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Reprint

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Reprint
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www.thelancet.com
Efficacy and safety of ustekinumab, a human
interleukin-12/23 monoclonal antibody, in patients
with psoriasis: 76-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 1)
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Craig L Leonardi, Alexa B Kimball, Kim A Papp, Newman Yeilding, Cynthia Guzzo,
Yuhua Wang, Shu Li, Lisa T Dooley, Kenneth B Gordon, for the PHOENIX 1 study
investigators
Lancet 2008; 371: 1665–74
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Articles
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Notice No responsibility is assumed by Elsevier for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
Efficacy and safety of ustekinumab, a human
interleukin-12/23 monoclonal antibody, in patients
with psoriasis: 76-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 1)
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Craig L Leonardi, Alexa B Kimball, Kim A Papp, Newman Yeilding, Cynthia Guzzo, Yuhua Wang, Shu Li, Lisa T Dooley, Kenneth B Gordon, for the
PHOENIX 1 study investigators*
Summary
Background Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab,
a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis.
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Methods In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe
psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then
every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients
who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least
75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40
to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done
with a minimisation method via a centralised interactive voice response system. The primary endpoint was the
proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with
ClinicalTrials.gov, number NCT00267969.
Findings All randomised patients were included in the efficacy analysis. 171 (67·1%) patients receiving ustekinumab
45 mg, 170 (66·4%) receiving ustekinumab 90 mg, and eight (3·1%) receiving placebo achieved PASI 75 at week 12
(difference in response rate vs placebo 63·9%, 95% CI 57·8–70·1, p<0·0001 for 45 mg and 63·3%, 57·1–69·4,
p<0·0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and
172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and
160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance
ustekinumab than in those withdrawn from treatment at week 40 (p<0·0001 by log-rank test). During the
placebo-controlled phase, adverse events occurred in 278 (54·5%) of the 510 patients receiving ustekinumab and
123 (48·2%) of the 255 receiving placebo. Serious adverse events occurred in six (1·2%) of 510 patients receiving
ustekinumab and in two (0·8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the
same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase.
Interpretation Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every
12 weeks maintains efficacy for at least a year in most patients.
Funding Centocor Inc.
Introduction
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Psoriasis is a chronic immune-mediated inflammatory
disease of the skin that significantly impairs patients’
physical and mental functioning and wellbeing.1 The
condition affects about 2–3% of the population
worldwide.2 Characterisation of the immunopathophysiological basis of psoriasis has led to the
development of novel therapeutic agents that selectively
target aberrant immune responses putatively involved in
psoriasis, including agents that target leucocyte
function-associated antigen-3, CD11a, and tumour
necrosis factor α.3 However, currently available
therapeutic options have left substantial unmet need for
treatments that are convenient, effective, and well
tolerated, especially for long-term treatment.4
Lancet 2008; 371: 1665–74
See Comment page 1639
See Articles page 1675
*Investigators listed at end of
paper
Saint Louis University Medical
School, St Louis, MO, USA
(Prof C L Leonardi MD); Harvard
Medical School, Boston, MA,
USA (A B Kimball MD); Probity
Medical Research, Waterloo
and University of Western
Ontario, London, ON, Canada
(K A Papp MD); Centocor Inc,
Malvern, PA, USA
(N Yeilding MD, C Guzzo MD,
Y Wang PhD, S Li MS,
L T Dooley DrPH); and
Northwestern University
Feinberg School of Medicine
and Evanston Northwestern
Healthcare, Chicago, IL, USA
(K B Gordon MD)
Correspondence to:
Dr Kenneth B Gordon, Division of
Dermatology, Evanston
Northwestern Healthcare,
9977 Woods Drive, Skokie,
IL 60077, USA
[email protected]
Interleukins 12 and 23 have an important role in the
pathophysiology of psoriasis. Genetic polymorphisms
in the genes that encode the shared p40 subunit of these
cytokines (interleukin 12B), and one of the interleukin-23
receptor subunits, have been linked to psoriasis.5
Furthermore, an uncommon variant of the interleukin-23
receptor subunit that confers protection against Crohn’s
disease6 has also been shown to confer protection
against psoriasis.7 The p40 subunit of interleukins 12
and 23 is overexpressed in psoriasis plaques,8 and
preclinical studies implicate p40-containing cytokines
in the pathogenesis of psoriasis.9 Many current therapies
used in the treatment of psoriasis modulate levels of
interleukins 12 and 23, which are speculated to
contribute to their efficacy,10 and agents that specifically
www.thelancet.com Vol 371 May 17, 2008
1665
Placebo-controlled phase
Screen
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Placebo crossover and active treatment phase
Randomised withdrawal phase
R
Group 1
Ustekinumab 45 mg at weeks 0, 4 → every 12 weeks
Placebo → Retreatment
R
Group 2
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45 mg every 12 weeks
3a
Group 3
Placebo at weeks 0, 4
3b
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Week 28:*
PASI <50: D/C
PASI 50 to <75: every 8 weeks
PASI ≥75: every 12 weeks
Week -4
R
0
12
28
Week 40:†
PASI<75: every 8 weeks
PASI ≥75: entered
randomised withdrawal
40
76
Figure 1: Study schema from week 0 through week 76, including the placebo-controlled phase (week 0–12), the placebo crossover and active treatment phase
(week 12–40), and the randomised withdrawal phase (week 40–76)
D/C=discontinued. PASI=psoriasis area and severity index. R=randomisation. *At week 28, in all groups, non-responders (PASI<50) discontinued study agent, partial
responders (PASI 50 to <75) began dosing every 8 weeks, and PASI responders (PASI ≥75) received dosing every 12 weeks. †At week 40, PASI responders to dosing
every 12 weeks in groups 1 or 2 were randomised to either placebo or continued to receive ustekinumab every 12 weeks at their original dose. Individuals in group 3
received placebo. At loss of therapeutic effect, patients receiving placebo began retreatment at their dosing regimen before withdrawal. In all groups, non-responders
or partial responders were adjusted to dosing every 8 weeks. Patients already receiving dosing every 8 weeks continued this dosing schedule.
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target these cytokines improved psoriasis in early
clinical trials.11,12
Ustekinumab (CNTO 1275, Centocor Inc, Malvern, PA,
USA) is a human monoclonal antibody that binds to the
shared p40 protein subunit of human interleukins 12
and 23 with high affinity and specificity (unpublished
data), thereby preventing interaction with their cell
surface IL12Rβ1 receptor. A phase II trial showed
improvements in psoriasis that were dependent on dose
and exposure after ustekinumab was given once or
weekly for 4 weeks, with clinical effects that were
sustained for many weeks.11 The phase III PHOENIX 1
study, together with PHOENIX 2,13 examined the safety
and efficacy of ustekinumab compared with placebo for
12 weeks in patients with moderate-to-severe plaque
psoriasis and also used a randomised withdrawal design
to assess the safety and efficacy of long-term ustekinumab
treatment for up to 76 weeks.
Methods
Patients
This phase III, double-blind, placebo-controlled,
multicentre trial was done between December, 2005, and
September, 2007, at 48 sites in the USA, Canada, and
Belgium. Eligible patients were at least 18 years old, had a
diagnosis of plaque psoriasis for at least 6 months, were
candidates for phototherapy or systemic therapy, had a
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baseline psoriasis area and severity index (PASI) score
of 12 or higher, and had at least 10% body surface area
involvement. Patients were to have no history or
symptoms of active tuberculosis; however, those with
latent tuberculosis (a positive Mantoux tuberculin skin
test without radiological evidence of tuberculosis) could
be enrolled if treatment for latent tuberculosis according
to local country guidelines for immunocompromised
patients was initiated either before or simultaneous to the
first administration of study agent.
Patients were ineligible if they had non-plaque forms of
psoriasis, had a recent serious systemic or local infection,
had a known malignancy (except treated basal cell skin
cancer or squamous cell skin cancer for at least 5 years),
had previous treatment with any agent that targets
interleukins 12 or 23 specifically, had received biological or
investigational agents within the previous 3 months, had
received conventional systemic psoriasis therapy or
phototherapy within the previous 4 weeks, or had received
topical psoriasis treatment within the previous 2 weeks.
All patients provided written informed consent, and
institutional review boards or ethics committees at all
sites approved the protocol.
Procedures
The safety and efficacy of ustekinumab were assessed over
three phases: a placebo-controlled phase (weeks 0–12), a
withdrawn from active treatment (placebo). Patients
withdrawn from treatment at week 40 were retreated when
they lost at least 50% of PASI improvement. Patients not
achieving PASI 75 at week 28 or 40 were not re-randomised,
and their dosing was discontinued or modified (figure 1).
Patients received placebo injections as needed to preserve
the blind. The study sponsor was unblinded to treatment
assignments at week 52 for analysis purposes. Site
monitors, investigators, site personnel involved in study
conduct, and patients remained blinded until week 76.
Patients were allocated to treatment groups at weeks 0
and 40 with a minimisation method with biased coin
assignment14 via a centralised interactive voice response
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placebo-crossover and active treatment phase (weeks 12–40),
and a randomised withdrawal phase (weeks 40–76;
figure 1). At baseline, patients were randomly assigned in
equal proportions to receive subcutaneous injections of
ustekinumab 45 or 90 mg at weeks 0 and 4 and every
12 weeks thereafter or placebo at weeks 0 and 4, with half
randomised to crossover to ustekinumab 45 mg and half to
ustekinumab 90 mg at week 12 (figure 1). At week 40,
patients who had initially been randomised to receive
ustekinumab who achieved long-term response (at least
75% improvement from baseline in PASI score [PASI 75]
at weeks 28 and 40) were re-randomised to continue
maintenance treatment with ustekinumab or were
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984 screened
766 randomised
1 discontinued study
agent
0 lack of efficacy
0 adverse event
1 other
Placebo crossover
(week 12)
agent*
19 lack of efficacy
11 adverse event
8 other
66 adjusted to every
8 weeks dosing and
completed study agent
through week 76
Randomised withdrawal
(week 40)
1 received no treatment
10 discontinued study agent
1 lack of efficacy
2 adverse event
7 other
agent*
6 lack of efficacy
7 adverse event
6 other
8 weeks dosing and
through week 76
77 randomised to
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73 randomised to
placebo → retreatment
256 ustekinumab 90 mg every 12 weeks regimen
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255 ustekinumab 45 mg every 12 weeks regimen
agent
0 lack of efficacy
2 adverse event
2 other
69 completed study
agent through week 76
87 randomised to
agent
0 lack of efficacy
0 adverse event
0 other
agent
0 lack of efficacy
1 adverse event
1 other
77 completed study
85 completed study
agent*
7 lack of efficacy
2 adverse event
2 other
8 weeks dosing and
through week 76
85 randomised to
agent
0 lack of efficacy
3 adverse event
1 other
80 completed study
255 placebo
12 discontinued study agent
3 lack of efficacy
6 adverse event
3 other
123 crossed over to 45 mg
ustekinumab every
12 weeks regimen
120 crossed over to 90 mg
ustekinumab every
12 weeks regimen
agent*
2 lack of efficacy
1 adverse event
2 other
8 weeks dosing and
through week 76
68 switched to
92 switched to
agent
1 lack of efficacy
0 adverse event
1 other
agent
0 lack of efficacy
1 adverse event
0 other
67 completed study
89 completed study
Figure 2: Trial profile
*Includes patients who were adjusted to dosing every 8 weeks and discontinued treatment after week 40.
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Ustekinumab
45 mg (n=255)
Ustekinumab
90 mg (n=256)
Placebo
(n=255)
Age (years)
44·8 (12·5)
46·2 (11·3)
44·8 (11·3)
Sex (male)
175 (68·6%)
173 (67·6%)
183 (71·8%)
Weight (kg)
93·7 (23·8)
93·8 (23·9)
94·2 (23·5)
Duration of psoriasis (years)
19·7 (11·7)
19·6 (11·1)
20·4 (11·7)
Involved body surface area
27·2% (17·5)
25·2% (15·0)
27·7% (17·4)
114 (44·7%)
109 (42·6%)
112 (43·9%)
Psoriasis area and severity index
20·5 (8·6)
19·7 (7·6)
20·4 (8·6)
Dermatology life quality index
11·1 (7·1)
11·6 (6·9)
Patients with psoriatic arthritis
74 (29·0%)
94 (36·7%)
Treated previously with
Topical agent†
245 (96·1%)
239 (93·4%)
Phototherapy‡
173 (67·8%)
169 (66·0%)
Conventional systemics§
141 (55·3%)
141 (55·1%)
Biologicals¶
134 (52·5%)
130 (50·8%)
8 (3·1%)
7 (2·7%)
Patients with latent tuberculosis||
11·8 (7·4)
90 (35·3%)
242 (94·9%)
150 (58·8%)
142 (55·7%)
128 (50·2%)
10 (3·9%)
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Data are mean (SD) or n (%). *Rated as cleared (0), minimal (1), mild (2), moderate (3), marked (4), or severe (5).
†Patients had to have discontinued topical therapies (except moisturisers and shampoos) 2 weeks, conventional
systemic therapies 4 weeks, and biological agents at least 3 months before randomisation. ‡Includes ultraviolet B light
and psoralen plus ultraviolet A. §Includes psoralen plus ultraviolet A, methotrexate, acitretin, and ciclosporin.
¶Includes etanercept, alefacept, efalizumab, infliximab, or adalimumab. ||Latent tuberculosis was identified by a
positive purified protein derivative test without evidence of active tuberculosis.
Table 1: Demographic and clinical characteristics at baseline
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system (ClinPhone; East Windsor, NJ, USA). Baseline
randomisation was stratified by investigational site,
weight (≤90 kg or >90 kg), and the number of conventional
systemic therapies to which patients had an inadequate
response, intolerance, or contraindication (<3 or ≥3).
Week 40 randomisation was stratified by investigational
site and baseline weight (≤90 kg or >90 kg).
Key efficacy parameters, including PASI, physician’s
global assessment, and dermatology life quality index,
were assessed until week 76. PASI response indicates the
extent and severity of psoriasis, yielding an overall scale
of 0 (no psoriasis) to 72 (severe).15 With the physician’s
global assessment, a patient’s psoriasis is assessed as
cleared (0), minimal (1), mild (2), moderate (3),
marked (4), or severe (5). The dermatology life quality
index is a 10-item questionnaire that determines whether
psoriasis affects patient-reported quality of life, with
overall scores ranging from 0 (not at all) to 30 (very
much).16 Adverse events and routine haematology and
chemistry laboratory tests and haemoglobin A₁c levels
were monitored until week 76, and serum samples
collected up to week 76 were tested for antibodies to
ustekinumab with a bridging immunoassay.17 Fasting
glucose, C-reactive protein (CRP), and D-dimer levels
were monitored during the placebo-controlled phase.
The primary efficacy endpoint was the proportion of
patients achieving PASI 75 at week 12. Major secondary
endpoints included: the proportion of patients with a
physician’s global assessment score of cleared or minimal
at week 12; the change in dermatology life quality index
from baseline at week 12; and, in the randomised withdrawal
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phase, time to loss of PASI 75 response in the group
receiving maintenance ustekinumab compared with the
group withdrawn from treatment at week 40.
Statistical analysis
The study was designed to enrol 750 patients to assess
both the primary and major secondary endpoints and to
characterise the efficacy and safety of long-term
treatment. The sample size calculations took into account
the results of the phase II trial11 and assumed PASI 75
response rates of 50% (≤90 kg) and 40% (>90 kg) in each
ustekinumab group and 10% for the placebo group. On
the basis of simulation studies in SAS (version 8.02)
using Cochran-Mantel-Haenszel χ² tests stratified by
weight, the trial with 250 patients per group provided
more than 99% power to detect at least one pairwise
treatment effect in the primary endpoint based on Holm’s
procedure at an overall 5% level of significance. To
maintain an overall type I error rate of 0·05, the primary
and major secondary analyses were done sequentially
with each endpoint tested at an alpha level of 0·05. All
other statistical tests were two-sided.
Efficacy data from all randomised patients were analysed
according to the assigned treatment group, whereas safety
analyses were based on actual treatment in patients
receiving at least one administration of study agent. For
patients randomly assigned to placebo at baseline, only
those who crossed over to active treatment at week 12 were
included in subsequent efficacy summaries. Patients who
discontinued study treatment due to unsatisfactory
therapeutic effect or who started a protocol-prohibited
therapy that could improve psoriasis were deemed to be
treatment failures. For analyses in such cases, baseline
values were assigned for continuous endpoints and
patients were deemed to be non-responders for
dichotomous endpoints.
In the primary efficacy and week 12 binary PASI and
physician’s global assessment analyses, patients with
missing data were deemed to be non-responders. For
analyses of time to loss of PASI 75 response, intermittent
missing values were imputed by linear interpolation. For
other efficacy analyses, missing data were not imputed
and were treated as missing.
Dichotomous endpoints were analysed with the
Cochran-Mantel-Haenszel χ² test stratified by site
(pooled) and weight, and continuous variables were
compared with an analysis of variance (ANOVA) on the
van der Waerden normal scores with weight as a binary
covariate. Time to loss of PASI 75 response was analysed
with the log-rank test stratified by weight.
This trial is registered with ClinicalTrials.gov, number
NCT00267969. All analyses were done with SAS version
8.02.
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Physician’s global assessment—marked or severe*
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Role of the funding source
Employees of the study sponsor were involved in the
design of this study together with members of the
Results
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The trial profile is shown in figure 2. Baseline
demographic and clinical characteristics were much the
same across treatment groups (table 1) and among
patients re-randomised at week 40 (data not shown).
About two-thirds of patients in each group were men. On
average, patients had a 20-year history of psoriasis and
about a quarter of their body surface area affected by
psoriasis. Over 90% of patients had used topical
treatments previously, and at least 50% each had
previously used conventional systemic or biological
therapies. 25 patients diagnosed with latent tuberculosis
infection before or at screening received isoniazid during
the study (table 1).
Significantly more patients in both the 45 and 90 mg
ustekinumab groups achieved the primary endpoint—
PASI 75 at week 12—than did those in the placebo group
(table 2; difference in response rate 63·9%, 95% CI
57·8–70·1, p<0·0001 for the 45 mg group vs placebo
and 63·3%, 57·1–69·4, p<0·0001 for the 90 mg group vs
placebo; figure 3). Onset of efficacy was rapid, with
higher proportions of ustekinumab-treated patients
achieving at least 50% improvement from baseline in
PASI (PASI 50) by week 2 (p=0·0008 for the 45 mg group
vs placebo and p=0·0005 for the 90 mg group vs placebo)
and PASI 75 by week 4 (p<0·0001 for each comparison vs
placebo; figure 3). Ustekinumab-treated patients showed
greater improvement in their psoriasis compared with
placebo at every PASI or physician’s global assessment
threshold assessed at week 12 (figure 3). Cleared or
minimal disease based on the physician’s global
assessment was achieved by more patients receiving
ustekinumab than by those receiving placebo (table 2;
difference in response 56·5%, 95% CI 50·0–62·9,
p<0·0001 for 45 mg vs placebo and 57·8%, 51·4–64·2,
p<0·0001 for 90 mg vs placebo).
Efficacy
continued
to
increase
after
the
placebo-controlled portion of the study (figure 3).
Maximum efficacy was observed at about week 24 in both
the 45 mg and 90 mg groups (PASI 75 response in
191 [76·1%] of 251 patients in the 45 mg group and
209 [85·0%] of 246 patients in the 90 mg group; figure 3).
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steering committee, with input from study investigators.
The steering committee reviewed study progress. Study
investigators collected data, which were maintained in a
database by the study sponsor. Statisticians and
programmers at the study sponsor did the data analyses.
An independent safety monitoring committee reviewed
safety data during the study. All authors had full access to
the data, and the steering committee had final
responsibility for the decision to submit for publication.
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Week 12
Ustekinumab 45 mg
(n=255)
Reported by the physician
Week 28
Ustekinumab 90 mg
(n=256)
Placebo
(n=255)
Ustekinumab
45 mg (n=250)
Ustekinumab
90 mg (n=243)
Placebo to
Placebo to
ustekinumab 45 mg ustekinumab 90 mg
(n=123)
(n=119)
Improvement in psoriasis area and severity index (PASI) score
At least 50% (PASI 50)
100% (PASI 100)
213 (83·5%)*
220 (85·9%)*
26 (10·2%)
228 (91·2%)
234 (96·3%)
118 (95·9%)
117 (98·3%)
171 (67·1%)*
170 (66·4%)*
8 (3·1%)
178 (71·2%)
191 (78·6%)
81 (65·9%)
101 (84·9%)
106 (41·6%)*
94 (36·7%)*
5 (2·0%)
123 (49·2%)
135 (55·6%)
55 (44·7%)
74 (62·2%)
32 (12·5%)*
28 (10·9%)*
0 (0·0%)
52 (20·8%)
71 (29·2%)
24 (19·5%)
40 (33·6%)
Percentage improvement in psoriasis area and severity index (PASI) score
n
Mean
Median
Physician’s global assessment
Cleared
Marked or severe
251
75·6 (27·04)
77·2 (23·67)
85·98
(65·8 to 94·7)*
85·55
(66·2 to 93·8)*
253
250
243
123
119
7·0 (30·77)
80·3 (23·65)
85·2 (19·40)
80·4 (20·60)
88·2 (15·73)
2·82
(–7·5 to 21·7)
89·38
(69·7 to 97·9)
91·43
(77·8 to 100·0)
86·43
(67·8 to 97·6)
93·48
(81·8 to 100·0)
47 (18·4%)*
45 (17·6%)*
1 (0·4%)
66 (26·4%)
86 (35·4%)
28 (22·8%)
48 (40·3%)
154 (60·4%)*
158 (61·7%)*
10 (3·9%)
147 (58·8%)
161 (66·3%)
75 (61·0%)
87 (73·1%)
5 (2·0%)*
14 (5·5%)*
105 (41·2%)
15 (6·0%)
5 (2·1%)
1 (0·8%)
2 (1·7%)
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Cleared or minimal
255
Reported by the patient
Change in dermatology life quality index (DLQI) score
n
Mean
Median
DLQI score of 0 or 1
254
249
–8·0 (6·87)
–8·7 (6·47)
–6·00
(–12·0 to –3·0)*
–7·00
(–12·0 to –4·0)*
135 (53·1%)*
131 (52·4%)*
252
–0·6 (5·97)
249
241
123
118
–8·1 (7·23)
–9·6 (7·17)
–8·7 (7·56)
–9·6 (6·75)
0·00
(–3·0 to 3·0)
–7·00
(–12·0 to –3·0)
–8·00
(–13·0 to –4·0)
–8·00
(–13·0 to –4·0)
–8·00
(–14·0 to –4·0)
15 (6·0%)
146 (58·6%)
167 (69·0%)
74 (60·2%)
90 (76·3%)
Data are mean (SD), median (IQR), or n (%) unless specified otherwise. *p<0·0001 vs placebo.
Table 2: Clinical responses at week 12 and week 28 as reported by physicians and patients
1669
A
B
Proportion of patients (%)
100
80
60
40
20
0
0 2 4
8
12 16 20 24 28 32 36 40
0 2 4
8
12 16 20 24 28 32 36 40
0 2 4
8
12 16 20 24 28 32 36 40
D
C
80
60
40
20
Week
0
0 2 4
8
12 16 20 24 28 32 36 40
Placebo
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Proportion of patients (%)
100
Placebo→ustekinumab 45 mg
Ustekinumab 45 mg
Placebo→ustekinumab 90 mg
Ustekinumab 90 mg
Figure 3: Proportion of patients achieving clinical response from baseline through week 40
PASI 75 (A), physician’s global assessment of cleared or minimal (0 or 1; B), PASI 90 (C), and PASI 50 (D); all
patients randomised at baseline. For week 28 PASI 50 non-responders, data at week 28 were carried forward to
weeks 32, 36, and 40. Solid arrows indicate visits at which ustekinumab was administered to patients randomised
to receive ustekinumab at baseline; broken arrows indicate visits at which ustekinumab was administered to those
randomised to receive placebo at baseline and crossover to ustekinumab at week 12.
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More than 90% of patients in both ustekinumab groups
achieved PASI 50 (table 2), and about half of patients in
both ustekinumab groups achieved at least
90% improvement from baseline in PASI (PASI 90) at
week 28 (table 2). These response rates were generally
maintained through week 40 (figure 3), when long-term
responders underwent randomised withdrawal. Patients
randomised to placebo at baseline achieved similar
response rates after crossover at week 12 (figure 3).
Among patients re-randomised at week 40, maintenance
of PASI 75 (ie, time to loss of PASI 75 response) was
better in patients receiving maintenance therapy than in
patients withdrawn from therapy through at least 1 year
(p<0·0001). The median percentage improvement in
PASI remained stable to at least week 76 in the
maintenance therapy groups (figure 4). Patients receiving
maintenance therapy also generally sustained PASI 50,
PASI 75, PASI 90, and physician’s global assessment
responses to at least week 76 (data not shown). By
contrast, the median percentage improvement in PASI
in the withdrawal groups began to decrease gradually by
week 44, with the decline in PASI improvement
accelerating after week 52, decreasing over time from
over 96% in both withdrawal groups at week 40 to
about 40% at week 64 (after which point the median PASI
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improvement in these groups cannot be accurately
assessed because PASI data were carried forward from
retreatment visits in about half the patients). The median
time to loss of PASI 75 in patients withdrawn from
treatment was about 15 weeks; rebound psoriasis18 was
not reported in patients withdrawn from treatment. Of
the 195 patients who re-initiated ustekinumab,
167 (85·6%) achieved PASI 75 within 12 weeks of
re-initiating therapy, with similar response rates observed
in all treatment groups.
Patient-reported outcomes, as measured by
dermatology life quality index, paralleled improvements
in psoriasis (table 2), with improvements seen as early
as week 2 in the ustekinumab groups (data not shown).
More than half of patients in the ustekinumab groups
achieved a dermatology life quality index score of 0 or 1
by week 12 (p<0·0001 vs placebo for both groups;
table 2). At week 12, median changes in dermatology
life quality index were greater in patients receiving
ustekinumab than they were in patients receiving
placebo (median of differences vs placebo –7·0, 95% CI
–7·0 to –5·0, p<0·0001 for 45 mg group and –7·0,
–8·0 to –6·0, p<0·0001 for 90 mg group). Dermatology
life quality index responses seen at week 12 were
sustained to the end of the study in patients maintained
on ustekinumab but worsened in patients withdrawn
from therapy (figure 4).
Table 3 shows the number of adverse events
experienced during the three phases of the trial. In
general, adverse events were mild, non-serious, and did
not require treatment adjustment, with the most
commonly reported adverse events being upper
respiratory tract infection, nasopharyngitis, headache,
and arthralgia. The number of infections, and the
number of adverse events that led to discontinuation of
treatment, were much the same across groups (table 3).
Serious adverse events occurred in two of the 255 patients
receiving placebo (one patient with pneumonia and one
with a psychotic disorder), two of 255 patients receiving
ustekinumab 45 mg (one with stroke and one with
hypertension), and in four of 255 patients receiving
ustekinumab 90 mg (two patients with serious
infections; one patient with coronary artery disease who
was hospitalised for coronary artery bypass grafting; and
one patient with psoriasis that began worsening during
the screening period and who was managed with topical
emollients only, continued receiving ustekinumab and
subsequently responded; table 3). The two serious
infections reported in patients receiving ustekinumab
(one patient with bilateral lower extremity cellulitis and
another with herpes zoster affecting the left
T8 dermatome with 19 cutaneous vesicles disseminated
beyond the primary dermatome) resolved with
appropriate therapy. No malignancies were reported
during the placebo-controlled phase (table 3), and rates
of laboratory abnormalities were much the same
between treatment groups (data not shown).
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Week
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A
B
Median percentage
100
80
60
40
20
0
48 52
56 60 64
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68
72
76
40 44
FO
40 44
Ustekinumab 45 mg
Placebo
Every 12 weeks
C
48 52
56 60 64
68
72
76
Ustekinumab 90 mg
Placebo
Every 12 weeks
D
Median change
4
0
–4
–8
–12
–16
Week 40
Week 52
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The general patterns of common adverse events seen
during the placebo crossover and randomised withdrawal
phases were much the same as those seen during the
placebo-controlled phase, although absolute event rates
differed across study phases consistent with different
lengths of follow-up (table 3). No dose response was seen
in the rates of adverse events, serious adverse events, or
adverse events leading to study agent discontinuation.
Patients receiving maintenance therapy did not
experience higher adverse event rates than did patients
receiving interrupted therapy in the randomised
withdrawal phase (table 3). The most common serious
adverse events observed in the placebo crossover and
randomised withdrawal phases included infections (a
patient with a viral syndrome in the 45 mg group and a
diabetic patient with a foot ulcer and osteomyelitis in the
90 mg group in the placebo crossover phase, and a patient
with gastroenteritis in the interrupted therapy group in
the randomised withdrawal phase); malignancies (one
patient each with prostate and thyroid cancer in the
45 mg group in the crossover phase and one patient with
colon cancer in the interrupted therapy group in the
withdrawal phase); and cardiovascular events (two
patients with myocardial infarctions [one each in the
45 mg group and placebo to 90 mg crossover group] and
another who experienced a stroke in the placebo to 45 mg
crossover group, all in the crossover phase). Patterns and
rates of adverse events were comparable among patients
in the placebo crossover group (who did not undergo
randomised withdrawal) and were similar before and
after dose adjustment in patients who did not achieve
PASI 75 at week 28 or 40 and switched to dosing
every 8 weeks (data not shown), with one additional
serious infection reported (appendicitis), and one patient
each reporting lentigo maligna, breast cancer, and
transitional cell carcinoma (in a patient who had a
perioperative myocardial infarction post-nephrectomy).
No cases of mycobacterial or salmonella infection were
observed.
The proportions of patients with abnormalities in
haematology and chemistry laboratory measures,
including liver and renal function tests, were low and
generally comparable between the placebo and
ustekinumab groups through week 12 and during
randomised withdrawal (data not shown). Ustekinumab
had no effect on glucose, haemoglobin A₁c levels,11
neutrophil counts,19 or D-dimer levels (data not shown).
A greater reduction in mean CRP levels during the
placebo-controlled phase was seen in patients receiving
ustekinumab than in individuals on placebo. Of the
patients with an abnormal CRP at baseline (about 30% of
patients overall), a higher proportion of ustekinumabtreated patients normalised their CRP at week 12 than
did those on placebo (28 [36·4%] of 77 patients in the
45 mg group, 31 [40·8%] of 76 in the 90 mg group, and
17 [22·1%] of 77 in the placebo group). Antibodies to
ustekinumab had developed in 38 (5·1%) of the
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Ustekinumab 45 mg
Placebo
Every 12 weeks
Week 76
Week 40
Week 52
Week 76
Ustekinumab 90 mg
Placebo
Every 12 weeks
Figure 4: Median percentage improvement from baseline in disease scores from weeks 40 to 76
Median improvement in PASI in patients treated with ustekinumab 45 mg (A) or ustekinumab 90 mg (B) from
week 40 through week 76; all patients randomised at week 40. For patients withdrawn from therapy (placebo),
data at the visit of ustekinumab re-initiation were carried forward to subsequent visits. Median change from
baseline in dermatology life quality index score in patients treated with ustekinumab 45 mg (C) or ustekinumab
90 mg (D) from week 40 through week 76; all patients randomised at week 40. Arrows indicate visits at which
active treatment was administered to patients randomised at week 40 to receive ustekinumab every 12 weeks.
Error bars are IQR.
746 patients for whom data were available by week 76;
these were predominantly low titre (<1/320) and not
associated with injection site reactions. Rates of injection
site reaction were low (ie, 32 in 4559 injections of
ustekinumab and 37 of 16 063 placebo injections). All
injection site reactions with ustekinumab were mild, and
no anaphylactic reactions or serum-sickness-like
reactions associated with the study agent were noted.
Discussion
Our findings, together with the results of the PHOENIX 2
study,13 suggest that ustekinumab, administered at 45 mg
or 90 mg every 12 weeks, is efficacious for the treatment
of mild-to-moderate psoriasis. Our results also lend
support to the notion that interleukins 12 and 23 have a
role in the immunopathophysiology of psoriasis.11,12
These cytokines participate in immune function through
activation of natural killer cells and CD4+ T-cell
differentiation. Interleukin 12 induces differentiation
towards the T helper 1 (Th1) response and expression of
type 1 cytokines, such as interferon γ and tumour
necrosis factor α, which are important in the
pathophysiology of psoriasis.20,21 Interleukin 23 induces
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Mean duration of follow-up (weeks)
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Placebo-controlled phase (weeks 0–12)
Placebo crossover phase (weeks 12–40)
Ustekinumab Ustekinumab Placebo
45 mg
90 mg
(n=255)
(n=255)
(n=255)
Ustekinumab
45 mg
(n=255)
12·2
Patients with one or more adverse events 147 (57·6%)
12·1
12·1
27·2
Ustekinumab Placebo to
90 mg
ustekinumab
(n=251)
45 mg (n=123)
27·5
131 (51·4%)
123 (48·2%)
146 (57·3%)
161 (64·1%)
Common adverse events†
Randomised withdrawal
phase (weeks 40–76)*
Placebo to
ustekinumab
90 mg (n=120)
28·0
28·2
79 (64·2%)
69 (57·5%)
Maintenance
therapy
(n=161)
36·0
Interrupted
therapy
(n=160)
35·6
108 (67·1%)
121 (75·6%)
21 (13·1%)
18 (7·1%)
16 (6·3%)
16 (6·3%)
19 (7·5%)
28 (11·2%)
9 (7·3%)
9 (7·5%)
22 (13·7%)
Nasopharyngitis
26 (10·2%)
21 (8·2%)
22 (8·6%)
25 (9·8%)
22 (8·8%)
18 (14·6%)
13 (10·8%)
16 (9·9%)
17 (10·6%)
Arthralgia
7 (2·7%)
6 (2·4%)
7 (2·7%)
11 (4·3%)
8 (3·2%)
5 (4·1%)
4 (3·3%)
3 (1·9%)
12 (7·5%)
Headache
10 (3·9%)
8 (3·2%)
6 (4·9%)
1 (0·8%)
6 (3·7%)
4 (2·5%)
7 (2·7%)
5 (2·0%)
2 (1·6%)
1 (0·8%)
3 (1·9%)
3 (1·9%)
8 (3·1%)
4 (1·6%)
2 (1·6%)
2 (1·7%)
1 (0·6%)
7 (4·4%)
76 (47·5%)
14 (5·5%)
13 (5·1%)
6 (2·4%)
Adverse events leading to withdrawal of
study agent
1 (0·4%)
4 (1·6%)
6 (2·4%)
Serious adverse events‡
2 (0·8%)
4 (1·6%)
2 (0·8%)
Adverse events of special interest
80 (31·4%)
66 (25·9%)
68 (26·7%)
79 (31·0%)
106 (42·2%)
46 (37·4%)
44 (36·7%)
71 (44·1%)
Serious infections
0 (0·0%)
2 (0·8%)
1 (0·4%)
1 (0·4%)
1 (0·4%)
0 (0·0%)
0 (0·0%)
0 (0·0%)
2 (1·3%)
Cutaneous cancers§
0 (0·0%)
0 (0·0%)
0 (0·0%)
1 (0·4%)
0 (0·0%)
1 (0·8%)
0 (0·0%)
2 (1·2%)
0 (0·0%)
Non-cutaneous cancers¶
0 (0·0%)
0 (0·0%)
0 (0·0%)
2 (0·8%)
0 (0·0%)
0 (0·0%)
0 (0·0%)
0 (0·0%)
1 (0·6%)
Cardiovascular events||
1 (0·4%)
0 (0·0%)
0 (0·0%)
1 (0·4%)
0 (0·0%)
1 (0·8%)
1 (0·8%)
0 (0·0%)
0 (0·0%)
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Infections
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Upper respiratory tract infection
*Includes only patients who were randomised at week 40 and subsequently treated. †Occurred in at least 5% of patients in any treatment group. ‡An adverse event that resulted in any of the following
outcomes: death, a life-threatening condition, in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, or a congenital anomaly or birth defect,
irrespective of its relationship to study agent. §Basal-cell carcinomas only. ¶Include prostate, colon, and thyroid cancer. ||Any serious adverse events of sudden cardiac death, myocardial infarction, or stroke.
Table 3: Adverse events during the three phases of the trial
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differentiation towards a T helper 17 (Th17) phenotype,22
expression of interleukin 17, and increased keratinocyte
expression of inducible nitric oxide synthase, which has
also been implicated in the pathophysiology of
psoriasis.23,24 Cytokines produced by Th17 cells, including
interleukin 20 and interleukin 22, have been implicated
in the keratinocyte hyperproliferative response in
psoriasis.25,26 Although the mechanisms by which
interleukin 12 and 23 contribute to the pathophysiology
of psoriasis are incompletely understood, the shared p40
protein might have a key role in the inflammatory
cascade.27
Treatment with two 45 or 90 mg injections of
ustekinumab at week 0 and week 4, followed by dosing
every 12 weeks, led to PASI 75 response in more than
three quarters of patients with moderate-to-severe
psoriasis in both PHOENIX 1 and PHOENIX 2.13 More
than 90% of patients experienced clinically meaningful
improvements,28 and the PHOENIX 2 study further
characterised determinants of treatment resistance as
well as potential therapeutic approaches for the treatment
resistant subpopulation.13 Clinical improvements were
paralleled by improvements in patient-reported
outcomes, measured by dermatology life quality index.
Onset of response was seen within 2 weeks of the first
dose of ustekinumab, and psoriasis response was
generally maintained for at least a year and a half in
patients who received the drug every 12 weeks. In
patients withdrawn from ustekinumab, psoriasis
gradually recurred—showing that temporary blockade of
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interleukins 12 and 23 did not reverse the underlying
causal mechanisms of psoriasis—and quality of life
improvements were lost. Combined, these observations
suggest that maintaining response and quality-of-life
improvements could require continuous maintenance
dosing. Among patients withdrawn from ustekinumab,
response was generally restored within 12 weeks of
reinitiating treatment.
Rates and types of adverse events, serious adverse
events, adverse events leading to treatment
discontinuation, and laboratory abnormalities were
generally comparable between patients receiving
placebo, ustekinumab 45 mg, and ustekinumab 90 mg
during both the placebo-controlled and randomised
withdrawal phases. No dose-response in safety events
was apparent throughout the study. The observation of
higher rates of hyperglycaemia in ustekinumab-treated
patients in a previous trial11 was not apparent in this
larger study. Rates of serious infections and
malignancies were low in all treatment groups during
the placebo-controlled phase and comparative rates did
not suggest an association with ustekinumab. Similarly,
serious cardiovascular events, which were observed in a
previous trial11 and which are reported to be a population
risk in patients with psoriasis,29,30 were uncommon
during the placebo-controlled phase of the study. No
increase in the frequency of adverse events or serious
adverse events, including serious infections,
malignancies, or cardiovascular events, was apparent
over time with maintenance dosing. No mycobacterial
FO
E Tschen (Academic Dermatology Associates, Albuquerque, NM, USA),
P Yamauchi (Clinical Research Specialists Inc, Santa Monica, CA, USA),
R Bissonnette (Innovaderm Research Inc, Quebec, Canada), M Bourcier
(Dermatology Clinic, New Brunswick, Canada), W Carey (Siena Medical
Research, Quebec, Canada), D Gratton (International Dermatology
Research Inc, Quebec, Canada), L Guenther (Guenther Dermatology
Research Centre, Ontario, Canada), Z Tomi (New Lab Clinical Research
Inc, NL, Canada), R Langley (Eastern Canada Cutaneous Research
Associates, Nova Scotia, Canada), B Lasko (Manna Research, Ontario,
Canada), K Papp (K Papp Clinical Research, Ontario, Canada), Y Poulin
(Centre Dermatologique du Quebec Metropolitain, Quebec, Canada),
C Maari (Innovaderm Research Laval Inc, Quebec, Canada), L Rosoph
(North Bay Dermatology Centre, Ontario, Canada), J Tan (Windsor
Clinical Research, Ontario, Canada), J-S Gauthier (replaced M Tolszczuk,
Q&T Research Inc, Quebec, Canada), D Toth (XLR8 Research, Ontario,
Canada), N Wasel (Stratica Medical, Alberta, Canada), M Heenen
(Erasmus University Hospital, Brussels, Belgium), J Lambert
(Universitair Ziekenhuis Antwerpen, Edegem, Belgium), P Ghislain
(Catholic University of Louvain, Brussels, Belgium).
Conflict of interest statement
CLL has served as a consultant for Abbott, Amgen, Centocor, and
Genentech, as an investigator for Abbott, Allergan, Altana, Alza, Amgen,
Astellas, Celgene, Centocor, Genentech, Bristol Myers, Eli Lilly, Fujisawa,
Galderma, CombinatoRx, 3M Pharmaceuticals, Perrigo Isreal
Pharamceutical, ScheringPlough, Serono, RTL, Novartis, Vitae, and
Wyeth, and as a speaker for Abbott, Amgen, Centocor, Genentech, and
Warner Chilcott. ABK has served as an investigator and consultant for
Abbott, Amgen, and Centocor and has been a study steering committee
member, speaker, and fellowship funding recipient from Centocor. KAP
has served as a consultant and advisory board member for Abbott, Alza,
Amgen, Celgene, Centocor, Johnson and Johnson, Isotechnika, Janssen
Ortho Biotech, Medimmune, MerckSerono, and Wyeth. KBG has served
as a consultant for Abbott, Amgen, Astellas, Centocor, and Genentech
and has received grant support from Abbott, Astellas, and Centocor. NY,
CG, YW, SL, and LTD are employees of Centocor and own stock in
Johnson and Johnson.
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or salmonella infections, which have been reported in
individuals congenitally deficient in interleukin 12 p40
or interleukin 12 receptor β1,31,32 and no cases of
lymphoma or demyelinating disease were reported
throughout the study. Our results do not reveal any
major safety concerns in blocking interleukin 12 and 23
for periods as long as a year and a half. However, the
size and duration of the trial do not rule out a potential
effect of ustekinumab on uncommon events or events
that occur after longer duration of exposure or in larger
patient populations, although additional follow-up will
result from long-term extension of this study for a total
of 5 years of treatment. Together with the safety profile
observed in the PHOENIX 2 trial,13 these results indicate
that ustekinumab is well tolerated during treatment
lasting at least a year.
Our results suggest that ustekinumab could be an
important therapeutic agent for treating patients with
psoriasis. Recognising the limitations of comparisons
across studies, the high level of efficacy noted in this
study compares favourably with that reported for
currently available intramuscularly or subcutaneously
administered biological therapeutic agents for
psoriasis.33 The high level of efficacy was generally
maintained with dosing every 12 weeks, a schedule that
could offer a novel level of convenience for patients and
physicians. These attributes might be particularly
important for treatment compliance, which is low in
patients with psoriasis and could, at least in part, result
from dissatisfaction with effectiveness or convenience
of available treatments.34,35
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Contributors
The steering committee consisted of CLL, ABK, KAP, and KBG. NY, YW,
and KBG wrote the original draft of the manuscript. All authors
participated in the design and conduct of the study, the analysis or
interpretation of the data, and the writing and review of the manuscript.
All authors agreed to submit the manuscript for publication and
approved the final version.
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PHOENIX 1 study investigators
D Nieves (Psoriasis Treatment Center of New Jersey, East Windsor, NJ,
USA), D Baker (Allergy, Asthma and Dermatology Research, Lake
Oswego, OR, USA), F Behringer Jr (Renstar Medical Research, Ocala,
FL, USA), C Birbara (Clinical Pharmacology Study Group, Worcester,
MA, USA), D Fiorentino (Stanford University School of Medicine,
Stanford, CA, USA), S Fretzin (Dawes Fretzin Clinical Research Group,
Indianapolis, IN, USA), B Goffe (Dermatology Associates, Seattle, WA,
USA), T Hamilton (Atlanta Dermatology, Vein and Research Center,
Alpharetta, GA, USA), D Johnson (Honolulu, HI, USA), S Kempers
(Minnesota Clinical Study Center, Fridley, MN, USA), W Ko (Radiant
Research, Phoenix, AZ, USA), C Leonardi (Central Dermatology, St
Louis, MO, USA), J Zeichner (Mt Sinai School of Medicine, New York,
NY, USA), M Ling (MedaPhase Inc, Newman, GA, USA), K Loven
(Rivergate Dermatology, Goodlettsville, TN, USA), J Maloney (Cherry
Creek Research Inc, Denver, CO, USA), R Matheson (Oregon Medical
Research Center, Portland, OR, USA), A Menter (Baylor Research
Institute, Dallas TX, USA), S Mings (Covance CRU Inc, Boise, ID, USA),
E Monroe (Advanced Healthcare, Milwaukee, WI, USA), A Nayak
(Sneeze, Wheeze and Itch Associates, Normal, IL, USA), J Powers
(Radiant Research, Scottsdale, AZ, USA), P Rich (Oregon Dermatology
and Research Center, Portland, OR, USA), M Saruk (Atlantic Skin and
Cosmetic Surgery Group, Malvern PA, USA), J Schlessinger (Skin
Specialists, Omaha, NE, USA), S Smith (Dermatology and Advanced
Aesthetics, Lake Charles, LA, USA), H Sofen (Los Angeles, CA, USA),
Acknowledgments
This study was supported by Centocor Inc. The authors thank Y You for
her programming and analysis support, J Benson for her critical review
of the manuscript, and C Arnold for her writing support; all are
employees of Centocor.
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