Accepted Manuscript

Placebo-responses in randomized controlled trials for systemic therapy in atopic

dermatitis: a systematic review and meta-analysis

Harrison H. Lee, BS, Kevin R. Patel, BS, Supriya Rastogi, BA, Vivek Singam, BLA,
Paras P. Vakharia, PharmD, Rishi Chopra, MS, Jonathan I. Silverberg, MD, PhD,
MPH
PII: S0190-9622(19)30970-3
DOI: https://doi.org/10.1016/j.jaad.2019.05.102
Reference: YMJD 13531

To appear in: Journal of the American Academy of Dermatology

Received Date: 3 April 2019

Revised Date: 10 May 2019
Accepted Date: 30 May 2019

Please cite this article as: Lee HH, Patel KR, Rastogi S, Singam V, Vakharia PP, Chopra R, Silverberg
JI, Placebo-responses in randomized controlled trials for systemic therapy in atopic dermatitis: a
systematic review and meta-analysis, Journal of the American Academy of Dermatology (2019), doi:
https://doi.org/10.1016/j.jaad.2019.05.102.

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 ACCEPTED MANUSCRIPT

Placebo-responses in randomized controlled trials for systemic therapy in atopic

dermatitis: a systematic review and meta-analysis

Short title: Placebo-responses in AD

Harrison H Lee, BS1, Kevin R Patel, BS1, Supriya Rastogi, BA1, Vivek Singam, BLA1, Paras P.
Vakharia, PharmD1, Rishi Chopra, MS1, Jonathan I. Silverberg, MD, PhD, MPH2,3

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1. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago,
IL

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2. Department of Dermatology, Preventive Medicine and Medical Social Sciences, Northwestern
University Feinberg School of Medicine, Chicago, IL
3. Northwestern Medicine Multidisciplinary Eczema Center, Chicago, IL

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Word count abstract: 200
Word count text: 2,464
Capsule summary: 43

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Figures: 2
Tables: 1
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Supplemental Figure: 3 (available at https://data.mendeley.com/datasets/nxs2z5z5jr/1)

Abbreviations used: AD, atopic dermatitis; RCT, randomized controlled trial; SCORAD index,
Scoring Atopic Dermatitis index; EASI, Eczema Area and Severity Index; IGA, Investigator’s
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Global Assessment, DLQI, dermatology life quality index

Key words: atopic dermatitis; eczema; randomized controlled trial; systematic review; meta-
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analysis; placebo-responses; systemic therapy

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Corresponding author:
Jonathan I. Silverberg, MD, PhD, MPH
676 N. Saint Clair St
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Suite 1600
Chicago, IL 60611
Phone: 312-503-4985
Fax: 312-695-0537
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Email: JonathanISilverberg@Gmail.com
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JI Silverberg had full access to all the data in the study and takes responsibility for the integrity
of the data and accuracy of the data analysis.
Study concept and design: JI Silverberg
Acquisition of Data: P Vakharia, R Chopra, HH Lee, KR Patel, V Singam, S Rastogi
Analysis and interpretation of data: JI Silverberg, HH Lee, P Vakharia, R Chopra
Drafting of the manuscript: JI Silverberg, HH Lee
Critical revision of the manuscript for important intellectual content: JI Silverberg, HH Lee, KR
Patel, P Vakharia, R Chopra
Statistical analysis: HH Lee, J Silverberg
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Obtained funding: JI Silverberg

Administrative technical or material support: None
Study supervision: None
Financial disclosures: None
Funding Support: This publication was made possible with support from the Dermatology
Foundation.
Design and conduct of the study? No

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Collection, management, analysis and interpretation of data? No
Preparation, review, or approval of the manuscript? No
Decision to submit the manuscript for publication? No

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Conflicts of interest: There are no conflicts of interest to declare for JI Silverberg, HH Lee, KR
Patel, PP Vakharia, R Chopra, V Singam, or S Rastogi.

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Abstract

Background: Atopic dermatitis (AD) has variable disease course, intermittent triggers, and

responses to topical therapy, which may impact placebo-response in AD trials.

Objective: To determine the predictors of placebo-response in randomized controlled trials

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(RCT) of AD.

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Methods: We performed a systematic review and meta-analysis of RCT for systemic therapy in

AD from 2007-2018. Cochrane Library, MEDLINE, EMBASE, GREAT, LILACS and Scopus

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were searched. Two authors performed study selection and data extraction. Multivariable mixed

models were constructed for Cohen’s D of EASI, SCORAD, NRS-/VAS-itch and DLQI.

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Results: Overall, 64 RCT were included. Use of concomitant prescription topical therapy, study
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duration ≥3 months, and fewer treatment arms were associated with increased placebo-response

for EASI, NRS-/VAS-itch and DLQI. For EASI, placebo-response was increased in studies with
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a higher proportion of males, mild-moderate mean baseline EASI scores, and no blinding. For
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NRS-/VRS-itch, placebo-response was associated with a higher proportion of males, moderate-

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severe mean baseline itch scores. For DLQI, placebo-response was associated with a higher

proportion of males, moderate-severe mean baseline itch scores.

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Conclusions: Placebo-responses can be reduced in clinical trials of systemic therapy in AD by

incorporating double/triple-blinding, balancing the sex distribution of patients, disallowing

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concomitant prescription topical therapy, and having shorter study duration.

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Introduction

Strong placebo-responses can lead to non-significant differences from an investigational

drug and impact the interpretation of clinical trials. Understanding of the predictors of placebo-

responses is essential for appropriate study design, sample size calculation, and interpretation of

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results. However, little is known about predictors of placebo-responses in AD trials. Due to the

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lack of evidence justifying the decision making for study designs, there is considerable

heterogeneity among AD trial designs, inclusion criteria and outcomes9-11.

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Variable clinical course and persistence of AD likely plays an important role in clinical

trials. More severe disease, older age of onset, and already persistent disease were found to be

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predictors of prolonged AD persistence5. AD is influenced by climate6 and other environmental
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factors7. Seasonal and other intermittent triggers may result in AD patients experiencing self-

limited flares that abate with resolution of triggers. AD patients have variable responses to
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emollients and prescription topical therapy, which certainly impact the long-term control of AD
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signs and symptoms. All of these nuances may impact the course and placebo-responses of AD
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patients in the clinical setting and enrolled in clinical trials. Patients may experience spontaneous

disease remittance in the clinical setting owing to one or more of these factors. In addition, there
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is a well-established phenomenon of placebo-response, which has complex neurobiological

mechanisms8. We sought to determine the predictors of placebo-responses in randomized

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controlled trials (RCT) of systemic therapy in AD.

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Methods

Literature search

The following databases were searched for articles from January 1, 2007 to January 21,

2018: Cochrane Library, MEDLINE, EMBASE, Global Resource of EczemA Trials (GREAT),

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Latin American and Caribbean Health Sciences (LILACS) and Scopus. The search strategy was

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based on a previous Cochrane review of AD12 and results were limited to clinical trials in human

subjects (Table 1).

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Inclusion criteria were: any RCT with a systemic pharmacological intervention (oral,

subcutaneous, intramuscular, intravenous or other systemic route), with a placebo control group,

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published online, in print, or in press, in any language from January 1, 2007 to January 21, 2018.
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Exclusion criteria were studies of complementary or alternative medicine or that did not evaluate

a systemic pharmacological therapy. Title and abstract review was performed independently by
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at least two reviewers (H.L., K.P., R.C. P.V.), with conflicts resolved by discussion. Studies were
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excluded based on the title and/or abstract if there was no clear indication they were RCT of
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systemic therapy in AD. The remaining articles underwent full-text review. If data were

duplicated in more than one study, the most recent and complete study was included.
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This study was exempt from Institutional Review Board approval at Northwestern

University Feinberg School of Medicine as data were gathered from published literature.
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Data extraction

The following data were collected: first author; year of publication; funding source; study

design; comparison/control arm; geographical region; type of intervention; number of patients;

distribution of age, gender, race/ethnicity; individual outcome measures, including values at

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baseline and all available follow-up time-points; target population; severity inclusion criteria

thresholds; concurrent prescription topical therapy usage; and emollient use.

Missing data were requested from the corresponding and/or secondary authors of each

manuscript. Graphical data were extracted using WebPlotDigitizer (Austin, TX).

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Data analysis

Whenever possible, all outcome measures were converted to mean and standard deviation

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(SD). Median and range were converted to mean ([minimum+2*median+maximum]/4) and SD

(square root [[1/12]*[[[minimum-2*median+maximum][minimum-

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2*median+maximum]/4]+[maximum-minimum]*[maximum-minimum]]]. 95% CI of a mean
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was converted to SD (square root[[[high 95% CI–mean)/1.96]/N]).

Standardized effect-sizes were estimated using Cohen’s D ([meanbaseline–

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meanoutcome]/SDwithin-study), where SDwithin-study=square-root[((Nbaseline–1)*SDbaseline2+(Noutcome–

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1)*SDoutcome2)/(Nbaseline+Noutcome–2)]. A higher magnitude of Cohen’s D indicates a greater effect-

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size for improvement of an outcome compared to baseline.

In several studies, the SD for outcome measures were reported as absolute or relative
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percent change. SDwithin-study was estimated in those instances by SDbaseline*square-root(2*(1-rho))

where rho is the correlation between pre and post measures. Sensitivity analyses were performed
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for rho of 0, 0.25, 0.50, and 0.75.

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Multivariable generalized linear mixed models were constructed to determine the

association of potential predictors of placebo-response. The dependent variables were Cohen’s D

for EASI, SCORAD, NRS-/VAS-itch and DLQI. The independent variables were concomitant

prescription topical therapy usage (allowed, not), mean age of study participants (< 18, ≥18
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years), percent females (<50, ≥50%), outcome measure timepoint (<3, ≥3 months), number of

treatment arms (≤2, >2 arms including placebo group), baseline severity (severe vs. mild-

moderate, moderate-severe vs. mild), and blinding (double/triple, none/unspecified). Differences

in least square means and 95% CI were estimated. P<0.05 was considered statistically significant

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for all analyses.

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All statistical analyses were generated using SAS version 9.4 (SAS Institute, Cary, NC).

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Results

Literature search

Overall, 15,549 non-duplicate citations were identified in the database search; 14,071

were excluded during title/abstract review; 1414 were excluded during full-text review. In total,

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64 RCT met inclusion/exclusion criteria (all English language) and were included in this

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systematic review as outlined in the Preferred Reporting Items for Systematic Reviews and

Meta-Analyses17 flow diagram (Figure 1).

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Study characteristics

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The studies were published from 2007-2018, and conducted across 38 countries, with a
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mean age of 26.8 years (range: 0.4-44.9 years), and 45.99% females in the placebo arms. Thirty-

two (50.0%) studies included adults, 25 (39.1%) children, and 7 (10.9%) both children and
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adults. Race/ethnicity was reported in only 22 (34.4%) trials, with only 10 (15.6%) reporting any
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black subjects. The regional distribution included: 10 (15.6%) multi-continental, 27 (42.2%)

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Asia, 22 (34.4%) Europe, 3 (4.7%) North America, 1 (1.6%) Australia, and 1 (1.6%) unspecified.

Trial interventions included: oral biologic (n=2, 3.1%), other oral agents (n=44, 68.8%),
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injectable biologic (n=16, 25%) and other injectable (n=2, 3.1%) agents. Both oral biologic agent

trials were conducted internationally.

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Sixty-two (96.9%) studies specified whether prescription topical therapy was allowed,
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with 49 (76.6%) allowing and 13 disallowing (20.3%) usage. Only 54 (84.4%) specified whether

emollient use was allowed, with 52 (81.3%) allowing and 2 (3.1%) disallowing usage. Most

studies were double-blinded (n=56, 87.5%), with fewer unblinded (n=2, 3.1%) or not mentioning

whether blinding was performed (n=6, 9.4%). Only 37 (57.8%) specified the target severity of
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the study population, including moderate-to-severe (n=23, 35.9%), mild-to-moderate (n=8,

12.5%), mild-to-severe (n=2, 3.1%), moderate (n=2, 3.1%), and severe (n=2, 3.1%).

Outcome measures

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Many (n=67) different outcome measures were used. For AD signs, 9 (13.4%) different

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measures were used, e.g. Eczema Area and Severity Index [EASI], objective-Scoring AD

[SCORAD] index. For AD symptoms, 13 (19.4%) different measures were used, e.g. Numerical

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Rating Scale [NRS] or Visual Analog Scale [VAS]-itch. For quality of life, 10 (14.9%) measures

were used, e.g. Dermatology Life Quality Index [DLQI]). Thirty-four (50.7%) different

laboratory tests were assessed.

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The most commonly used outcome measures were NRS/VAS-itch (n=206 observations),

SCORAD (n=143), and EASI (n=106). There was a broad range of baseline mean severity levels
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across studies for SCORAD (6.2-81.0), EASI (5.8-37.4), NRS/VAS-itch (2.9-7.8) and DLQI
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(4.8-17.9). Overall, the mean (std. dev.) percent decreases for these outcome measures were
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22.4% (18.4%), 28.3% (13.8%), 14.1% (13.1%) and 25.8% (14.2%) in the placebo group,

respectively.
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Impact of baseline characteristics

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In multivariable mixed models of Cohen’s D for EASI scores (n=56 observations) with a
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rho of 0.25, significantly increased effect-size was observed in the placebo arms of studies with a

higher proportion of males. Lower effect-sizes were observed in studies with severe vs. mild-

moderate mean baseline EASI scores (Figure 2).

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For SCORAD (n=63 observations), there were no significant differences of effect-size in

the placebo arms of studies based on the proportion of females, mean age or baseline SCORAD

moderate-severe vs. mild.

For NRS/VAS-itch (n=113 observations), increased effect-size was also observed in the

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placebo arms of studies with a higher proportion of males. However, studies with moderate-

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severe vs. mild baseline NRS/VAS-itch had increased placebo-response. There were no

observations with mean age <18 years that reported NRS/VAS-itch.

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For DLQI (n=30 observations), increased effect-size was observed in the placebo arm of

studies with baseline severe vs. mild-moderate DLQI. However, there were no significant

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differences of placebo-responses in studies based on the proportion of females. There were no
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studies with mean age <18 years that reported DLQI.
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Impact of study design

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Increased effect-size (Cohen’s D) was observed in the placebo arm of studies with vs.
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without concomitant prescription topical therapy for EASI and for NRS/VAS-itch, with

numerically increased effect-size for DLQI, and no differences for SCORAD.

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Moreover, studies with double/triple vs. no/single/unspecified blinding of treatment

allocation had decreased effect-size in the placebo arm for EASI, but not SCORAD or
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NRS/VAS-Itch. No unblinded or single-blinded studies were performed that used DLQI.

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Studies with 2 (including placebo) vs. ≥3 arms had increased placebo-response for EASI,

NRS/VAS-itch, and DLQI; but no significant differences for SCORAD.

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Increased placebo effect-sizes were seen for EASI, NRS/VAS-itch, and DLQI endpoints

when assessed at time-points ≥3 months compared to earlier time-points; there were only

numerically increased effects for SCORAD assessed at ≥3 vs. <3 months.

Similar results were found for all analyses in sensitivity analyses using models with rho

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of 0, 0.5 and 0.75 (Supplemental Figures 1-3. Available at

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https://data.mendeley.com/datasets/nxs2z5z5jr/1). The only difference was for EASI scores by

baseline EASI severity, which was significant for rhos of 0 and 0.25, but not 0.5 and 0.75.

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Discussion

There were high placebo-responses observed for AD signs (EASI, SCORAD), symptoms

(NRS-/VAS-itch) and QOL (DLQI). However, each outcome measure performed differently. For

EASI, NRS-/VAS-itch and DLQI, study duration ≥3 months was associated with significantly

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increased placebo-response, but only numerically increased for SCORAD. EASI scores showed

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increased placebo-responses in studies that were unblinded, and had only 2 treatment arms, mild-

moderate severity at baseline, more males, and allowed concomitant topical therapy. NRS-/VAS-

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itch scores also showed increased placebo-responses in studies that had more males, concomitant

topical therapy, only 2 treatment arms, and severe itch at baseline. DLQI scores also showed

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increased placebo-responses in studies of patients that had more severe QOL impairment at
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baseline and had only 2 treatment arms. There were no additional significant predictors of

placebo-responses in SCORAD. These findings are important considerations in clinical trial

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design, as strong placebo-responses can lead to non-significant differences from an

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investigational drug.
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A previous meta-analysis examined reduction of itch in the placebo groups of RCTs in

AD, psoriasis, or urticaria18. In that meta-analysis, placebo-responses for itch were greater in the
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RCTs of systemic therapy in psoriasis and urticaria than for topical therapy in AD. The authors

suggested that patients had higher expectations with the systemic route of administration used in
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the psoriasis (-1.04) and urticaria (-1.71) studies compared to topical therapy in the AD studies (-
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0.75). We found similar placebo-responses for itch (-1.02 or -14.1%) as in the aforementioned

studies of topical therapy in AD. The findings of both studies demonstrate high placebo-

responses of AD symptoms and signs in clinical trials, which are influenced by study design and

clinical factors19, 20.

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Previous studies regarding the placebo-effects on itch examined potential mechanisms

(expectancy learning, conditioning, visual or verbal cues) and individual patient traits

(neuroticism, pessimistic vs. optimistic) that may predispose patients to placebo-response21-23.

They found that expectation mechanisms, e.g. persistent worrying about negative consequences

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and personality traits, e.g. neuroticism were consistent predictors of itch severity. None of these

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studies examined AD patients specifically.

We found decreased placebo-response in EASI and increased placebo-response in NRS-

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itch and DLQI with higher baseline severity. A systematic review and meta-analysis of 75

studies across medicine examined the predictors of placebo-response. The most consistent factor

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for increased placebo-response was lower baseline severity, demonstrated in 18 studies across
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multiple disorders24. However, there were 5 neurological and psychiatric studies in their analysis

and multiple studies not included in their analysis that demonstrated an opposite association
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where higher baseline severity was a predictor for increased placebo-response24-26. Higher
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baseline severity may differentially impact placebo-responses of for different outcome measures
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in AD.

EASI and NRS-/VAS-itch had increased placebo-responses in studies with male

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predominance. In contrast, three studies of neuro-psychiatric conditions found increased placebo-

response in studies with higher proportions of females24. Most studies found no association
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between sex and placebo-responses28, 29. The male predominance found with EASI and NRS-
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/VAS-itch placebo-responses may be attributable to confounding from other study quality issues.

However, there may be disease specific differences for males having increased placebo-response

in AD.
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Studies allowing concomitant use of prescription topical therapy had increased placebo-

responses for EASI and NRS-/VAS-itch scores, but not for SCORAD. Many RCT in AD

allowed use of concomitant TCS to be more “real-world” and bolster participant recruitment and

retention. A position statement by the International Eczema Council identified two contrasting

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issues: disallowing TCS during RCTs may bias toward select less severe patients and

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subsequently increase placebo-response; whereas, permitting TCS usage dramatically increases

placebo-response. Either position may inflate placebo-responses and limit the interpretation of

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effect-size for an intervention34-36.

Unblinded studies compared to double or triple blinded studies had increased placebo-

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responses for EASI scores. This finding may be attributable to confounding effects of poor study
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design in unblinded studies. Alternatively, patients receiving placebo in unblinded clinical trials

may experience co-intervention bias, by maximizing use of all permitted medications (e.g. TCS)
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and even trying therapies outside the study protocol37.

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Fewer treatment arms was associated with increased placebo-response for EASI, NRS-
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/VAS-itch and DLQI. Increased number of treatment arms contributes increases the probability

that a study participant receives placebo and expectations for disease improvement. Other studies
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also found relationships between higher probability of receiving drug to placebo-responses25, 38.

Strengths of this study include use of a comprehensive literature search, examination of

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multiple AD outcomes, multivariable models to simultaneously adjust for clinical and design
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factors, and exclusion of non-placebo controlled RCT. There are potential limitations. Season of

subject enrollment was unavailable in virtually any studies. Therapeutic studies of inflammatory

diseases may have higher placebo/vehicle effects when they end in the summer months. Future

studies should specify the months of subject enrollment and consider stratifying results by season
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of enrollment/completion. Our results are not generalizable to studies of topical therapy in AD.

There was considerable heterogeneity in the outcome measures used (52 different outcome

measures). The inconsistent use of outcome measures limited the number of studies that could be

included in the meta-analysis. The Harmonizing Outcome Measures in Eczema group reached

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international consensus that EASI is the preferred measure for AD signs in clinical trials39. While

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no consensus was achieved on a preferred QOL measure, DLQI and ADQOL were considered as

potential options40. More consistent use of EASI and DLQI/ADQOL in future studies should

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allow for more robust studies of placebo-responses and comparative efficacy.

In conclusion, the results suggest that placebo-responses can be reduced in clinical trials

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of systemic therapy in AD by incorporating double/triple-blinding and balancing the sex
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distribution of patients. Disallowing concomitant prescription topical therapy should reduce

placebo-responses, though other ethical and practical considerations must be weighed. Sample
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size determinations should account for increased placebo-responses in studies ≥3 months

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duration, with fewer treatment arms and different baseline severities. Finally, use of an active
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comparator with another available treatment, as is typically done in studies conducted in Europe,

may mitigate issues of placebo response.

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References

1. Silverberg JI , Simpson EL. Association between severe eczema in children and multiple
comorbid conditions and increased healthcare utilization. Pediatric allergy and
immunology : official publication of the European Society of Pediatric Allergy and
Immunology 2013;24:476-86.
2. Silverberg JI, Garg NK, Paller AS, Fishbein AB , Zee PC. Sleep disturbances in adults with

PT
eczema are associated with impaired overall health: a US population-based study. The
Journal of investigative dermatology 2015;135:56-66.
3. Silverberg JI , Hanifin JM. Adult eczema prevalence and associations with asthma and

RI
other health and demographic factors: a US population-based study. The Journal of allergy
and clinical immunology 2013;132:1132-8.
4. Silverberg JI. Public Health Burden and Epidemiology of Atopic Dermatitis. Dermatol Clin

SC
2017;35:283-9.
5. Kim JP, Chao LX, Simpson EL , Silverberg JI. Persistence of atopic dermatitis (AD): A
systematic review and meta-analysis. Journal of the American Academy of Dermatology
2016;75:681-7 e11.

U
6. Silverberg JI, Hanifin J , Simpson EL. Climatic factors are associated with childhood
eczema prevalence in the United States. The Journal of investigative dermatology
AN
2013;133:1752-9.
7. Hanifin J , Rajka G. Diagnostic features of atopic eczema. Acta dermato-venereologica
1980;92:44-7.
M

8. Zubieta JK , Stohler CS. Neurobiological mechanisms of placebo responses. Annals of the

New York Academy of Sciences 2009;1156:198-210.
9. Chopra RV, P; Simpson, E; Paller, A; Silverberg, JI. Severity assessments used for inclusion
D

criteria and baseline severity evaluation in atopic dermatitis clinical trials: a systematic
review. JEADV 2017.
TE

10. Hoare C, Li Wan Po A , Williams H. Systematic review of treatments for atopic eczema.
Health Technol Assess 2000;4:1-191.
11. Vakharia PP, Chopra R , Silverberg JI. Systematic Review of Diagnostic Criteria Used in
Atopic Dermatitis Randomized Controlled Trials. American journal of clinical dermatology
EP

2017.
12. Nankervis H, Pynn EV, Boyle RJ, Rushton L, Williams HC, Hewson DM et al. House dust
mite reduction and avoidance measures for treating eczema. The Cochrane database of
C

systematic reviews 2015;1:CD008426.

13. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ , Graeber M. The eczema area and
AC

severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group.
Experimental dermatology 2001;10:11-8.
14. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the
European Task Force on Atopic Dermatitis. Dermatology 1993;186:23-31.
15. Reich A, Heisig M, Phan NQ, Taneda K, Takamori K, Takeuchi S et al. Visual analogue
scale: evaluation of the instrument for the assessment of pruritus. Acta dermato-
venereologica 2012;92:497-501.
16. Basra MK, Fenech R, Gatt RM, Salek MS , Finlay AY. The Dermatology Life Quality Index
1994-2007: a comprehensive review of validation data and clinical results. The British
journal of dermatology 2008;159:997-1035.
 ACCEPTED MANUSCRIPT

17. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP et al. The PRISMA
statement for reporting systematic reviews and meta-analyses of studies that evaluate
health care interventions: explanation and elaboration. PLoS Med 2009;6:e1000100.
18. van Laarhoven AIM, van der Sman-Mauriks IM, Donders ART, Pronk MC, van de Kerkhof
PCM , Evers AWM. Placebo effects on itch: a meta-analysis of clinical trials of patients with
dermatological conditions. The Journal of investigative dermatology 2015;135:1234-43.
19. Darragh M, Chang JW, Booth RJ , Consedine NS. The placebo effect in inflammatory skin

PT
reactions: the influence of verbal suggestion on itch and weal size. J Psychosom Res
2015;78:489-94.
20. Papoiu AD, Wang H, Coghill RC, Chan YH , Yosipovitch G. Contagious itch in humans: a

RI
study of visual 'transmission' of itch in atopic dermatitis and healthy subjects. The British
journal of dermatology 2011;164:1299-303.
21. Bartels DJ, van Laarhoven AI, van de Kerkhof PC , Evers AW. Placebo and nocebo effects

SC
on itch: effects, mechanisms, and predictors. Eur J Pain 2016;20:8-13.
22. Darragh M, Booth RJ , Consedine NS. Trait predictors of placebo responses in itch.
Psychol Health Med 2016;21:769-75.
23. Evers AW, Bartels DJ , van Laarhoven AI. Placebo and nocebo effects in itch and pain.

U
Handbook of experimental pharmacology 2014;225:205-14.
AN
24. Weimer K, Colloca L , Enck P. Age and sex as moderators of the placebo response - an
evaluation of systematic reviews and meta-analyses across medicine. Gerontology
2015;61:97-108.
25. Nierenberg AA, Ostergaard SD, Iovieno N, Walker RS, Fava M , Papakostas GI. Predictors
M

of placebo response in bipolar depression. International clinical psychopharmacology

2015;30:59-66.
26. Shin CW, Hahn S, Park BJ, Kim JM, Park EO , Jeon B. Predictors of the placebo response
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in clinical trials on Parkinson's disease: A meta-analysis. Parkinsonism & related disorders

2016;29:83-9.
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27. Meissner K. Preferring patient-reported to observer-reported outcomes substantially

influences the results of the updated systematic review on placebos by Hrobjartsson and
Gotzsche. Journal of internal medicine 2005;257:394; author reply 5-6.
28. Brown WA, Johnson MF , Chen MG. Clinical features of depressed patients who do and
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do not improve with placebo. Psychiatry Res 1992;41:203-14.

29. Bridge JA, Birmaher B, Iyengar S, Barbe RP , Brent DA. Placebo response in randomized
controlled trials of antidepressants for pediatric major depressive disorder. The American
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journal of psychiatry 2009;166:42-9.

30. Rheims S, Cucherat M, Arzimanoglou A , Ryvlin P. Greater response to placebo in
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children than in adults: a systematic review and meta-analysis in drug-resistant partial

epilepsy. PLoS Med 2008;5:e166.
31. Vitiello B, Davis M, Greenhill LL , Pine DS. Blindness of clinical evaluators, parents, and
children in a placebo-controlled trial of fluvoxamine. J Child Adolesc Psychopharmacol
2006;16:219-25.
32. Waschbusch DA, Pelham WE, Jr., Waxmonsky J , Johnston C. Are there placebo effects in
the medication treatment of children with attention-deficit hyperactivity disorder? Journal
of developmental and behavioral pediatrics : JDBP 2009;30:158-68.
33. Rothner AD, Wasiewski W, Winner P, Lewis D , Stankowski J. Zolmitriptan oral tablet in
migraine treatment: high placebo responses in adolescents. Headache 2006;46:101-9.
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34. Paller AS, Kabashima K , Bieber T. Therapeutic pipeline for atopic dermatitis: End of the
drought? The Journal of allergy and clinical immunology 2017;140:633-43.
35. Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K et al.
Guidelines of care for the management of atopic dermatitis: section 2. Management and
treatment of atopic dermatitis with topical therapies. Journal of the American Academy of
Dermatology 2014;71:116-32.
36. Leshem YA, Bissonnette R, Paul C, Silverberg JI, Irvine AD, Paller AS et al. Optimization

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of placebo use in clinical trials with systemic treatments for atopic dermatitis: an
International Eczema Council survey-based position statement. Journal of the European
Academy of Dermatology and Venereology : JEADV 2019.

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37. Hrobjartsson A, Kaptchuk TJ , Miller FG. Placebo effect studies are susceptible to
response bias and to other types of biases. Journal of clinical epidemiology 2011;64:1223-
9.

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38. Freeman R, Emir B , Parsons B. Predictors of placebo response in peripheral
neuropathic pain: insights from pregabalin clinical trials. Journal of pain research
2015;8:257-68.
39. Schmitt J, Spuls PI, Thomas KS, Simpson E, Furue M, Deckert S et al. The Harmonising

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Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema
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in trials. The Journal of allergy and clinical immunology 2014;134:800-7.
40. Heinl D, Prinsen CA, Deckert S, Chalmers JR, Drucker AM, Ofenloch R et al. Measurement
properties of adult quality-of-life measurement instruments for eczema: a systematic
review. Allergy 2016;71:358-70.
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Figure Legends.

Figure 1. PRISMA flow diagram.

Figure 2. Impact of clinical and study design factors on placebo responses for EASI,

SCORAD, NRS-/VAS-itch and DLQI. Multivariate mixed model were constructed with

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Cohen's D for EASI, SCORAD, NRS-/VAS-itch, and DLQI scores as the dependent variable,

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and proportion of subjects who were female (<50%, ≥50%), use of topical prescription therapy

(no, yes), mean age (<18, ≥18 years), time of study endpoint (<3, ≥3 months), number of treatment

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arms (2, ≥3), baseline severity of scores (EASI: <21, ≥21; SCORAD: <25, ≥25; NRS-/VAS-itch: <4, ≥4;

DLQI: <11, ≥11) and study blinding (none/single/unspecified, double/triple). Least squares mean

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estimates and 95% CI were estimated. Difference in least squares mean estimates are plotted in the
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Forest-plot.
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Table 1. Literature search strategies.

Database Search strategy
Cochrane #1 MeSH descriptor: [Dermatitis, Atopic] explode all trees
#2 MeSH descriptor: [Eczema] explode all trees
#3 MeSH descriptor: [Neurodermatitis] explode all trees
#4 "atopic dermatitis":ti,ab,kw (Word variations have been searched)

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#5 "dermatitis atopic":ti,ab,kw (Word variations have been searched)
#6 "childhood eczema":ti,ab,kw (Word variations have been searched)
#7 "infantile eczema":ti,ab,kw (Word variations have been searched)

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#8 "besnier's prurigo":ti,ab,kw (Word variations have been searched)
#9 "neurodermatitis":ti,ab,kw (Word variations have been searched)
#10 "eczema":ti,ab,kw (Word variations have been searched)

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#11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10
Publication Year from 2007 to 2016, in Trials
EMBASE21 Updated: 'atopic dermatitis'/exp OR 'atopic dermatitis' OR 'eczema'/exp OR
'eczema' OR 'neurodermatitis'/exp OR 'neurodermatitis' OR 'atopic

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dermatitis':ab,ti OR 'dermatitis atopic':ab,ti OR 'childhood eczema':ab,ti
OR 'infantile eczema':ab,ti OR 'besniers prurigo':ab,ti OR 'eczema':ab,ti OR
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'neurodermatitis':ab,ti AND [2007-2016]/py AND ('crossover procedure':de
OR 'double-blind procedure':de OR 'randomized controlled trial':de OR
'single-blind procedure':de OR random*:de,ab,ti OR factorial*:de,ab,ti OR
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crossover*:de,ab,ti OR (cross NEXT/1 over*):de,ab,ti OR

placebo*:de,ab,ti OR (doubl* NEAR/1 blind*):de,ab,ti OR (singl*
NEAR/1 blind*):de,ab,ti OR assign*:de,ab,ti OR allocat*:de,ab,ti OR
volunteer*:de,ab,ti) NOT ([animals]/lim NOT [humans]/lim)
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GREAT "atopic dermatitis" OR "eczema"; Any treatment; publication year 2007-

2016
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LILACS (tw:("atopic dermatitis")) OR (tw:("dermatitis atopic")) OR

(tw:("eczema")) OR (tw:("childhood eczema")) OR (tw:("infantile
eczema")) OR (tw:("besniers prurigo")) OR (tw:("neurodermatitis")) AND
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(instance:"regional") AND (type_of_study:("clinical_trials") AND

limit:("humans")
MEDLINE 1 ("clinical trial" or "clinical trial, phase i" or "clinical trial, phase ii" or
22
clinical trial, phase iii or clinical trial, phase iv or controlled clinical
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trial or "multicenter study" or "randomized controlled trial").pt. or

double-blind method/ or clinical trials as topic/ or clinical trials,
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phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials,

phase iii as topic/ or clinical trials, phase iv as topic/ or controlled
clinical trials as topic/ or randomized controlled trials as topic/ or
early termination of clinical trials as topic/ or multicenter studies as
topic/ or ((randomi?ed adj7 trial*) or (controlled adj3 trial*) or
(clinical adj2 trial*) or ((single or doubl* or tripl* or treb*) and
(blind* or mask*))).ti,ab,kw. or ("4 arm" or "four arm").ti,ab,kw.

2 (("clinical trial" or "clinical trial, phase i" or "clinical trial, phase ii"
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or clinical trial, phase iii or clinical trial, phase iv or controlled

clinical trial or "multicenter study" or "randomized controlled
trial").pt. or double-blind method/ or clinical trials as topic/ or clinical
trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical
trials, phase iii as topic/ or clinical trials, phase iv as topic/ or
controlled clinical trials as topic/ or randomized controlled trials as
topic/ or early termination of clinical trials as topic/ or multicenter

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studies as topic/ or ((randomi?ed adj7 trial*) or (controlled adj3
trial*) or (clinical adj2 trial*) or ((single or doubl* or tripl* or treb*)
and (blind* or mask*))).ti,ab,kw. or ("4 arm" or "four arm").ti,ab,kw.)

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not (exp animals/ not humans.sh.)
3 exp DERMATITIS, ATOPIC/
4 atopic dermatitis.mp.

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5 dermatitis atopic.mp
6 exp ECZEMA/
7 eczema.mp.
8 childhood eczema.mp.

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9 infantile eczema.mp.
10 neurodermatitis.mp.
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11 exp Neurodermatitis/
12 Besnier's prurigo.mp.
13 or/3-12
14 2 and 13
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15 Limit 14 to yr=”2007 –Current”

SCOPUS24 (TITLE-ABS-KEY ("atopic dermatitis") OR TITLE-ABS-KEY
("dermatitis atopic") OR TITLE-ABS-KEY (neurodermatitis) OR TITLE-
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ABS-KEY (eczema) OR TITLE-ABS-KEY ("infantile eczema") OR

TITLE-ABS-KEY ("childhood eczema") OR TITLE-ABS-KEY ("besniers
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prurigo")) AND SUBJAREA (mult OR agri OR bioc OR immu OR neur

OR phar OR mult OR medi OR nurs OR vete OR dent OR heal) AND
(PUBYEAR > 2006) AND (INDEXTERMS ("clinical trials" OR "clinical
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trials as a topic" OR "randomized controlled trial" OR "Randomized

Controlled Trials as Topic" OR "controlled clinical trial" OR "Controlled
Clinical Trials" OR "random allocation" OR "Double-Blind Method" OR
"Single-Blind Method" OR "Cross-Over Studies" OR "Placebos" OR
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"multicenter study" OR "double blind procedure" OR "single blind

procedure" OR "crossover procedure" OR "clinical trial" OR "controlled
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study" OR "randomization" OR "placebo")) OR (TITLE-ABS-KEY

(("clinical trials" OR "clinical trials as a topic" OR "randomized controlled
trial" OR "Randomized Controlled Trials as Topic" OR "controlled clinical
trial" OR "Controlled Clinical Trials as Topic" OR "random allocation" OR
"randomly allocated" OR "allocated randomly" OR "Double-Blind
Method" OR "Single-Blind Method" OR "Cross-Over Studies" OR
"Placebos" OR "cross-over trial" OR "single blind" OR "double blind" OR
"factorial design" OR "factorial trial"))) OR (TITLE-ABS (clinical trial*
OR trial* OR rct* OR random* OR blind*))
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