Articles

Efficacy and safety of dupilumab in adults with moderate-

to-severe atopic dermatitis inadequately controlled by
topical treatments: a randomised, placebo-controlled,
dose-ranging phase 2b trial
Diamant Thaçi, Eric L Simpson, Lisa A Beck, Thomas Bieber, Andrew Blauvelt, Kim Papp, Weily Soong, Margitta Worm, Jacek C Szepietowski,
Howard Sofen, Makoto Kawashima, Richard Wu, Steven P Weinstein, Neil M H Graham, Gianluca Pirozzi, Ariel Teper, E Rand Sutherland,
Vera Mastey, Neil Stahl, George D Yancopoulos, Marius Ardeleanu

Summary
Background Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic Published Online
dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody October 8, 2015
http://dx.doi.org/10.1016/
that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults
S0140-6736(15)00388-8
with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments.
See Online/Comment
http://dx.doi.org/10.1016/
Methods In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who S0140-6736(15)00389-X
had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate Comprehensive Center for
response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Inflammation Medicine,
University Hospital Schleswig-
Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned
Holstein, Campus Lübeck,
(1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator’s Global Assessment) and region Lübeck, Germany
(Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every (Prof D Thaçi MD); Department
2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central of Dermatology, Oregon
Health and Science University,
randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking
Portland, OR, USA
to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks (E L Simpson MD); Department
received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary of Dermatology, University of
outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) Rochester Medical Center,
Rochester, NY, USA
from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study
(Prof L A Beck MD);
drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. Department of Dermatology
and Allergy, University of
Findings Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were Bonn, Bonn, Germany
(Prof T Bieber MD); Oregon
randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every
Medical Research Center,
2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo Portland, OR, USA
[n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (A Blauvelt MD); K Papp Clinical
(−74% [SE 5·16]), 300 mg every 2 weeks (−68% [5·12]), 200 mg every 2 weeks (−65% [5·19]), 300 mg every 4 weeks Research and Probity Medical
Research, Waterloo, ON,
(−64% [4·94]), 100 mg every 4 weeks (−45% [4·99]); placebo (−18% [5·20]). 258 (81%) of 318 patients given dupilumab Canada (K Papp MD); Alabama
and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most Allergy & Asthma Center,
frequent (28% and 26%, respectively). Birmingham, AL, USA
(W Soong MD); Department of
Dermatology and Allergy,
Interpretation Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose- Charité University, Berlin,
dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of Germany
atopic dermatitis. (Univ-Prof M Worm MD);
Department of Dermatology,
Venereology and Allergology,
Funding Sanofi and Regeneron Pharmaceuticals. Wroclaw Medical University,
Wroclaw, Poland
Introduction and long-term application of topical corticosteroids (Prof J C Szepietowski MD);
Atopic dermatitis is a chronic skin disorder characterised carries the risk of side-effects.2,3 Systemic immuno- UCLA School of Medicine, Los
Angeles, CA, USA (H Sofen MD);
by intense pruritus, disruption of skin-barrier function, suppressant drugs for atopic dermatitis are generally Tokyo Women’s Medical
and type 2 inflammation.1,2 Atopic dermatitis typically more effective than topical treatments, but they also University, School of Medicine,
features intermittent flares, but moderate-to-severe have substantial potential for more severe toxic effects.4–7 Tokyo, Japan
disease rarely clears without effective treatment. Topical Furthermore, systemic corticosteroids and ciclosporin (Prof M Kawashima MD);
Regeneron Pharmaceuticals,
corticosteroids have been the foundation of have been associated with marked rebound effects after Tarrytown, NY, USA (R Wu PhD,
pharmacological treatments for atopic dermatitis, but treatment discontinuation.4–7 Except for ciclosporin, S P Weinstein MD,
for many patients with moderate-to-severe atopic which is approved in some countries, systemic N M H Graham MD,
V Mastey MS, N Stahl PhD,
dermatitis, the efficacy of topical treatments is limited, immunosuppressant treatments are not approved for

www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8 1

 Articles

G D Yancopoulos MD,
M Ardeleanu MD); Sanofi,
Bridgewater, NJ, USA
(G Pirozzi MD, A Teper MD); and
Sanofi, Cambridge, MA, USA
(E R Sutherland MD)
Correspondence to:
Prof Diamant Thaçi,
Comprehensive Centre for
Inflammation Medicine,
University Hospital Schleswig-
Holstein, Campus Lübeck,
23538 Lübeck, Germany
diamant.thaci@uksh.de
Panel: Research in context
Evidence before this study
Findings of previous phase 1 and 2a studies showed preliminary
efficacy and a favourable safety profile of dupilumab in patients
with atopic dermatitis, asthma, and chronic sinusitis with nasal
polyposis. To obtain information about the unmet need for
systemic treatment of atopic dermatitis, we searched PubMed
and Embase on Feb 27, 2015, for randomised, controlled, blinded
clinical trials of systemic immunosuppressant treatments and oral
glucocorticoids for treatment of moderate-to-severe atopic
dermatitis published in English language. Additionally, we
searched the reference lists of recent treatment guidelines and a
recent systematic review of systemic treatments in patients with
atopic dermatitis. We used the following search terms: “atopic
dermatitis”, “eczema”, “cyclosporine”, “ciclosporin”,
“methotrexate”, “azathioprine”, “mycophenolate”, “interferon-γ”,
“intravenous immunoglobulin”, “prednisone”, “prednisolone”,
“dexamethasone”, “beclomethasone”, and “methylprednisolone”.
Overall, we identified 22 randomised, controlled, blinded studies.
Systemic immunosuppressant treatments were effective in
moderate-to-severe atopic dermatitis, but were associated with
toxic effects, especially with long-term treatment, and systemic
corticosteroids were associated with rebound effects. As noted in
current guidelines, with the exception of ciclosporin, which is
approved in some countries, most systemic immunosuppressant
treatments are not approved for moderate-to-severe atopic
dermatitis, except in cases of refractory disease, indicating a
substantial unmet need.
Added value of this study
Our results showed the clinical efficacy of dupilumab at five
different dose regimens in patients with moderate-to-severe
atopic dermatitis, with the most consistent benefits recorded
with dose regimens of 300 mg once a week and 300 mg every
2 weeks. Consistent with findings of previous phase 1 and 2a
studies, dupilumab had a favourable safety profile with no
dose-limiting toxic effects. Our findings confirmed the efficacy
reported in the previous early-phase studies. Our study used the
longest duration of treatment reported up to now for this drug;
was the first study of dupilumab in atopic dermatitis assessing
several dose regimens given less frequently than weekly,
including less-frequent doses lower than 300 mg, which
provided data to optimise treatment regimens; and was the
largest study of dupilumab so far and, therefore, provides
important safety information.
Implications of all the available evidence
There is an unmet need for a safe and effective systemic
treatment for patients with moderate-to-severe atopic
dermatitis (especially those with an inadequate response or who
cannot tolerate current treatment) because approved treatments
are often ineffective or associated with adverse effects and,
therefore, are unsuitable for the long-term management of
atopic dermatitis. Our findings showed a positive benefit–risk
ratio for dupilumab, which specifically targets the Th2-mediated
inflammation driving atopic dermatitis. Phase 3 confirmatory
studies are underway investigating dupilumab as monotherapy,
and in combination with topical corticosteroids; these studies are
larger and of longer duration than the present study, and will
further evaluate the efficacy and safety of dupilumab at doses of
300 mg once a week and every 2 weeks, the two dose regimens
selected from the present study, in patients with moderate-to-
severe atopic dermatitis.

atopic dermatitis, which suggests substantial unmet
need.4–7
The prevalence of atopic dermatitis is about 3–10% in
adults and up to 20% in children, and has a substantial
effect on quality of life.8–11 Patients with atopic dermatitis
have increased risk of other atopic disorders, including
asthma, allergic rhinitis, and chronic sinusitis with nasal
polyposis.10,12–14 Atopic dermatitis is also associated with
increased risk of mental health disorders related to the
psychological and social burden of disease.15,16 As with
other atopic disorders, Th2 cytokines and their
downstream effects are prominent in atopic dermatitis,
although other inflammatory pathways, including
Th1-mediated and Th22-mediated processes, might also
contribute to the pathogenesis of atopic dermatitis.17–19
Dupilumab is a fully-human monoclonal antibody
directed against the interleukin (IL)-4 receptor α (IL-4Rα)
subunit that blocks signalling of both IL-4 and IL-13, key
Th2 cytokines.20 In early-stage clinical trials, dupilumab
showed significant improvements in atopic dermatitis,20
asthma,21 and chronic sinusitis with nasal polyposis,22
suggesting that the IL-4 and IL-13 pathways are requisite
drivers of these atopic diseases. In these studies,
dupilumab was well-tolerated with a favourable safety
profile.20–22 The present phase 2b study assessed the
efficacy and safety of several dupilumab dose regimens
compared with placebo in adults with moderate-to-severe
atopic dermatitis.
Methods
Study design
This randomised, placebo-controlled, double-blind,
parallel-group, dose-ranging phase 2b study was
undertaken at 91 study centres, including hospitals,
clinics, and academic institutions, in Canada, Czech
Republic, Germany, Hungary, Japan, Poland, and the
USA. Study drug (dupilumab or placebo) was given once
a week for 16 weeks (baseline [week 0] to week 15),
followed by a 16-week follow-up period. Rescue treatment
for atopic dermatitis (drug or phototherapy or both) was
given at the investigators’ discretion; patients who
received rescue treatment were discontinued from study
treatment, but were asked to continue with study
assessments.

2 www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8


The study was undertaken in accordance with Good
Clinical Practice guidelines and adhered to the
Declaration of Helsinki. All study documents and
procedures were approved by the appropriate institutional
review boards and ethics committees at each study site;
each patient provided written informed consent before
study participation.
Patients
We enrolled adults (aged ≥18 years) diagnosed with
moderate-to-severe atopic dermatitis not adequately
controlled by topical treatments, or for whom topical
treatment was inadvisable. Inclusion criteria comprised:
chronic atopic dermatitis present for 3 years or longer
before screening; Eczema Area and Severity Index (EASI)
score 12 or higher at screening and 16 or higher at baseline;
Investigator’s Global Assessment (IGA) score of 3 or
higher at screening and baseline; atopic dermatitis
involvement of 10% or more of body surface area at
screening and baseline; and patients with a documented
history (within 6 months) of inadequate response to topical
treatments or those for whom topical treatments were
inadvisable. Moderate-to-severe disease was defined based
on: IGA scores of 3 or higher at screening and baseline,
consistent with the categories of moderate (IGA=3) and
severe (IGA=4); and EASI scores of 12 or higher at
screening and 16 or higher at baseline, consistent with the
categories of moderate (EASI score 7·1–21·0), severe
(21·1–50·0), and very severe (50·1–72·0) as reported in a
recent study that evaluated the interpretability of EASI.23
Key exclusion criteria were: previous treatment with
dupilumab; active acute or chronic infections; use of
topical treatments for atopic dermatitis (other than bland
emollients) within 1 week of baseline; systemic
immunosuppressive or immunomodulating drugs
within 4 weeks of baseline; or significant comorbidities
or laboratory abnormalities. The appendix provides
detailed exclusion criteria. Patient recruitment was
managed separately by each centre; recruitment occurred
from existing patient databases and local advertising.
Randomisation and masking
Patients were randomly assigned (1:1:1:1:1:1) to receive
subcutaneous dupilumab at 300 mg once a week, 300 mg
every 2 weeks, 200 mg every 2 weeks, 300 mg every
4 weeks, or 100 mg every 4 weeks; or placebo once a week.
Randomisation was stratified by disease severity
(moderate [IGA=3] vs severe [IGA=4]) and region (Japan
vs rest of world). We used a central randomisation
scheme, provided by an interactive voice response system
to the designated study pharmacist or qualified designee.
Study patients, principal investigators, study centre
personnel, Regeneron and Sanofi personnel, and contract
research organisation personnel in regular contact with
study centres were masked to treatment assignment
during the study, and allocation was concealed. Drug kits
were coded, providing masking to treatment assignment.
www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8
Articles
Patients on regimens given every 2 weeks and every
4 weeks received volume-matched placebo every week
when dupilumab was not given to ensure double blinding.
Procedures
On their first day of treatment, patients received a loading
dose of two 2 mL subcutaneous injections containing:
600 mg dupilumab for patients receiving 300 mg once a
week, 300 mg every 2 weeks, or 300 mg every 4 weeks;
400 mg dupilumab for patients receiving 200 mg every
2 weeks or 100 mg every 4 weeks; or placebo for the
placebo group. On each subsequent week through
week 15, patients received one 2 mL injection of study
drug, according to treatment group. Placebo was
prepared with the same formulation as dupilumab
without addition of the active agent. Patients were
required to apply stable amounts of a topical emollient
(moisturiser) twice a day for 7 days or longer before and
after baseline, and could continue using a topical
emollient during the study. They were not permitted to
apply topical corticosteroids or calcineurin inhibitors
during the 7 days before baseline or during study
treatment. With the exception of antihistamines and
antibiotics, all other concomitant drugs and procedures
indicated for the treatment of atopic dermatitis were
prohibited during the study (appendix).
From baseline through week 16, patients underwent
weekly assessments. Most assessments were done
through clinical trial visits, although five visits (weeks 5,
7, 9, 11, and 13) were made via telephone. After the end-of-
treatment visit at week 16 (1 week after the final dose of
study drug), visits occurred every 2 weeks from week 18
through week 32. Throughout the study, the pruritus
numeric rating scale (NRS)24 was completed every day by
patients. At baseline and weeks 1–4, 6, 8, 10, 12, and 14–16,
investigators assessed the severity of atopic dermatitis
using IGA, EASI,25 SCORing Atopic Dermatitis See Online for appendix
(SCORAD),26 and percentage of body surface area affected
by atopic dermatitis (appendix). Health-related quality of
life was assessed through the Dermatology Life Quality
Index (DLQI),27 a patient-reported outcome measure, at
baseline and weeks 2, 4, 8, 12, and 16.
Outcomes
The primary efficacy endpoint was the percentage change
in EASI score from baseline to week 16 (appendix); this
endpoint was reported by investigators and was not
centrally assessed. Of note, EASI has been designated as
a core outcome measure in atopic dermatitis by the
Harmonising Outcome Measures for Eczema group.28
Secondary efficacy endpoints (appendix) included:
proportion of patients achieving IGA response at week 16
(IGA=0 [clear] or IGA=1 [almost clear] on a scale of 0–4
[4 representing severe atopic dermatitis]); absolute and
percentage change from baseline to week 16 in peak
pruritus NRS scores (scored on a scale of 0–10); absolute
change in EASI score from baseline to week 16; absolute
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and percentage change in SCORAD scores from baseline
to week 16; and proportion of patients achieving 50%,
75%, or 90% reduction from baseline in EASI score
(EASI-50, EASI-75, or EASI-90, respectively) at week 16.
Exploratory efficacy endpoints included: percentage
change in EASI, pruritus NRS, and SCORAD scores
from baseline for each study visit until week 16;
proportion of patients with pruritus NRS score response
(reduction in score of ≥3 from baseline); absolute and
percentage change at each study visit from baseline to
week 16 for body surface area percentage affected by
atopic dermatitis; and absolute and percentage change
from baseline to week 16 for DLQI (appendix).
Safety outcomes, including treatment-emergent adverse
events, serious treatment-emergent adverse events, vital
signs, clinical laboratory values, and electrocardiogram
results, were monitored from baseline to week 32. Adverse
events, including injection-site reactions, were reported by
patients in response to a general health inquiry, and
severity of adverse events was determined by investigators
according to pre-specified criteria. Treatment-emergent
adverse events were coded using Medical Dictionary for
Regulatory Activities (MedDRA) version 16.0. Injection-
site reactions were identified by the clinician and included
any signs (eg, erythema, oedema, inflammation) or
symptoms (eg, pain).
Statistical analyses
For the primary endpoint, enrolment of 40 patients per
group provided 94% power to detect a 40% difference
between dupilumab and placebo with respect to percentage
change in EASI scores from baseline to week 16, assuming
a common SD of 50%, and a mean baseline EASI score of
about 30, with a two-sided test at the 0·05 significance
level. Values used for this estimate were based on results
from the R668-AD-1117 phase 2a study (NCT01548404).20
The full analysis set, which was used to assess efficacy
endpoints, comprised all randomly assigned patients who
received one or more doses of study drug; patients were
analysed as randomly assigned. In view of the key objective

452 patients assessed for eligibility 72 were ineligible for the study
53 did not meet eligibility criteria
12 withdrew consent
1 lost to follow-up
6 other
380 randomly assigned

61 assigned to receive 65 assigned to receive 65 assigned to receive 62 assigned to receive 64 assigned to receive 63 assigned to receive
placebo once a week dupilumab 100 mg dupilumab 300 mg dupilumab 200 mg dupilumab 300 mg dupilumab 300 mg
every 4 weeks every 4 weeks every 2 weeks every 2 weeks once a week

61 received ≥1 dose of 65 received ≥1 dose of 65 received ≥1 dose of 61 received ≥1 dose of 64 received ≥1 dose of 63 received ≥1 dose of
study treatment study treatment study treatment study treatment* study treatment study treatment

8 withdrew by week 16
1 adverse event
6 lack of efficacy
1 lost to follow-up
6 withdrew by week 16 2 withdrew by week 16 11 withdrew by week 16 3 withdrew by week 16 3 withdrew by week 16
2 adverse event 1 adverse event 3 adverse event 1 adverse event 1 adverse event
3 lack of efficacy 1 withdrawal by patient 2 lack of efficacy 2 lost to follow-up 1 lost to follow-up
1 lost to follow-up 1 lost to follow-up 1 withdrawal by patient
1 withdrawal by patient
1 protocol violation
3 other

53 completed to week 16 59 completed to week 16 63 completed to week 16 51 completed to week 16 61 completed to week 16 60 completed to week 16

19 withdrew from study 23 withdrew from study 10 withdrew from study 28 withdrew from study 12 withdrew from study 11 withdrew from study
2 adverse event 2 adverse event 1 adverse event 3 adverse event 1 adverse event 2 adverse event
9 lack of efficacy 7 lack of efficacy 3 withdrawal by patient 5 lack of efficacy 1 lack of efficacy 1 lack of efficacy
2 lost to follow-up 3 lost to follow-up 3 physician decision 3 lost to follow-up 2 lost to follow-up 1 lost to follow-up
2 withdrawal by patient 2 withdrawal by patient 3 other 4 withdrawal by patient 3 withdrawal by patient 6 withdrawal by patient
1 physician decision 4 physician decision 1 physician decision 3 physician decision 1 physician decision
3 other 5 other 11 other 2 other
1 protocol violation

42 completed study 42 completed study 55 completed study 34 completed study 52 completed study 52 completed study

Figure 1: Trial profile

*One patient withdrew after randomisation but before first dose.

4 www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8

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of dose-finding, few patients were expected to be randomly
assigned but not treated; therefore, we deemed this
efficacy analysis population to be appropriate in this
context. The safety analysis set comprised all randomly
assigned patients who received any study drug, and
patients were analysed by study drug and dose regimen
received. An independent data safety monitoring
committee monitored patient safety throughout the study.
We analysed the primary efficacy endpoint and
continuous secondary efficacy endpoints with analysis of
covariance, controlling for treatment and randomisation
strata, with the relevant baseline value as the covariate. We
analysed categorical efficacy endpoints with a Cochran-
Mantel-Haenszel test, stratified by randomisation strata.
Least-squares mean estimates by treatment group were
generated as well as the difference of these estimates
versus placebo, with corresponding standard errors (SEs)
and associated 95% CI. Least-squares means were used to
compare improvement from baseline for each of the
dupilumab groups versus placebo. The statistical tests
were two-sided at the 5% level. For the primary endpoint,
we controlled for multiplicity with a hierarchical testing
procedure, from the highest dose to the lowest dose until
statistical significance at the 5% level is not achieved. The
study was not powered for statistical comparisons among
dupilumab dosing levels. Between-dose differences were
not tested inferentially. For responder analyses, patients
who withdrew or who received rescue treatment (ie,
topical [other than emollients] or systemic drugs for atopic
dermatitis) were regarded as non-responders.
Data recorded after dropout, data recorded after rescue
treatment, and missing data were accounted for with the
method of last observation carried forward for continuous
endpoints. We did a sensitivity analysis using a mixed-
effects model with repeated measures for continuous
variables. Missing data points were not imputed directly,
but were estimated in the model. The results of the
mixed-effects model with repeated measures sensitivity
analyses were consistent with the last observation carried
forward analyses and are presented in the appendix. We
assessed responder analyses (ie, proportions of patients
with EASI-50, EASI-75, EASI-90, IGA scores of 0–1, and
improvement of ≥3 in pruritus NRS scores) in the full
analysis set, and included all recorded values with
censoring after rescue drug use. Patients with missing
data were treated as non-responders at those timepoints.
A preplanned interim analysis was done at week 12 to
choose the dose for the phase 3 study. The study
management team that oversaw the completion of the
study after week 12 remained masked throughout the
study until after final database lock.
The analysis used SAS (version 9.2).
This trial is registered with ClinicalTrials.gov, number
NCT01859988, and with the EU Clinical Trials Register,
EudraCT Number 2012-003651-11.
Role of the funding source
The funders had a role in the conception and design of
the study; analysis and interpretation of the data; drafting
and critical revision of the report; and gave approval to
submit. The corresponding author had full access to all
the data in the study and had final responsibility for the
decision to submit for publication.
Results
From May 15, 2013, to Jan 27, 2014, 452 patients were
assessed for eligibility; 72 were ineligible for the study, and
380 were randomly assigned. 379 patients (61 in the
placebo group and 318 in the dupilumab group) received
one or more doses of study treatment (figure 1) and
347 (53 [87%] given placebo and 294 [92%] given
dupilumab) completed the 16 weeks of treatment.
Treatment groups had similar baseline characteristics
(table 1). The mean duration of atopic dermatitis at

All dupilumab Dupilumab 300 mg Dupilumab 300 mg Dupilumab 200 mg Dupilumab 300 mg Dupilumab 100 mg Placebo once a week
combined once a week every 2 weeks every 2 weeks every 4 weeks every 4 weeks (n=61)
(n=318) (n=63) (n=64) (n=61) (n=65) (n=65)
Age (years) 37·0 (12·1), 18–75 36·2 (10·7), 19–66 39·4 (12·1), 21–68 35·8 (14·9), 18–75 36·8 (10·8), 18–59 36·6 (11·6), 19–66 37·2 (13·1), 18–69
Sex
Men 194 (61%) 43 (68%) 41 (64%) 36 (59%) 40 (62%) 34 (52%) 40 (66%)
Disease duration (years)* 27·6 (13·6), 3–63 27·9 (13·3), 3–58 30·5 (15·8), 3–61 25·2 (12·8), 3–61 26·5 (11·4), 5–50 27·9 (14·7), 4–63 29·8 (13·5), 5–64
Body surface area with 50·4 (24%) 48·4 (21%) 53·2 (25%) 50·8 (25%) 50·8 (23%) 48·7 (24%) 51·1 (24%)
atopic dermatitis
involvement†
EASI score 31·7 (13·4) 30·1 (11·2) 33·8 (14·5) 32·9 (15·5) 29·4 (11·5) 32·2 (13·5) 32·9 (13·8)
Total SCORAD score 67·4 (13·3) 65·0 (12·2) 68·5 (12·6) 68·3 (14·0) 67·2 (12·3) 68·2 (15·0) 67·1 (13·6)
IGA score
3‡ 168 (53%) 32 (51%) 34 (53%) 31 (51%) 37 (57%) 34 (52%) 32 (53%)
4§ 150 (47%) 31 (49%) 30 (47%) 30 (49%) 28 (43%) 31 (48%) 29 (48%)

Data are mean (SD), range (min–max); or n (%). EASI=Eczema Area and Severity Index. SCORAD=SCORing Atopic Dermatitis. IGA=Investigator’s Global Assessment. *n=379. †n=378. ‡Denotes moderate.
§Denotes severe.

Table 1: Baseline demographic and clinical characteristics by treatment group (N=379)

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baseline was similar in the placebo (29·8 years [SD 13.5]) nearly half the patients had severe disease as reflected by
and dupilumab (27·6 years [13·6]) groups (median their IGA score, percentage of body surface area affected,
duration per treatment group, 23–34 years); at baseline, and EASI score (table 1).

Dupilumab 300 mg Dupilumab 300 mg Dupilumab 200 mg Dupilumab 300 mg Dupilumab 100 mg Placebo once a
once a week (n=63) every 2 weeks every 2 weeks every 4 weeks (n=65) every 4 weeks (n=65) week (n=61)
(n=64) (n=61)
EASI score
Baseline 30·1 (11·2) 33·8 (14·5) 32·9 (15·5) 29·4 (11·5) 32·2 (13·5) 32·9 (13·8)
Week 16 7·2 (8·8) 10·7 (12·9) 10·9 (12·4) 9·8 (11·2) 17·4 (15·3) 25·6 (18·3)
LS mean % change from baseline (SE) −73·7% (5·2) −68·2% (5·1) −65·4% (5·2) −63·5% (4·9) −44·8% (5·0) −18·1% (5·2)
LS mean % difference vs placebo (SE) −55·7% (6·7) −50·1% (6·7) −47·4% (6·8) −45·4% (6·7) −26·8% (6·7) ..
95% CI −68·9 to −42·4 −63·3 to −37·0 −60·6 to −34·1 −58·5 to −32·3 −39·8 to −13·7 ..
p value vs placebo <0·0001 <0·0001 <0·0001 <0·0001 <0·0001 ..
SCORAD score
Baseline 65·0 (12·2) 68·5 (12·6) 68·3 (14·0) 67·2 (12·3) 68·2 (15·0) 67·1 (13·6)
Week 16 26·1 (17·1) 31·7 (20·6) 35·4 (22·8) 32·6 (19·5) 48·1 (24·8) 54·7 (22·2)
LS mean % change from baseline (SE) −56·9% (4·1) −51·2% (4·1) −46·0% (4·1) −48·8% (4·0) −26·6% (4·0) −13·8% (4·1)
LS mean % difference vs placebo (SE) −43·1% (5·4) −37·4% (5·4) −32·2% (5·4) −35·0% (5·3) −12·8% (5·3) ..
95% CI –53·7 to –32·5 –47·9 to –26·9 –42·9 to –21·6 –45·4 to –24·6 –23·3 to –2·3 ..
p value vs placebo <0·0001 <0·0001 <0·0001 <0·0001 0·0172 ..
Percent body surface area with atopic dermatitis involvement
Baseline 48·4 (20·9) 53·2 (24·8) 50·8 (25·4) 50·8 (22·6) 48·7 (23·9) 51·1 (23·5)
Week 16 15·1 (17·2) 22·5 (23·0) 21·1 (23·0) 23·2 (21·3) 32·3 (27·0) 43·9 (27·1)
LS mean % change from baseline (SE) –65·6% (6·7) –52·1% (6·6) –54·5% (6·7) –48·8% (6·4) –26·2% (6·4) –7·7% (6·7)
LS mean % difference vs placebo (SE) –57·9% (8·7) –44·4% (8·6) –46·8% (8·7) –41·1% (8·6) –18·5% (8·6) ..
95% CI –74·9 to −40·9 –61·3 to −27·6 –63·8 to −29·7 –57·9 to –24·3 –35·3 to –1·7 ..
p value vs placebo <0·0001 <0·0001 <0·0001 <0·0001 0·0313 ..
Peak weekly pruritus NRS scores
Baseline 6·54 (1·54) 6·74 (2·07) 6·98 (2·32) 6·84 (1·85) 6·71 (1·88) 6·34 (1·83)
Week 16 3·07 (2·15) 3·64 (2·39) 4·21 (2·76) 3·99 (2·45) 5·26 (2·47) 6·05 (2·31)
LS mean % change from baseline (SE) −46·90% (4·61) −40·06% (4·54) −34·12% (4·72) −32·63% (4·52) −15·67% (4·49) 5·15% (4·77)
LS mean % difference vs placebo (SE) −52·05% (6·14) −45·21% (6·13) −39·27% (6·28) −37·77% (6·14) −20·81% (6·11) ..
95% CI –64·13 to −39·97 –57·27 to −33·15 –51·63 to −26·91 –49·85 to −25·70 –32·82 to −8·80 ..
p value vs placebo <0·0001 <0·0001 <0·0001 <0·0001 0·0007 ..
Proportion of patients at week 16 with IGA response (0=clear or 1=almost clear)
Number (%) 21 (33%) 19 (30%) 17 (28%) 14 (22%) 8 (12%) 1 (2%)
95% CI 21·95 to 46·34 18·91 to 42·42 17·15 to 40·83 12·31 to 33·49 5·47 to 22·82 0·04 to 8·80
Difference in % of responders (95% CI) 31·7 (19·63–43·76) 28·0 (16·41–39·69) 26·2 (14·54–37·92) 19·9 (9·41–30·39) 10·7 (2·07–19·27) ..
p value vs placebo <0·0001 <0·0001 <0·0001 0·0004 0·0242 ..
Proportion of patients at week 16 with pruritus NRS response (improvement in pruritus NRS scores of ≥3)
Number (%) 34 (54%) 26 (41%) 22 (36%) 24 (37%) 13 (20%) 5 (8%)
95% CI 40·94 to 66·61 28·51 to 53·63 24·16 to 49·37 25·28 to 49·80 11·10 to 31·77 2·72 to 18·10
Difference in % of responders (95% CI) 45·8 (31·67–59·87) 32·4 (18·57–46·29) 27·9 (13·99–41·75) 28·7 (15·12–42·33) 11·8 (−0·11 to 23·72) ..
p value vs placebo <0·0001 <0·0001 0·0002 <0·0001 0·0487 ..
DLQI score
Baseline 15·0 (7·80) 14·5 (7·20) 15·0 (7·07) 13·3 (7·29) 15·7 (6·61) 12·8 (6·20)
Week 16 4·3 (4·88) 6·6 (6·77) 7·1 (7·61) 6·8 (6·85) 11·9 (8·28) 11·4 (7·18)
LS mean % change from baseline (SE) −59·0% (7·14) −39·6% (7·01) −43·3% (7·18) −37·4% (6·88) −11·9% (6·88) 2·6 (7·34)
LS mean % difference vs placebo (SE) −61·6% (9·41) −42·3% (9·33) −45·9% (9·50) −40·1% (9·24) −14·6% (9·35) ..
95% CI −80·1 to −43·1 −60·6 to −23·9 −64·6 to −27·2 −58·3 to −21·9 −33·0 to 3·8 ..
p value vs placebo <0·0001 <0·0001 <0·0001 <0·0001 0·1200 ..

Data are mean (SD) or n (%) unless stated otherwise. EASI=Eczema Area and Severity Index. LS=least-squares. SCORAD=SCORing Atopic Dermatitis. NRS=numeric rating scale. IGA=Investigator’s Global
Assessment. DLQI=Dermatology Life Quality Index.

Table 2: Efficacy outcomes, baseline to week 16 (last observation carried forward analysis)

6 www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8

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At week 16, all dupilumab groups showed marked regimens. We noted a significant improvement from
improvement from baseline in EASI score, the primary baseline compared with placebo as early as week 1
efficacy outcome, compared with placebo (table 2; (figure 2A, appendix).
p<0·0001 for all pairwise comparisons). Least-squares At week 16, the proportion of patients with an EASI-50
mean percentage change from baseline to week 16 in response was greater for dupilumab 300 mg once a week
EASI scores for all groups was: dupilumab 300 mg (n=52 [83%]; p<0·0001), 300 mg every 2 weeks (n=50 [78%];
once a week −73·7% (SE 5·2), 300 mg every 2 weeks p<0·0001), 200 mg every 2 weeks (n=38 [62%]; p=0·0003),
−68·2% (5·1), 200 mg every 2 weeks −65·4% (5·2), and 300 mg every 4 weeks (n=46 [71%]; p<0·0001)
300 mg every 4 weeks −63·5% (4·9), and 100 mg every compared with placebo (n=18 [30%]). The dupilumab
4 weeks −44·8% (5·0); placebo −18·1% (5·2; p<0·0001 100 mg every 4 weeks (n=29 [45%]) dose remained
for each). The effects were numerically dose-dependent numerically, but not significantly different from placebo
with the greatest effects recorded for the dupilumab at 16 weeks (p=0·0797; figure 3A) because the initial
300 mg once a week and 300 mg every 2 weeks benefit after loading diminished with time after the

A B
10 0

0 –10
LS mean % change in SCORAD from baseline
LS mean % change in EASI from baseline

–10 –20
–20
–30
–30
–40
–40
–50
–50
–60
–60
–70
–70

–80 –80

–90 –90

–100 –100
Placebo Dupilumab 200 mg every 2 weeks* Placebo Dupilumab 200 mg every 2 weeks‡
Dupilumab 100 mg every 4 weeks* Dupilumab 300 mg every 2 weeks† Dupilumab 100 mg every 4 weeks§ Dupilumab 300 mg every 2 weeks‡
Dupilumab 300 mg every 4 weeks* Dupilumab 300 mg once a week‡ Dupilumab 300 mg every 4 weeks* Dupilumab 300 mg once a week‡

C D
10 20

0 10
LS mean % change in pruritus NRS from baseline
LS mean % change in % body surface area

–10 0
with AD involvement from baseline

–10
–20
–20
–30
–30
–40
–40
–50
–50
–60
–60
–70
–70
–80 –80
–90 –90
–100 –100
0 4 8 12 16 0 4 8 12 16
Week Week
Placebo Dupilumab 200 mg every 2 weeks† Placebo Dupilumab 200 mg every 2 weeks†
Dupilumab 100 mg every 4 weeks¶ Dupilumab 300 mg every 2 weeks|| Dupilumab 100 mg every 4 weeks** Dupilumab 300 mg every 2 weeks‡
Dupilumab 300 mg every 4 weeks† Dupilumab 300 mg once a week|| Dupilumab 300 mg every 4 weeks† Dupilumab 300 mg once a week‡

Figure 2: Least-squares mean percentage change from baseline for (A) EASI, (B) SCORAD, (C) body surface area with atopic dermatitis involvement, and
(D) peak weekly pruritus NRS scores (last observation carried forward analysis)
LS=least-squares. EASI=Eczema Area and Severity Index. SCORAD=SCORing Atopic Dermatitis. AD=atopic dermatitis. NRS=numeric rating scale. *p≤0·0001 vs
placebo, weeks 1–16. †p<0·05, weeks 1–2; and p≤0·0001 vs placebo, weeks 3–16. ‡p<0·05, week 1; and p≤0·0001 vs placebo, weeks 2–16. §p<0·05 vs placebo, weeks
1–16; and p=0·0172 vs placebo, week 16. ¶p<0·05 vs placebo, weeks 1–16; and p=0·0313 vs placebo, week 16. ||p<0·05, week 2; and p≤0·0001 vs placebo, weeks
3–16. **p<0·05 vs placebo, weeks 1–16; and p=0·0007 vs placebo, week 16. Exact p values are listed in the appendix.

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400 mg loading dose. Similarly, the proportions of EASI-75
and EASI-90 responders were greater for dupilumab
300 mg once a week, 300 mg every 2 weeks, 200 mg every
2 weeks, and 300 mg every 4 weeks (p<0·0001 for each)
and dupilumab 100 mg every 4 weeks (p<0·05) versus
placebo (figure 3B, 3C). Furthermore, more patients in the
dupilumab groups achieved an IGA of 0 (clear) or
1 (almost clear), with the greatest response recorded with
dupilumab 300 mg once a week, 300 mg every 2 weeks,
and 200 mg every 2 weeks (p<0·0001 for each vs placebo),
followed by 300 mg every 4 weeks (p=0·0004 vs placebo)
and 100 mg every 4 weeks (p= 0·0242 vs placebo; table 2).
We also noted marked improvement from baseline to
week 16 in SCORAD score with all dose regimens of
dupilumab (p<0·0001 for each except 100 mg every 4 weeks
[p=0·0172]) versus placebo (table 2, figure 2B).
Least-squares mean percentage change in SCORAD score
from baseline favoured dupilumab versus placebo as early
as week 1 (300 mg once a week, p=0·0027; 300 mg every
2 weeks and 200 mg every 2 weeks, p=0·0002 for each;
300 mg every 4 weeks, p<0·0001; and 100 mg every
4 weeks, p=0·0006; figure 2B, appendix). As with other
endpoints, improvement in SCORAD score appeared to be
dose-dependent, with the greatest improvement recorded
for dupilumab 300 mg once a week and 300 mg every
2 weeks.
Additionally, dupilumab showed a greater improvement
versus placebo from baseline to week 16 for percentage of
body surface area with atopic dermatitis involvement
(p<0·0001 for each dose regimen except 100 mg every
4 weeks [p=0·0313]; table 2, figure 2C, appendix). Least-
squares mean percentage change in percentage of body

A B
100 100

90 90
Proportion of patients achieving EASI-50 (%)

Proportion of patients achieving EASI-75 (%)

80 80

70 70

60 60

50 50

40 40

30 30

20 20

10 10

0 0
0 4 8 12 16 0 4 8 12 16
Week Week
C
100

90
Proportion of patients achieving EASI-90 (%)

80

70 A
Placebo Dupilumab 200 mg every 2 weeks‡
60
Dupilumab 100 mg every 4 weeks* Dupilumab 300 mg every 2 weeks†
Dupilumab 300 mg every 4 weeks† Dupilumab 300 mg once a week†
50

40
B
Placebo Dupilumab 200 mg every 2 weeks||
Dupilumab 100 mg every 4 weeks§ Dupilumab 300 mg every 2 weeks**
30
Dupilumab 300 mg every 4 weeks¶ Dupilumab 300 mg once a week**
20
C
Placebo Dupilumab 200 mg every 2 weeks§§
10
Dupilumab 100 mg every 4 weeks†† Dupilumab 300 mg every 2 weeks¶¶
0 Dupilumab 300 mg every 4 weeks‡‡ Dupilumab 300 mg once a week||||
0 4 8 12 16
Week

Figure 3: Proportion of patients achieving EASI-50 (A), EASI-75 (B), or EASI-90 (C), defined as a 50%, 75%, or 90% reduction from baseline, respectively, in the
EASI score
EASI=Eczema Area and Severity Index. *p<0·05 vs placebo, weeks 1–2 and weeks 8–14; p≤0·0001, weeks 3–6; and p=0·0797, week 16. †p<0·05, weeks 1–2; and
p≤0·0001 vs placebo, weeks 3–16. ‡p<0·05, weeks 2 and 10; p≤0·0001 vs placebo, weeks 3–8 and weeks 12–15; and p=0·0003, week 16. §p<0·05 vs placebo, weeks
2–3 and weeks 8–16; p≤0·0001, weeks 4 and 6; and p=0·0147, week 16. ¶p<0·05, week 2; and p≤0·0001 vs placebo, weeks 3–16. ||p<0·05, weeks 2–6; and p≤0·0001
vs placebo, weeks 8–16. **p<0·05, weeks 2 and 3; and p≤0·0001 vs placebo, weeks 4–16. ††p<0·05 vs placebo, weeks 3–6 and 10–16; and p=0·0242, week 16.
‡‡p<0·05, weeks 3–12; and p≤0·0001 vs placebo, weeks 14–16. §§p<0·05, weeks 4–12; and p≤0·0001 vs placebo, weeks 14–16. ¶¶p<0·05, weeks 3–10; and p≤0·0001,
weeks 12–16. ||||p<0·05, weeks 3–8; and p≤0·0001 vs placebo, weeks 10–16. Exact p values are listed in the appendix.

8 www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8

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surface area affected favoured dupilumab versus placebo
as early as week 1 (200 mg every 2 weeks, p=0·0009;
300 mg every 4 weeks, p=0·0004; and 100 mg every
4 weeks, p=0·0053) and week 2 (300 mg once a week,
p=0·0032; and 300 mg every 2 weeks, p=0·0242; figure 2C,
appendix). The greatest improvement in percentage of
body surface area with atopic dermatitis involvement was
recorded for dupilumab 300 mg once a week.
Importantly, along with improvement in objective
measures of clinical efficacy, treatment with dupilumab
resulted in marked improvement in patients’ assessment
of pruritus as measured by the pruritus NRS score at
week 16 (table 2), with significant reduction as early as
week 1 (dupilumab 300 mg once a week, p=0·0012;
300 mg every 2 weeks, p=0·0013; 200 mg every 2 weeks,
p=0·0079; 300 mg every 4 weeks, p=0·0161; and 100 mg
every 4 weeks, p=0·0013 vs placebo; figure 2D, appendix).
Improvement in peak weekly pruritus NRS scores
appeared to be dose-dependent: at week 16, all dupilumab
dose regimens, except for 100 mg every 4 weeks, resulted
in least-squares mean percentage reductions in pruritus
of roughly 33–47% (p<0·0001 vs placebo), with the
greatest improvement reported for doses of 300 mg every
2 weeks and 300 mg once a week. Dupilumab also
resulted in a greater proportion of pruritus NRS
responders (defined as those achieving improvement in
pruritus NRS scores of ≥3) at week 16 for each dose
regimen compared with placebo (table 2). Because
pruritus NRS was not an enrolment criterion, 17 patients
(placebo: n=2; dupilumab: 300 mg once a week, n=2;
300 mg every 2 weeks, n=3; 200 mg every 2 weeks, n=4;
300 mg every 4 weeks, n=4; and 100 mg every 4 weeks,
n=2) enrolled with scores lower than 3, and thus were
treated as non-responders in the analysis. Additionally,
dupilumab resulted in improvement of patients’
assessment of quality of life: dupilumab improved DLQI

All dupilumab Dupilumab Dupilumab Dupilumab Dupilumab Dupilumab Placebo once a

combined 300 mg once 300 mg every 200 mg every 300 mg every 100 mg every week (n=61)
(n=318) a week (n=63) 2 weeks (n=64) 2 weeks (n=61) 4 weeks (n=65) 4 weeks (n=65)
Total number of treatment-emergent adverse events 1131 256 207 207 212 249 184
Total number of serious treatment-emergent adverse events† 16 1 2 3 3 7 4
Patients with:
Any treatment-emergent adverse event 258 (81%) 53 (84%) 50 (78%) 46 (75%) 56 (86%) 53 (82%) 49 (80%)
Any serious treatment-emergent adverse event 12 (4%) 1 (2%) 2 (3%) 1 (2%) 3 (5%) 5 (8%) 4 (7%)
Discontinuation due to treatment-emergent adverse event 21 (7%) 1 (2%) 4 (6%) 3 (5%) 3 (5%) 10 (15%) 3 (5%)
Upper respiratory tract infections (HLT) 119 (37%) 24 (38%) 24 (38%) 18 (30%) 28 (43%) 25 (39%) 25 (41%)
Nasopharyngitis (PT) 89 (28%) 16 (25%) 16 (25%) 16 (26%) 21 (32%) 20 (31%) 16 (26%)
Upper respiratory tract infection (PT) 23 (7%) 5 (8%) 6 (9%) 2 (3%) 5 (8%) 5 (8%) 11 (18%)
Bacterial infections NEC (HLT) 25 (8%) 7 (11%) 4 (6%) 4 (7%) 4 (6%) 6 (9%) 7 (12%)
Herpes viral infections (HLT) 26 (8%) 3 (5%) 5 (8%) 6 (10%) 4 (6%) 8 (12%) 1 (2%)
Oral herpes (PT) 13 (4%) 0 3 (5%) 2 (3%) 3 (5%) 5 (8%) 0
Herpes simplex (PT) 12 (4%) 1 (2%) 2 (3%) 3 (5%) 1 (2%) 5 (8%) 0
Eczema herpeticum (PT) 2 (<1%) 1 (2%) 0 1 (2%) 0 0 0
Herpes virus infection (PT) 1 (<1%) 0 0 0 0 1 (2%) 0
Herpes zoster (PT) 1 (<1%) 1 (2%) 0 0 0 0 1 (2%)
Skin structures and soft tissue infections (HLT) 21 (7%) 3 (5%) 5 (8%) 5 (8%) 3 (5%) 5 (8%) 5 (8%)
Urinary tract infections (HLT) 19 (6%) 1 (2%) 3 (5%) 6 (10%) 4 (6%) 5 (8%) 4 (7%)
Viral infections NEC (HLT) 17 (5%) 5 (8%) 4 (6%) 2 (3%) 3 (5%) 3 (5%) 6 (10%)
Dermatitis and eczema (HLT) 63 (20%) 12 (19%) 14 (22%) 9 (15%) 12 (19%) 16 (25%) 12 (20%)
Atopic dermatitis exacerbation (PT) 54 (17%) 8 (13%) 14 (22%) 8 (13%) 10 (15%) 14 (22%) 11 (18%)
Headaches NEC (HLT) 34 (11%) 8 (13%) 5 (8%) 9 (15%) 5 (8%) 7 (11%) 2 (3%)
Headache (PT) 34 (11%) 8 (13%) 5 (8%) 9 (15%) 5 (8%) 7 (11%) 2 (3%)
Nausea and vomiting symptoms (HLT) 10 (3%) 2 (3%) 1 (2%) 4 (7%) 1 (2%) 2 (3%) 4 (7%)
Musculoskeletal and connective tissue pain and discomfort (HLT) 15 (5%) 3 (5%) 4 (6%) 1 (2%) 3 (5%) 4 (6%) 5 (8%)
Back pain (PT) 9 (3%) 2 (3%) 2 (3%) 0 2 (3%) 3 (5%) 5 (8%)
Conjunctival infections, irritations, and inflammation (HLT) 21 (7%) 7 (11%) 3 (5%) 6 (10%) 4 (6%) 1 (2%) 2 (3%)
Injection-site reactions (HLT) 22 (7%) 6 (10%) 3 (5%) 4 (7%) 5 (8%) 4 (6%) 2 (3%)

Data are n or n (%). HLT=MedDRA high-level term. PT=MedDRA preferred term. NEC=not otherwise classified. *A patient who reported two or more treatment-emergent adverse events with the same PT was
counted only once for that term; a patient who reported two or more treatment-emergent adverse events with different PTs within the same system organ class was counted only once in that system organ class.
†Treatment-emergent adverse events were categorised as serious if they were life-threatening or resulted in admittance to hospital, disability, congenital anomaly, or death; or were deemed an important
medical event.

Table 3: Treatment-emergent adverse events (MedDRA HLT or PT) occurring in 5% or more of patients in the placebo or combined dupilumab doses groups*

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scores from baseline to week 16 in a dose-dependent
manner for all dose regimens (p<0·0001) except 100 mg
every 4 weeks (table 2).
Dupilumab was well tolerated in this study, with most
treatment-emergent adverse events classified as mild or
moderate. Serious treatment-emergent adverse events
were reported in 12 (4%) of 318 patients in all dupilumab
groups combined and four (7%) of 61 in the placebo group
(table 3; appendix). Serious exacerbations of atopic
dermatitis were balanced in all dupilumab groups
combined (five [2%]) and the placebo group (one [2%];
appendix). Serious infectious treatment-emergent adverse
events were rare in both groups: three (<1%) patients in all
dupilumab groups combined and none in the placebo
group. These events comprised cellulitis (one patient in
the 100 mg every 4 weeks group), peritonsillar abscess
(one patient in the 300 mg every 4 weeks group), and 1 day
admittance to hospital for a presumed viral illness
(one patient in the 300 mg once a week group); the
appendix provides patient narratives. Serious treatment-
emergent adverse events of respiratory disorder were
reported in two (<1%) of 379 patients; asthma in one (2%)
of 65 patients in the dupilumab 100 mg every 4 weeks
group; and respiratory failure associated with anaphylactic
shock due to a nut allergy in one (2%) of 61 patients in the
dupilumab 200 mg every 2 weeks group (appendix).
Treatment-emergent adverse events that led to drug
and study discontinuation were reported in 21 (7%) of
318 patients in all dupilumab groups combined,
including ten from the dupilumab 100 mg every 4 weeks
group, one of whom reported asthma; and three patients
in the placebo group. No patients died during the study.
The most common treatment-emergent adverse events
(MedDRA preferred term) in the combined dupilumab
doses group were nasopharyngitis, exacerbation of atopic
dermatitis, headache, and upper respiratory tract
infection (table 3). Herpes viral infections (MedDRA
high-level term) were more frequent in patients given
dupilumab than in those given placebo (8% vs 2%,
respectively). All herpes viral infections were mild to
moderate, with most cases presenting as simple localised
lesions in the perioral area. Injection-site reactions were
reported in 22 (7%) of 318 patients in the combined
dupilumab doses group and 2 (3%) of 61 patients in the
placebo group; these reactions were not clearly dose-
dependent (table 3). Laboratory values, vital signs, and
electrocardiographic findings were similar between
treatment groups (data not shown).
Discussion
Our results show that treatment with dupilumab provides
significant improvement in the clinical signs and
symptoms of atopic dermatitis in adult patients with
moderate-to-severe atopic dermatitis. Importantly, these
patients had previously had inadequate control of their
atopic dermatitis by standard-of-care topical treatment.
The robustness of these findings was supported by
10 www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8
substantial improvements from baseline with dupilumab
treatment compared with placebo in all major primary and
secondary severity measures, including EASI, IGA, and
SCORAD scores; percentage of body surface area with
atopic dermatitis involvement; measures of symptoms
(ie, pruritus NRS scores); and quality of life (ie, DLQI
scores). Although the study was not powered to compare
different dupilumab dose regimens and differences
between doses were not tested inferentially, we recorded
numerical dose-dependent relationships consistently in
most outcome measures. This finding suggests that the
number of patients and the effect size were sufficient to
discern differences between the dupilumab dosing
regimens. Patients given 300 mg once a week and 300 mg
every 2 weeks dose regimens had better outcomes than
those given the lower doses, with no important differences
in safety parameters. Importantly, the 100 mg every
4 weeks dose group lost the initial response recorded after
the loading dose in all efficacy outcome measures, which
could suggest that stable responses cannot be induced
after short-term treatment and that the 100 mg every
4 weeks dose regimen is suboptimum. Improvements in
disease activity were recorded as early as week 1 and
persisted throughout the study. By week 16, 82·5% of
patients achieved EASI-50, 60·3% achieved EASI-75, and
36·5% achieved EASI-90 in patients given 300 mg
dupilumab once a week, compared with 29·5%, 11·5%,
and 3·3%, respectively, of patients in the placebo group
(p<0·0001 for each). These results are consistent with
those of a previous 12-week, randomised, double-blind,
placebo-controlled phase 2a study of dupilumab in patients
with moderate-to-severe atopic dermatitis, in which
EASI-50 was achieved by 85% (p<0·001) and EASI-75 by
62% (p<0·0001) of patients given 300 mg dupilumab once
a week, compared with 35% and 15%, respectively, of
patients in the placebo group.20 Of note, in the present
study, the placebo group had roughly 20% improvement
from baseline in EASI scores at week 16. This placebo
response rate was consistent with that reported in other
studies of atopic dermatitis.29,30
EASI, IGA, and body surface area scores are based on
objective assessments of disease severity and extent,
whereas pruritus NRS scores are based on patients’
subjective assessment of pruritus; DLQI scores are based
on patients’ assessment of quality of life; and SCORAD
has both objective (extent and severity) and subjective
(pruritus and sleep) assessments. Thus, these endpoints
allow the assessment of different perspectives of
treatment response. Dupilumab resulted in marked
improvements from baseline compared with placebo for
each of the clinical measures, including reductions in the
extent and clinical severity of atopic dermatitis, and
improvements in patients’ experience of their symptoms.
In particular, dupilumab resulted in improvement in
pruritus as measured by the pruritus NRS, which is a
subjective assessment reported by patients. Pruritus is
regarded as a significant contributor to the effect of

atopic dermatitis on quality of life for patients with
moderate-to-severe atopic dermatitis,31,32 and the degree
of benefit potentially provided by dupilumab with regard
to pruritus in this severe population could hopefully be
life-changing for many patients. Indeed, as measured by
the DLQI, we recorded significant improvements in
quality of life during the 16-week study period. Future
studies of longer duration, and in combination with
topical treatment, will supplement these data.
We did not record any dose-limiting toxic effects in this
study. Most treatment-emergent adverse events were
mild or moderate, and there was no imbalance in
treatment-emergent adverse events, serious treatment-
emergent adverse events, or discontinuations due to
treatment-emergent adverse events between the
combined dupilumab doses group and the placebo
group. We recorded an increased incidence of cutaneous
herpes infections in dupilumab-treated patients.
However, there was no direct dose–response relationship;
the greatest incidence of herpes viral infections was
recorded with the lowest dose regimen and vice versa.
Up to now, blockade of IL-4 or IL-13 signalling has not
been implicated as a risk factor for primary cutaneous
herpes simplex infection or reactivation, and increased
incidence of herpesvirus infections has not been reported
in previously published dupilumab clinical trials.20–22 It
will be important to determine if this finding is replicated
in subsequent larger studies; additionally, ongoing
studies will provide more insight into the safety of longer-
term treatment with dupilumab.
In previous early-phase studies in adults with
moderate-to-severe atopic dermatitis, investigators
assessed 75 mg, 150 mg, or 300 mg dupilumab once a
week monotherapy for 4 weeks; 300 mg once a week
monotherapy for 12 weeks; or 300 mg once a week for
4 weeks concurrent with topical glucocorticoids.20 In
these studies, dupilumab resulted in rapid and dose-
dependent improvements in EASI, IGA, pruritus NRS
scores, and EASI-50, and had an acceptable safety
profile.20 The present 16-week phase 2b study confirmed
the efficacy of dupilumab as recorded in these previous
studies and expands on the results. The present study
assessed dupilumab during 16 weeks, the longest
treatment duration reported to date. Also, the present
study assessed several less-frequent dosing regimens,
not used in previous trials, including less-frequent
regimens of doses lower than 300 mg, thereby generating
data to optimise treatment regimens. This is the largest
study done up to now with dupilumab and, therefore,
provides important safety information.
This study had some limitations. We studied
dupilumab use as monotherapy, whereas in clinical
practice dupilumab might be used in combination with
topical drugs. In a phase 2a, 4-week trial of dupilumab in
combination with topical glucocorticoids in 31 patients
with moderate-to-severe atopic dermatitis, 100% of
patients given dupilumab (300 mg once a week) plus
www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8
Articles
topical glucocorticoids achieved EASI-50 and 62%
achieved EASI-75, compared with 50% and 40%,
respectively, of patients given placebo plus topical
glucocorticoids.20 More definitive data for combination
therapy will come from a larger 52-week phase 3 study in
progress (NCT02260986). Additionally, the present study
assessed several dose regimens of dupilumab; although
the study was not powered to directly compare different
dose regimens and between-dose differences were not
tested inferentially, trends for differences could be
discerned, with the 300 mg once a week and 300 mg
every 2 weeks doses providing the most consistent
benefits. Also, although not necessarily a limitation, the
study assessed dupilumab only in adult patients with
atopic dermatitis, and did not provide any information
about its effect in the paediatric population, which has a
higher incidence and prevalence of atopic dermatitis.8–10
A phase 2a clinical trial has been initiated to assess the
clinical efficacy and safety of dupilumab in children with
atopic dermatitis aged between 6 and 18 years
(NCT02407756).
Treatment guidelines recommend the use of systemic
immunosuppressant treatments (eg, systemic gluco-
corticoids, ciclosporin, methotrexate, mycophenolate,
or azathioprine) for patients with moderate-to-severe or
refractory atopic dermatitis when topical drugs or
phototherapy are ineffective.4–6 These broad immuno-
suppressant treatments, although effective, are associated
with adverse effects potentially more severe than those
seen with topical treatments;2–7 thus there is unmet need
for a more targeted treatment.
In the present study, dupilumab showed dose-dependent
efficacy and no dose-limiting toxic effects in adults with
moderate-to-severe atopic dermatitis inadequately
controlled by topical drugs. Dose regimens of 300 mg
dupilumab once a week and 300 mg every 2 weeks
provided the most consistent benefits, and these dose
regimens are now being assessed in phase 3 studies
(NCT02277743, NCT02277769, NCT02395133, and
NCT01949311). Dupilumab is directed against the IL-4Rα
subunit; by binding to IL-4Rα, dupilumab blocks both IL-4
and IL-13 signalling.20 Expression profiling of affected skin
in patients with atopic dermatitis given dupilumab
showed that dupilumab reversed transcriptional
abnormalities that serve as biomarkers of atopic
dermatitis.18 The efficacy of dupilumab in atopic dermatitis
recorded in the present study is consistent with the
outcomes of clinical trials of dupilumab in two other
atopic disorders, asthma21 and chronic sinusitis with nasal
polyposis.22 The emerging data with dupilumab in
multiple atopic diseases provides the first compelling
clinical data to support a single unifying hypothesis
regarding the drivers of allergic and atopic diseases in
general (ie, that IL-4 and IL-13 are key drivers of signs and
symptoms in these clinical settings), and suggests that
their blockade might also be effective in other atopic
settings.
11
 Articles
Contributors
DT, ELS, RW, SPW, NMHG, GP, VM, NS, GDY, and MA conceived of
and designed the study. DT, ELS, LAB, TB, AB, KP, WS, MW, JCS, HS,
and MK acquired the data. All authors contributed to the analysis and
interpretation of the data and the critical revision of the report; are
accountable for the accuracy and integrity of the report; and provided
final approval to submit.
Declaration of interests
DT has current consulting and advisory board agreements or receives
honoraria for lecturing with AbbVie, Amgen, Astellas, Biogen-Idec,
Boehringer Ingelheim, Celgene, Dignity, Dermira, Janssen-Cilag,
Leo Pharma, Mitsubishi, Lilly, MedImmune, MSD, Novartis, Pfizer,
Regeneron Pharmaceuticals, Sandoz, Sanofi, and UCB. ELS has received
grants or research support from Amgen, Celgene, Chugai, Galderma,
and Regeneron Pharmaceuticals, and is a consultant for Anacor, Asubio,
Celgene, Galderma, Genentech, Medicis, and Merck. LAB is an
investigator and consultant for Regeneron Pharmaceuticals, and receives
honoraria, advisory board, or consulting fees from AbbVie, Array
Biopharma, Celgene, Genentech Ironwood, Janssen, Leo Pharma,
MedImmune, Novartis, Regeneron Pharmaceuticals, and Unilever.
TB is an investigator and consultant for Regeneron Pharmaceuticals;
receives honoraria, advisory board, or consulting fees from Astellas,
Atopix, and Novartis; and receives grant support from Astellas, Atopix,
and MSD. AB is an investigator and consultant for AbbVie, Amgen,
Anacor, Boehringer Ingelheim, Celgene, Genentech, Janssen, Lilly,
Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, and Sandoz.
KP has the following declaration of interests: AbbVie (investigator,
consultant, advisory board), Akesis (consultant), Akros (investigator,
consultant), Allergan (investigator, consultant), Alza (investigator,
consultant), Amgen (investigator, consultant, advisory board), Anacor
(investigator, consultant, advisory board), Applied Molecular Evolution
(investigator, consultant), Astellas (investigator, consultant, advisory
board), Baxter (investigator, consultant, advisory board), Bayer
(investigator, consultant, advisory board), Biogen Idec (investigator,
consultant), Celgene (investigator, consultant, advisory board), Celtic
(investigator, consultant), Centocor (investigator, consultant, advisory
board), Cipher (investigator, consultant), Coherus (investigator,
consultant), Dermira (investigator, consultant), Dow Pharma
(investigator, consultant, advisory board), Eli Lilly (investigator,
consultant, advisory board), Forward Pharma (investigator, consultant),
Galderma (investigator, consultant, advisory board), Genentech
(investigator, consultant, advisory board), Genexion (consultant),
GlaxoSmithKline (investigator, consultant, advisory board), Janssen
(investigator, consultant, advisory board), Kyowa Hakko Kirin
(investigator, consultant), Leo Pharma (investigator, consultant, advisory
board), Lypanosys (investigator, consultant), MedImmune (investigator,
consultant, advisory board), Merck (investigator, consultant, advisory
board), Mylan (investigator, consultant), Novartis (investigator,
consultant, advisory board), Pfizer (investigator, consultant, advisory
board), Regeneron Pharmaceuticals (investigator, consultant), Roche
(investigator, consultant), Merck-Serono (investigator, consultant,
advisory board), Stiefel (investigator, consultant, advisory board),
Takeda (investigator, advisory board), and UCB (investigator, consultant,
advisory board). WS is an investigator and consultant for Regeneron
Pharmaceuticals and has received honoraria, advisory board, or
consulting fees from MEDA, Merck, Regeneron Pharmaceuticals, Shire,
and TEVA. MW is an investigator for Regeneron Pharmaceuticals and
receives honoraria, advisory board, or consulting fees provided by
Astellas, Biogen Idec, Leo Pharma, MSD, Novartis, and Pfizer. JCS is on
advisory boards for Leo Pharma, Merck-Serono, Novartis, Pierre-Frabre,
Sandoz, and Toray Corporation; has received fees as a consultant for
AbbVie, Biogenetica International Laboratories; serves as a consultant
for Fresenius, and Toray Corporation; serves on a data monitoring
committee for Sandoz; is a speaker for AbbVie, Actavis, Adamed,
Astellas, Berlin-Chemie/Mennarini, Fresenius, Janssen-Cilag, Leo
Pharma, Mitsubishi Pharma, Novartis, Pfizer, Takeda, and Vichy; and is
an investigator for and has received honoraria from AbbVie, Actelion,
Amgen, Janssen-Cilag, Merck, Mitsubishi Pharma, Novartis, and
Regeneron Pharmaceuticals. HS is an investigator for AbbVie, Amgen,
AstraZeneca, Celgene, Janssen, Genentech, Novartis, and Regeneron
Pharmaceuticals; serves on advisory boards for Celgene, Genentech,
12 www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8
Novartis, and Regeneron Pharmaceuticals; is a consultant for Regeneron
Pharmaceuticals; and has received honoraria from AbbVie, Celgene,
Janssen, Genentech, and Novartis. MK is an investigator for Regeneron
Pharmaceuticals; and receives honoraria, advisory board, or consulting
fees from Daiichi Sankyo Healthcare, Galderma, Maruho, Mitsubishi
Tanabe, and Sanofi.RW, SPW, NMHG, VM, NS, GDY, and MA are
employees and shareholders of Regeneron Pharmaceuticals. GP, AT, and
ERS are employees and shareholders of Sanofi.
Acknowledgments
This study was funded by Sanofi and Regeneron Pharmaceuticals.
Editorial assistance was provided by Vicki Schwartz of Excerpta Medica,
funded by Sanofi and Regeneron Pharmaceuticals. We thank the
patients who participated in this study, the co-investigators for their
contribution to the study (listed in the appendix) and staff at the
participating centres, and the following contributors from the sponsors
for providing support with the publication process and critical review of
the manuscript content: Linda Williams, Warren Brooks, Judith Cusick,
Jacqueline Kuritzky, Diane Roth, Elizabeth Bucknam, Nelson Rita,
Yuhwen Soo, Haobo Ren, Qin Li, Mi Young Kwon, Jennifer Hamilton,
Usman Chaudhry, and Bolanle Akinlade (Regeneron Pharmaceuticals);
and Paul Cavanaugh, Jeffrey Ming, and Pauline Wijnand (Sanofi).
References
1 Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the
management of atopic dermatitis. Section 1. Diagnosis and
assessment of atopic dermatitis. J Am Acad Dermatol 2014; 70: 338–51.
2 Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic
eczema (atopic dermatitis) Part 1. J Eur Acad Dermatol Venereol 2012;
26: 1045–60.
3 Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the
management of atopic dermatitis. Section 2. Management and
treatment of atopic dermatitis with topical therapies.
J Am Acad Dermatol 2014; 71: 116–32.
4 Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic
eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol
2012; 26: 1176–93.
5 Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the
management of atopic dermatitis. Section 3. Management and
treatment with phototherapy and systemic agents.
J Am Acad Dermatol 2014; 71: 327–49.
6 Katayama I, Kohno Y, Akiyama K, et al. Japanese guidelines for
atopic dermatitis 2014. Allergol Int 2014; 63: 377–98.
7 Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J. Efficacy and
safety of systemic treatments for moderate-to-severe atopic dermatitis:
a systematic review. J Allergy Clin Immunol 2014; 133: 429–38.
8 Muto T, Hsieh SD, Sakurai Y, et al. Prevalence of atopic dermatitis
in Japanese adults. Br J Dermatol 2003; 148: 117–21.
9 Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI,
and the ISAAC Phase Three Study Group. Global variations in
prevalence of eczema symptoms in children from ISAAC Phase
Three. J Allergy Clin Immunol 2009; 124: 1251–58.
10 Silverberg JI, Hanifin JM. Adult eczema prevalence and
associations with asthma and other health and demographic factors:
a US population-based study. J Allergy Clin Immunol 2013;
132: 1132–38.
11 McKenna SP, Doward LC. Quality of life of children with atopic
dermatitis and their families. Curr Opin Allergy Clin Immunol 2008;
8: 228–31.
12 Asher MI, Montefort S, Björkstén B, et al. Worldwide time trends
in the prevalence of symptoms of asthma, allergic
rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One
and Three repeat multicountry cross-sectional surveys. Lancet
2006; 368: 733–43.
13 Punekar YS, Sheikh A. Establishing the incidence and prevalence of
clinician-diagnosed allergic conditions in children and adolescents
using routinely collected data from general practices.
Clin Exp Allergy 2009; 39: 1209–16.
14 Chandra RK, Lin D, Tan B, et al. Chronic rhinosinusitis in the
setting of other chronic inflammatory diseases. Am J Otolaryngol
2011; 32: 388–91.
15 Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity
in patients with atopic dermatitis. J Allergy Clin Immunol 2013;
131: 428–33.

16 Simpson EL. Comorbidity in atopic dermatitis. Curr Dermatol Rep
2012; 1: 29–38.
17 Kaesler S, Volz T, Skabytska Y, et al. Toll-like receptor 2 ligands
promote chronic atopic dermatitis through IL-4–mediated
suppression of IL-10. J Allergy Clin Immunol 2014; 134: 92–99.
18 Hamilton JD, Suárez-Fariñas M, Dhingra N, et al. Dupilumab
improves the molecular signature in skin of patients with
moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 2014;
134: 1293–300.
19 Suárez-Fariñas M, Dhingra N, Gittler J, et al. Intrinsic atopic
dermatitis shows similar TH2 and higher TH17 immune activation
compared with extrinsic atopic dermatitis.
J Allergy Clin Immunol 2013; 132: 361–70.
20 Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in
adults with moderate-to-severe atopic dermatitis. N Engl J Med 2014;
371: 130–39.
21 Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent
asthma with elevated eosinophil levels. N Engl J Med 2013;
368: 2455–66.
22 Bachert C, Mannent L, Naclerio RM, et al. Dupilumab in chronic
sinusitis with nasal polyposis, with and without asthma. Allergy
2015; 70 (suppl 1): 107 (abstr 1516).
23 Leshem YA, Hajar T, Hanifin JM, Simpson EL. What the Eczema
Area and Severity Index score tells us about the severity of atopic
dermatitis: an interpretability study. Br J Dermatol 2015;
172: 1353–57.
24 Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity:
prospective study on validity and reliability of the visual analogue
scale, numerical rating scale and verbal rating scale in 471 patients
with chronic pruritus. Acta Derm Venereol 2012; 92: 502–07.
www.thelancet.com Published online October 8, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00388-8
Articles
25 Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M.
The eczema area and severity index (EASI): assessment of reliability
in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;
10: 11–18.
26 European Task Force on Atopic Dermatitis. Severity scoring of
atopic dermatitis: the SCORAD index. Consensus report of the
European Task Force on Atopic Dermatitis. Dermatology 1993;
186: 23–31.
27 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI):
a simple practical measure for routine clinical use.
Clin Exp Dermatol 1994; 19: 210–16.
28 Schmitt J, Spuls PI, Thomas KS, et al. The Harmonising Outcome
Measures for Eczema (HOME) statement to assess clinical signs of
atopic eczema in trials. J Allergy Clin Immunol 2014; 134: 800–07.
29 Eichenfield LF, Miller BH, on behalf of a Cutivate Lotion Study
Group. Two randomized, double-blind, placebo-controlled studies
of fluticasone propionate lotion 0.05% for the treatment of atopic
dermatitis in subjects from 3 months of age. J Am Acad Dermatol
2006; 54: 715–17.
30 Bangert C, Strober BE, Cork M, et al. Clinical and cytological effects
of pimecrolimus cream 1% after resolution of active atopic
dermatitis lesions by topical corticosteroids: a randomized
controlled trial. Dermatology 2011; 222: 36–48.
31 Chrostowska-Plak D, Reich A, Szepietowski JC. Relationship
between itch and psychological status of patients with atopic
dermatitis. J Eur Acad Dermatol Venereol 2013; 27: e239–42.
32 Sánchez-Pérez J, Daudén-Tello E, Mora AM, Surinyac NL. Impact of
atopic dermatitis on health-related quality of life in Spanish
children and adults: the PSEDA study. Actas Dermosifiliogr 2013;
104: 44–52.
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