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original article
The
new england journal
of
medicine
n engl j med 371;4 nejm.org july 24, 2014
326
Secukinumab in Plaque Psoriasis —
Results of Two Phase 3 Trials
Richard G. Langley, M.D., Boni E. Elewski, M.D., Mark Lebwohl, M.D.,
Kristian Reich, M.D., Ph.D., Christopher E.M. Griffiths, M.D., Kim Papp, M.D., Ph.D.,
Lluís Puig, M.D., Ph.D., Hidemi Nakagawa, M.D., Ph.D., Lynda Spelman, M.B., B.S.,
Bárður Sigurgeirsson, M.D., Ph.D., Enrique Rivas, M.D., Tsen-Fang Tsai, M.D.,
Norman Wasel, M.D., Stephen Tyring, M.D., Ph.D., Thomas Salko, B.A.,
Isabelle Hampele, Ph.D., Marianne Notter, M.S., Alexander Karpov, Ph.D.,
Silvia Helou, M.D., Ph.D., and Charis Papavassilis, M.D., Ph.D.,
for the ERASURE and FIXTURE Study Groups*
From Dalhousie University, Halifax, NS
(R.G.L.), Clinical R esearch (K.P.) and Probity
Medical Re search (K.P., L.S.), Waterloo, ON,
and Stratica Medical and Probity Medical
Research, Edmonton, AB (N.W.) — all in
Canada; University of Alabama, Birming-
ham (B.E.E.); Mount Sinai Hospital, New
York (M.L.); Dermatologikum Hamburg
and Georg-August-Universität, Göttingen,
Germany (K .R.); Dermatol ogy Centre, Sal-
ford Royal Hospital, University of Man-
chester, Manchester Academic Health Sci-
ence Centre , Manchester, United Kingd om
(C.E.M.G.); Hospital de Sant Pau, Barce-
lona (L.P.); Jikei University School of Me d-
icine, Tokyo (H.N.); Veracity Clinical Re-
search, Woolloongabba, QLD, Australia
(L.S.); Faculty of Medicine, Department
of Dermatology, University of Iceland,
Reyk javik (B.S.); Dermos, Guatemala City,
Guatemala (E. R.); Depar tment of Derma-
tology, National Taiwan University Hospi-
tal and Nation al Tai wan University Colle ge
of Medicine, Taipei (T.-F.T.); University of
Texas Health Science Center and Center
for Clinical Studies, Houston (S.T.); and
Novartis Ph arma, Basel, Switzer land (T.S.,
I.H., M.N., A.K., S.H., C.P.). Address re-
print requests to Dr. Langley at 4195 Dick-
son Bldg., 5820 Uni versity Ave., Dalhousi e
University, Halifax, NS B3H 1V7, Canada,
or at richardgblangley@gmail.com.
Drs. Langley and Elewski contributed
equally to this ar ticle.
* A complete list of the investigators in
the Efficacy of Response and Safety of
Two Fixed Secukinumab Regimens in
Psoriasis (ERASURE) and the Full Year
Investigative Examination of Secukin-
umab versus Etanercept Using Two
Dosing Regimens to Determine Effica-
cy in Psoriasis (FIXTURE ) Study Groups
is provided in the Supplementary Ap-
pendix, available at NEJM.org.
This article was publish ed on July 9, 2014,
at NEJM.org.
N Engl J Med 2014;371:326-38.
DOI: 10.1056/NEJMoa1314258
Copyright © 2014 Massachusetts Medical Society.
ABSTRACT
BACKGROUND
Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We
evaluated secukinumab, a fully human anti–interleukin-17A monoclonal antibody,
in patients with moderate-to-severe plaque psoriasis.
METHODS
In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and
Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year
Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens
to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE
study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab
at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every
4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg
(administered twice weekly for 12 weeks, then once weekly). The objective of each
study was to show the superiority of secukinumab over placebo at week 12 with respect
to the proportion of patients who had a reduction of 75% or more from baseline in the
psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost
clear) on a 5-point modified investigator’s global assessment (coprimary end points).
RESULT S
The proportion of patients who met the criterion for PASI 75 at week 12 was higher
with each secukinumab dose than with placebo or etanercept: in the ERASURE study,
the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinu-
mab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg
of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and
4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The propor-
tion of patients with a response of 0 or 1 on the modified investigator’s global assess-
ment at week 12 was higher with each secukinumab dose than with placebo or etan-
ercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab,
51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study,
the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinu-
mab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab
dose vs. comparators). The rates of infection were higher with secukinumab than with
placebo in both studies and were similar to those with etanercept.
CONCLUSIONS
Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-
17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and
FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.)
The New England Journal of Medicine
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Secukinumab in Plaque Psoriasis
n engl j med 371;4 nejm.org july 24, 2014
327
P
soriasis is a chronic, immune-
mediated inflammatory skin disease that
is associated with substantial impairment
of physical and psychological quality of life.
1,2
Our understanding of the pathogenesis of pso-
riasis was advanced by the discovery of the class
of type 17 helper T (Th17) cells, which regulates
innate and adaptive immunity. The proinflam-
matory cytokine interleukin-17A is the primary
effector of Th17 cells, but it is also produced by
other cell types in psoriatic lesions, including
γδ T cells, neutrophils, and possibly mast cells.
3-7
Interleukin-17A stimulates keratinocytes to se-
crete chemokines and other proinf lammatory
mediators that recruit additional inflammatory
cells, including neutrophils, Th17 cells, den-
dritic cells, and innate lymphoid cells.
8-10
Inter-
leukin-17A thus potentially acts as a master
cytokine in the pathogenesis of psoriasis. In ad-
dition, a substantial body of genetic research
and early data from clinical trials of therapeutic
inhibitors of interleukin-17A has shown that
this cytokine plays a crucial role in the patho-
genesis of several other immune-mediated dis-
eases, including rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, and multiple
sclerosis.
10,11
Secukinumab (Novartis Pharmaceuticals) is
a recombinant, high-affinity, fully human im-
munoglobulin G1κ monoclonal antibody that
selectively binds and neutralizes interleukin-17A.
To confirm the findings of basic research and
early clinical studies regarding the crucial role
of interleukin-17A in psoriasis, we conducted
two randomized, phase 3 trials to assess the
efficacy and safety of secukinumab, at a dose
of 300 mg or 150 mg, administered as induction
therapy (with assessment at week 12) and main-
tenance therapy (with assessment at week 52)
in patients with moderate-to-severe plaque pso-
riasis. The ERASURE (Efficacy of Response and
Safety of Two Fixed Secukinumab Regimens in
Psoriasis) study compared secukinumab with
placebo, and the FIXTURE (Full Year Investigative
Examination of Secukinumab vs. Etanercept Us-
ing Two Dosing Regimens to Determine Efficacy
in Psoriasis) study compared secukinumab with
placebo and etanercept, the first tumor necrosis
factor (TNF) inhibitor approved by the Food
and Drug Administration for moderate-to-severe
plaque psoriasis.
12
METHODS
STUDY POPULATION
The eligibility criteria were similar in the two
studies. Patients were 18 years of age or older
with moderate-to-severe plaque psoriasis that
had been diagnosed at least 6 months before ran-
domization and that was poorly controlled with
topical treatments, phototherapy, systemic thera-
py, or a combination of these therapies. In addi-
tion, patients had a score of 12 or higher on the
psoriasis area-and-severity index (PASI; on a scale
from 0 to 72, with higher scores indicating more
severe disease),
13
a score of 3 or 4 on the modi-
fied investigator’s global assessment (on a scale
from 0 to 4, with higher scores indicating more
severe disease),
14
and involvement of 10% or
more of the body-surface area. Patients with
forms of psoriasis other than chronic plaque-
type psoriasis or with drug-induced psoriasis
were excluded.
The use of medications that might confound
efficacy was not allowed (see the Supplementary
Appendix, available with the full text of this
article at NEJM.org). In the FIXTURE study, pa-
tients who had used etanercept at any time be-
fore screening were excluded.
STUDY OVERSIGHT
Both studies were sponsored by Novartis Phar-
maceuticals and designed by the scientific steer-
ing committee and Novartis Pharmaceuticals
personnel. The site investigators collected the
data, Novartis Pharmaceuticals conducted the
data analyses, and all the authors had access to
the data. All the authors vouch for the complete-
ness and accuracy of the data and analyses for
their respective studies and vouch for the fidelity
of this report to the study protocols. Agreements
between Novartis Pharmaceuticals and the in-
vestigators included provisions relating to confi-
dentiality of the study data. The initial draft of
the manuscript was written by a medical writer
paid by Novartis Pharmaceuticals, with subse-
quent revisions by all the authors. All the au-
thors made the decision to submit the manu-
script for publication.
The study protocols, available at NEJM.org,
were approved by the institutional review board
or ethics committee at each participating site,
and the studies were conducted in accordance
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new england journal
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n engl j med 371;4 nejm.org july 24, 2014
328
with the ethical principles of the Declaration of
Helsinki. U.S. sites maintained compliance with
Health Insurance Portability and Accountability
Act regulations. Eligible patients provided written
informed consent.
STUDY DESIGN
Both studies were multicenter, randomized, double-
blind, placebo-controlled, parallel-group, phase 3
trials; the FIXTURE study was also active-controlled.
The ERASURE study was conducted from June
2011 through April 2013 at 88 sites worldwide;
the FIXTURE study was conducted from June
2011 through June 2013 at 231 sites. The partici-
pating study sites are listed in the Supplemen-
tary Appendix.
Each study consisted of a screening period
of 1 to 4 weeks, a 12-week induction period, a
40-week maintenance period, and an 8-week
follow-up period (Fig. S1 and S4 in the Sup ple-
mentary Appendix). Patients in the ERASURE
study were randomly assigned in a 1:1:1 ratio to
receive secukinumab at a dose of 300 mg, secu-
kinumab at a dose of 150 mg, or placebo; those
in the FIXTURE study were randomly assigned
in a 1:1:1:1 ratio to receive secukinumab at a
dose of 300 mg or 150 mg, etanercept, or pla-
cebo (see the Supplementary Appendix).
Patients randomly assigned to secukinumab
in either study received either two 150-mg sub-
cutaneous secukinumab injections (i.e., 300 mg
total) or one 150-mg injection plus one placebo
injection, with both injections administered once
weekly at baseline and at weeks 1, 2, 3, and 4
and then every 4 weeks until week 48. Patients
randomly assigned to etanercept received 50 mg
administered subcutaneously twice weekly from
baseline until week 12 and then once weekly
through week 51, in accordance with the stan-
dard dosing regimen.
15
In the FIXTURE study,
the placebo group received placebo injections
corresponding to the secukinumab and the etan-
ercept regimens, and the secukinumab and
etanercept groups received placebo injections
corresponding to the other active-drug regimen,
in order to maintain a double-dummy design. In
the ERASURE study, patients randomly assigned
to placebo received placebo injections corres-
ponding to the secukinumab regimens.
In each study, patients in the placebo group
who did not meet the criteria for a reduction of
75% or more in the baseline PASI score (PASI 75)
at week 12 underwent randomization again in a
1:1 ratio to receive secukinumab at a dose of
either 300 mg or 150 mg (see the Supplementary
Appendix); those who met the criteria for PASI 75
at week 12 continued to receive placebo. The ef-
ficacy data for the patients who underwent ran-
domization twice (i.e., first to placebo and sub-
sequently to one of two doses of secukinumab)
are not reported here.
ASSESSMENTS
Efficacy assessments were conducted throughout
each study, with key assessments at the end of
the induction period before the week-12 dose
was administered and at the end of the mainte-
nance period at week 52 (i.e., 1 week after the
last dose of etanercept or its matching placebo
and 4 weeks after the last dose of secukinumab
or its matching placebo). Disease activity was as-
sessed with the use of PASI (a composite evaluation
instrument for psoriasis severity, with subscores
for erythema, induration, scaling, and percentage
of body-surface area affected)
13
and the modified
investigator’s global assessment (a static, 5-point
instrument for rating the clinician’s impression
of the overall severity of the psoriasis, on a scale
from 0 [clear skin] to 4 [severe disease]) (Table S1
in the Supplementary Appendix).
14
A response on
the modified investigator’s global assessment was
defined as a score of 0 (clear) or 1 (almost clear)
and a reduction from baseline of at least 2 points.
Patients performed a self-assessment of symptoms
using the validated Psoriasis Symptom Diary
16
and
reported on quality of life with the Dermatology
Life Quality Index (DLQI), a validated instrument
for dermatologic conditions (scores range from 0 to
30 points, with higher scores indicating a greater
effect on quality of life).
17
We evaluated safety by monitoring adverse
events, including the severity of the event and
the relationship of the event to study drug, and
by obtaining clinical laboratory measurements,
assessing vital signs, and performing physical
examinations at each study visit. An independent
cardiovascular and cerebrovascular safety adju-
dication committee was established to review and
adjudicate major adverse cardiovascular events,
which were reported in a blinded manner.
Blood samples were obtained at baseline and at
weeks 12, 24, 52, and 60 for an assessment of
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Secukinumab in Plaque Psoriasis
n engl j med 371;4 nejm.org july 24, 2014
329
the immunogenicity of secukinumab with the
use of a homogeneous Meso Scale Discovery
bridging assay (see the Supplementary Appen-
dix) and a three-tiered approach (screening, con-
firmation, and quasiquantification by means of
titration).
18
OBJECTIVES AND END POINTS
The objective in each study was to assess the su-
periority of secukinumab over placebo with re-
spect to the coprimary efficacy end points of
PASI 75 and a response of 0 or 1 on the modified
investigator’s global assessment at week 12. Key
secondary efficacy objectives in the ERASURE
study were to determine the superiority of secu-
kinumab over placebo with respect to the pro-
portion of patients who met the criteria for a re-
duction of 90% or more in the PASI score from
baseline at week 12 (PASI 90); the superiority of
secukinumab over placebo with respect to patient-
reported psoriasis-related itching, pain, and scal-
ing on the Psoriasis Symptom Diary at week 12;
maintenance of PASI 75 from week 12 through
week 52; and maintenance of a response of 0 or
1 on the modified investigator’s global assess-
ment from week 12 through week 52. Other end
points included PASI 50, PASI 100 (reductions of
50% and 100%, respectively, in the baseline PASI
score), PASI 75, PASI 90, and a response of 0 or 1
on the modified investigator’s global assessment
at each study visit until week 52 and a score of 0
or 1 on the DLQI at weeks 12 and 52. Each end
point was assessed by means of a between-group
comparison of the proportion of patients who
met the criterion for that end point.
The key secondary objectives in the FIXTURE
study included assessments of the superiority of
secukinumab over placebo with respect to the
proportion of patients who met the criteria for
PASI 90 at week 12; the superiority of secu-
kinumab over etanercept with respect to the
proportion of patients who met the criteria for
PASI 75 at week 12; the noninferiority of secu-
kinumab to etanercept with respect to the pro-
portion of patients who met the criteria for PASI
75 at week 12; the superiority of secukinu mab
over etanercept with respect to the proportion of
patients who met the criteria for a response of 0
or 1 on the modified investigator’s global assess-
ment at week 12; the superiority of secukinu mab
over etanercept with respect to the proportion of
patients who met the criteria for PASI 75 or a
response of 0 or 1 on the modified investigator’s
global assessment at week 12 and who contin-
ued to have that response at week 52; and the
superiority of secukinumab over placebo with
respect to patient-reported, psoriasis-related itch-
ing, pain, and scaling scores on the Psoriasis
Symptom Diary at week 12. Other end points
included PASI 50, PASI 75, PASI 90, PASI 100,
and the response of 0 or 1 on the modified in-
vestigator’s global assessment until week 52 and
a DLQI score of 0 or 1 at weeks 12 and 52.
STATISTICAL ANALYSIS
In each study, the analyses of the efficacy end
points included all the patients who underwent
randomization according to the treatment as-
signed at randomization. Closed testing proce-
dures
19
(see the Supplementary Appendix) were
used to evaluate the study hypotheses. Under these
procedures, hypotheses regarding the 300-mg and
150-mg doses of secukinumab were evaluated in-
dependently, each at the 0.025 significance level,
to control the family-wise error rates (Fig. S2 and
S5 in the Supplementary Appendix). For the co-
primary efficacy end points, between-group com-
parisons were made with the use of the stratified
Cochran–Mantel–Haenszel test, with geographic
region and body weight as strata. Missing values
for the PASI score and the score on the modified
investigator’s global assessment were conserva-
tively imputed as nonresponses, regardless of the
reason for the missing data.
Per the study protocols, the PASI score was
calculated with the use of the percentage of the
affected body-surface area rounded to integers;
these results are reported here. For both studies,
a sensitivity analysis was performed for the
coprimary end point of PASI 75 with the use of
nonrounded numbers for the body-surface area.
We calculated sample sizes such that the stud-
ies would have more than 99% power to show
response rates of 55.0% for PASI 75 and 30.0% for
the modified investigator’s global assessment
score of 0 or 1 in each secukinumab-dose group,
assuming response rates of 5.0% for both PASI 75
and the modified investigator’s global assessment
score of 0 or 1 in the placebo group, on the basis
of a two-group Fisher’s exact test of equal propor-
tions (see the Supplementary Ap pendix). Safety
end points were evaluated for all the patients who
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330
received at least one dose of study drug; these end
points were summarized descriptively.
RESULTS
CHARACTERISTICS OF THE PATIENTS
The demographic and baseline clinical character-
istics of the patients in each study were well bal-
anced across the study groups (
Table 1
). In the
ERASURE study, 738 patients underwent random-
ization at baseline. A total of 700 patients (94.9%)
completed the 12-week induction period, and 623
(84.4%) completed the entire 52-week treatment
period (Fig. S3 in the Supplementary Appendix).
A total of 737 patients were included in the eff icacy
analyses; 1 patient signed the informed-consent
Table 1. Demographic and Baseline Clinical Characteristics of the Patients.*
Characteristic ERASURE FIXTURE
Secukinumab,
300 mg
(N = 245)
Secukinumab,
150 mg
(N = 245) Placebo
(N = 248)
Secukinumab,
300 mg
(N = 327)
Secukinumab,
150 mg
(N = 327) Etanercept
(N = 326) Placebo
(N = 326)
Age — yr 44.9±13.5 44.9±13.3 45.4±12.6 44.5±13.2 45.4±12.9 43.8±13.0 44.1±12.6
Male sex — no. (%) 169 (69.0) 168 (68.6) 172 (69.4) 224 (68.5) 236 (72.2) 232 (71.2) 237 (72.7)
Race — no. (%)†
White 171 (69.8) 171 (69.8) 176 (71.0) 224 (68.5) 219 (67.0) 219 (67.2) 218 (66.9)
Asian 52 (21.2) 54 (22.0) 46 (18.5) 73 (22.3) 72 (22.0) 74 (22.7) 72 (22.1)
Other or unknown 22 (9.0) 20 (8.2) 26 (10.5) 30 (9.2) 36 (11.0) 33 (10.1) 36 (11.0)
Weight — kg 88.8±24.0 87.1±22.3 89.7±25.0 83.0±21.6 83.6±20.8 84.6±20.5 82.0±20.4
Body-mass index‡ 30.3±7.2 29.8±6.8 30.3±7.8 28.4±6.4 28.4±5.9 28.7±5.9 27.9±6.1
Time since psoriasis diagnosis — yr 17.4±11.1 17.5±12.0 17.3±12.4 15.8±12.3 17.3±12.2 16.4±12.0 16.6±11.6
PASI score§ 22.5±9.2 22.3±9.8 21.4±9.1 23.9±9.9 23.7±10.5 23.2±9.8 24.1±10.5
Body-surface area involved — % 32.8±19.3 33.3±19.2 29.7±15.9 34.3±19.2 34.5±19.4 33.6±18.0 35.2±19.1
Modified investigator’s global assess-
ment score — no. (%)¶
3154 (62.9) 161 (65.7) 151 (60.9) 203 (62.1) 206 (63.0) 195 (59.8) 202 (62.0)
491 (37.1) 84 (34.3) 97 (39.1) 124 (37.9) 121 (37.0) 131 (40.2) 124 (38.0)
Psoriatic arthritis — no. (%) 57 (23.3) 46 (18.8) 68 (27.4) 50 (15.3) 49 (15.0) 44 (13.5) 49 (15.0)
Previous systemic treatment — no. (%)
Any 163 (66.5) 156 (63.7) 146 (58.9) 206 (63.0) 212 (64.8) 214 (65.6) 204 (62.6)
Conventional agent‖ 128 (52.2) 125 (51.0) 108 (43.5) 195 (59.6) 198 (60.6) 204 (62.6) 199 (61.0)
Biologic agent 70 (28.6) 73 (29.8) 73 (29.4) 38 (11.6) 45 (13.8) 45 (13.8) 35 (10.7)
TNF inhibitor 48 (19.6) 44 (18.0) 51 (20.6) 12 (3.7) 15 (4.6) 21 (6.4) 12 (3.7)
Anti−interleukin-12 and anti–
interleukin-23 agent 32 (13.1) 37 (15.1) 31 (12.5) 23 (7.0) 23 (7.0) 22 (6.7) 21 (6.4)
No response to previous use of TNF
inhibitor — no. (%) 17 (6.9) 18 (7.3) 21 (8.5) 10 (3.1) 9 (2.8) 10 (3.1) 3 (0.9)
* Plus–minus values are means ±SD. In each study, there were no significant between-group differences in the baseline characteristics listed.
ERASURE denotes Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis, FIXTURE Full Year Investigative
Examination of Secukinumab versus Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis, and TNF tumor necrosis
factor.
† Race was self-reported.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Scores on the psoriasis area-and-severity index (PASI) range from 0 to 72, with higher scores indicating more severe disease.
13
¶ Scores on the modified investigator’s global assessment range from 0 (clear skin) to 4 (severe disease); a score of 3 indicates moderate
disease.
14
‖ Conventional systemic agents included methotrexate, cyclosporine, glucocorticoids, and fumaric acid esters.
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Secukinumab in Plaque Psoriasis
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331
form after starting study procedures and as a re-
sult of the protocol deviation was excluded from
efficacy and safety analyses. In the FIXTURE study,
1306 patients who had not received etanercept
previously underwent randomization, of whom
1233 (94.4%) completed the induction period and
1100 (84.2%) completed the maintenance period
(Fig. S6 in the Supplementary Appendix). A total
of 1305 patients were included in the efficacy
analyses; 1 patient signed the informed-consent
form after starting the study procedures and was
excluded from the efficacy and safety analyses.
COPRIMARY EFFICACY END POINTS IN BOTH
STUDIES
In both studies, secukinumab was shown to be
superior to the comparators (or noninferior,
when noninferiority was assessed) with respect to
all the coprimary and key secondary end points
that were evaluated in the testing procedures
(Tables S2 and S7 in the Supplementary Appen-
dix). The criteria for the coprimary end points
— PASI 75 response and the response of 0 or 1 on
the modified investigator’s global assessment at
week 12 — were met by significantly greater pro-
portions of patients in each secukinumab-dose
group than in the placebo group in each study
(P<0.001 for all comparisons) (
Tables 2 and 3
).
Across all efficacy end points, the 300-mg dose
of secukinumab was associated with rates of re-
sponse that were numerically superior to the
rates observed with the 150-mg dose.
SECONDARY EFFICACY END POINTS
ERASURE Study
Secukinumab at the 300-mg and 150-mg doses
was shown to be superior to placebo with respect
to the key secondary end point of PASI 90 re-
sponse at week 12 (P<0.001 for both comparisons)
(
Table 2
). The proportion of patients who met the
criteria for PASI 100 at week 12 was also signifi-
cantly greater with each secukinumab dose than
with placebo (P<0.001 for both comparisons).
Each dose of secukinumab was superior to
placebo with respect to patient reports of itch-
ing, pain, and scaling on the Psoriasis Symptom
Diary at week 12, another prespecified key sec-
ondary end point (P<0.001 for all comparisons)
(Table S3 in the Supplementary Appendix). The
proportion of patients with a DLQI score of 0 or 1,
indicating no impairment of health-related quality
of life, was significantly higher at week 12 in each
secukinumab-dose group than in the placebo
group (P<0.001 for both comparisons) (
Table 2
,
and the Supplementary Appendix).
FIXTURE Study
Secukinumab was superior to etanercept and pla-
cebo with respect to all key secondary end points
(
Table 3
, and Table S8 in the Supplementary Ap-
pendix). The proportion of patients with a DLQI
score of 0 or 1 at week 12 was significantly higher
in each secukinumab-dose group than in the etan-
ercept or placebo group (P<0.001 for all compari-
sons) (
Table 3
, and the Supplementary Appendix).
As specified per protocol, the percentage change
from baseline in the PASI score was assessed ac-
cording to study visit and treatment group. The
median time to a 50% reduction from baseline
in the mean PASI score was significantly short-
er with secukinumab at the doses of
300 mg
and 150 mg than with etanercept (3.0 weeks
and
3.9 weeks, respectively, vs. 7.0 weeks; P<0.001
for both comparisons) (Fig. 1).
RESPONSE OVER TIME
Inspection of the curves showing response over
time suggests that the rates of response on the
PASI and the modified investigator’s global assess-
ment increased during the period from week 12 to
week 16 and then stabilized after week 16 (Fig. 2).
In the FIXTURE study, the rates of response ac-
cording to PASI 75, PASI 90, PASI 100, and a score
of 0 or 1 on the modified investigator’s global
assessment were higher with secukinumab than
with etanercept through week 52 (Fig. 2B).
SAFETY
During the induction period in the ERASURE
study, the proportion of patients who had at least
one adverse event was higher in the secukinumab
groups (55.1% in the 300-mg group and 60.4% in
the 150-mg group) than in the placebo group
(47.0%) (Table S4 in the Supplementary Appen-
dix). There were also higher proportions of pa-
tients with infections and infestations in the
secukinumab groups (29.4% in the 300-mg group
and 26.9% in the 150-mg group) than in the pla-
cebo group (16.2%) during the induction period.
The most common adverse events in the induc-
tion period and the entire treatment period in
this study were nasopharyngitis, headache, and
upper respiratory tract infection (Table S4 in the
Supplementary Appendix). The incidence of ad-
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Table 3. Efficacy End Points in FIXTURE.*
End Point Secukinumab,
300 mg Secukinumab,
150 mg Etanercept Placebo
Coprimary efficacy end points at wk 12 — no./total no. (%)
PASI 75 249/323 (77.1)†‡ 219/327 (67.0)†‡ 142/323 (44.0) 16/324 (4.9)
Response of 0 or 1 on modified investigator’s global
assessment 202/323 (62.5)†‡ 167/327 (51.1)†‡ 88/323 (27.2) 9/324 (2.8)
Key secondary efficacy end points — no./total no. (%)
PASI 90 at wk 12 175/323 (54.2)†‡ 137/327 (41.9)†‡ 67/323 (20.7) 5/324 (1.5)
Maintenance of PASI 75 from wk 12 to wk 52 210/249 (84.3)† 180/219 (82.2)§ 103/142 (72.5) NE
Maintenance of 0 or 1 response on modified investi-
gator’s global assessment from wk 12 to wk 52 161/202 (79.7)† 113/167 (67.7)¶ 50/88 (56.8) NE
Other efficacy end points
PASI 100 at wk 12 — no./total no. (%) 78/323 (24.1)†‖ 47/327 (14.4)†‖ 14/323 (4.3) 0/324
DLQI — mean score
Baseline 13.3 13.4 13.4 13.4
Wk 12 2.9 3.7 5.5 11.5
Absolute change –10.4 –9.7 –7.9 –1.9
* In the statistical analyses, missing data were imputed as nonresponses. The criteria for the noninferiority of secukinumab to etanercept with
regard to PASI 75 at week 12, one of the key secondary end points, were met for each secukinumab dose.
† P<0.001 for the comparison with etanercept.
‡ P<0.001 for the comparison with placebo.
§ P = 0.009 for the comparison with etanercept.
¶ P = 0.002 for the comparison with etanercept.
‖ No comparison with placebo was performed because there were no patients with a response in the placebo group.
Table 2. Efficacy End Points in ERASURE.*
End Point Secukinumab,
300 mg Secukinumab,
150 mg Placebo
Coprimary efficacy end points at wk 12 — no./total no. (%)
PASI 75 200/245 (81.6)† 174/243 (71.6)† 11/246 (4.5)
Response of 0 or 1 on modified investigator’s global assessment‡ 160/245 (65.3)† 125/244 (51.2)† 6/246 (2.4)
Key secondary efficacy end points
PASI 90 at wk 12 — no./total no. (%) 145/245 (59.2)† 95/243 (39.1)† 3/246 (1.2)
Maintenance of PASI 75 from wk 12 to wk 52 — no./total no. (%) 161/200 (80.5) 126/174 (72.4) NE
Maintenance of 0 or 1 response on modified investigator’s global
assessment from wk 12 to wk 52 — no./total no. (%)‡ 119/160 (74.4) 74/125 (59.2) NE
Other efficacy end points
PASI 100 at wk 12 — no./total no. (%) 70/245 (28.6)† 31/243 (12.8)† 2/246 (0.8)
DLQI — mean score§
Baseline 13.9 13.4 12.0
Wk 12 2.5 3.3 10.9
Absolute change –11.4 –10.1 –1.1
* In the statistical analyses, missing data were imputed as nonresponses. PASI 75, PASI 90, and PASI 100 responses indicate reductions from
baseline in the PASI score of 75% or more, 90% or more, and 100%, respectively. NE denotes not evaluated.
† P<0.001 for the comparison with placebo.
‡ A response on the modified investigator’s global assessment was defined as a score of 0 (clear) or 1 (almost clear) and an improvement of
2 or more points from baseline.
§ Scores on the Dermatology Life Quality Index (DLQI) range from 0 to 30, with higher scores indicating a greater effect of the disease on
quality of life.
17
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Secukinumab in Plaque Psoriasis
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333
verse events in other system organ classes was
similar among the study groups. Additional data
on adverse events in this study are provided in
the Supplementary Appendix.
The incidences of adverse events during the
induction period and the entire treatment period
in the FIXTURE study were similar in the secu-
kinumab and etanercept groups (
Table 4
). The
most common adverse events in the secukinu-
mab groups during induction and the entire
treatment period were nasopharyngitis, headache,
and diarrhea. The incidence of injection-site
reactions during the entire study was lower in
the combined secukinumab groups than in the
etan ercept group (7 patients [0.7%] vs. 36 pa-
tients [11.1%]), although the difference was not
assessed for significance.
The proportions of patients in the FIXTURE
study who had infections and infestations during
the induction period were 26.7% with the 300-mg
dose of secukinumab, 30.9% with the 150-mg dose
of secukinumab, 24.5% with etanercept, and 19.3%
with placebo (
Table 4
). Can dida infections were
more common with secukinu mab than with
etanercept during the entire treatment period:
22 patients in the 300-mg secukinumab group
(4.7%) and 11 in the 150-mg secukinumab
group (2.3%) reported mild or moderate candida
infection. None of the infections resulted in
chronic mucocutaneous candidiasis or discon-
tinuation of the study drug, and all resolved on
their own or with standard therapy. In the etan-
ercept group, 4 patients (1.2%) had candida infec-
tion, 2 of whom had an infection that was
graded as severe. Grade 3 neutropenia occurred
in 9 patients (1.0%) in the combined secukinumab-
dose groups and in no patients in the etanercept
group; no infections or any other adverse events
were reported in these patients. Grade 4 neutro-
penia occurred in no patient who received secu-
kinumab and in 1 patient (0.3%) in the etaner-
cept group (see the Supplementary Appendix).
Results for candida infection and neutropenia
were similar in the two studies (see the Supple-
mentary Appendix).
There were no deaths during the treatment
period in either study, although there was one
death unrelated to psoriasis (suicide) during the
screening period in the FIXTURE study. In the
ERASURE study, the rates of serious adverse
Percentage Change from Baseline
in PASI Score
0
−20
−40
−60
−80
0 1 2 3 4 8 12
Week
Bootstrap median time to 50% reduction
in mean PASI score, with 95% CI
Etanercept
(N=323)
Secukinumab, 150 mg
(N=327)
Secukinumab, 300 mg
(N=323)
3.0 (2.8–3.2)
3.9 (3.7–4.2) 7.0 (6.3–7.7)
Figure 1. Speed of Response.
The speed of response among patients in the Full Year Investigative Examination of Secukinumab versus Etanercept
Using Two Dosing Regimens to Determine Efficacy in Psoriasis (FIXTURE) study was evaluated according to the
median time to a 50% reduction from baseline in the mean score on the psoriasis area-and-severity index (PASI;
scores range from 0 to 72, with higher scores indicating more severe disease). A repeated-measures, mixed-effects
model was used to analyze the mean percentage change from baseline in the PASI score. Symbols without black
outlining indicate the least-squares means, and I bars the 95% confidence intervals (CIs). The median time to a
50% reduction in the mean PASI score (dashed line) was estimated from parametric bootstrap samples with the
use of linear interpolation between time points. A 50% reduction in the mean PASI score was not observed in the
placebo group, so an analysis of the median time to 50% reduction was not conducted.
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Patients with Response (%)
100
80
60
40
20
0
0 84 1612 20 24 28 36 44 5232 40 48
0 84 1612 20 24 28 36 44 5232 40 48
0 84 1612 20 24 28 36 44 5232 40 48
0 84 1612 20 24 28 36 44 5232 40 48
100
80
60
40
20
0
Week
Modified IGA Response of 0 or 1
PASI 90 Response
PASI 75 Response
AERASURE
PASI 100 Response
Patients with Response (%)
100
80
60
40
20
0
100
80
60
40
20
0
Patients with Response (%)
100
80
60
40
20
0
100
80
60
40
20
0
Week
Modified IGA Response of 0 or 1
PASI 90 Response
PASI 75 Response
BFIXTURE
PASI 100 Response
Patients with Response (%)
0 84 1612 20 24 28 36 44 5232 40 48
0 84 1612 20 24 28 36 44 5232 40 48
0 84 1612 20 24 28 36 44 5232 40 48
0 84 1612 20 24 28 36 44 5232 40 48
100
80
60
40
20
0
100
80
60
40
20
0
Secukinumab,
300 mg (N=245)
Secukinumab,
300 mg (N=245)
Secukinumab,
300 mg (N=245)
Secukinumab,
300 mg (N=245)
Secukinumab,
150 mg (N=244)
Secukinumab,
150 mg (N=243)
Secukinumab,
150 mg (N=243)
Secukinumab,
150 mg (N=243)
Placebo
(N=246)
Placebo
(N=246)
Placebo
(N=246)
Placebo
(N=246)
Secukinumab,
300 mg (N=323)
Secukinumab,
300 mg (N=323)
Secukinumab,
300 mg (N=323)
Secukinumab,
150 mg (N=327)
Secukinumab,
300 mg (N=323)
Secukinumab,
150 mg (N=327)
Secukinumab,
150 mg (N=327)
Secukinumab,
150 mg (N=327)
Etanercept
(N=323)
Etanercept
(N=323)
Etanercept
(N=323)
Etanercept
(N=323)
Placebo
(N=324)
Placebo
(N=324)
Placebo
(N=324)
Placebo
(N=324)
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335
events during the entire treatment period were
6.3 events per 100 patient-years in the 300-mg
secukinumab group, 6.4 events per 100 patient-
years in the 150-mg secukinumab group, and
7.4 events per 100 patient-years in the placebo
group. In the FIXTURE study, the rates of seri-
ous adverse events were 6.8 events per 100 pa-
tient-years in the 300-mg secukinumab group,
6.0 events per 100 patient-years in the 150-mg
secukinumab group, 7.0 events per 100 patient-
years in the etanercept group, and 8.3 events per
100 patient-years in the placebo group (
Table 4
).
There were no clinically apparent differences in
the type of serious adverse events among the
various study groups (Tables S5 and S9 in the
Supplementary Appendix). Rates of cancer, seri-
ous infection, and major adverse cardiovascular
events are shown in Tables S6 and S10 in the
Supplementary Ap pendix. Discontinuations due
to adverse events were more frequent in the etan-
ercept group than in either secukinumab group
in the FIXTURE study.
Anti-secukinumab antibodies were detected in
4 patients after the start of secukinumab treat-
ment in the FIXTURE study (0.4% of the 980
secukinumab-treated patients tested). No patient
had neutralizing antibodies, and there was no
association with adverse events or loss of efficacy.
Samples from 19 patients were positive for anti-
secukinumab antibodies at baseline (before treat-
ment), and antibodies persisted after baseline in
7 of these patients. Samples from 2 patients who
received placebo and 4 who received etanercept
were positive for new-onset anti-secukinumab
antibodies after baseline. No testing was per-
formed for anti-etanercept antibodies. In the
ERASURE study, anti-secukinumab antibodies
that developed during treatment were detected in
2 of 702 (0.3%) secukinumab-treated patients test-
ed; additional immunogenicity data from this
study are provided in the Supplementary Appendix.
DISCUSSION
The results of these phase 3 studies validate
interleukin-17A as an important therapeutic
target in moderate-to-severe plaque psoriasis,
confirming earlier findings from basic research
and phase 2 trials of secukinumab that suggested
that interleukin-17A plays a role in the pathogen-
esis of psoriasis.
11,20,21
The superiority (or the non-
inferiority, when that was assessed) of secukinu-
mab over the comparators was shown with respect
to the coprimary efficacy end points and all key
secondary end points in both studies. Secukinu-
mab was associated with a rapid reduction in
psoriasis symptoms, elicited significantly greater
PASI 75 rates and higher rates of 0 or 1 responses
on the modified investigator’s global assessment
than placebo at week 12, and with continued
treatment was associated with sustained high re-
sponse rates in a majority of patients through
week 52. The FIXTURE study showed the supe-
rior efficacy of secukinumab over the TNF inhibi-
tor etanercept over a period of 52 weeks, a dura-
tion that exceeds the 12-week study duration in a
previous phase 3, blinded, direct comparison of
biologic therapies for psoriasis.
22
Responses at week 12 were sustained in the
majority of patients through week 52 with con-
tinued secukinumab therapy every 4 weeks. The
maintenance of response was rigorously evaluat-
ed, given that missing data were imputed as non-
responses, providing a conservative assessment.
23
Clinical response (i.e., a 50% reduction in
the mean PASI score) occurred more rapidly
with each secukinumab dose (median, 3.0 weeks
with 300 mg and 3.9 weeks with 150 mg)
than with etanercept (median, 7.0 weeks) in the
FIXTURE study. The investigator-assessed reduc-
tion in signs and symptoms in each study was
accompanied by a reduction in patient-reported
itching, pain, and scaling on the Psoriasis Symp-
tom Diary and an improvement in the health-
related quality of life on the DLQI.
These studies were not designed to statisti-
cally differentiate efficacy between the two secu-
Figure 2 (facing page). Efficacy over Time.
Panel A shows the results in the Efficacy of Response
and Safety of Two Fixed Secukinumab Regimens in
Psoriasis (ERASURE) study, and Panel B the results in
the FIXTURE study. Shown are the proportions of pa-
tients who met the criteria for prespecified efficacy end
points at each visit to week 52. The PASI 75, PASI 90,
and PASI 100 responses indicate reductions from base-
line in the PASI score of 75% or more, 90% or more,
and 100%, respectively. Missing values were imputed
as nonresponses. Only patients who could be evaluated
for a response were included. IGA denotes investigator’s
global assessment.
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Table 4. Adverse Events during the Induction Period and the Entire 52-Week Study Period in FIXTURE.*
Variable Induction Period Entire Study Period†
Secukinumab,
300 mg
(N = 326)
Secukinumab,
150 mg
(N = 327) Etanercept
(N = 323) Placebo
(N = 327)
Any
Secukinumab,
300 mg
(N = 467)
Any
Secukinumab,
150 mg
(N = 469) Etanercept
(N = 323) Placebo
(N = 327)
Exposure to study treatment — days 82.8±9.8 83.3±11.6 82.6±9.4 81.7±11.4 320.7±75.3 317.5±75.4 331.9±89.7 95.3±61.0
no. of patients with event (percent) no. of patients with event (no. of cases per 100 patient-yr)
Any adverse event 181 (55.5) 191 (58.4) 186 (57.6) 163 (49.8) 376 (252.0) 364 (236.4) 253 (243.4) 168 (329.7)
Death 0 0 0 0 0 0 0 0
Nonfatal serious adverse event 4 (1.2) 7 (2.1) 3 (0.9) 6 (1.8) 27 (6.8) 24 (6.0) 20 (7.0) 7 (8.3)
Discontinuation due to adverse
event‡ 4 (1.2) 2 (0.6) 6 (1.9) 3 (0.9) 14 10 12 3
Infection or infestation 87 (26.7) 101 (30.9) 79 (24.5) 63 (19.3) 269 (105.4) 240 (91.9) 170 (91.4) 65 (89.5)
Common adverse event§
Nasopharyngitis 35 (10.7) 45 (13.8) 36 (11.1) 26 (8.0) 122 (35.2) 108 (31.4) 86 (35.7) 26 (32.8)
Headache 30 (9.2) 16 (4.9) 23 (7.1) 23 (7.0) 58 (15.7) 47 (12.4) 40 (15.2) 24 (29.6)
Diarrhea 17 (5.2) 12 (3.7) 11 (3.4) 6 (1.8) 38 (9.9) 36 (9.3) 22 (7.9) 7 (8.4)
Pruritus 8 (2.5) 12 (3.7) 8 (2.5) 11 (3.4) 16 (4.0) 21 (5.3) 16 (5.7) 11 (13.2)
Arthralgia 5 (1.5) 14 (4.3) 12 (3.7) 10 (3.1) 24 (6.0) 33 (8.5) 23 (8.2) 10 (12.1)
Upper respiratory tract infection 7 (2.1) 10 (3.1) 7 (2.2) 3 (0.9) 26 (6.6) 26 (6.6) 18 (6.4) 3 (3.5)
Back pain 8 (2.5) 8 (2.4) 9 (2.8) 6 (1.8) 31 (7.9) 20 (5.1) 26 (9.3) 6 (7.1)
Cough 11 (3.4) 5 (1.5) 4 (1.2) 4 (1.2) 30 (7.6) 15 (3.7) 12 (4.2) 4 (4.8)
Hypertension 5 (1.5) 10 (3.1) 5 (1.5) 4 (1.2) 20 (5.0) 22 (5.6) 14 (4.9) 4 (4.7)
Nausea 8 (2.5) 6 (1.8) 4 (1.2) 7 (2.1) 11 (2.7) 10 (2.5) 7 (2.4) 7 (8.3)
Oropharyngeal pain 9 (2.8) 5 (1.5) 4 (1.2) 7 (2.1) 25 (6.3) 20 (5.0) 10 (3.5) 7 (8.3)
* Plus–minus values are means ±SD. The induction period was defined as the period from baseline through week 12, and the entire study period as the period from baseline through
week 52.
† Patients in the placebo group who did not meet the criteria for PASI 75 at week 12 underwent randomization again to secukinumab at a dose of 300 mg or 150 mg. In the analysis for
the entire study period, the placebo group includes all the patients who received placebo during the induction period, which includes the 16 patients who met the criteria for PASI 75 at
week 12, who continued to receive placebo during the maintenance period (week 13 through week 52).
‡ Exposure-adjusted incidence rates were not calculated for discontinuations due to adverse events.
§ The most common adverse events are expressed according to the preferred term in the Medical Dictionary for Regulatory Activities, version 16.0, and were events that occurred in at least
2.0% of the patients in the combined secukinumab groups during the induction period or events that had an incidence rate of at least 5.0 cases per 100 patient-years in the combined
secukinumab groups during the entire treatment period. Adverse events are listed in decreasing order of frequency in the combined secukinumab groups during the induction period.
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337
kinumab doses. However, the results suggest
that the 300-mg dose may have been more effec-
tive than the 150-mg dose, a finding that was
consistent across efficacy end points.
Secukinumab had a safety profile consistent
with that observed in previous phase 2 trials. In
both of our studies, the incidences of adverse
events, notably infectious adverse events, were
higher in the secukinumab groups than in the
placebo group during the induction period. The
incidences of adverse events in the secukinumab
groups during induction and the entire 52-week
treatment period in the FIXTURE study were
similar to the incidence with etanercept. There
were no apparent dose-related differences be-
tween the secukinumab groups with respect to
adverse events, with the exception of mild and
moderate candida infections.
Interleukin-17A plays a key role in host de-
fense, specifically in mucocutaneous microbial
surveillance.
24
Continued vigilance with respect
to the potential for candida infection will be
necessary for interleukin-17A inhibitors. Neutro-
penia may also be of potential concern because
of the reported role of interleukin-17A in the
stimulation of granulopoiesis and neutrophil
trafficking.
25
Anti-secukinumab antibodies were detected
during treatment in 2 of 702 patients (0.3%) re-
ceiving secukinumab in the ERASURE study and
in 4 of 980 (0.4%) in the FIXTURE study. The
presence of anti-secukinumab antibodies was not
associated with adverse events or reduced efficacy.
The assay used in these studies is highly sensi-
tive and therefore capable of detecting very low
levels of antibodies that can bind to secu kin u-
mab. Consequently, non–treatment-related, nat u-
rally occurring antidrug antibodies may lead to
a confirmed positive response. The observa-
tions of anti-secukinumab antibodies in some
patients at baseline or while they were receiving
placebo or etanercept were not considered to be
clinically relevant, because the antidrug anti-
bodies were not associated with secukinumab
treatment; therefore, they were not explored
further.
A limitation of these studies was that few pa-
tients continued to receive placebo after week 12,
which limited the comparisons with this group
during the maintenance periods. In addition, the
trial populations, although sufficient for assess-
ing efficacy and common adverse events, may
have been too small to detect rare adverse
events. Extension studies evaluating long-term
eff icacy are ongoing.
In conclusion, these phase 3 studies showed
the efficacy of secukinumab over a period of
52 weeks in patients with moderate-to-severe
plaque psoriasis.
Supported by Novartis Pharmaceuticals.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank t he patients who participated in the st udies; Dr. Jörg
Prinz for advice regarding the development of an earlier version
of the manuscript; Dr. Izabella Messina, Mr. Vamsidhar Chatur-
vedula, Mr. Noel Ny Tovo, and Mr. Abhishek Dhanuka for help
with the conduct of the ERASURE study; Ms. Katherine Kramp,
Ms. Nancy Rikken, Ms. Diane Ryan, and Mr. Varun Jain (clinical
managers) and Mr. Kevin Poirier (clinical scientist), all from
Novartis Pharmaceuticals, for help with the conduct of the
FIXTURE study; Dr. Achim Gütt ner of Novartis Pharmaceuticals
for discussions regarding the design of both studies; Dr. Oliver
Sander of Novartis Pharmaceuticals for discussions regarding
the design of the FIXTURE study; Ms. Claudia Seper of Novartis
Pharm aceuticals for support of st udy conduct; Dr. Kirtida Pandya
of Novartis Pharmaceuticals for medical communications leader-
ship; and Dr. Barry Weichman and Dr. Andrew Horgan of Bio-
Science Communications for assistance in writing the first draft
of the manuscript.
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