
86.60
- 50.0
275.9
24
8 . 04
53 . 50
- 5 3 .4
119.8
24
3 0.62
8 5 . 17
- 98.2
229.3
24
Treatme n t
comparison
(pa i red t - testl
p • 0 . 35
VI SIT 4
Me a n
SD
Mi n imum
Maximum
Number
VISIT 5
(END OF T REATMENT)
Me an
so
Minimum
Ma x i mum
Number
p
= 0 .091
Page94 of108
13 August 2002
FUH9401 DK
Table 54: Skin surface contour roughness parameter, D horinzontal, at baseline and at
Visit
Fucidin-H
parame t er D horizontal
Hydrocortisone
Difference
(n•24)
(n•2 4 )
(nc24)
3.17
1. 35
1.0
6.0
24
3.43
1.19
1.3
5.3
24
- 0.26
1.23
- 2.7
1.7
24
3 . 22
1.31
1.0
6.0
24
3 . 83
1.04
2.0
6.0
24
- 0.61
1. 22
- 3.3
1.7
24
3.07
1. 26
1.3
6.0
19
3.28
1.28
1.3
6.0
19
-0.21
1.50
- 2.3
4.0
19
3.20
1.19
1.3
5.0
22
3 .14
1.04
1.7
5.7
22
0 . 06
1 . 38
- 2.3
2.3
22
3 . 31
1.15
1.3
6.0
24
3 . 21
1.43
1.0
6.7
24
0.10
1.67
- 5 .3
3.0
24
VISIT 1 (BASELINE)
Mean
so
Minimum
Maximum
Number
VISIT 2
Mean
SD
Minimum
Maximum
Number
VISIT 3
Mean
so
Minimum
Maximum
Number
VISIT 4
Mean
so
· Minimum
Maximum
Number
VIS I T 5
(END OF TREATMENT)
Mean
so
Minimum
Maximum
Number
Table 55: Change in skin surface contour roughness parameter, D horinzontal, from
baseline to subsequent visits (Intention-To-Treat pop~lation)
Fucidin-H
Hydrocortisone
Difference
(n=24)
(n=24)
0.06
1. 30
- 2.3
3 .o
24
0 . 40
1.11
- 2. 0
2.7
24
-0.35
1 .39
- 2.7
2.0
24
-0 . 04
1 . 49
-3. 3
2 .3
19
0.0 0
1.51
-2 .0
3.0
19
-0 . 04
1. 68
-2.7
3.0
19
Mean
o.oo
Minimum
Maximum
1 .44
- 2.3
2.0
22
- 0 . 35
1.36
- 2.7
2.3
22
0.35
1.89
- 2.7
4. 7
22
0. 14
1. 39
- 4.3
2.0
24
- 0.2 2
1.42
- 3.3
2.0
24
0.36
2 .10
-6.3
3 .3
24
Visit
contour parameters
0 horizonta l
VISIT 2
Mean
so
Minimum
Maximum
Number
(n=24)
Treatment
comparison
(paired t - test)
p • 0.23
VISIT 3
Mean
so
Minimum
Maximum
Number
VISIT 4
so
Number
Mean
so
Minimum
Maximum
Number
p •
0.41
13 A ugust 2002
FUH9401DK
Page 95 of108
Table 56: Percentage change m skin surface contour roughness parameter, D
population)
Visit
Percentage change in s k in
s urface contour p aramet ers
0 horizone a l
VISI T 2
Mean
so
Minimum
Maximum
Number
VI SIT 3
Mean
SD
Minimum
Maximum
Number
VI SIT 4
Mean
SD
Mi nimum
Maximum
Nu mber
Mean
so
Mi n imum
Maximum
Number
l'ucidin -H
< n~2 4l
11.12
44 . 64
- 50 . 1
133. 0
Hydr ocort i sone
Difference
(n~24 )
< n~2 4)
22.93
50.83
- 40 . 0
20 0. 8
24
- 11.81
55 .00
- 172 . 0
79.0
24
- 58.9
2 00 . 0
19
8. 70
47 . 36
-50 . 2
100 . o
19
6 .17
63 . 64
- 78 . 6
125.4
19
12. 83
52.33
- 50. 0
150. 4
22
- 1.19
38 . 77
- 53.4
70.3
22
14. 02
60 . 02
- 103.0
124 . 8
22
21 . 86
57. 31
-76 . 5
167 . 0
24
0 .01
43 .38
- 76 .9
125 . 6
24
21.85
75.70
- 139 . 7
181 . 2
24
24
14. 8 7
62 . 94
Treaeme nt:
compari son
(paired t -test l
p • 0.3 0
p
~
0. 17
Skin surface contour data in individual patients are given in Appendix II, Table
11.12 to Table 1!.17.
12.8.3
Bacteriology
with respect to eradication of pre-treatment pathogens: Staphylococcus aureus
and beta-haemolytic streptococci were considered pathogens if culture yielded
growth of more than 5 colonies. Nine (37.5%) of the 24 patients had pretreatment pathogens at both sides and were evaluable with respect to
qualitative microbiological response. Success was d efined as eradication of pretreatment pathogens (evaluation including phage-type) during treatment, i.e. at
all control visits. Failure was defined as presence of a pre-treatment pathogen
during treatment. Three of the 9 evaluable patients responded equally on the
two treatment sides (2 success, 1 failure). The remaining 6 patients had their
pre-treatment pathogens eradicated on the Fucidin-H side (success) but not on
Page 96 of108
13 A ugust 2002
FUH9401 DK
the Hydrocortisone side (failure). The difference between the treatments was
statistically significant (P = 0.031).
The quantitative microbiological response is accounted for in Table 57 to Table
61.
Table 57: Quantitative microbiological response at visit 1
Organism
Fucidin- H
Hydrocortisone
(n• 24)
Number
of CFU
Staphylococcus
aureus
Phage
Phage
Phage
Pha g e
Phage
Phage
Phage
Phage
Phage
Phage
Total
t ype
type
type
type
type
t ype
type
type
c ype
cype
77
85
95
29/52
3a/3c/55/71u
3c/55/71
54/81
55/71
95u
NT
Staphylococcus
epidermidis
Haemolyt i c
s t reptococci
(n a 24 )
Number of
patients
Number
of CPU
Number of
patie nts
200
1012
650
180
200
1000
500
550
5
1
1
1
1
1
1
4 292
12
2254
75
406
600
11
4
1
1
1
300
800
177
600
3
2972
1
2
13
35 57
11
5
1
56
6
1
1
Gram-negative
bacteria
89
Tocal number of CFU
Total numbe r of pat ien ts with CFU
5
6635
6590
21
19
Organism
Fuci din· H
(n:24)
Number
of CFU
Staphylococ cus
a u r eus
Phage
Phage
Phage
Phage
Phage
Pha ge
Phage
Phage
Tot al
type
type
t ype
type
type
type
type
type
81
95
28ui
29/52
3a/3c/71u
52/6 1
77/81
95u
Staphylococcus
e p idermidi s
Haemolytic
streptococ c i
Gram-negative
bact er i a
Tota l number of CFU
Total number of patients with CPU
225
Number of
pat ient s
2
Hydrocort isone
(n: 24)
Number
of CFU
Number of
patients
12
205
1
3
1
8
7
4 00
2
225
2
22 9
865
1
1
2
10
265 3
10
2161
11
19
1
13
l
60
6
85
6
1
2957
3124
15
18
13 August 2002
FUH 9401 DK
Page 97 of108
Or ganism
Fucidin- H
Hydrocortisone
<n~24)
Number
of CFU
Staphylococcus
aureus
Phage
Phage
Phage
Phage
TOtal
Number of
pati ent s
t.ype 81
type ~s
type ~5u
type NT
1
32
462
5
417
2 066
o~ca
1
1837
12
13
. "t4
response at VlSl
Number
of CFU
Total number of CFU
Total number of patients with CFU
4
1
Fucidin- H
(n•24)
Staphyloco ccus
epidermidis
Haemolyt ic
s treptococci
Gram-negat ive
bacteria
208
1180
Organism
Phage type ~5u
Phage t ype 52/75/81
Total
1
4
9
bact eria
T able 60: Quan titafwe mzcro w
Number of
patiencs
1
1
1
1
1603
s treptoc occi
Gram- n e g a t ive
Total number of CFU
Total number of patients with CFU
Number
of CFU
3
200
Staphylococcus
epidermidis
Haemolytic
Staphylococcus
aureus
<n~24)
Number o f
patients
Hydrocortisone
(ns24 )
Number
of CFU
Number of
patients
4
1
4
1
68
20
88
2
813
10
9n
11
129
6
106
7
946
1
1
1191
13
14
Table 61: Quantitative microbiological res]Jonse at visit 5
Organism
Fuci d in-H
(0=24)
Numbe r
of CFU
Staphylococcus
aur eus
Phage
Phage
Phag e
Phage
Total
type
type
type
type
52
95
29/52
Ntu
Staphylococcus
epidermidis
Haemolytic
Number of
patients
Hydrocortisone
<n=24)
Number
of CFU
Number of
pat ients
500
8
1
1
5
1
1
8
516
1
5
1932
13
1949
16
185
13
77
~
3
streptococci
Gram-neg at ive
bacteria
Total number of CFU
Total numbe r of patients with CFU
2122
2542
20
21
13 August 2002
Page 98 of108
FUH9401 DK
Bacteriology data are given for individual patients in Appendix II, Table Il.18.
12.8.4
There was no statistically significant difference between the treatments with
respect to the proportion of patients obtaining 'marked improvement' or
'clearance' according to the investigator's overall efficacy assessments.
The distribution of the investigator's overall assessment of efficacy at each
treatment arm are given for each post randomisation visit in Table 62.
Table 62: Investigator's overall assessment of efficacy at control visits (Intention-ToTreat population)
Visi t
Invescigacor's overal l
assessment
Pucidin-H
(n• 24)
Number of
patients
VISIT 2
Worse
No c hange
Minimal improvement
Moderate improvement
Marked improvement
Complete l y cleared
To t al
VISI T 3
Worse
No change
Minimal improvement
Marked improvement
Comp le tely cleared
Total
VISIT 4
Worse
Minimal i mprovement
Moderate i mprovement
Marked improvement
Completely cle ared
Total
worse
No change
Minimal improvement
Marked improvement
Comple tely cleared
Total
Hydrocorti sone
(n=24)
%
0
0
3
12.5
29.2
7
5
8
20.8
33.3
Number o f
pat i ents
0
0
8
6
9
1
4.2
1
24
100.0
24
0
0
5.3
5.3
0
0
1
1
4
12
1
19
0
2
5
11
4
22
1
1
3
2
9
8
24
21 . 1
63.2
5.3
100 . 0
1
7
10
1
19
0
9.1
0
22.7
5
12
50.0
18.2
100.0
4.2
1
4
22
0
0
33 . 3
25 . 0
37.5
4.2
100.0
0
0
5. 3
36 . 8
52.6
5.3
100.0
0
4.5
22.7
54 . 5
18.2
100 .0
2
8 .3
1
4.2
16 . 7
4.2
12.5
8.3
37.5
33.3
100.0
%
4 .2
4
10
6
24
41 .7
25 . 0
100 .0
The number of patients achieving 'marked improvement' or 'clearance' at one
arm,
but not the other, are given by treatment arm and visit in Table 63.
13 August 2002
FUH9401DK
Page 99 oj108
Table 63: Treatment arm obtaining 'marked improvement' or 'clearance' according to
investigator's overall assessment of efficacy at control visits (Intention-ToTrea t popu lati on)
Vi sit
Mar ked improvement or cl ea r ance
at one arm but not t he other
VI SIT 2
Puc idi n- H arm
Number of
pat i ents
19
8.3
12 .5
79 .2
24
100 . 0
2
Hydroco rti sone arm
3
No side d if ferenc e
Total number o f patie nts
Treatmen t compar ison
1
%
p
3
1 .0 0
p •
1. 00
VI SIT 3
Fucidin -H arm
5
Hydrocor t i sone arm
No side difference
To t a l number of patients
3
11
26 . 3
15 . 8
57.9
19
100.0
VISI T 4
Fuci din· H arm
Hydrocort i sone arm
No s i de difference
Tot al number of pat i ents
2
9.1
3
17
22
l3 . 6
100. 0
VI SI T 5 (END OF TREATMENT)
Fuc i d in· H arm
2
8.3
1
4. 2
21
24
100 . 0
Hydrocorti s one arm
No s i de d if f erenc e
Tota l number o f pa t i ents
77.3
67.5
1 ) McNemar' s t e st wi t h calcul at i on of exact P-va lue .
Individual patient data on investigator's overall efficacy assessment are given
in Appendix II, Table 11.19
12.9
USE
OF
AND
COMPLIANCE
WITH
PRESCRIBED
STUDY
MEDICATION
All patients used the medication twice daily as described except for a minor
deviation: One patient missed one evening application. For details see
Appendix II, Table II.20.
The amount of study medication used during the 2 weeks treatment is
accounted for in Table 64.
Used/unused Fucidin-H/Hydrocortisone tubes were to be returned at visit 4
and visit 5. The amou nt of study medication used was calculated by subtracting
the weight of the used tubes from the mean weight of full tubes.
Page 100 of108
13 August 2002
Via it
Amount of drug used (g)
Pucid in-H
(n • 24 )
VI SIT 1 (BASELINE) TO VISIT 4
( l ' t week)
Mean
(n~ 24 )
0.11
0.82
- 1. 8
1.8
24
7.61
5.33
1 .4
23 . 1
24
7.85
5. 77
0.9
2 2. 8
24
- 0 .24
0 . 93
- 2.0
1. 5
24
15.58
10 .17
3.2
46. 5
24
15 . 71
10.52
3.4
46 .4
24
-0.12
1 .04
- 2. 4
2.1
24
VISIT 4 TO VISIT 5 (END OF TREATMENT)
! 2"" week)
Mean
SD
Minimum
Maximum
Number
Maximum
Number
Diff e rence
7 . 86
s.o8
1.8
23 . 6
24
Minimum
Maximum
Number
Mi nimum
Hydrocort isone
(0• 24 )
7 . 97
5 . 23
1.8
23. 4
24
so
BASELI NE TO END OF TREATMENT
(2 weeks)
Mean
SD
FUH9401DK
For drug accountability data in individual patients, see Appendix II, Table II.21.
12.10
DURATION AND EXTENT OF EXPOSURE TO TREATMENT WITH
STUDY MEDICATION
The mean duration of treatment in all randomised patients was 14.1 days (range
13 to 16).
The total 'exposure' to the study medication in terms of patient-treatmentweeks was 338 weeks.
12.11
CONCOMIT ANT TREATMENT
Concomitant drug treatment at baseline is described in section 2.7.3. During
treatment there was only one change, see Appendix II, Table II.22.
12.12
SAFETY EVALUATION
A total of 5 patients reported mild adverse events.
r
13 August 2002
FUH9401 DK
Page 101 of108
Table 65: Adverse events listed by system-organ class 1
Sys t em- o r gan c lass 1
Fucidin - H
treat ed
arm only
Hydrocortisone
treat ed arm
only
(n=24)
(n=24)
Number of
patients
Number of
patients
Not arm dependent
adverse
event
(n• 24)
All patients
<n• 24l
comparison
Number of
patients
Number of
patients
(McNemar's
test)
Treatme nt
Skin and appendages
disorders
1
l
5
Total number of adverse
events 1
Total number of
pat i ent s (\)
l
l
1 (4. 2 )
1 (4 .2)
5
(12.5)
5 (20.8)
p
= 1. 00
1) Classification according to the WHO Adverse Reaction Dictionary, 31. December 1992.
2) Different adverse events within the same c lass and i nvol ving the same pat ient have been counted
as one. A singl e patient coul d appear in multiple c l a sses.
For details on the adverse events, see Appendix II, Table II.23.
·::::.;·
Page 102 of108
13 August 2002
FUH9401DK
· - - - - - - - - -- - -- -- - - - - - - - -- -- - · --- ... -· ·- - - .. ·--·--··•• »•
FUH9401DK
13
13 August 2002
Page 103 of108
DISCUSSION
The objectives of the present study was to compare the effect of Fucidin-H
cream with that of Hydrocortisone cream in children with a flare-up of atopic
dermatitis with special emphasis on:
• disease severity measured by bioengineering techniques
• eradication of pre-treatment pathogens (Staph. aur. and beta-haemolytic
streptococci).
The study demonstrated that Fucidin-H cream was statistically significantly
superior to Hydrocortisone cream regarding eradication of pre-treatment
pathogens. The study showed no statistically significant difference between the
creams regarding disease severity measured by bioengineering techniques or
regarding the investigator's overall assessment of treatment efficacy.
The study was randomised, double-blind, right-left comparative study.
The superiority of Fucidin-H cream to Hydrocortisone cream regarding
bacteriological effect was expected and the finding gives validity to the rightleft comparative study design and the conduct of the study.
The lack of a treatment difference regarding disease severity measured by
bioengineering techniques requires further discussion.
The protocol called for 24 patients in the study to detect a treatment difference
of 20% points regarding percentage change in TEWL from baseline to end of
treatment (2 weeks). Twenty-four patients were randomised and they all
provided data after 2 weeks of treatment. The observed treatment difference
was 3.5% points (95% confidence interval -6.3 to 13.2), that is smaller than the
stipulated 20%. The sample size calculation assumed a standard deviation of
25%. The observed standard deviation was 23%, that is in agreement with the
Page 104 o/108
13 August 2002
FUH9401DK
stipulated. These findings show that the statistical power of the study was
sufficient.
The lack of a statistically significant difference regarding the investigator's
overall assessment of treatment efficacy might be due to low power for this end
point. The difference between Fucidin-H and Hydrocortisone in the percentage
of patients who obtained "marked improvement" or "clearance" was 4% points
(95% confidence interval-11 to 19% points).
There were no compliance problems. The mean duration of treatment was 14.1
days (range 13 to 16).
Summing up, the design and conduct of the study provided a good basis for
concluding on the results.
The explanation for the lack of a treatment difference regarding disease severity
measured by bioengineering techniques could be:
• lack of a treatment difference regarding the measured parameters
• lack of sensitivity of the bioengineering measurements.
FUH9401DK
14
13 August 2002
Page 105 of108
CONCLUSION
There was no statistically significant difference between Fucidin-H cream and
Hydrocortisone regarding the effect measured by bioengineering techniques.
with respect to eradication of pre-treatment pathogens.
Fucidin-H was not statistically significantly superior to Hydrocortisone
regarding the investigator's overall assessment of efficacy.
Page 106 of108
13 August 2002
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15
Page 107 of108
REFERENCES
1. Larsen FS, Hanifin JM.
Secular change in the occurrence of atopic dermatitis.
Acta Derm Venereol (Stockh) 1992; Suppl176: 7-12
2.
Lapidus CS, Schwarz DF, Honig P}.
Atopic dermatitis in children: Who cares? Who pays?
JAm Acad Dermatol1993; 28:966-703
3. Hanifin JM, Rajka G.
Diagnostic feature of atopic dermatitis.
Acta Derm Venereol Suppl. (Stockh) 1980; 92:44-47
4.
Abeck D, Ruzicka T.
Bacteria and atopic eczema (T. Ruzicka, J. Ring, B. Przybilla eds.), pp 221220, Springer-Verlag Berlin Heidelberg 1991.
5. Goodyear HM, Watson PJ, Egan SA, Price EH, Kenny PA, Harper Jl.
Skin microflora of atopic eczema in first time hospital attenders.
Clin Exper Dermatol1993; 18:300-304.
6.
Ring J, Abick D, Neuber K.
Atopic eczema: role of microorganisms on the skin surface.
Allery 1992; 47:265-269.
7.
Neuber K, Konig W, Ring J.
Staphylococcus aureus und atopisches eksem.
Hautarzt 1993; 44: 135-142.
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Fucidin-H vs. Hydrocortisone in Atopic Dermatitis

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