Clinical trial NCT03738423
Conditions: Atopic Dermatitis
Keywords: Moderate Severe
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-11-13; Completion date: 2020-07-24
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to assess the efficacy of REGN3500 monotherapy in Atopic dermatitis (AD), as well as understand the dose-response relationship, compared with placebo treatment, in adult patients with moderate-to-severe AD.

Secondary objectives are to:

* Assess the safety and tolerability of subcutaneous (SC) doses of REGN3500 monotherapy in adult patients with moderate-to-severe AD
* Assess the Pharmacokinetics (PK) of REGN3500 in adult patients with moderate-to-severe AD
* Assess the immunogenicity of REGN3500 in adult patients with moderate-to-severe AD

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: Matching placebo
Interventions: intervention 1: REGN3500 intervention 2: REGN3500-Matching Placebo
Intervention descriptions: intervention 1: Administered subcutaneous (SC) intervention 2: Administered subcutaneous (SC)

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R3500-AD-1805 Amendment 3 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 83 
CONFIDENTIAL 
IND Number: 138118 
EudraCT Number: 2018-001544-64 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP, DOSE-RANGING STUDY 
INVESTIGATING THE EFFICACY, SAFETY, AND 
PHARMACOKINETIC PROFILES OF REGN3500 ADMINISTERED TO 
ADULT PATIENTS WITH MODERATE-TO-SEVERE ATOPIC 
DERMATITIS 
Compound: 
REGN3500 
Clinical Phase: 
2b 
Protocol Number: 
R3500-AD-1805 
Protocol Version: 
R3500-AD-1805 Amendment 3 
Amendment 3 Date of Issue: 
See appended electronic signature page 
Amendment 2 Date of Issue: 
29 Nov 2018 
Amendment 1 Date of Issue: 
26 Sep 2018 
Original Date of Issue: 
23 May 2018  
Medical /Study Director: 
  
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
. 
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 NCT03738423


Clinical Study Protocol 
 
R3500-AD-1805 Amendment 3 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 83 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 3 
This amendment incorporates recommendations from a European clinical trial review and 
corrections to a number of inconsistencies.  The following table outlines the changes made to the 
protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
Changes based on recommendation from the European 
clinical trial review: 
Added secondary safety and pharmacokinetic (PK) 
endpoints. 
Synopsis, Secondary Endpoints, Statistical Plan 
Section 4.2.2 Secondary Endpoints 
Section 10.1 Statistical Hypothesis 
Added study stopping rules 
Section 5.1.1 Study Stopping Rules (added) 
Section 5.1.2 End of Study Definition (section number 
changed, no content change) 
Section 5.3.1 Independent Data Monitoring Committee 
Administrative changes to correct inconsistencies: 
In Amendment 2, Inclusion Criterion #1 was revised to add 
an upper age limit of 75 years.  This change was not 
incorporated in the Target Population section of the 
Synopsis and is incorporated in Amendment 3. 
Synopsis, Target Population 
In Amendment 2, text was added in Exclusion 
Criterion #12 to specify that patients with a positive 
tuberculosis (TB) QuantiFERON test result will be 
excluded from the study.  This change was not 
incorporated in Section 8.2.1 and Section 8.2.3.5 and is 
incorporated in these sections in Amendment 3.  This 
change was incorporated in Table 2 in Amendment 2, but 
not listed in “Section Changed”, and is now added. 
Amendment History, Amendment 2  
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit  
Section 8.2.3.5 Laboratory Testing 
Amendment 2 
This amendment incorporates recommendations from the European Union clinical trial review.  
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
Revised the text regarding onsite monitoring after each 
administration of study drug to indicate that the minimum 
30 minutes monitoring may be extended to up to 2 hours as 
per country-specific requirements. 
Synopsis Study Design 
Section 5.1 Study Description and Duration 
Section 7.1 Investigational and Reference Treatments 
Section 8.1.1 Footnotes for the Schedule of Events Table,
#3 
Revised Inclusion Criterion #1 to add an upper age limit of 
75 years. 
Section 6.2 Study Population 
Section 6.2.1 Inclusion Criteria, #1 
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CONFIDENTIAL 
Change and Rationale for Change 
Section Changed 
Added text in Exclusion Criterion #12 to specify that 
patients with a positive tuberculosis (TB) QuantiFERON 
test result will be excluded from the study. 
Table 2 Schedule of Events 
Section 6.2.2 Exclusion Criteria, # 12 
Section 8.1.1 Footnotes for the Schedule of Events Table, 
#9 
Exclusion Criterion # 20:  Added myocardial infarction, 
unstable arterial hypertension, unstable angina, and 
cerebrovascular accident as examples of uncontrolled 
cerebrocardiovascular conditions that will exclude a patient 
from the study. 
Section 6.2.2 Exclusion Criteria, # 20 
Exclusion Criterion #25:  Added clarification that the 
reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient, based on Clinical Trial 
Facilitation Group guideline on contraception. 
Section 6.2.2 Exclusion Criteria, # 25 
Added note in Table 1 Dosing Regimen and added text in 
Footnote #3 for the Schedule of Events Table to clarify 
that in order to maintain blinding, all patients will receive 
every 2 weeks (Q2W) subcutaneous (SC) injections.  For 
the REGN3500 300 mg SC every 4 weeks (Q4W) group, 
REGN3500 100 mg SC Q4W group, and REGN3500 30 
mg SC every 8 weeks (Q8W) group, there will be SC 
injection(s) of placebo in between REGN3500 doses so the 
injection frequency will match the other 2 groups 
(REGN3500 Q2W and placebo Q2W). 
Section 7.1 Investigational and Reference Treatments, 
Table 1 
Section 8.1.1 Footnotes for the Schedule of Events Table, 
#3 
Changed the neutrophil count criterion for permanent 
discontinuation of study drug from ≤0.5×103/μL to 
≤1.0×103/μL and for temporary discontinuation of study 
drug from ≤1.0×103/µL but >0.5×103/L to ≤1.5×103/µL 
but >1.0×103/L. 
Section 7.4.2.1 Reasons for Permanent Discontinuation of 
Study Drug 
Section 7.4.2.2 Reasons for Temporary Discontinuation of 
Study Drug 
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CONFIDENTIAL 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
Modified exclusion criterion #4 to decrease the length of the 
washout period from 12 weeks to 4 weeks before the 
baseline visit for immunosuppressive/immunomodulating 
drugs 
(eg, 
systemic 
corticosteroids, 
cyclosporine, 
mycophenolate-mofetil, interferon-gamma [IFN-γ], Janus 
kinase inhibitors, azathioprine, methotrexate, etc) and 
phototherapy. These washout changes are consistent with 
the prior dupilumab adult atopic dermatitis phase 3 studies 
(eg, R668-AD-1224) and should be acceptable for patients 
enrolled in this study. 
Section 6.2.2 Exclusion Criteria, #4 
Removed statements that oral antibiotic use ≤7 days was 
considered rescue treatment for atopic dermatitis (AD). 
Patients are allowed to receive oral antibiotics for up to 14 
days per course to treat infections and this is not 
considered rescue treatment for AD.  This change is 
consistent with prior dupilumab adult atopic dermatitis 
phase 3 studies (eg, R668-AD-1224).  
Synopsis, Treatments 
Section 7.3 Rescue Treatment 
Section 7.4.2.1 Reasons for Permanent Discontinuation of 
Study Drug 
Section 7.4.2.2 Reasons for Temporary Discontinuation of 
Study Drug 
Section 7.7.2 Permitted Medications and Procedures 
Section 7.7.2.1 Prohibited Concomitant Medications or 
Procedures as Rescue Treatment 
Removed mandatory ophthalmological eye exams.  Instead, 
limit an ophthalmological exam during screening to those 
patients who have history of certain eye disorders 
(conjunctivitis, blepharitis, or keratitis) within the last 12 
months and, after randomization, to patients who experience 
adverse events of special interest (AESIs) related to eye 
disorders.  This change is to reduce patient burden yet allow 
a robust and comprehensive evaluation of baseline disease 
status of patients with history of these disorders, as well as 
of any treatment-emergent adverse events (TEAEs) falling 
under this category.  These ophthalmologic exam changes 
are consistent with the dupilumab pediatric phase 3 study 
R668-AD-1652. 
Table 2 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events Table, 
Footnote #8, #17 
Section 8.2.1 
Procedures 
Performed 
Only 
at 
the 
Screening/Baseline Visit 
Section 8.2.3.7 Ophthalmologic (Eye) Examinations 
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
Updated exclusion criterion #11 to be consistent with prior 
dupilumab adult atopic dermatitis phase 3 studies (eg, 
R668-AD-1224).  Active chronic or acute infection 
requiring systemic treatment with antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks 
(was previously 8 weeks before the screening visit) before 
the baseline visit, or superficial skin infections within 1 
week (was previously 4 weeks before the screening visit) 
before the baseline visit. NOTE: patients may be 
rescreened after the infection resolves.   
Section 6.2.2 Exclusion Criteria, #11 
As recommended from the FDA for Protocol R3500-AD-
1798, added urine pregnancy tests at week 20 and week 28. 
Table 2 Schedule of Events 
Removed hematology and chemistry from visit 3, visit 5, 
visit 7, and visit 9 to reduce the patient burden of blood 
draws.   
Table 2 Schedule of Events 
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Change and Rationale for Change 
Section Changed 
To address FDA comments, Footnote #20 added to state 
that in the event a patient sample is positive in the 
REGN3500 ADA assay at Week 16 or the first time point 
analyzed, the Week 4 PK sample may be analyzed in the 
ADA assay. 
Table 2 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events Table,
Footnote #20 
Minor editorial changes 
Table 2 Schedule of Events 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Dose-Ranging Study Investigating the Efficacy, Safety, and Pharmacokinetic 
Profiles of REGN3500 Administered to Adult Patients with Moderate-to-
Severe Atopic Dermatitis 
Site Locations 
Approximately 100 multinational study sites  
Objectives 
The primary objective of the study is to assess the efficacy of REGN3500 
monotherapy in atopic dermatitis (AD), as well as understand the dose-response 
relationship, compared with placebo treatment, in adult patients with 
moderate-to-severe AD. 
The secondary objectives of the study are: 
 
To assess the safety and tolerability of subcutaneous (SC) doses of 
REGN3500 monotherapy in adult patients with moderate-to-severe 
AD 
 
To assess the pharmacokinetics (PK) of REGN3500 in adult patients 
with moderate-to-severe AD 
 
To assess the immunogenicity of REGN3500 in adult patients with 
moderate-to-severe AD 
The exploratory objectives of the study are to assess the effects of REGN3500 
monotherapy on skin and blood biomarkers of inflammation, quality-of-life 
(QOL), and patient-reported measures of pain and sleep quality in comparison 
with placebo.   
Study Design 
This is a randomized, double-blind, placebo-controlled, double-dummy, 
parallel-group study to assess the dose-response profile of various REGN3500 
monotherapy dosing regimens in adult patients with moderate-to-severe AD.  
Eligible patients must have a documented history of inadequate response or 
intolerance to treatment with topical AD medications.   
After providing informed consent, patients will be assessed for study eligibility 
at a screening visit (within 5 weeks [ie, 35 days] prior to randomization).  
During the screening period, treatments for AD will be washed out, as 
applicable, according to eligibility requirements.  Patients may be re-screened 
once if they fail the screening evaluation for reasons related to incidental 
transitory conditions (eg, medication use, concomitant illness, medical 
condition), unless the reason for the screen failure is related to failing the 
disease severity inclusion criteria. 
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Patients will be required to apply moisturizers (bland emollients) at least twice 
daily for at least 7 consecutive days immediately before randomization 
(ie, baseline/randomization visit would be eighth day) and throughout the study.  
However, to allow adequate assessment of skin dryness, moisturizers should 
not be applied on any area(s) of lesional or non-lesional skin designated for such 
assessments for at least 8 hours before each clinic visit. 
Patients who meet eligibility criteria during the screening period will undergo 
day 1/baseline assessments.  Patients who continue to meet eligibility criteria at 
baseline will be randomized in a 1:1:1:1:1 ratio to receive 1 of 5 treatment 
regimens (4 active, 1 placebo) for a 16-week double-blind treatment period 
followed by a 20-week post-treatment follow up. 
Randomization will be stratified by baseline disease severity (moderate 
[Investigator’s Global Assessment (IGA=3)] vs. severe [IGA=4] AD).  It is 
planned that at least approximately 50% of patients randomized will have an 
IGA score of 4.  To ensure enrollment according to intended distribution of 
disease severity, alerts will be built into the interactive voice/web response 
system to limit enrolling patients with an IGA score <4. 
Patients will remain at the study site for a minimum of 30 minutes after 
administration of study drug, and the monitoring period may be extended up to 
2 hours as per country-specific requirements.  During the 16-week treatment 
period, patients will have study visits every other week.  If medically necessary 
(ie, to control intolerable AD symptoms), patients may receive rescue treatment 
(eg, systemic and topical corticosteroids) at the discretion of the investigator. 
The end-of-treatment visit will occur at week 16, which is 2 weeks after the last 
dose of study drug.  The primary endpoint will be evaluated at week 16.  The 
duration of the 20-week post-treatment follow-up period corresponds to 
approximately 5 half-lives of REGN3500 (half-life ~30 days).  The end-of-
study visit will occur at week 36. 
Study Duration 
Each patient’s participation in the study will be up to 41 weeks, including an up 
to 5-week (ie, 35 days) screening period, 16-week double-blind treatment 
period, and 20-week post-treatment follow-up period. 
End of Study Definition 
The end of the study for this study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately 300 patients will be randomized (60 per treatment group). 
 
Target Population: 
Male or female adult patients (≥18 to 75 years of age) with moderate-to-severe 
AD whose disease cannot be adequately controlled with topical medications or 
for whom topical treatments are medically inadvisable (eg, intolerance, other 
important side effects or safety risks).  
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Treatment(s) 
 
 
Study Drug 
 
 
Dose/Route/Schedule: 
REGN3500 is supplied in vials as a lyophilized powder for reconstitution and 
SC administration. 
REGN3500 SC: 300 mg SC every 2 weeks (Q2W), 300 mg SC every 4 weeks 
(Q4W), 100 mg SC Q4W, or 30 mg SC every 8 weeks (Q8W) from day 1 
through week 14 
 
Placebo 
 
 
 
 
Route/Schedule: 
Placebo that matches REGN3500 (REGN3500-matching placebo) will be 
prepared in the same formulation as REGN3500, without the addition of 
protein, for SC administration. 
 
REGN3500-matching placebo SC administration schedule is driven by the 
treatment assignment to achieve blinding across treatment groups. 
 
Treatment Regimens: 
REGN3500 300 mg SC Q2W:  2 injections of REGN3500 (300 mg total dose) 
plus 1 injection of REGN3500-matching placebo administered SC on day 1 and 
week 8; and 2 injections of REGN3500 (300 mg total dose) administered SC at 
weeks 2, 4, 6, 10, 12, and 14. 
REGN3500 300 mg SC Q4W:  2 injections of REGN3500 (300 mg total dose) 
plus 1 injection of REGN3500-matching placebo administered SC on day 1 and 
week 8; 2 injections of REGN3500 (300 mg total dose) administered SC at 
weeks 4 and 12; and 2 injections of REGN3500-matching placebo administered 
SC at weeks 2, 6, 10, and 14. 
REGN3500 100 mg SC Q4W:  1 injection of REGN3500 (100 mg total dose) 
plus 2 injections of REGN3500-matching placebo administered SC on day 1 
and week 8; 1 injection of REGN3500 (100 mg total dose) plus 1 injection of 
REGN3500-matching placebo administered SC at weeks 4 and 12; and 
2 injections of REGN3500-matching placebo administered SC at weeks 2, 6, 
10, and 14. 
REGN3500 30 mg SC Q8W:  1 injection of REGN3500 (30 mg total dose) 
plus 2 injections of REGN3500-matching placebo administered SC on day 1 
and week 8; and 2 injections of REGN3500-matching placebo administered SC 
at weeks 2, 4, 6, 10, 12, and 14. 
Placebo SC Q2W:  3 injections of REGN3500-matching placebo on day 1 and 
week 8; and 2 injections of REGN3500-matching placebo administered SC at 
weeks 2, 4, 6, 10, 12, and 14. 
 
Background 
Treatment: 
All patients must apply moisturizers (bland emollients) at least twice daily for 
at 
least 
7 
consecutive 
days 
immediately 
before 
randomization 
(ie, baseline/randomization visit would be the eighth day) and throughout study 
participation.  However, to allow adequate assessment of skin dryness, 
moisturizers should not be applied on any area(s) of lesional or non-lesional 
skin designated for such assessments for at least 8 hours before each clinic visit.  
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Rescue Treatment: 
If medically necessary (ie, to control intolerable AD symptoms), patients may 
receive rescue treatment for AD at the discretion of the investigator.  If rescue 
treatment consists of topical medications (eg, topical corticosteroids, topical 
calcineurin inhibitors, or topical crisaborole) the patient can continue study 
treatment.  If rescue treatment consists of systemic corticosteroids or non-
steroidal systemic immunosuppressive drugs, study treatment will be 
permanently discontinued immediately. 
Endpoint(s) 
 
 
Primary: 
The primary endpoint in the study is the percent change in Eczema Area and 
Severity Index (EASI) score from baseline to week 16. 
 
Secondary: 
The secondary endpoints are: 
Efficacy: 
• 
Proportion of patients achieving EASI-50, EASI-75, and EASI-90 
(≥50%, ≥75%, and ≥90% improvement from baseline) at week 16 
• 
Absolute change in EASI scores from baseline to week 16 
• 
Proportion of patients with both an IGA score of 0 or 1 (on a 5-point 
scale) and a reduction from baseline of ≥2 points at week 16 
• 
Change (absolute and percent) from baseline to week 16 in weekly 
average of daily peak Pruritus Numerical Rating Scale (NRS)  
• 
Proportion of patients with improvement (reduction) of weekly 
average of daily peak pruritus NRS ≥4 from baseline at week 16  
• 
Time to onset of effect on pruritus during the 16-week treatment period 
(≥4-point reduction of weekly average of daily peak Pruritus NRS 
from baseline) 
• 
Percent change from baseline to week 16 in SCORing Atopic 
Dermatitis (SCORAD) 
• 
Change from baseline to week 16 in percent Body Surface Area (BSA) 
of AD involvement  
Safety: 
• 
Incidence of treatment-emergent adverse events (TEAEs) from 
baseline through end of treatment (week 16) 
• 
Incidence of treatment-emergent serious adverse events (SAEs) from 
baseline through end of treatment (week 16) 
• 
Incidence of treatment-emergent adverse events of special interest 
(AESIs) from baseline through end of treatment (week 16) 
• 
Incidence of TEAEs from baseline through end of study (week 36) 
• 
Incidence of treatment-emergent SAEs from baseline through end of 
study (week 36) 
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• 
Incidence of treatment-emergent AESIs from baseline through end of 
study (week 36) 
Pharmacokinetic (PK): 
• 
Concentrations of functional REGN3500 in serum by treatment 
regimen at each assessment time point from baseline to end of study 
(week 36) 
Note:  The safety and PK endpoints will not be included in the testing hierarchy. 
Procedures and Assessments 
A variety of parameters will be collected during the study to assess the efficacy, 
including various measures of AD severity (EASI, SCORAD, IGA, Pruritus 
NRS, Pain NRS, Sleep Quality NRS, Global Individual Signs Score, and BSA) 
and patient reported measures of AD symptoms and QOL (Dermatology Life 
Quality Index [DLQI], Patient Orientated Eczema Measure [POEM], and 
Hospital Anxiety and Depression Scale [HADS]). 
Safety and tolerability will be monitored by clinical assessment of adverse 
events (AEs) and by repeated measurements of clinical evaluation including 
vital signs (body temperature and sitting blood pressure, pulse, and respiration 
rate), physical examinations, eye examinations 12-lead electrocardiograms 
(ECGs), and laboratory assessment including standard hematology, chemistry, 
and urinalysis. 
Blood samples for the determination of functional REGN3500 and anti-drug 
antibody (ADA) in serum will be collected.  Serum and plasma samples will be 
collected for analysis of additional biomarkers, including total interleukin-33 
(IL-33), thymus and activation-regulated chemokine (CCL17; TARC), total 
immunoglobulin E (IgE), high-sensitivity C-reactive protein (hs-CRP), and 
serum amyloid A (SAA). 
Whole blood samples will also be collected for DNA and RNA extraction and 
pharmacogenomics evaluation.  Plasma and serum will be banked for future 
biomedical research. 
Statistical Plan 
For the primary endpoint, the enrollment of 60 patients per treatment group will 
provide 96% power to detect a 35% difference between the most efficacious 
REGN3500 SC dose and the placebo group with respect to percent change in 
EASI score from baseline to week 16, assuming the common standard deviation 
(SD) is 50%, with a 2-sided test at the 0.05 significance level.  The 50% SD 
along with the 35% difference in the mean percent were estimated based on 
results from 2 phase 3 dupilumab AD studies (R668-AD-1334 and 
R668-AD-1416). 
The efficacy endpoints will be analyzed using the full analysis set (FAS) which 
includes all randomized patients.  Efficacy analyses will be based on the 
treatment allocated at randomization (as randomized).  To control the overall 
family-wise type I error rate of 5%, a hierarchical procedure from high to low 
dose will be performed for the primary endpoint and selected secondary efficacy 
endpoints (eg, EASI-75, IGA score of 0 or 1 and a reduction from baseline of 
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≥2 points responder at week 16) across the REGN3500 dose regimens versus 
placebo. 
Continuous endpoints will be analyzed using an analysis of covariance 
(ANCOVA) model, which includes treatment group, stratification variable 
(moderate [IGA=3] vs. severe [IGA=4] AD) and relevant baseline value as 
covariates.  The efficacy data will be set to missing after rescue treatment is 
used, then all missing data from the FAS will be imputed 40 times under missing 
at random assumption to generate a complete dataset at each imputation by 
using the multiple imputation (MI) Statistical Analysis System (SAS) 
procedure.  These complete datasets will be analyzed using an ANCOVA model 
and the SAS MIANALYZE procedure will be used to generate valid statistical 
inferences by combining results from these multiple analyses using Rubin’s 
formula.  Sensitivity analyses such as ANCOVA model with last observation 
carried forward, MI method with ANCOVA model on all observed data 
regardless of rescue treatment use will be conducted.  Categorical endpoints 
will be analyzed using a Cochran-Mantel-Haenszel test stratified by baseline 
disease severity stratum.  Patients will be considered as non-responders at the 
time point where data are missing (regardless of reason for missingness, eg, due 
to drop-out or data set to missing after rescue treatment). 
Safety analyses will be based on the safety analysis set (SAF), which includes 
all randomized patients who received any study drug.  Reported TEAEs and 
other safety information (ie, clinical laboratory evaluations, vital signs, and 12-
lead ECG results) will be summarized by treatment group. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BSA 
Body surface area (of involvement of atopic dermatitis) 
Cmin 
Minimum concentration 
COPD 
Chronic obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CSR 
Clinical study report 
DLQI 
Dermatology Life Quality Index 
DMC 
Data Monitoring Committee 
EASI 
Eczema Area and Severity Index 
EASI-50 
≥50% improvement in EASI score 
EASI-75 
≥75% improvement in EASI score 
EASI-90 
≥90% improvement in EASI score 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
e-diary 
electronic patient diary 
EOS 
End-of-study 
EOT 
End-of-treatment 
ET 
Early termination 
FAS 
Full analysis set 
FBR 
Future Biomedical Research 
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GISS 
Global Individual Signs Score 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
GWA 
Genome wide association 
HADS 
Hospital Anxiety and Depression Scale 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotrophin 
HCV Ab 
Hepatitis C virus antibody 
HDM 
House dust mite extract 
HIV 
Human immunodeficiency virus 
HIV Ab 
Human immunodeficiency virus antibody 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon-gamma 
IGA 
Investigator’s Global Assessment 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IL1RL1 
Interleukin-1 receptor-like 1 
IL-4Rα 
Interleukin-4 receptor alpha 
ILC2 
Type 2 innate lymphoid cells 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MI 
Multiple imputation 
NRS 
Numerical Rating Scale 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
POEM 
Patient Oriented Eczema Measure 
PT 
Preferred term 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Q1 
First quartile 
Q2W 
Every 2 weeks 
Q3 
Third quartile 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
QOL 
Quality of life 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCORAD 
SCORing Atopic Dermatitis 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TARC 
Thymus and activation-regulated chemokine (CCL17) 
TB 
Tuberculosis 
TCI 
Topical calcineurin inhibitor 
TCS 
Topical corticosteroids 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
ULN 
Upper limit of normal 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................12 
1. 
INTRODUCTION ......................................................................................................21 
2. 
STUDY OBJECTIVES ..............................................................................................22 
2.1. 
Primary Objective .......................................................................................................22 
2.2. 
Secondary Objectives .................................................................................................22 
2.3. 
Exploratory Objectives ...............................................................................................23 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................23 
3.1. 
Hypothesis ..................................................................................................................23 
3.2. 
Rationale .....................................................................................................................23 
3.2.1. 
Background .................................................................................................................23 
3.2.2. 
Rationale for Study Design .........................................................................................25 
3.2.3. 
Rationale for Dose Selection ......................................................................................26 
4. 
STUDY VARIABLES................................................................................................27 
4.1. 
Demographic and Baseline Characteristics ................................................................27 
4.2. 
Primary and Secondary Endpoints..............................................................................27 
4.2.1. 
Primary Endpoint ........................................................................................................27 
4.2.2. 
Secondary Endpoints ..................................................................................................27 
4.3. 
Pharmacokinetic Variables .........................................................................................28 
4.4. 
Anti-Drug Antibody Variables ...................................................................................28 
5. 
STUDY DESIGN .......................................................................................................28 
5.1. 
Study Description and Duration .................................................................................28 
5.1.1. 
Study Stopping Rules .................................................................................................30 
5.1.2. 
End of Study Definition ..............................................................................................30 
5.2. 
Planned Interim Analysis ............................................................................................30 
5.3. 
Study Committees .......................................................................................................30 
5.3.1. 
Independent Data Monitoring Committee ..................................................................30 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............31 
6.1. 
Number of Patients Planned .......................................................................................31 
6.2. 
Study Population .........................................................................................................31 
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6.2.1. 
Inclusion Criteria ........................................................................................................31 
6.2.2. 
Exclusion Criteria .......................................................................................................32 
6.3. 
Premature Withdrawal from the Study .......................................................................35 
6.4. 
Replacement of Patients .............................................................................................35 
7. 
STUDY TREATMENTS............................................................................................36 
7.1. 
Investigational and Reference Treatments ..................................................................36 
7.2. 
Background Treatment ...............................................................................................37 
7.3. 
Rescue Treatment .......................................................................................................38 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................38 
7.4.1. 
Dose Modification ......................................................................................................38 
7.4.2. 
Study Drug Discontinuation .......................................................................................38 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................38 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................40 
7.5. 
Method of Treatment Assignment ..............................................................................40 
7.5.1. 
Blinding ......................................................................................................................40 
7.5.2. 
Emergency Unblinding ...............................................................................................41 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................41 
7.6. 
Treatment Logistics and Accountability .....................................................................41 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................41 
7.6.2. 
Supply and Disposition of Treatments .......................................................................42 
7.6.3. 
Treatment Accountability ...........................................................................................42 
7.6.4. 
Treatment Compliance ................................................................................................42 
7.7. 
Concomitant Medications and Procedures .................................................................42 
7.7.1. 
Prohibited Medications and Procedures .....................................................................42 
7.7.2. 
Permitted Medications and Procedures ......................................................................43 
7.7.2.1. 
Prohibited Concomitant Medications or Procedures as Rescue Treatment ................44 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................44 
8.1. 
Schedule of Events .....................................................................................................44 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................48 
8.1.2. 
Early Termination Visit ..............................................................................................50 
8.1.3. 
Unscheduled Visits .....................................................................................................50 
8.2. 
Study Procedures ........................................................................................................50 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................50 
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8.2.2. 
Efficacy Procedures ....................................................................................................50 
8.2.2.1. 
Pruritus Numeric Rating Scale (NRS) ........................................................................50 
8.2.2.2. 
Peak Pain Numeric Rating Scale (NRS) .....................................................................51 
8.2.2.3. 
Sleep Quality Numeric Rating Scale (NRS) ...............................................................51 
8.2.2.4. 
Hospital Anxiety Depression Scale (HADS) ..............................................................51 
8.2.2.5. 
Dermatology Life Quality Index (DLQI) ...................................................................52 
8.2.2.6. 
Patient Oriented Eczema Measure (POEM) ...............................................................52 
8.2.2.7. 
Investigator’s Global Assessment (IGA) ....................................................................52 
8.2.2.8. 
Eczema Area and Severity Index (EASI) ...................................................................52 
8.2.2.9. 
Body Surface Area (BSA) Involvement of Atopic Dermatitis ...................................53 
8.2.2.10. 
Global Individual Signs Score (GISS) ........................................................................53 
8.2.2.11. 
SCORing Atopic Dermatitis (SCORAD) ...................................................................53 
8.2.3. 
Safety Procedures .......................................................................................................53 
8.2.3.1. 
Vital Signs ..................................................................................................................53 
8.2.3.2. 
Physical Examination .................................................................................................53 
8.2.3.3. 
Body Weight and Height ............................................................................................54 
8.2.3.4. 
Electrocardiogram .......................................................................................................54 
8.2.3.5. 
Laboratory Testing ......................................................................................................54 
8.2.3.6. 
Research Samples .......................................................................................................55 
8.2.3.7. 
Ophthalmologic (Eye) Examinations .........................................................................55 
8.2.4. 
Drug Concentration and Measurements .....................................................................56 
8.2.5. 
Anti-Drug Antibody Measurements and Samples ......................................................56 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................56 
8.2.6.1. 
Thymus and Activation-Regulated Chemokine (CCL17; TARC) .............................56 
8.2.6.2. 
Total Immunoglobulin E (IgE) ...................................................................................57 
8.2.6.3. 
Total Interleukin-33 (IL-33) .......................................................................................57 
8.2.6.4. 
High-Sensitivity C-Reactive Protein (hs-CRP) ..........................................................57 
8.2.6.5. 
Serum Amyloid A (SAA) ...........................................................................................57 
8.2.7. 
Future Biomedical Research (FBR) ............................................................................57 
8.2.7.1. 
Pharmacogenomics Analysis ......................................................................................58 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................58 
9.1. 
Obligations of Investigator .........................................................................................58 
9.2. 
Obligations of Sponsor ...............................................................................................58 
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9.3. 
Definitions ..................................................................................................................59 
9.3.1. 
Adverse Event .............................................................................................................59 
9.3.2. 
Serious Adverse Event ................................................................................................59 
9.3.3. 
Adverse Events of Special Interest .............................................................................60 
9.4. 
Recording and Reporting Adverse Events ..................................................................60 
9.4.1. 
Adverse Events ...........................................................................................................60 
9.4.2. 
Serious Adverse Events ..............................................................................................60 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................60 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................61 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................62 
9.4.6. 
Follow-up ....................................................................................................................62 
9.5. 
Evaluation of Severity and Causality .........................................................................62 
9.5.1. 
Evaluation of Severity ................................................................................................62 
9.5.2. 
Evaluation of Causality ...............................................................................................63 
9.6. 
Safety Monitoring .......................................................................................................65 
9.7. 
Investigator Alert Notification ....................................................................................65 
10. 
STATISTICAL PLAN................................................................................................65 
10.1. 
Statistical Hypothesis ..................................................................................................65 
10.2. 
Justification of Sample Size........................................................................................66 
10.3. 
Analysis Sets ...............................................................................................................66 
10.3.1. 
Efficacy Analysis Set ..................................................................................................66 
10.3.2. 
Safety Analysis Set .....................................................................................................66 
10.3.3. 
Pharmacokinetic Analysis Set ....................................................................................66 
10.3.4. 
Pharmacodynamic Analysis Set .................................................................................66 
10.3.5. 
Anti-Drug Antibody Analysis Set ..............................................................................66 
10.4. 
Statistical Methods ......................................................................................................66 
10.4.1. 
Patient Disposition ......................................................................................................67 
10.4.2. 
Demography and Baseline Characteristics .................................................................67 
10.4.3. 
Efficacy Analyses .......................................................................................................67 
10.4.3.1. 
Primary Analysis of the Study ....................................................................................68 
10.4.4. 
Safety Analysis ...........................................................................................................68 
10.4.4.1. 
Adverse Events ...........................................................................................................68 
10.4.4.2. 
Other Safety ................................................................................................................69 
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10.4.4.3. 
Treatment Exposure ....................................................................................................70 
10.4.4.4. 
Treatment Compliance ................................................................................................70 
10.4.5. 
Pharmacokinetics ........................................................................................................70 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................70 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................70 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................70 
10.5. 
Additional Statistical Data Handling Conventions .....................................................71 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........71 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................71 
11.1. 
Data Management .......................................................................................................71 
11.2. 
Electronic Systems ......................................................................................................72 
12. 
STUDY MONITORING ............................................................................................72 
12.1. 
Monitoring of Study Sites ...........................................................................................72 
12.2. 
Source Document Requirements ................................................................................72 
12.3. 
Case Report Form Requirements ................................................................................72 
13. 
AUDITS AND INSPECTIONS .................................................................................73 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................73 
14.1. 
Good Clinical Practice Statement ...............................................................................73 
14.2. 
Patients Confidentiality and Data Protection ..............................................................74 
14.3. 
Institutional Review Board/Ethics Committee ...........................................................74 
15. 
PROTOCOL AMENDMENTS ..................................................................................75 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................75 
16.1. 
Premature Termination of the Study ...........................................................................75 
16.2. 
Close-out of a Site ......................................................................................................75 
17. 
STUDY DOCUMENTATION ...................................................................................76 
17.1. 
Certification of Accuracy of Data ...............................................................................76 
17.2. 
Retention of Records ..................................................................................................76 
18. 
DATA QUALITY ASSURANCE ..............................................................................76 
19. 
CONFIDENTIALITY ................................................................................................77 
20. 
FINANCING AND INSURANCE .............................................................................77 
21. 
PUBLICATION POLICY ..........................................................................................77 
22. 
REFERENCES ...........................................................................................................77 
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23. 
INVESTIGATOR’S AGREEMENT ..........................................................................80 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................83 
 
LIST OF TABLES 
Table 1: 
Dosing Regimens ........................................................................................................36 
Table 2: 
Schedule of Events .....................................................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................29 
 
LIST OF APPENDICES 
APPENDIX 1: INVESTIGATOR’S GLOBAL ASSESSMENT (IGA) SCALE .......................81 
 
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1. 
INTRODUCTION 
Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by intense 
pruritus (ie, itchiness), xerosis (skin dryness), and eczematous lesions whose features include 
erythema, infiltration/papulation, oozing with crusting, excoriations, and lichenification.  It is often 
associated with other atopic disorders, such as allergic rhinitis, asthma, and food allergy.  Severe 
disease can be extremely disabling due to several factors:  major psychological problems, 
significant sleep loss, and impaired quality of life (QOL) that lead to a high socioeconomic cost.  
An estimated 2% to 10% of adults are affected by AD (Bieber, 2008).  The pathophysiology of 
AD is influenced by a complex interplay between inflammation, environmental factors, genetics, 
and skin barrier dysfunction.  Both the disturbances in epidermal barrier function and hyperactive 
immune response are associated with changes in the skin microbiome.  Flares of AD are associated 
with an expansion of Staphylococcus aureus on lesional skin and a substantial loss of biodiversity 
in skin microbiome (Williams, 2017). 
Skin-infiltrating leukocytes are thought to play a pivotal role in the initiation and amplification of 
atopic inflammation.  The key cells involved in the pathophysiologic mechanism of AD are 
classified into 4 general subgroups.  First, dendritic cell subtypes including Langerhans cells and 
inflammatory dendritic epithelial cells polarize T-helper cells via Immunoglobulin E (IgE) – and 
non-IgE-mediated mechanisms.  Dendritic cells in the skin present allergens to lymphocytes, 
causing a Type 2 helper T cell (Th2) polarization and subsequent release of pro-inflammatory 
cytokines, which include interleukin (IL)-4, IL-5, and IL-13.  The T-helper cells are the second 
group of cells.  In acute exudative skin lesions, CCR4+ (chemokine ‘C’ receptor) Th2 cells are 
abundant and secrete cytokines IL-4, IL-13, and IL-5, whereas Type 1 helper T cells (Th1), which 
secrete interferon-gamma (IFN-γ), are also seen in chronic, lichenified lesions.  Activated 
eosinophils are the third group of cells, causing local inflammation at lesional sites.  Keratinocytes 
are the fourth cell-type involved in the pathophysiology of AD.  These skin cells express high 
levels of the Th2 polarizing cytokine and thymic stromal lymphopoietin in AD lesions, which may 
amplify and sustain the allergic response (Suarez-Farinas, 2013).  For patients with moderate-to-
severe AD, topical therapies have limited efficacy, and systemic treatments are associated with 
substantial toxic effects.  Dupilumab, a human monoclonal antibody (mAb) directed against the 
IL-4 receptor alpha (IL-4Rα) subunit, blocks IL-4 and IL-13 signaling.  Dupilumab has been 
shown to be safe and efficacious and, as of March 2018, has been approved in the United States, 
European Union, and Japan, as well as in other countries, for treatment of adults with moderate-
to-severe AD. 
Interleukin-33 is a proinflammatory cytokine that initiates and amplifies innate and adaptive 
inflammatory cascades (Cayrol, 2014).  Interleukin-33 is released by damaged epithelial tissue 
cells in response to insults such as allergens, viruses, or smoke.  Interleukin-33 signaling activates 
multiple downstream inflammatory pathways, resulting in effects characteristic of both Type 1 and 
Type 2 inflammation.  Genetic and experimental evidence suggest a role for IL-33 in pathogenesis 
of AD.  Transgenic mice overexpressing IL-33 in the skin epithelium develop spontaneous AD-
like symptoms associated with pruritus and immune cell infiltration (Imai, 2013).  Experimentally-
induced AD in mice results in IL-33-dependent infiltration of Type 2 innate lymphoid cells (ILC2), 
which are the source of Type 2 inflammatory cytokines (Salimi, 2013), however, this result 
appears to be strain dependent (Kim, 2013).  Human genetic data (Hirota, 2012) (Paternoster, 
2015) (Bonnelykke, 2013) (Shimizu, 2005) suggest that variants in the IL-33 pathways confer 
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susceptibility to AD.  Data from AD patients suggest that IL-33 and IL1RL1 (interleukin-1 
receptor-like 1 [the IL-33 receptor]) are upregulated in lesional skin (Savinko, 2012) (Salimi, 
2013).  Taken together, these data suggests that blockade of IL-33 may be efficacious in targeting 
inflammatory pathways active in AD. 
Recently, publicly available results disclosed from an uncontrolled phase 2a study evaluating a 
single intravenous (IV) dose of an anti-IL-33 mAb (ANB020, AnaptysBio) in 
12 moderate-to-severe adult AD patients offer mechanistic support for anti-IL-33 approach to 
improving AD disease severity (Ogg, 2018).  In this proof-of-concept (POC) study, 83% of 
patients were reported to have achieved a ≥50% improvement in Eczema Area and Severity Index 
(EASI) score (EASI-50) at day 29 and an average EASI reduction of 62% by day 57 following 
dosing.  Pruritus, as measured by 5-D Pruritus Scale score, was reduced by 21% at day 57. 
REGN3500 (also referred to as SAR440340) is a human IgG4P mAb that binds IL-33 with 
subnanomolar affinity.  REGN3500 has been studied in 3 phase 1 clinical studies evaluating the 
safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) effects of REGN3500 in 
healthy volunteers and in patients with asthma. 
In summary, genetic and experimental data, preclinical studies, and human clinical studies support 
further evaluation of REGN3500 in patients with moderate-to-severe AD.  Additional background 
information on the study drug and development program can be found in the REGN3500 
Investigator’s Brochure. 
The current study is proposed to assess the efficacy of multiple REGN3500 dose regimens, 
compared with placebo, in adult patients with moderate-to-severe AD who are intolerant of, or 
who are not adequately controlled with, topical treatments. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to assess the efficacy of REGN3500 monotherapy in AD, as 
well as understand the dose-response relationship, compared with placebo treatment, in adult 
patients with moderate-to-severe AD. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To assess the safety and tolerability of subcutaneous (SC) doses of REGN3500 
monotherapy in adult patients with moderate-to-severe AD 
 To assess the PK of REGN3500 in adult patients with moderate-to-severe AD 
To assess the immunogenicity of REGN3500 in adult patients with 
moderate-to-severe AD 
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2.3. 
Exploratory Objectives 
The exploratory objectives of the study are to assess the effects of REGN3500 monotherapy on 
skin and blood biomarkers of inflammation, QOL, and patient-reported measures of pain and sleep 
quality in comparison with placebo. 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Based on the mechanism of action of REGN3500, inhibition of IL-33, REGN3500 is expected to 
be efficacious in treatment of AD.  This hypothesis will be tested by analysis of the changes from 
baseline in objective and subjective measures of skin inflammation, after treatment with different 
doses of REGN3500 or placebo to find an optimal dose regimen. 
3.2. 
Rationale  
3.2.1. 
Background 
Dupilumab was approved as a safe and effective treatment for moderate-to-severe AD.  Despite 
the significant clinical improvement provided by dupilumab in the majority of AD patients, there 
continues to exist an unmet medical need for additional therapies for AD. 
Genetic and experimental evidence suggest a role for IL-33 in pathogenesis of AD.  Transgenic 
mice overexpressing IL-33 in the skin epithelium develop spontaneous AD-like symptoms 
associated with pruritus and immune cell infiltration (Imai, 2013).  Experimentally-induced AD in 
mice results in IL-33-dependent infiltration of ILC2 (Salimi, 2013), however this result appears to 
be strain dependent (Kim, 2013).  In a separate experimental AD model, IL-33 signal transduction 
via the ST2-MyD88 pathway is pivotal for development of the AD phenotype (Li, 2017).  
Furthermore, an anti-IL-33 antibody has been shown to improve symptoms associated with AD in 
a mouse model of AD (Peng, 2018). 
Large genome wide association (GWA) studies identified the IL1RL1 (ST2) locus as significantly 
associated with AD (Hirota, 2012) (Paternoster, 2015).  Another recent GWA study identified a 
common 3 prime untranslated region (3’ UTR) variant in IL1RL1 that was associated with allergic 
sensitization (Bonnelykke, 2013).  Polymorphism in IL1RL1 correlates with an increased risk of 
AD (Shimizu, 2005). 
In humans, IL-33 it is absent in normal human skin and induced by acute inflammation (Sundnes, 
2015).  Lesional AD skin expressed higher levels of IL1RL1 and IL-33 compared with healthy 
skin (Salimi, 2013) and non-lesional skin (Savinko, 2012).  Interleukin-33 serum levels were 
reported to be higher in AD patients than in healthy controls or in urticaria or psoriasis patients 
(Tamagawa-Mineoka, 2014), however, assays may not accurately report circulating levels, and 
itch-induced tissue damage may cause release of IL-33 to circulation.  Immune cells respond to 
IL-33 stimulation when IL-33 binds to its cognate receptor, ST2, and subsequently engages the 
co-receptor IL-1RAcP (interleukin-1 receptor accessory protein) to initiate signaling. 
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Preclinically, REGN3500 efficacy was evaluated in a 15-week model of allergen-induced lung 
inflammation using IL-33-humanized mice (REGN3500-MX-16008).  Compared with unexposed 
Il-33hu/hu mice, mice exposed to house dust mite extract (HDM) for 15 weeks that were untreated 
or administered isotype control antibody showed significant increases in tissue remodeling and 
gross pathology (increased lung weight), lung eosinophil infiltration, lung tissue levels of MPO 
protein, a marker for neutrophilic tissue infiltration (Bradley, 1982), and Type 2 cytokines 
expression (IL-5 and IL-13).  The HDM-exposed Il-33hu/hu mice administered REGN3500 after 
4 weeks of HDM exposure had significantly reduced lung weights compared with untreated HDM-
exposed mice and with HDM-exposed mice administered isotype control antibody.  In this study, 
REGN3500 1 mg/kg SC dosed twice weekly was found to be the minimum efficacious dose for 
all endpoints evaluated, and an average serum concentration of 17 μg/mL (ie, 17 mg/L) was 
observed in mice in this dose group at the end of the study.  REGN3500 blocked several pathologic 
markers of Type 1 and Type 2 immune responses in a 15-week HDM-induced lung inflammation 
in mouse model.  Efficacy was associated with detectable concentrations of REGN3500. 
REGN3500 has been studied in 3 phase 1 clinical studies evaluating the safety, tolerability, PK, 
and PD effects of REGN3500 in healthy volunteers and patients with asthma.  To date, no serious 
adverse events (SAEs) have been reported in healthy adult subjects after single doses of 
REGN3500 up to 10 mg/kg IV in the first-in-human (FIH) study (R3500-HV-1551) or in asthmatic 
patients during the ongoing first-in-patient study after multiple doses of REGN3500 up to 150 mg 
SC (R3500-AS-1619).  A phase 1 bronchial allergen challenge study (R3500-AS-1633), which has 
a cohort of REGN3500 (10 mg/kg IV on day 1) in combination with dupilumab (600 mg total 
loading dose on day 1 and 300 mg on day 15), is currently ongoing.  In blinded data to date, no 
SAEs have been reported.  In the phase 1 clinical studies, REGN3500 appears to have linear and 
dose-proportional PK with a half-life of approximately 30 days and no evidence of target mediated 
clearance, even at the lowest doses evaluated (0.3 mg/kg IV).  The PK of REGN3500 appears to 
be similar between healthy volunteers and patients with asthma. 
REGN3500 monotherapy and REGN3500 in combination with dupilumab are also being studied 
in a 12-week, phase 2a POC study (SAR440340-ACT15102) in adult patients with 
moderate-to-severe asthma who are not well controlled on inhaled corticosteroids plus long-acting 
beta 2 adrenergic agonist therapy.  The SC doses of REGN3500 (300 mg) and dupilumab (300 
mg) used in this POC study in asthmatic patients are the same as those to be used in the current 
POC study in AD patients.  The POC study in asthmatic patients is currently ongoing, with the 
first patient enrolled in April 2018.  In blinded data to date, no SAEs have been reported. 
In addition to this phase 2b dose-ranging study in AD, clinical studies evaluating REGN3500 will 
include POC studies in patients with asthma, chronic obstructive pulmonary disease (COPD), and 
AD.  These studies will evaluate monotherapy efficacy in addition to combination efficacy with 
dupilumab. 
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An anti-IL-33 mAb (ANB020, AnaptysBio) has also been evaluated in patients with 
moderate-to-severe AD.  Publicly available results disclosed from an uncontrolled phase 2a study 
evaluating a single IV dose of an anti-IL-33 mAb (ANB020) in 12 moderate-to-severe adult AD 
patients offer mechanistic support for anti-IL-33 approach to improving AD disease severity (Ogg, 
2018).  In this study, 83% of patients were reported to have achieved EASI-50 at day 29 and an 
average EASI reduction of 62% by day 57 following dosing.  Pruritus, as measured by 5-D Pruritus 
Scale score, was reduced by 21% at day 57.  These results await confirmation in larger 
placebo-controlled phase 3 studies.  Nevertheless, they may offer support for an anti-IL-33 
approach to improving disease severity for patients with moderate-to-severe AD. 
In summary, genetic and experimental data, preclinical studies, and human clinical studies support 
further evaluation of REGN3500 in patients with moderate-to-severe AD. 
3.2.2. 
Rationale for Study Design 
This is a phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging 
study investigating the efficacy, safety, and PK profiles of REGN3500 administered to adult 
patients with moderate-to-severe AD over 16 weeks of treatment.  This study is intended to provide 
information regarding 4 different REGN3500 monotherapy dosing regimens.  Each REGN3500 
dosing regimen will be compared with placebo to enable robust assessment of efficacy and safety. 
The primary objective of this study is to assess the efficacy of REGN3500 monotherapy in AD, as 
well as understand the dose-response relationship, compared with placebo, in adult patients with 
moderate-to-severe AD whose disease cannot be adequately controlled with topical medications 
or for whom topical treatment is medically inadvisable (side effects or safety risks).  The primary 
objective of this study will be assessed using EASI scores.  Secondary objectives are to assess the 
safety, tolerability, PK, and immunogenicity of REGN3500 monotherapy compared with placebo 
treatment in adult patients with moderate-to-severe AD. 
Study treatment will be administered for 16 weeks and will constitute the double-blind, 
placebo-controlled treatment period.  The 16-week treatment period is considered sufficient to 
assess treatment effect as measured by EASI, an endpoint allowing assessment of disease severity.  
A follow-up period of 20 weeks (approximately 5 half-lives of REGN3500) off study drug will 
enable appropriate assessment of safety and PK. 
The choice of placebo as a control is appropriate for the objectives of this study as it will provide 
the most robust assessment of the efficacy and safety of REGN3500 monotherapy. 
Additionally, for the primary endpoint, the enrollment of 60 patients per treatment group will 
provide 96% power to detect a 35% difference between the most efficacious REGN3500 SC dose 
and the placebo group with respect to percent change in EASI score from baseline to week 16. 
The target population includes adults with moderate-to-severe AD who cannot be adequately 
controlled with topical medications or for whom topical treatment is otherwise inadvisable 
(eg, intolerance, other important side effects or safety risks).  There remains an unmet need within 
this population for therapeutics intended to alleviate disease burden.  Patients will be evaluated for 
chronic (at least 3 years) AD according to the American Academy of Dermatology Consensus 
Criteria and will be screened based on EASI and Investigator’s Global Assessment (IGA) scores, 
as well as extent of body surface area (BSA) of AD involvement. 
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3.2.3. 
Rationale for Dose Selection 
The dose regimens selected for this study are: 
1. REGN3500 SC 300 mg every 2 weeks (Q2W) (high anchor, to be studied in phase 2a) 
2. REGN3500 SC 300 mg every 4 weeks (Q4W) 
3. REGN3500 SC 100 mg Q4W 
4. REGN3500 SC 30 mg every 8 weeks (Q8W) (low anchor) 
5. Placebo SC Q2W 
The highest dosing regimen proposed for this study is 300 mg SC Q2W.  The highest dose in the 
FIH single-ascending dose study (R3500-HV-1551) shown to have adequate safety was 10 mg/kg 
IV, which provides single-dose exposure and safety coverage for the 300 mg SC dose in this study.  
Safety after repeated dose administration of REGN3500 is supported by the results of the chronic 
safety study in cynomolgus monkeys where doses as high as 100 mg/kg were administered weekly 
SC for 26 weeks.  Based on this no-observed-adverse-effect level and human exposure predictions 
from a standard linear 2-compartmental model, there is approximately a 30-fold exposure multiple 
for both maximum concentration at steady state and cumulative area under the curve for the highest 
regimen of 300 mg SC Q2W administered for 24 weeks.  Thus, there are adequate safety data to 
support the selected dosing regimens in the current study administered over the treatment duration 
(16 weeks). 
In addition to safety, PK-PD factors were considered.  Based on results of an HDM-induced 
chronic lung inflammation mouse model, efficacy was observed at REGN3500 exposure levels of 
1.5 mg/L (0.25 mg/kg) and 17 mg/L (1 mg/kg dose), although efficacy across multiple endpoints 
was demonstrated most consistently at 17 mg/L.  Based on modeling of R3500-HV-1551 FIH drug 
concentrations, the regimens selected for the current study are expected (based on PK simulation) 
to achieve a range of minimum concentration (Cmin) at steady state which brackets the 17 mg/L 
concentration threshold for efficacy identified in the HDM animal model.  Specifically, the low 
anchor dosing regimen of REGN3500 30 mg SC Q8W regimen is expected to achieve a Cmin at 
steady state (5 mg/L) which is close to the lower HDM efficacy threshold observed in the HDM 
animal model (1.5 mg/L).  The high anchor dosing regimen of 300 mg SC Q2W is expected to 
achieve a Cmin at steady state which is approximately 5-fold higher than the 17 mg/L concentration 
(higher HDM efficacy threshold).  The higher exposure of the 300 mg SC Q2W regimen should 
conservatively ensure all patients are above the efficacy threshold when taking into account PK 
inter-individual variability, as well as the uncertainty in translating the PD of REGN3500 from the 
HDM mouse model to AD in humans. 
Based on the above rationales, the 300 mg SC Q2W regimen of REGN3500 is currently being 
studied in other POC studies that are already underway (eg, SAR440340-ACT15102 [asthma], 
SAR440340-ACT15104 [COPD]). 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography, disease characteristics including 
medical history, and medication history for each patient. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint in the study is the percent change in EASI score from baseline to week 16. 
4.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
Efficacy: 
 Proportion of patients achieving EASI-50, EASI-75, and EASI-90 (≥50%, ≥75%, and 
≥90% improvement from baseline) at week 16 
 Absolute change in EASI scores from baseline to week 16 
 Proportion of patients with both an IGA score of 0 or 1 (on a 5-point scale) and a 
reduction from baseline of ≥2 points at week 16 
 Change (absolute and percent) from baseline to week 16 in weekly average of daily 
peak Pruritus Numerical Rating Scale (NRS) 
 Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥4 from baseline to week 16 
 Time to onset of effect on pruritus during the 16-week treatment period (≥4-point 
reduction of weekly average of daily peak Pruritus NRS from baseline) 
 Percent change from baseline to week 16 in SCORing Atopic Dermatitis (SCORAD) 
 Change from baseline to week 16 in percent BSA of AD involvement 
Safety: 
 Incidence of treatment-emergent adverse events (TEAEs) from baseline through end of 
treatment (week 16) 
 Incidence of treatment-emergent serious adverse events (SAEs) from baseline through 
end of treatment (week 16) 
 Incidence of treatment-emergent adverse events of special interest (AESIs) from 
baseline through end of treatment (week 16) 
 Incidence of TEAEs from baseline through end of study (week 36) 
 Incidence of treatment-emergent SAEs from baseline through end of study (week 36) 
 Incidence of treatment-emergent AESIs from baseline through end of study (week 36) 
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Pharmacokinetic: 
 Concentrations of functional REGN3500 in serum by treatment regimen at each 
assessment timepoint from baseline to end of study (week 36) 
Any exploratory endpoints will be described in the statistical analysis plan (SAP). 
Note:  The safety and PK endpoints will not be included in the testing hierarchy. 
4.3. 
Pharmacokinetic Variables 
Pharmacokinetic sampling will be limited and focus on the pre-dose concentration of REGN3500. 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include ADA response status against REGN3500 and titer as 
follows: 
 Pre-existing immunoreactivity 
 Treatment-emergent ADA response 
 Treatment-boosted ADA response 
 Titer category 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤10,000) 
 High (titer >10,000)  
5. 
Study Design 
5.1. 
Study Description and Duration 
This is a randomized, double-blind, placebo-controlled, double-dummy, parallel group study to 
assess the dose-response profile of various REGN3500 monotherapy dosing regimens in adult 
patients with moderate-to-severe AD.  Eligible patients must have a documented history of 
inadequate response or intolerance to treatment with topical AD medications.  Approximately 
60 patients per treatment group will be randomized with approximately 300 patients enrolled from 
approximately 100 multinational study sites. 
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit.  Patients will undergo screening within 5 weeks (ie, 35 days) prior to randomization.  During 
the screening period, treatments for AD will be washed out, as applicable, according to eligibility 
requirements (see Section 6.2).  Patients may be re-screened once if they fail the screening 
evaluation for reasons related to incidental transitory conditions (eg, medication use, concomitant 
illness, medical condition), unless the reason for the screen failure is related to failing the disease 
severity inclusion criteria. 
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Patients who meet eligibility criteria during the screening period will undergo day 1/baseline 
assessments.  Patients who continue to meet eligibility criteria at baseline will be randomized in a 
1:1:1:1:1 ratio to 1 of 5 treatment regimens (REGN3500 300 mg SC Q2W, REGN3500 300 mg 
SC Q4W, REGN3500 100 mg SC Q4W, REGN3500 30 mg SC Q8W, or placebo SC Q2W) during 
the 16-week double-blind treatment phase (refer to Section 7 for additional information about 
study treatments) followed by a 20-week post-treatment follow-up period (Figure 1). 
Figure 1: 
Study Flow Diagram 
 
D:  day; EASI:  Eczema Area and Severity Index; EOS:  end-of-study; Q2W:  every 2 weeks; Q4W:  every 4 weeks; 
Q8W:  every 8 weeks; R:  randomization; W:  week. 
Patients will be required to apply moisturizers (bland emollients) at least twice daily for at least 
7 consecutive days immediately before randomization (ie, baseline/randomization visit would be 
the eighth day) and throughout the study.  However, to allow adequate assessment of skin dryness, 
moisturizers should not be applied on any area(s) of lesional or non-lesional skin designated for 
such assessments for at least 8 hours before each clinic visit. 
Randomization will be stratified by baseline disease severity (moderate [IGA=3] vs. severe 
[IGA=4] AD).  It is planned that at least approximately 50% of patients randomized will have an 
IGA score of 4.  To ensure enrollment according to intended distribution of disease severity, alerts 
will be built into the interactive voice response system/interactive web response system 
(IVRS/IWRS) to limit enrolling patients with an IGA score <4. 
Patients will remain at the study site for a minimum of 30 minutes after administration of study 
drug, and the monitoring period may be extended up to 2 hours as per country-specific 
requirements.  During the 16-week treatment period, patients will have study visits every other 
week.  Safety laboratory tests, collection of samples for REGN3500 concentrations and ADA, 
biomarkers, and clinical assessments will be performed at specified clinic visits.  The 
end-of-treatment (EOT) visit will occur at week 16, which is 2 weeks after the last dose of study 
drug.  The primary endpoint will be evaluated at week 16. 
Post-treatment follow-up visits will occur Q4W from week 20 through week 36.  The duration of 
the 20-week post-treatment follow-up period is based on the time expected for REGN3500 drug 
levels to reach zero (below the lower limit of quantification) in most patients after the last dose of 
REGN3500.  The 20-week post-treatment follow-up period corresponds to approximately 5 half-
lives of REGN3500 (half-life ~30 days).  The end-of-study (EOS) visit will occur at week 36. 
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Efficacy, safety, and laboratory assessments, and samples for REGN3500 concentration and 
potential ADA response to REGN3500, as well as research samples, will be performed or collected 
at specified time points throughout the study. 
Samples for DNA and RNA analysis will also be collected from patients. 
5.1.1. 
Study Stopping Rules 
The independent Data Monitoring Committee (DMC) will monitor unblinded data on an ongoing 
basis to assess the risk/benefit profile of REGN3500 (see more detail in Section 5.3.1).  If at any 
time the DMC has significant concerns regarding a meaningful imbalance in TEAEs, treatment-
emergent SAEs, or treatment-emergent AESIs, the DMC may make a recommendation to the 
sponsor to halt the study or make other changes in study conduct.  This will prompt a review by 
the sponsor who will make a decision to implement, modify, or reject the recommendation.  
Applicable regulatory procedures will be adhered to as required by local laws in relation to any 
decisions related to a change in study conduct, temporary halt, study termination, or study restart. 
5.1.2. 
End of Study Definition 
The end of the study for this study is defined as the last visit of the last patient. 
5.2. 
Planned Interim Analysis 
No interim analysis is planned, but may be conducted at a future date.  An unblinded primary 
analysis of the study may be performed once all patients in the study have completed the 16-week 
treatment period as specified in the protocol (week 16 visit or earlier for those patients who are 
withdrawn prematurely from the study).  If performed, this primary analysis of the study will be 
considered the final analysis for the primary and secondary efficacy endpoints.  Unblinded PK and 
ADA data through week 16 would also be included in this analysis. 
A description of the statistical methods to be employed and blinding implications are in 
Section 10.4.3 and Section 10.4.3.1. 
5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An independent DMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of accumulated safety data 
and perform a risk-benefit assessment. 
The DMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study.  The DMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the study execution. 
All activities and responsibilities of the DMC are described in the DMC charter. 
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 300 patients will be randomized (60 per treatment group) from approximately 
100 multinational study sites. 
6.2. 
Study Population 
The study population consists of adult (≥18 to 75 years of age) male or female patients with 
moderate-to-severe AD whose disease cannot be adequately controlled with topical medications 
or for whom topical treatments are medically inadvisable (eg, intolerance, other important side 
effects or safety risks). 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female, 18 to 75 years  
2. Chronic AD, according to American Academy of Dermatology Consensus Criteria 
(Eichenfield, 2014), that has been present for at least 3 years before the screening visit 
3. EASI score ≥16 at the screening and baseline visits 
4. IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at screening 
and baseline visits 
5. ≥10% BSA of AD involvement at the screening and baseline visits 
6. Baseline peak Pruritus NRS score for maximum itch intensity ≥4  
NOTE: 
 
Baseline peak Pruritus NRS score for maximum itch intensity will be determined based on the average 
of daily NRS scores for maximum itch intensity (the daily score ranges from 0 to 10) during the 7 days 
immediately preceding randomization.  A minimum of 4 daily scores out of the 7 days is required to 
calculate the baseline average score.  For patients who do not have at least 4 daily scores reported during 
the 7 days immediately preceding the planned randomization date, randomization should be postponed 
until this requirement is met, but without exceeding the 35-day maximum duration for screening. 
7. Documented recent history (within 6 months before the screening visit) of inadequate 
response to topical AD medication(s) or for whom topical treatments are medically 
inadvisable (eg, intolerance, because of important side effects, or safety risks). 
NOTE: 
 
Inadequate response is defined as failure to achieve and maintain remission or a low disease activity 
state (comparable to IGA 0=clear to 2=mild) despite treatment with a daily regimen of topical 
corticosteroids (TCS) of medium to higher potency (± topical calcineurin inhibitor [TCI] as appropriate), 
applied for at least 28 days or for the maximum duration recommended by the product prescribing 
information (eg, 14 days for super-potent TCS), whichever is shorter. 
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 
Patients with documented systemic treatment for AD (eg, systemic immunosuppressant drugs like 
cyclosporine, methotrexate, corticosteroids, etc) in the past 6 months are also considered to be inadequate 
responders to topical treatments and are potentially eligible for treatment with REGN3500 after 
appropriate washout. 
 
Important side effects or safety risks are those that outweigh the potential treatment benefits and include 
intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic effects, as 
assessed by the investigator or by the patient’s treating physician. 
 
Acceptable documentation includes contemporaneous chart notes that record topical medication 
prescription and treatment outcome, or investigator documentation based on communication with the 
patient’s treating physician.  If documentation is inadequate, potential patients may be offered a course 
of treatment with a daily regimen of TCS of medium or higher potency (±TCI as appropriate), applied 
for at least 28 days during the screening period, or for the maximum duration recommended by the 
product prescribing information, whichever is shorter.  Patients who demonstrate inadequate response 
during this period, as defined above, will be eligible for inclusion in the study following appropriate 
washout. 
8. Have applied a stable dose of topical bland emollient (moisturizer) at least twice daily for 
at 
least 
the 
7 consecutive 
days 
immediately 
before 
the 
baseline 
visit 
(ie, baseline/randomization visit would be the eighth day; see exclusion criterion 7 
regarding restrictions on the kind of emollients permitted during the study). 
9. Willing and able to comply with all clinic visits and study-related procedures 
10. Provide informed consent signed by study patient or legally acceptable representative  
11. Able to understand and complete study-related questionnaires 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Participation in a prior anti-IL-33 class medication clinical study 
2. Body mass index <16 kg/m2 
3. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), 
whichever is longer, before the baseline visit 
4. Having used any of the following treatments within 4 weeks before the baseline visit or 
any condition that, in the opinion of the investigator, is likely to require such treatment(s) 
during the first 4 weeks of study treatment: 
 Immunosuppressive/immunomodulating 
drugs 
(eg, 
systemic 
corticosteroids, 
cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, 
methotrexate, etc) 
 Phototherapy for AD 
5. Treatment with TCS, TCI, or topical crisaborole within 1 week before the baseline visit 
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6. Treatment with biologics as follows: 
 Any cell-depleting agents including but not limited to rituximab:  within 6 months 
before the baseline visit, or until lymphocyte count returns to normal, whichever is 
longer 
 Other biologics (including dupilumab): within 5 half-lives (if known) or 16 weeks prior 
to baseline visit, whichever is longer 
7. Initiation of treatment of AD with prescription moisturizers or moisturizers containing 
additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during 
the screening period (patients may continue using stable doses of such moisturizers if 
initiated before the screening visit) 
8. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the 
baseline visit 
9. Planned or anticipated use of any prohibited medications and procedures during study 
treatment 
10. Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit 
11. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit, or 
superficial skin infections within 1 week before the baseline visit.  NOTE:  patients may 
be re-screened after infection resolves    
12. Known or suspected history of immunosuppression, including history of invasive 
opportunistic 
infections 
(eg, 
tuberculosis 
[TB]*, 
histoplasmosis, 
listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution:  or 
unusually frequent, recurrent, or prolonged infections, per investigator judgment 
* Patients with a positive TB QuantiFERON test result at screening will be excluded from 
the study. 
13. History of human immunodeficiency virus (HIV) infection or positive HIV serology at 
screening 
14. Positive with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or 
hepatitis C virus antibody (HCV Ab) at the screening visit 
15. At baseline, presence of any conditions listed as criteria for study drug discontinuation 
16. Presence of skin comorbidities that may interfere with study assessments 
17. History of cancer, with the exceptions of: 
 Patients with adequately treated basal cell carcinoma or carcinoma in situ of the cervix  
 Patients with other malignancies that have been successfully treated for >10 years prior 
to screening where, in the judgement of both the investigator and the treating physician, 
appropriate follow-up has revealed no evidence of recurrence through time of 
screening. 
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18. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic 
infection, unless clinical and (if necessary) laboratory assessment have ruled out active 
infection before randomization 
19. History of alcohol or drug abuse within 2 years of the screening visit 
20. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect 
the patient’s participation in the study.  Examples include, but are not limited to, patients 
with short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c [HbA1c] 
≥9%), patients with uncontrolled cerebrocardiovascular conditions (eg, myocardial 
infarction, unstable arterial hypertension, unstable angina, cerebrovascular accident, and 
stage III or IV cardiac failure according to the New York Heart Association classification), 
severe renal conditions (eg, patients on dialysis), hepatobiliary conditions (eg, Child-Pugh 
class B or C), neurological conditions (eg., demyelinating diseases), active major 
autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc), 
other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic 
diseases.  The specific justification for patients excluded under this criterion will be noted 
in study documents (chart notes, case report forms [CRFs], etc) 
21. Any other medical or psychological condition (including relevant laboratory abnormalities 
at screening) that, in the opinion of the investigator, may suggest a new and/or 
insufficiently understood disease, may present an unreasonable risk to the study patient as 
a result of his/her participation in this clinical study, may make patient’s participation 
unreliable, or may interfere with study assessments.  The specific justification for patients 
excluded under this criterion will be noted in study documents (chart notes, CRFs, etc) 
22. Planned or anticipated major surgical procedure during the patient’s participation in this 
study 
23. Patient is a member of the investigational team or his/her immediate family 
24. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study 
25. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the study, 
and for at least 20 weeks after the last dose of study drug.  Highly effective contraceptive 
measures include: 
a. stable use of oral contraceptives associated with inhibition of ovulation (such as 
contraceptives containing estrogen/progesterone or high dose progesterone) initiated 2 
or more menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS) 
c. bilateral tubal ligation 
d. vasectomized partner with confirmed sterility (ie, patient’s medical record) 
e. and/or sexual abstinence†, ‡. 
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f. contraception for male patients is not required§ 
* 
Postmenopausal women must be amenorrheic for at least 12 months (without an alternative medical 
cause) in order not to be considered of childbearing potential.  Amenorrheic status should be 
confirmed by demonstrating follicle-stimulating hormone levels (FSH) consistent with 
postmenopausal status according to laboratory ranges.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
† 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the patient. 
‡ 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception.  Female condom and male condom should not be used together.  
§ 
Based on the known target biology of the study drugs and the extremely low levels of study drug 
expected to reach the fetus via seminal fluid, the use of contraception in treated males to prevent 
female partner and/or fetal exposure is considered unnecessary. 
26. Known sensitivity to doxycycline and/or tetracycline or to any of the components of the 
investigational product formulation. 
27. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities will be excluded from this study (as required by 
country regulations). 
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.4.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from study or study drug will not be replaced. 
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7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
REGN3500 is supplied in vials as a lyophilized powder.  Each vial is reconstituted with 2.5 mL 
sterile Water For Injection, resulting in 2.0 mL withdrawable volume of 100 mg/mL REGN3500.  
Placebo that matches REGN3500 (REGN3500-matching placebo) is prepared in the same 
formulation as REGN3500 but without the addition of protein (ie, active substance, 
anti-IL-33 mAb).  REGN3500 300 mg (or matching placebo) is administered as one 2.0 mL 
injection and one 1.0 mL injection, REGN3500 100 mg (or matching placebo) as one 1.0 mL 
injection, and REGN3500 30 mg (or matching placebo) as one 0.3 mL injection. 
Study drug (REGN3500, REGN3500-matching placebo) will be prepared by an unblinded 
pharmacist (or qualified designee) and administered SC by a blinded study nurse (or other qualified 
study personnel) on day 1/baseline and then as noted below through week 14.  The last dose of 
study treatment will be administered at week 14.  Patients will be monitored at the study site for a 
minimum of 30 minutes after each administration of study drug, and the monitoring period may 
be extended up to 2 hours as per country-specific requirements. 
Patients will be randomly assigned 1:1:1:1:1 to receive one of the following treatment regimens: 
Table 1: 
Dosing Regimens 
Dose Regimen 
Injections During 
Visit 
Study Drug 
Administered 
Injection Volume (mL) 
Day 1 (Visit 2) and Week 8 (Visit 6) 
REGN3500 300 mg SC Q2W 
3 
Placebo 
0.3 
REGN3500 
1.0 
REGN3500 
2.0 
REGN3500 300 mg SC Q4W 
3 
Placebo 
0.3 
REGN3500 
1.0 
REGN3500 
2.0 
REGN3500 100 mg SC Q4W 
3 
Placebo 
0.3 
REGN3500 
1.0 
Placebo 
2.0 
REGN3500 30 mg SC Q8W 
3 
REGN3500 
0.3 
Placebo 
1.0 
Placebo 
2.0 
Placebo SC Q2W 
3 
Placebo 
0.3 
Placebo 
1.0 
Placebo 
2.0 
Weeks 2 (Visit 3), 6 (Visit 5), 10 (Visit 7), and 14 (Visit 9) 
REGN3500 300 mg SC Q2W 
2 
REGN3500 
1.0 
REGN3500 
2.0 
REGN3500 300 mg SC Q4W 
2 
Placebo 
1.0 
Placebo 
2.0 
REGN3500 100 mg SC Q4W 
2 
Placebo 
1.0 
Placebo 
2.0 
REGN3500 30 mg SC Q8W 
2 
Placebo 
1.0 
Placebo 
2.0 
Placebo SC Q2W 
2 
Placebo 
1.0 
Placebo 
2.0 
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Dose Regimen 
Injections During 
Visit 
Study Drug 
Administered 
Injection Volume (mL) 
Weeks 4 (Visit 4) and 12 (Visit 8) 
REGN3500 300 mg SC Q2W 
2 
REGN3500 
1.0 
REGN3500 
2.0 
REGN3500 300 mg SC Q4W 
2 
REGN3500 
1.0 
REGN3500 
2.0 
REGN3500 100 mg SC Q4W 
2 
REGN3500 
1.0 
Placebo 
2.0 
REGN3500 30 mg SC Q8W 
2 
Placebo 
1.0 
Placebo 
2.0 
Placebo SC Q2W 
2 
Placebo 
1.0 
Placebo 
2.0 
SC:  subcutaneous; Q2W:  every 2 weeks; Q4W:  every 4 weeks; Q8W:  every 8 weeks. 
Note:  All patients will receive Q2W SC injections.  For the REGN3500 300 mg SC Q4W group, REGN3500 
100 mg SC Q4W group, and REGN3500 30 mg SC Q8W group, there will be SC injection(s) of placebo in 
between REGN3500 doses so the injection frequency will match the other 2 groups (REGN3500 300 mg SC Q2W 
and placebo SC Q2W) 
Instructions on dose preparation and administration are provided in pharmacy manual. 
Subcutaneous injection sites should be alternated among the different quadrants of the abdomen 
(avoiding navel and waist areas), upper thighs, and upper arms, so that the same site is not injected 
for 2 consecutive visits.  During the same dose administration, each injection must be given in a 
different anatomical location (eg, 1 injection administered in the right lower quadrant of the 
abdomen, another in the left lower quadrant of the abdomen, etc).  To allow for adequate 
assessment of possible injection site reactions (ISRs), study drug should be administered only into 
areas of normal-looking skin.  Instructions for recording and reporting ISRs will be provided in 
the study reference manual/site binder or file. 
7.2. 
Background Treatment 
All patients must apply moisturizers (bland emollients) at least twice daily for at least 
7 consecutive days immediately before randomization (ie, baseline/randomization visit would be 
the eighth day) and throughout study participation.  However, to allow adequate assessment of 
skin dryness, moisturizers should not be applied on any area(s) of lesional or non-lesional skin 
designated for such assessments for at least 8 hours before each clinic visit.  All types of 
moisturizers are permitted, but patients may not initiate treatment with prescription moisturizers 
or moisturizers containing additives during the screening period or during the study.  Patients may 
continue using stable doses of such moisturizers if initiated before the screening visit. 
Patients will report compliance with background treatment (bland emollients) during the study 
using an electronic patient diary (e-diary). 
Background treatment (bland emollients) is not provided by the sponsor. 
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7.3. 
Rescue Treatment 
If medically necessary (ie, to control intolerable AD symptoms), patients may receive rescue 
treatment for AD at the discretion of the investigator.  For the purpose of efficacy analysis, patients 
who receive rescue treatment during the study treatment period will be considered treatment 
failures, but they will continue study treatment if rescue consisted of topical medications.  Topical 
corticosteroids or topical crisaborole treatment may also be used as rescue treatment.  Topical 
calcineurin inhibitors may also be used for rescue, but should be reserved for problem areas only 
(eg, face, neck, intertriginous and genital areas, etc).  If possible, investigators should attempt to 
limit the first step of rescue therapy to topical medications, and escalate to systemic medications 
only for patients who do not respond adequately after at least 7 days of topical treatment.  If a 
patient receives rescue treatment with systemic corticosteroids or non-steroidal systemic 
immunosuppressive drugs (cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, etc), 
study treatment will be permanently discontinued immediately.  Treatment will remain blinded for 
these patients. 
Unless permanently discontinued from the study, all patients will complete the scheduled study 
visits and assessments whether or not they complete study treatment and whether or not they 
receive rescue treatment for AD.  Investigators should make every attempt to conduct efficacy and 
safety assessments (eg, disease severity scores, safety labs) immediately before administering any 
rescue treatment.  An unscheduled visit may be used for this purpose, if necessary. 
Rescue treatment is not provided by the sponsor. 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug but who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits and assessments per the visit 
schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 8.1.2 (Early Termination [ET]). 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 Anaphylactic reaction or other severe systemic reaction to study drug injection 
 Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin 
 Evidence of pregnancy 
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 Any infection that: 
 Requires parenteral treatment with antibiotic or oral or parenteral treatment with 
anti-fungal, anti-viral, anti-parasitic, or anti-protozoal agent 
 Requires oral treatment with antibiotic for longer than 14 days. 
 Is opportunistic, such as TB or other infections whose nature or course may suggest 
an immuno-compromised status 
 Severe laboratory abnormalities, such as: 
 Neutrophil count ≤1.0×103/L 
 Platelet count ≤50×103/L 
 Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values 
>3 × upper limit of normal (ULN) and total bilirubin >2×ULN, excluding 
confirmed Gilbert’s Syndrome 
 AST and/or ALT >5×ULN (for more than 2 weeks) 
 Creatine phosphokinase (CPK) >20×ULN 
NOTE: 
If the laboratory abnormality is considered causally related to study drug, study treatment will be 
permanently discontinued.  In cases in which a causal relationship to study drug can be reasonably 
excluded, (ie, an alternative cause is evident), study treatment will be suspended but it may be resumed 
when the laboratory abnormality is sufficiently normalized.  A decision to resume study treatment will 
be made jointly by the investigator and medical monitor (medical monitor’s written approval is required). 
 Patient withdraws consent 
 Other reasons that may lead to the permanent discontinuation of study treatment 
include: 
 Treatment with a live (attenuated) vaccine 
 Treatment with any prohibited concomitant medication or procedure (see 
Section 7.7.1).   
NOTE: 
Study drug does not need to be discontinued if a patient receives prohibited topical medication as 
rescue treatment (Section 7.3 and Section 7.7.2.1). 
The investigator may discontinue study treatment at any time, even without consultation with the 
medical monitor if the urgency of the situation requires immediate action and if this is determined 
to be in the patient’s best interest.  However, the medical monitor should be contacted as soon as 
possible in any case of study drug discontinuation. 
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7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily discontinued in the event of: 
 Clinically important laboratory abnormalities, such as: 
 Neutrophil count ≤1.5×103/µL but >1.0×103/L 
 Platelet count ≤100×103/µL but >50×103/L 
 CPK >10×ULN but ≤20×ULN 
 Other intercurrent major illnesses requiring hospitalization or major surgery 
 Treatment with a prohibited concomitant medication or procedure (Section 7.7.1).  
NOTE: 
Study drug does not need to be discontinued if a patient receives prohibited topical medication as rescue 
treatment (Section 7.3 and Section 7.7.2.1). 
After the condition leading to suspension of dosing resolves, study treatment may resume at the 
discretion of the investigator in consultation with the medical monitor.  A decision to temporarily 
discontinue study drug and/or to reinstitute study treatment should be discussed with the medical 
monitor. 
The investigator may suspend study treatment at any time, even without consultation with the 
medical monitor if the urgency of the situation requires immediate action and if this is determined 
to be in the patient’s best interest.  However, the medical monitor should be contacted as soon as 
possible in any case of study drug discontinuation. 
7.5. 
Method of Treatment Assignment 
On day 1/baseline, eligible patients will be randomized in a 1:1:1:1:1 ratio to receive double-blind 
treatment with REGN3500 SC 300 mg Q2W, REGN3500 SC 300 mg Q4W, REGN3500 SC 
100 mg Q4W, REGN3500 SC 30 mg Q8W, or placebo SC Q2W according to a central 
randomization scheme provided by an IVRS/IWRS to the designated study pharmacist (or 
qualified designee).  Randomization will be stratified according to baseline disease severity 
(moderate [IGA=3] vs. severe [IGA=4] AD). 
It is planned that at least approximately 50% of patients randomized will have an IGA score of 4.  
To ensure enrollment according to intended distribution of disease severity, alerts will be built into 
the IVRS/IWRS to limit enrolling patients with an IGA score <4. 
Patients who are permanently discontinued from study drug will not be replaced. 
7.5.1. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study.  The Regeneron Medical/Study Director, Study 
Monitor, and any other Regeneron and contract research organization (CRO) personnel who are 
in regular contact with the study site will remain blinded to all patient randomization assignments. 
Blinded study drug kits coded with a medication numbering system will be used.  To maintain the 
blind, lists linking these codes with product lot numbers will not be accessible to individuals 
involved in study conduct. 
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Anti-drug antibody and study drug concentration results will not be communicated to the sites, and 
the sponsor’s clinical operational team will not have access to results associated with patient 
identification until after the final database lock.  The bioanalytical analyst, bioanalytical team 
representatives, and clinical pharmacology representatives responsible for determining the study 
drug concentration measurements, ADAs, and biomarkers will not be blinded to the dosing 
information. 
7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
 If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected patients will be unblinded. 
 The IVRS/IWRS will provide the treatment assignment to the investigator. 
 The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator.  If there is no study pharmacist, the 
investigator for the site will unblind the patient 
 The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency.  In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
7.5.3. 
Unblinding for Regulatory Reporting Purposes 
Treatment assignments for certain patients may be unblinded to Pharmacovigilance personnel for 
the purpose of regulatory reporting of suspected unexpected serious adverse reactions (SUSARs). 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug.  Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging.  In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
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7.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed or returned to the 
sponsor or designee. 
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study drug: 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
Patients will be dosed under the supervision of appropriate study personnel.  All study drug 
compliance records must be kept current and made available for inspection by the sponsor and 
regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures  
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication.  This includes medications that were started before the study 
and are ongoing during the study. 
Information on concomitant medication for each patient will be recorded at each study visit from 
screening through the end of study. 
7.7.1. 
Prohibited Medications and Procedures 
Treatment with the following concomitant medications is prohibited during the study.  Study drug 
will be immediately discontinued if any of the following are used during the study (see 
Section 7.4.2.1): 
 Treatment with a live (attenuated) vaccine (a list of examples of such vaccines is 
below): 
 Chickenpox (Varicella) 
 FluMist-Influenza 
 Intranasal influenza 
 Measles (Rubeola) 
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 Measles-mumps-rubella combination 
 Measles-mumps-rubella-varicella combination 
 Mumps 
 Oral polio (Sabin) 
 Oral typhoid 
 Rubella 
 Smallpox (Vaccinia) 
 Yellow fever 
 Bacillus Calmette-Guerin 
 Rotavirus 
 Varicella Zoster (shingles; ie, Zostavax) 
 Treatment with an investigational drug (other than REGN3500) 
 Treatment with immunomodulating biologics 
 Treatment with systemic non-steroidal immunosuppressant (may be used as rescue, see 
Section 7.3 for details) 
 Treatment with systemic corticosteroids (may be used as rescue, see Section 7.3 for 
details) 
 Treatment with TCS or TCI (may be used as rescue in which study drug will not be 
discontinued, see Section 7.3 for details) 
 Treatment with topical crisaborole (may be used as rescue in which study drug will not 
be discontinued, see Section 7.3 for details) 
 Initiation of treatment of AD with prescription moisturizers 
The following concomitant procedures are prohibited during study participation: 
 Major elective surgical procedures 
 Phototherapy (ultraviolet A [UVA], ultraviolet B [UVB], narrowband UVB [nbUVB], 
high dose UVA, and psoralen and UVA [PUVA]) 
 Tanning in bed/booth 
7.7.2. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 7.7.1, treatment with concomitant 
medications are permitted during the study.  This includes basic skin care (cleansing and bathing, 
including bleach baths), bland emollients (required as background treatment; however, bland 
emollients should not be applied on any area(s) of lesional or non-lesional skin designated for 
assessment for at least 8 hours before each clinic visit), topical anesthetics, and antihistamines for 
any duration, and oral antibiotics for up to 14 days.  Medications used to treat chronic disease such 
as diabetes, hypertension, and asthma are also permitted; if there is any question regarding whether 
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a concomitant medication may be used during the study, the study site should contact the medical 
monitor. 
7.7.2.1. 
Prohibited Concomitant Medications or Procedures as Rescue Treatment 
If medically necessary (ie, to control intolerable AD symptoms), study patients may receive rescue 
treatment for AD at the discretion of the investigator (see Section 7.3).  If a patient receives rescue 
treatment with systemic corticosteroids or non-steroidal systemic immunosuppressive drugs, study 
treatment will be permanently discontinued immediately.  If rescue treatment consists of topical 
medications, the patient can continue study treatment.  
Blinded adjudication of concomitant medications may be performed to identify concomitant 
medications that confound study endpoints. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 2. 
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Table 2: 
Schedule of Events 
 
Screening 
Period13, 
14 
Double-Blind Treatment Period 
Follow-Up Period 
 
 
In-clinic Visit (V) 
Study Procedure1 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
EOT 
V10 
V11 
V12 
V13 
V14 
EOS 
V15 
Un-
sch16 
ET 
19 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
W32 
W36 
- 
- 
Day (D) 
D−35 to 
D−1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
D225 
D253 
- 
- 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
- 
Screening/Baseline:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ocular History8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient e-diary Training 
(Pruritus, Pain, and Sleep 
Quality NRS 
Assessments and 
Emollient Use)2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review patient e-diary 
data 
 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
Administration/ 
Dispensing/ 
Accountability3 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Meds/ 
Procedures 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus, Pain, and Sleep 
Quality NRS (daily)4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-reported HADS, 
DLQI, POEM5,6 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
EASI, IGA, GISS, 
SCORAD, BSA5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screening 
Period13, 
14 
Double-Blind Treatment Period 
Follow-Up Period 
 
 
In-clinic Visit (V) 
Study Procedure1 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
EOT 
V10 
V11 
V12 
V13 
V14 
EOS 
V15 
Un-
sch16 
ET 
19 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
W32 
W36 
- 
- 
Day (D) 
D−35 to 
D−1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
D225 
D253 
- 
- 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
- 
Safety:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
ECG 
X 
  
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmological Exam8 
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
X17  
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
X 
Laboratory Testing:1,11  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serologies (HIV Ab, 
HBsAg, HBcAb, 
HCV Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB QuantiFERON 
Testing 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (confirm 
menopausal status)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(WOCBP only)10 
Serum 
Urine 
 
Urine 
 
Uri-
ne 
 
Urine 
 
Ser-
um 
Urine 
Urine 
Urine 
Urine 
Ser-
um 
Uri-
ne 
Ser-
um 
Urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PK and ADA Samples:,1, 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum REGN3500 
Concentration (PK) 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X18 
X 
Anti-REGN3500 
Antibody (ADA)20 
 
X 
 
  
 
 
 
 
 
X 
 
 
 
 
X 
X18 
X 
Biomarkers:1, 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hs-CRP, SAA 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
TARC 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Total IgE 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Total IL-33 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X  
X 
FBR Samples 
(serum/plasma) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
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Screening 
Period13, 
14 
Double-Blind Treatment Period 
Follow-Up Period 
 
 
In-clinic Visit (V) 
Study Procedure1 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
EOT 
V10 
V11 
V12 
V13 
V14 
EOS 
V15 
Un-
sch16 
ET 
19 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
W32 
W36 
- 
- 
Day (D) 
D−35 to 
D−1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
D225 
D253 
- 
- 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
- 
Genomics Sample:1, 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood DNA12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood RNA12 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
ADA:  anti-drug antibody; BSA:  body surface area; D:  day; DLQI:  Dermatology Life Quality Index; EASI:  Eczema Area and Severity Index; ECG:  electrocardiogram; e-diary:  
electronic patient diary; EOS:  end-of-study; EOT:  end-of-treatment; ET:  early termination; FBR:  Future Biomedical Research; FSH:  follicle-stimulating hormone; GISS:  Global 
Individual Signs Score; HADS:  Hospital Anxiety and Depression Scale; HBcAb:  hepatitis B core antibody; HBsAg:  hepatitis B surface antigen; HCV Ab:  hepatitis C virus 
antibody; HIV Ab:  human immunodeficiency virus antibody; hs-CRP:  high-sensitivity C-reactive protein; ICF:  informed consent form; IGA:  Investigator’s Global Assessment; 
IgE:  immunoglobulin E; IL:  interleukin; Meds:  medications; NRS:  Numerical Rating Scale; PK:  pharmacokinetic; POEM:  Patient Oriented Eczema Measure; SAA:  serum 
amyloid A; SCORAD:  SCORing Atopic Dermatitis; TARC:  thymus and activation-regulated chemokine (CCL17); V:  visit; Unsch:  unscheduled visit; W:  week; WOCBP:  women 
of childbearing potential. 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. Assessments/procedures should be conducted in the following order:  patient reported 
outcomes, investigator assessments, safety and laboratory assessments (including sample 
collection for ADA, PK, biomarkers, DNA, and RNA), and then administration of study 
drug.   
2. Training of patients regarding completion of e-diary to record (1) completion of assessment 
of Pruritus, Pain, and Sleep Quality NRS scales and (2) emollient usage. 
3. All patients will receive Q2W SC injections.  For the REGN3500 300 mg SC Q4W group, 
REGN3500 100 mg SC Q4W group, and REGN3500 30 mg SC Q8W group, in order to 
maintain the blinding, there will be SC injection(s) of placebo in between REGN3500 
doses so the injection frequency will match the other 2 groups (REGN3500 300 mg SC 
Q2W and placebo SC Q2W) (see randomization and dosing regimen in Section 7.1 
Table 1).  Patients will be closely monitored at the study site at visits 2 through 9 (day 1 
through week 14) for a minimum of 30 minutes after the administration of study drug, and 
the monitoring period may be extended up to 2 hours as per country specific requirements.  
In addition to the predose assessments, patients will be assessed for adverse events (AEs) 
at 30 minutes (±10 minutes) postdose or until the end of the monitoring period (if 
applicable). 
4. Pruritus, Pain, and Sleep Quality NRS will be completed daily via electronic questionnaire 
(e-diary).  Reporting of these data begins the evening of visit 1 (screening). 
5. Questionnaires will be completed before any other assessments or invasive procedures 
(blood draws, study drug injection, etc). 
6. The questionnaires will be administered only to the subset of patients who speak fluently 
the language in which the questionnaire is presented (based on availability of validated 
translations in participating countries). 
7. Vital signs (sitting blood pressure, pulse, and respiratory rate) should be taken predose and 
30 minutes (±10 minutes) postdose.  In addition, body temperature should be taken 
predose.  
8. Ophthalmological exams at screening are limited to those patients who have a history of 
certain eye disorders (conjunctivitis, blepharitis or keratitis) within the last 12 months. 
Exams must be performed by an ophthalmologist (preferably with expertise in Cornea and 
External Eye Disease [‘front-of-the-eye’] subspecialty expert). Further evaluation will be 
performed including any additional tests, if applicable, as per the discretion of the 
ophthalmologist.  
9. Tuberculosis QuantiFERON testing at screening will be performed. 
10. Not required if postmenopausal status confirmed at screening. 
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11. Blood samples collected before the administration of study drug.  Pharmacokinetic samples 
will be collected for the determination of REGN3500 concentration and ADA samples for 
the immunogenicity assessment of REGN3500.  In the event of suspected SAEs, such as 
anaphylaxis or hypersensitivity, additional PK and ADA samples may be collected at or 
near the event.  At the visits where ADA samples are to be taken, the sample should be 
collected with the PK sample. 
12. One whole blood sample to extract DNA for pharmacogenomics analyses should be 
collected on day 1/baseline (visit 2), but can be collected at any visit.  Whole blood samples 
for RNA extraction should be collected according to time points in Table 2. 
13. Patients may be re-screened once if they fail the screening evaluation for reasons related 
to incidental transitory conditions (eg, medication use, concomitant illness, medical 
condition), unless the reason for the screen failure is related to failing the disease severity 
inclusion criteria. 
14. During the screening period, treatments for AD will be washed out, as applicable, 
according to eligibility requirements (see Section 6.2). 
15. Clinical sites will check patient data collected on the e-diary.  Baseline peak Pruritus NRS 
score for maximum itch intensity will be determined based on the average of daily NRS 
scores for maximum itch intensity during the 7 days immediately preceding randomization.  
A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average 
score.  For patients who do not have at least 4 daily scores reported during the 7 days 
immediately preceding the planned randomization date, randomization should be 
postponed until this requirement is met, but without exceeding the 35-day maximum 
duration for screening.  Patients are also required to have applied a stable dose of topical 
bland emollient (moisturizer) at least twice daily for at least the 7 consecutive days 
immediately before randomization (ie, baseline/randomization visit would be the eighth 
day). 
16. Unscheduled visits may be necessary to repeat testing following abnormal laboratory 
results, for follow-up of AEs, or for any other reason (eg, before a rescue 
medication/procedure is used), as warranted. 
17. Patients who experience adverse events of special interest (AESIs) related to eye disorders 
(refer to Section 9.4.3) must be referred to an ophthalmologist (preferably with expertise 
in Cornea and External Eye Disease [‘front-of-the-eye’] subspecialty expert). Further 
evaluation of these AEs will be performed including any additional tests, if applicable, as 
per the discretion of the ophthalmologist.  
18. If the unscheduled visit was due to an AE, collect samples for PK and ADA analysis. 
19. Patients who are withdrawn from the study will be asked to return to the clinic for ET 
assessments. 
20. In the event a patient sample is positive in the REGN3500 ADA assay at week 16 or the 
first time point analyzed, the week 4 PK sample may be analyzed in the ADA assay. 
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8.1.2. 
Early Termination Visit 
Patients who permanently discontinue study drug but who do not withdraw from the study will be 
asked to return to the clinic for all remaining study visits per the visit schedule (see Section 7.4.2 
and Table 2).  Patients who are withdrawn from the study will be asked to return to the clinic for 
ET assessments, only (Table 2). 
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason (eg, before a rescue medication/procedure is used), as warranted (Table 2 and 
Section 8.1.1). 
8.2. 
Study Procedures 
Assessments/procedures should be conducted in the following order:  patient reported outcomes, 
investigator assessments, safety and laboratory assessments and then administration of study drug.  
All questionnaires should be administered before any other assessments or invasive procedures 
(blood draws, study drug injection, etc). 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  obtaining informed consent, demographics, medical 
history (including diagnosis of chronic AD, prior treatments for AD, vaccination history for 
previous 6 months and history of other atopic diseases), height, human immunodeficiency 
antibody (HIV Ab), HBsAg, HBcAb, HCV Ab, TB QuantiFERON test, and serum FSH. 
Patients will be trained on using electronic questionnaires (e-diary) at the screening visit (visit 1).  
Patients will record Pruritus NRS scores and compliance with background treatment (ie, bland 
emollients) during the study using an electronic questionnaire (e-diary) beginning the evening of 
the screening visit (visit 1). 
8.2.2. 
Efficacy Procedures 
8.2.2.1. 
Pruritus Numeric Rating Scale (NRS) 
The Pruritus NRS is a simple assessment tool that patients will use to report the intensity of their 
pruritus (itch) during a 24-hour recall period using an electronic questionnaire.  Patients will be 
asked the following questions: 
 For maximum itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being 
the ‘worst itch imaginable’, how would you rate your itch at the worst moment during 
the previous 24 hours?” 
Patients will be instructed on using an electronic questionnaire to record their Pruritus NRS score 
at the screening visit.  Patients will complete the rating scale DAILY through the entire study 
(screening, treatment, and follow-up periods).  Clinical sites will check patient data collected using 
an e-diary for protocol compliance and remind patients to complete their e-diary throughout the 
study. 
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8.2.2.2. 
Peak Pain Numeric Rating Scale (NRS) 
The Peak Pain NRS is a simple assessment tool that patients will use to report the intensity of their 
pain during a 24-hour recall period using an electronic questionnaire.  Patients will be asked answer 
to the following question on a scale from 0 (no pain) to 10 (worst pain possible): 
For the question below, think about all the areas of your skin with eczema. 
“How would you rate your skin pain at its worst in the previous 24 hours?” 
Patients will be instructed on using an electronic questionnaire to record their Peak Pain NRS score 
at the screening visit.  Patients will complete the rating scale DAILY through the entire study 
(screening, treatment, and follow-up periods).  Clinical sites will check patient data collected using 
an e-diary for protocol compliance and remind patients to complete their e-diary throughout the 
study. 
8.2.2.3. 
Sleep Quality Numeric Rating Scale (NRS) 
The Sleep Quality NRS is a simple assessment tool that patients will use to report the quality of 
their sleep during a 24-hour recall period using an electronic questionnaire.  Patients will be asked 
the following question on a scale of 0 (best possible sleep) to 10 (worst possible sleep) upon 
awakening for the day: 
“Thinking about all the ways eczema affects your sleep, select the number that best describes 
your sleep last night.” 
Patients will be instructed on using an electronic questionnaire to record their Sleep Quality NRS 
score at the screening visit.  Patients will complete the rating scale DAILY through the entire study 
(screening, treatment, and follow-up periods).  Clinical sites will check patient data collected using 
an e-diary for protocol compliance and remind patients to complete their e-diary throughout the 
study. 
8.2.2.4. 
Hospital Anxiety Depression Scale (HADS) 
The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; 
repeated administration also provides information about changes to a patient’s emotional state 
(Zigmond, 1983) (Herrmann, 1997) (Bjelland, 2002).  The HADS consists of 14 items, 7 each for 
anxiety and depression symptoms; possible scores range from 0 to 21 for each subscale.  The 
following cut-off scores are recommended for both subscales:  7 to 8 for possible presence, 
10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.  The questionnaire 
will be administered only to the subset of patients who fluently speak a language in which the 
questionnaire is presented (based on availability of validated translations in participating 
countries), at time points according to Table 2. 
The HADS is provided in the study reference manual/site binder or file. 
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8.2.2.5. 
Dermatology Life Quality Index (DLQI) 
The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical studies to 
assess the impact of AD disease symptoms and treatment on QOL (Badia, 1999).  The format is a 
simple response (0 to 3 where 0 is “not at all” and 3 is “very much”) to 10 questions, which assess 
QOL over the past week, with an overall scoring system of 0 to 30; a high score is indicative of a 
poor QOL.  The questionnaire will be administered only to the subset of patients who fluently 
speak a language in which the questionnaire is presented (based on availability of validated 
translations in participating countries), at time points according to Table 2. 
The DLQI is provided in the study reference manual/site binder or file. 
8.2.2.6. 
Patient Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical studies to 
assess disease symptoms in children and adults (Charman, 2004).  The format is a response to 
7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency 
during the past week (ie, 0=no days, 1=1 to 2 days, 2=3 to 4 days, 3=5 to 6 days, and 4=all days) 
with a scoring system of 0 to 28; the total score reflects disease-related morbidity.  The 
questionnaire will be administered only to the subset of patients who fluently speak a language in 
which the questionnaire is presented (based on availability of validated translations in participating 
countries), at time points according to Table 2. 
The POEM is provided in the study reference manual/site binder or file. 
8.2.2.7. 
Investigator’s Global Assessment (IGA) 
The IGA is an assessment scale used in clinical studies to determine severity of AD and clinical 
response to treatment based on a 5-point scale ranging from 0 (clear) to 4 (severe).  The IGA score 
will be assessed at time points according to Table 2. 
The IGA is provided in the study reference manual/site binder or file and in Appendix 1. 
8.2.2.8. 
Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical studies to assess the severity 
and extent of AD (Hanifin, 2001).  The EASI is a composite index with scores ranging from 
0 to 72.  Four AD disease characteristics (erythema, thickness [induration, papulation, edema], 
scratching [excoriation], and lichenification) will each be assessed for severity by the investigator 
or designee on a scale of “0” (absent) through “3” (severe).  In addition, the area of AD 
involvement will be assessed as a percentage by body area of head, trunk, upper limbs, and lower 
limbs, and converted to a score of 0 to 6.  In each body region, the area is expressed as 0, 1 (1% to 
9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).  
The EASI will be collected at time points according to Table 2. 
The EASI assessment tool is provided in the study reference manual/site binder or file. 
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8.2.2.9. 
Body Surface Area (BSA) Involvement of Atopic Dermatitis 
Body surface area affected by AD will be assessed for each major section of the body (the possible 
highest score for each region is:  head and neck [9%], anterior trunk [18%], back [18%], upper 
limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a percentage of all 
major body sections combined.  Patients will undergo this assessment at time points according to 
Table 2. 
The BSA assessment tool is provided in the study reference manual/site binder or file. 
8.2.2.10. Global Individual Signs Score (GISS) 
Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and 
lichenification) will be rated globally (ie, each assessed for the whole body, not by anatomical 
region) on a 4-point scale (from 0=none to 3=severe) using the EASI severity grading criteria.  The 
GISS will be assessed at time points according to Table 2. 
The GISS assessment tool is provided in the study reference manual/site binder or file. 
8.2.2.11. SCORing Atopic Dermatitis (SCORAD) 
The SCORAD is a validated tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD (Dermatology, 1993).  There are 3 
components to the assessment:  A extent or affected body surface area, B=severity, and 
C=subjective symptoms.  The extent of AD is assessed as a percentage of each defined body area 
(see Section 8.2.2.9) and reported as the sum of all areas, with a maximum score of 100% (assigned 
as “A” in the overall SCORAD calculation).  The severity of 6 specific symptoms of AD (redness, 
swelling, oozing/crusting, excoriation, skin thickening/lichenification, dryness) is assessed using 
the following scale:  none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total 
points, assigned as “B” in the overall SCORAD calculation).  Subjective assessment of itch and 
sleeplessness is recorded for each symptom by the patient or relative on a visual analog scale 
(VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), 
with a maximum possible score of 20.  This parameter is assigned as “C” in the overall SCORAD 
calculation.  The SCORAD is calculated as:  A/5 + 7B/2 + C where the maximum is 103.  Patients 
will undergo this assessment at time points according to Table 2. 
The SCORAD assessment tool is provided in the study reference manual/site binder or file. 
8.2.3. 
Safety Procedures 
8.2.3.1. 
Vital Signs 
Vital signs (sitting blood pressure, pulse, and respiration rate) should be taken predose and 
30 minutes (±10 minutes) postdose (see Table 2).  In addition, body temperature should be taken 
predose. 
8.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 2.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history. 
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8.2.3.3. 
Body Weight and Height 
Body weight and height will be measured at time points according to Table 2 . 
8.2.3.4. 
Electrocardiogram 
Electrocardiograms (ECGs) should be performed before blood is drawn during visits requiring 
blood draws.  A standard 12-lead ECG will be performed at time points according to Table 2.  The 
ECG strips or reports will be retained with the source and the results will be documented in the 
electronic CRF (eCRF). 
Electrocardiogram results will be interpreted by a central reading center.  Instructions for 
performing the assessment and transmitting ECG data are provided in the study reference 
manual/site binder or file. 
8.2.3.5. 
Laboratory Testing 
Hematology, chemistry (including the CPK, ALT, AST, and lactate dehydrogenase [LDH] 
samples), urinalysis, and pregnancy testing samples will be analyzed by a central laboratory.  In 
addition to collecting blood and urine samples to measure overall patient health, total basophil and 
eosinophil counts are of particular interest in AD patients due to the occurrence of basophil 
histamine release and eosinophilia in this population.  Understanding the lymphocyte profiles of 
AD patients may help researchers understand disease heterogeneity. 
Detailed instructions for sample collection are in the study reference manual/site binder or file 
provided to study sites. 
Samples for laboratory testing will be collected at visits according to Table 2.  Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total and indirect bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen 
Triglycerides 
Carbon dioxide 
AST 
Uric acid 
Calcium 
ALT 
CPK 
Glucose 
Alkaline phosphatase 
 
Albumin 
LDH 
 
 
*(low-density lipoprotein and high-density lipoprotein) 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Pregnancy Testing 
Pregnancy testing (serum human chorionic gonadotropin [hCG] or urine hCG) will be performed 
for all WOCBP at visits according to Table 2. 
Other Laboratory Tests 
The following other laboratory tests will be performed at screening:  HIV, HBsAg, HBcAb, 
HCV Ab, and TB QuantiFERON test. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality.  When necessary, appropriate ancillary investigations 
should be initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study drug or its administration, the Medical/Study Director must be 
consulted. 
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.3.6. 
Research Samples 
Research samples (serum/plasma) will be collected at visits according to Table 2. 
Use and Storage of Research Samples (Serum/Plasma) 
Research serum and plasma samples will be collected to study IL-33 and IL-4/IL-13 pathways, 
effect of IL-33 and IL-4Rα inhibition with a mAb.  In addition, samples may be used to study 
immunology, inflammation, and atopic diseases.  Remaining samples may be stored for future use 
in experiments related to the above mentioned scope of research.  If necessary, the samples may 
also be used to identify markers associated with toxicity or predictive of efficacy.  Data from these 
analyses will not be reported in the clinical study report (CSR). 
8.2.3.7. 
Ophthalmologic (Eye) Examinations 
Patients who have a history of certain eye disorders (conjunctivitis, blepharitis, or keratitis) within 
the last 12 months of the screening visit will be referred during screening to an ophthalmologist 
(preferably with expertise in treating Cornea and External Eye Disease [‘front-of-the-eye’] 
subspecialty expert).   
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Patients who experience AESIs related to eye disorders (refer to Section 9.4.3 will also be referred 
to an ophthalmologist (preferably with expertise in treating patients or Cornea and External Eye 
Disease [‘front-of-the-eye’] subspecialty expert). Further evaluation of these AESIs will be 
performed including any additional tests, if applicable, as per the discretion of the ophthalmologist.   
8.2.4. 
Drug Concentration and Measurements 
Samples for study drug concentration will be collected at visits listed in Table 2.  The PK sample 
should be taken with the ADA sample when both are on the same day. 
Any unused samples may be used for exploratory biomarker research. 
8.2.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 2.  At the visits where 
ADA samples are to be taken, the sample should be collected with the PK sample.  Anti-drug 
antibody and PK samples are to be collected prior to administration of study drug.  
In the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional ADA samples 
may be collected at or near the event. 
Any unused samples may be used for exploratory biomarker research. 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore how REGN3500 may modify the 
underlying disease process in AD.  In particular, the role of IL-33 and the effect of REGN3500 on 
thymus and activation-regulated chemokine (CCL17; TARC), total serum IgE, total IL-33, high 
sensitivity C-reactive protein (hs-CRP), and serum amyloid A (SAA) will be explored. 
Biomarker samples will be collected at time points according to Table 2. Biomarker measurements 
will be performed in serum and plasma samples to determine effects on biomarkers of AD or 
relevant physiological and pathogenic processes.  The biomarkers studied are believed to be 
relevant to the pathophysiology of indication target engagement, mechanism of action of 
REGN3500 and possible toxicities.  Pharmacodynamic analysis will be described in the SAP and 
the results will be described in the CSR. 
8.2.6.1. 
Thymus and Activation-Regulated Chemokine (CCL17; TARC) 
The biomarker TARC is a chemokine induced by IL-4/IL-13, shown to be strongly associated with 
disease severity in AD, and may be involved in pathogenesis of the disease.  Baseline TARC levels 
will be assessed for potential predictive value for treatment response.  Post-treatment samples will 
be evaluated for PD effects of study treatment on TARC. 
TARC will be measured in serum from samples collected at time points indicated in Table 2. 
Detailed instructions for blood sample collection are provided in the study reference manual/site 
binder or file.  Data analysis will be described in the SAP and the results will be described in the 
CSR. 
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8.2.6.2. 
Total Immunoglobulin E (IgE) 
Patients with AD often have elevated IgE.  Total IgE levels have been found to modestly correlate 
with AD severity, and may be involved in the pathogenesis of the disease.  Changes in total IgE 
reflects not only on AD, but atopy in general.  Baseline IgE levels will be assessed for potential 
predictive value for treatment response.  Post-treatment samples will be evaluated for PD effects 
of study treatment on total IgE. 
Total IgE will be measured in serum from samples collected at time points indicated in Table 2. 
Detailed instructions for blood sample collection are provided in the study reference manual/site 
binder or file.  Data analysis will be described in the SAP and the results will be described in the 
CSR. 
8.2.6.3. 
Total Interleukin-33 (IL-33) 
Total IL-33 is a measure of target engagement for REGN3500.  Total IL-33 will be measured in 
serum from samples collected at time points indicated in Table 2. Data analysis will be described 
in the SAP and the results will be described in the CSR. 
8.2.6.4. 
High-Sensitivity C-Reactive Protein (hs-CRP) 
C-reactive protein (CRP) is a biomarker of Type 1 inflammation.  High-sensitivity CRP, which is 
more precise than standard CRP, can be used to measure of chronic inflammation or detect 
low-grade inflammation. 
Baseline hs-CRP levels may be assessed for potential predictive value for treatment response.  
Post-treatment samples may be evaluated for effects of study treatment on hs-CRP.  
High-sensitivity CRP may be measured in plasma from samples collected at time points indicated 
in Table 2. Detailed instructions for blood sample collection are provided in the study reference 
manual/site binder or file.  Data analysis will be described in the SAP and the results will be 
described in the CSR. 
8.2.6.5. 
Serum Amyloid A (SAA) 
Serum amyloid A is an early and sensitive blood biomarker for tissue injury and Type 1 
inflammation and has been indicated in many inflammatory diseases.  The level of SAA circulating 
in the blood is known to increase dramatically in response to tissue damage or inflammation, 
classifying it as an acute phase protein 
Serum amyloid A may be measured in samples collected at time points indicated in Table 2. 
Detailed instructions for sample collection are provided in the study reference manual/site binder 
or file.  Data analysis will be described in the SAP and the results will be described in the CSR. 
8.2.7. 
Future Biomedical Research (FBR) 
The unused biomarker samples for study-related research, as well as unused PK and ADA samples, 
will be stored for up to 15 years after the final date of the database lock.  The unused samples may 
be utilized for Future Biomedical Research (FBR) of AD, REGN3500 and its pathway and related 
diseases.  Additional samples will be collected for FBR.  After 15 years, any residual samples will 
be destroyed.  The results of these FBR analyses will not be presented in the CSR. 
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8.2.7.1. 
Pharmacogenomics Analysis 
Whole blood samples for DNA extraction should be collected on day 1/baseline (predose), but can 
be collected at a later study visit.  Whole blood samples for RNA extraction will be collected at 
time points according to Table 2. 
DNA and RNA samples will be collected for the pharmacogenomics analyses to understand the 
genetic determinants of efficacy and safety associated with the treatments in this study and the 
molecular basis of AD and related diseases.  These samples will be single-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15.  Samples will be stored for up to 15 
years after the final date of the database lock.  If there are specific site or country requirements 
involving the pharmacogenomics analyses which the sponsor is unable to comply with, samples 
will not be collected from patients at the site. 
The purpose of the pharmacogenomics analyses is to identify genomic associations with clinical 
or biomarker response to REGN3500, other AD clinical outcome measures and possible AEs.  In 
addition, associations between genomic variants and prognosis or progression of AD as well as 
related allergic/atopic diseases may also be studied.  These data may be used or combined with 
data collected from other studies to identify and validate genomic markers related to the study drug 
or AD and related diseases. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed.  The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period.  Results from the genomic analyses will not be 
reported in the CSR. 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients, according to local regulations.  This 
may include death from any cause and all SAEs related to the use of the study drug.  It is 
recommended that all SAEs be reported to the IRB/EC, according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (ie, SUSAR), to the health 
authorities, ECs/IRBs as appropriate, and to the investigators (in a blinded manner). 
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected.  Any worsening of or new onset of 
symptoms related to AD which occur during the screening period prior to study drug 
administration will be considered expected. 
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In addition, the sponsor will report in all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the study in the CSR to health authorities and ECs/IRB as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias, or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  See Section 9.4 for more 
information on recording and reporting SAEs. 
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9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.  Depending on the nature of the event, rapid communication by the 
study sponsor to other parties (eg, regulators) might also be warranted (Section 9.4.3). 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the EOS visit.  Refer to study reference manual/site binder or file for the procedures 
to be followed. 
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  Refer to the study reference manual/site binder or file for 
the procedure to be followed. 
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the EOS visit or within 140 days of last study drug 
administration if the patient early terminated from the study - the SAE will be reported 
to the sponsor.  The investigator should make every effort to obtain follow-up 
information on the outcome until the event is considered chronic and/or stable. 
 SAE with an onset day greater than 30 days from the EOS/ET visit - only fatal SAEs 
and those deemed by the investigator to be drug-related SAEs will be reported to the 
sponsor.  The investigator should make every effort to obtain follow-up information on 
the outcome of a drug-related SAE until the event is considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE, 
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Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female during the study or within 140 days of the last 
dose of study drug.  Any complication of pregnancy affecting a female study patient 
and/or fetus and/or newborn that meets the SAE criteria must be reported as an 
SAE.  Outcome for all pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest: All AESI, serious and non-serious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, 
per Section 9.4.2. Adverse events of special interest for this study include the 
following: 
 Anaphylactic reactions or acute allergic reactions that require immediate 
treatment 
 Severe ISRs that last longer than 24 hours 
 Mycosis fungoides or other forms of cutaneous T-cell lymphoma 
 Any severe infection; any infection requiring treatment with parenteral 
antibiotics/anti-viral/anti-fungal agent; any infection requiring treatment with 
oral antibiotic/anti-viral/anti-fungal for longer than 2 weeks; any clinical 
endoparasitosis; any opportunistic infection 
Note: 
Generally, all uncommon, atypical, peculiar, or unusually persistent infections, 
especially viral infections, should be reported as AESIs. 
 Conjunctivitis (any type or etiology), keratitis, or blepharitis (only events that 
are either severe or serious or lasting ≥4 weeks will be reported as AESIs) 
Any patient who experiences an AESI related to an eye disorder will be referred to 
an ophthalmologist.  Further evaluation of these AESIs will be performed including 
any additional tests, as per the discretion of the ophthalmologist.   
 Significant ALT elevation 
 ALT >3×ULN associated with total bilirubin >2×ULN; or  
 ALT >5×ULN in patients with baseline ALT ≤2×ULN; or  
 ALT >8×ULN if baseline ALT >2×ULN 
Refer to the study reference manual/site binder or file for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
Refer to the study reference manual/site binder or file for the procedures to be followed. 
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9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient normal functioning level.  It may 
be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms, but may be 
given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health.  Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
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Injection Site Reactions (ISRs) 
The severity of ISRs will be graded according to the following scale (semi-colon indicates “or” 
within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires 
emergency room visit or hospitalization; necrosis or exfoliative dermatitis 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the "blinded" investigator, and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related:  There is no reasonable possibility that the event may have been caused by 
the study drug 
Related:  There is a reasonable possibility that the event may have been caused by the 
study drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
 do not reappear or worsen when dosing with study drug is resumed 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
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 follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug  
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data  
Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the "blinded" investigator, and will 
be a clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related:  There is no reasonable possibility that the event may have been caused by 
study conduct 
Related:  There is a reasonable possibility that the event may have been caused by study 
conduct 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study conduct? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the course of the study 
 do not reappear or worsen when dosing with study participation is resumed 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the course of the study. 
 resolve or improve after discontinuation from study participation. 
 reappear or worsen when study participation is resumed 
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9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  
Safety monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on 
a periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical study, as well as 
in any other clinical study using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study.  The SAP may be revised during the 
study to accommodate amendments to the clinical study protocol and to make changes to adapt to 
unexpected issues in study execution and data that may affect the planned analyses.  The final SAP 
will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
For efficacy endpoints, the analyses will be the comparisons of the REGN3500 and the placebo 
groups.  The following null and alternative hypotheses of the primary endpoint will be tested for 
each REGN3500 group and the placebo group: 
H0:  No treatment difference between REGN3500 and placebo. 
H1:  There is treatment difference between REGN3500 and placebo. 
To control the overall family-wise type I error rate of 5%, a hierarchical procedure from high to 
low dose will be performed for the primary endpoint and selected secondary efficacy endpoints 
(eg, EASI-75, IGA score of 0 or 1 and a reduction from baseline of ≥2 points responder at week 16) 
across the REGN3500 dose regimens vs placebo.  The final hierarchy will be provided in the SAP 
that will be finalized prior to database lock. 
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10.2. 
Justification of Sample Size 
For the primary endpoint, the enrollment of 60 patients per treatment group will provide 96% 
power to detect a 35% difference between the most efficacious REGN3500 SC dose and the 
placebo group with respect to percent change in EASI score from baseline to week 16, assuming 
the common standard deviation (SD) is 50%, with a 2-sided test at the 0.05 significance level.  The 
50% SD along with the 35% difference in the mean percent were estimated based on results from 
2 phase 3 dupilumab AD studies (R668-AD-1334 and R668-AD-1416). 
Recently, publicly available results disclosed from an uncontrolled phase 2a study evaluating a 
single IV dose of an anti-IL-33 mAb (ANB020, AnaptysBio) in 12 moderate-to-severe adult AD 
patients offer mechanistic support for anti-IL-33 approach to improving AD disease severity (Ogg, 
2018).  In this study, 83% of patients were reported to have achieved EASI-50 at day 29 and an 
average EASI reduction of 62% by day 57 following dosing. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Set 
The full analysis set (FAS) includes all randomized patients; it is based on the treatment allocated 
(as randomized).  Efficacy endpoints will be analyzed using the FAS. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
10.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis set includes all randomized patients who received any study drug and who had at 
least 1 non-missing study drug concentration result following the first dose of study drug. 
10.3.4. 
Pharmacodynamic Analysis Set 
The PD analysis set population includes all randomized patients who received any study drug and 
who had at least 1 non-missing PD result following the first dose of study drug. 
10.3.5. 
Anti-Drug Antibody Analysis Set 
The ADA population includes all treated patients who received any amount of study drug 
(REGN3500 or REGN3500-matching placebo) and who had at least 1 non-missing ADA result 
following the first dose of study drug. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, SD, median, first quartile (Q1), third quartile 
(Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
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10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the informed consent form (ICF) 
 The total number of randomized patients:  received a randomization number 
 The total number of patients in each analysis set (eg, FAS, provided in Section 10.3.1) 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined. 
10.4.3. 
Efficacy Analyses 
The efficacy endpoints will be analyzed using the FAS which includes all randomized patients.  
Efficacy analyses will be based on the treatment allocated at randomization (as randomized). 
Continuous endpoints will be analyzed using the multiple imputation (MI) method with analysis 
of covariance (ANCOVA) model, which includes treatment group, stratification variable 
(moderate [IGA=3] vs. severe [IGA=4] AD) and relevant baseline value as covariates.  The 
efficacy data will be set to missing after rescue treatment is used, then all missing data from the 
FAS will be imputed 40 times under missing at random assumption to generate a complete dataset 
at each imputation by using the MI Statistical Analysis System (SAS) procedure.  These complete 
datasets will be analyzed using an ANCOVA model and the SAS MIANALYZE procedure will 
be used to generate valid statistical inferences by combining results from these multiple analyses 
using Rubin’s formula. 
Sensitivity analyses such as ANCOVA model with last observation carried forward, MI method 
with ANCOVA model on all observed data regardless of rescue treatment use will be conducted.  
Additional details on sensitivity analyses will be provided in the SAP. 
The categorical endpoints will be analyzed using a Cochran-Mantel-Haenszel test stratified by 
baseline disease severity stratum. 
Patients will be considered as non-responders at the time point where data are missing (regardless 
of reason for missingness, eg, due to drop-out or data set to missing after rescue treatment).  In 
addition, several sensitivity analyses will be performed including using MI imputing missing value 
(eg, EASI score) to determine whether or not met criteria (eg, EASI 75) for binary endpoints.  
Additional details on sensitivity analyses will be provided in the SAP. 
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10.4.3.1. Primary Analysis of the Study 
A primary analysis of the study may be performed when the last patient completes 16 weeks of 
treatment duration, in order to expedite the potential interactions with regulatory agencies to design 
future phase 3 studies.  No changes in the conduct of the study will be made based on this primary 
analysis of the study.  The assessment of primary and secondary endpoints specified in 
Section 4.2.1 and Section 4.2.2 performed during the analysis will be the final analysis of the 
primary endpoint and secondary endpoints.  Hence there will be no need for alpha adjustment due 
to the primary analysis of the study. 
If a decision is made to perform the primary analysis of the study, in order to maintain study 
integrity with respect to the post-treatment follow-up visits, safety visits and analyses, a 
dissemination plan will be written.  This plan will clearly identify the unblinded team (including 
the statistician) that will perform the primary analysis of the study and all related activities, restrict 
other clinical team members and other sponsor personnel from access to individual patient 
treatment allocation and site level analysis results (ie, remain blinded), and ensure that the 
dedicated unblinded team will not participate in the data review or data decisions for the 
subsequent post-treatment analyses.  However, the dedicated unblinded team can participate in the 
analysis following the final database lock. 
10.4.4. 
Safety Analysis 
The safety analysis will be based on the SAF.  This includes reported TEAEs and other safety 
information (ie, clinical laboratory evaluations, vital signs, and 12-lead ECG results).  A summary 
of safety results will be presented for each treatment group. 
10.4.4.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
 The treatment-emergent period is defined as the day from first dose of study drug to 
the end of study.  The treatment-emergent period includes the 16-week treatment period 
and follow-up period. 
 Treatment period:  date of the first dose of study drug to week 16 visit date (study 
day 113 starting from the first dose of study drug if week 16 visit date is 
unavailable) or ET date, whichever comes first. 
 Follow-up period:  date after week 16 visit date (study day 113 starting from first 
dose of study drug if week 16 visit date is unavailable) to EOS visit. 
Treatment-emergent AEs are defined as those that are not present at baseline or represent the 
exacerbation of a pre-existing condition during the treatment-emergent period. 
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Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group and for overall during the treatment-emergent period, 
during the 16-week treatment period, and during the follow-up period will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), presented 
by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
 Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent AEs leading to permanent treatment discontinuation will be listed and 
summarized by treatment group. 
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (body temperature and sitting blood pressure, pulse, and respiration rate) will be 
summarized by baseline and change from baseline to each scheduled assessment time with 
descriptive statistics. 
The number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable.  The criteria for treatment emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a PCSV at any postrandomization time point will be 
summarized for each clinical laboratory test. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
12-Lead ECG 
Electrocardiogram results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. 
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10.4.4.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment and calculated as: 
(date of last study drug injection – date of first study drug injection) + 14 days 
The number (%) of patients randomized and exposed to double-blind study drug will be presented 
by specific time periods for each treatment group.  The time periods of interest will be specified 
in the SAP. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of patients, means, SD, minimums, Q1, medians, Q3, and maximums. 
A summary of the number of doses by treatment group will be provided. 
10.4.4.4. Treatment Compliance 
The compliance with protocol-defined investigational product will be calculated as follows: 
Treatment compliance= 
(number of investigational product injections during exposure period)/(number of planned 
investigational product injections during exposure period) × 100% 
The treatment compliance will be presented by specific ranges for each treatment group.  The 
ranges of interest will be specified in the SAP. 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
No formal statistical analysis will be performed.  Trough functional REGN3500 concentration in 
serum will be summarized at each time point using descriptive statistics.  The data may be 
combined with data from other studies, as applicable, for analysis using population methods.  Any 
population PK analysis will be reported separately. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
The ADA variables described in Section 4.4 will be summarized.  Listings of treatment-emergent 
ADA and titers presented by patient, time point, and dose cohort (treatment group) will be 
provided.  The incidence of treatment-emergent ADA will be assessed as absolute occurrence (N) 
and percent of patients (%), grouped by dose cohort and ADA titer level. 
Association of treatment-emergent and treatment boosted ADA responses and titers with potential 
impact on PK, safety, or efficacy may be evaluated.  Drug concentration data will be examined 
and the influence of ADAs on individual concentration-time profiles will be evaluated. 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Biomarker results will be summarized by baseline, measured values, change from baseline and 
percent change from baseline to each scheduled assessment time with descriptive statistics.  Other 
exploratory analyses may be performed, but will not be described in the SAP or CSR. 
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10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline: 
 The baseline assessment will be the latest, valid pre-first-dose assessment available. 
General rules for handling missing data: 
 Rules for handling missing data for assessment (other than efficacy) 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study drug, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
drug date, then the start date by the study drug intake date will be imputed; otherwise, 
the missing day or month by the first day or the first month will be imputed. 
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed according 
to the CRF assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries.  If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (sponsor). 
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A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history/ophthalmic 
history) will be done using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC). 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system – randomization, study drug supply 
 EDC system – data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an eCRF).  Case report forms and source documents must be 
available at all times for inspection by authorized representatives of the sponsor and regulatory 
authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel.  All required CRFs must be completed for each and every patient 
enrolled in the study.  After review of the clinical data for each patient, the investigator must 
provide an electronic signature.  A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
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13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
Informing the sponsor of a planned inspection by the authorities as soon as notification is received, 
and authorizing the sponsor’s participation in the inspection 
Providing access to all necessary facilities, study data, and documents for the inspection or audit 
Communicating any information arising from inspection by the regulatory authorities to the 
sponsor immediately 
Taking all appropriate measures requested by the sponsor to resolve the problems found during 
the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient. 
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
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 Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
14.2. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor.  Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
14.3. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
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15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC 
and health authority, if required by local regulation, approved amendment. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely.  In the event of a 
close-out of a study site, no additional patients will be screened or enrolled.  Patients who are 
currently enrolled in the study will be followed up according to the protocol (see Table 2). 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others: 
 The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and health authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
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17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation.  Records must be destroyed in a manner that ensures 
confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination. 
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are summarized. 
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13). 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1). 
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All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data).  The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient final CRF (Section 12.3 
and Section 17.1). 
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.2). 
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2). 
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
22. 
REFERENCES 
Badia X, Mascaro JM, Lozano R.  Measuring health-related quality of life in patients with 
mild-to-moderate eczema and psoriasis:  Clinical validity, reliability and sensitivity to change of 
the DLQI.  Br J Dermatol 1999;141(4):698-702. 
Bieber T.  Mechanisms of disease:  atopic dermatitis.  N Engl J Med 2008;358(14):1483-94. 
Bjelland I, Dahl AA, Haug TT, Neckelmann D.  Review:  The validity of the hospital anxiety 
and depression scale, an updated literature review.  J Psychosom Res 2002;52(2):69-77. 
Bonnelykke K, Matheson MC, Pers TH, Granell R, Strachan DP, Alves AC, et al.  Meta-analysis 
of genome-wide association studies identifies ten loci influencing allergic sensitization.  Nat 
Genet 2013;45(8):902-6. 
Bradley PP, Priebat DA, Christensen RD, Rothstein G.  Measurement of cutaneous 
inflammation:  estimation of neutrophil content with an enzyme marker.  J Invest Dermatol 
1982;78(3):206-9. 
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Cayrol C, Girard JP.  IL-33:  An alarmin cytokine with crucial roles in innate immunity, 
inflammation and allergy.  Curr Opin Immunol 2014;31:31-7. 
Charman CR, Venn AJ, Williams H.  The patient-oriented eczema measure:  development and 
initial validation of a new tool for measuring atopic eczema severity from a patients’ perspective.  
Arch Dermatol 2004;140(12):1513-9. 
Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, 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(2):338-51. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber Ml.  The eczema area and 
severity index (EASI):  assessment of reliability in atopic dermatitis.  Exp Dermatol 
2001;10(1):11-8. 
Herrmann C.  International experiences with the hospital anxiety and depression scale – a review 
of validation data and clinical results.  J Psychosom Res 1997;42(1):17-41. 
Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Sakashita M, et al.  Genome-wide 
association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese 
population.  Nat Genet 2012;44(11):1222-6. 
Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T, et al.  Skin-specific 
expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like 
inflammation in mice.  Proc Natl Acad Sci USA 2013;110(34):13921-6. 
Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, et al.  TSLP elicits 
IL-33-independent innate lymphoid cell responses to promote skin inflammation.  Sci Transl 
Med 2013;5(170):170ra16. 
Li C, Maillet I, Mackowiak C, Viala C, Di Padova F, Li M, et al.  Experimental atopic dermatitis 
depends on IL-33R signaling via MyD88 in dendritic cells.  Cell Death Dis 2017;8(4):e2735. 
No authors listed.  Severity scoring of atopic dermatitis:  The SCORAD index.  Consensus report 
of the European task force on atopic dermatitis.  Dermatology 1993;186(1):23-31. 
Ogg G.  Proof-of-concept phase 2a clinical trial of ANB020 (anti-IL-33 antibody) in the 
treatment of moderate-to-severe adult atopic dermatitis.  American Academy of Dermatology 
Annual Meeting.  February 17 2018. 
Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, et al.  Multi-ancestry 
genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for 
atopic dermatitis.  Nat Genet 2015;47(12):1449-56. 
Peng G, Mu Z, Cui L, Liu P, Wang Y, Wu W, et al.  Anti-IL-33 antibody has a therapeutic effect 
in an atopic dermatitis murine model induced by 2, 4-dinitrochlorobenzene.  Inflammation 
2018;41(1):154-63. 
Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, et al.  A role for 
IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis.  J Exp Med 
2013;210(13):2939-50. 
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Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimäki S, et al.  IL-33 and 
ST2 in atopic dermatitis:  Expression profiles and modulation by triggering factors.  J Invest 
Dermatol 2012;132(5):1392-400. 
Shimizu M, Matsuda A, Yanagisawa K, Hirota T, Akahoshi M, Inomata N, et al.  Functional 
SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis.  Hum Mol 
Genet 2005;14(19):2919–27. 
Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, et al.  
Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared 
with extrinsic atopic dermatitis.  J Allergy Clin Immunol 2013;132(2):361-70. 
Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, et al.  Epidermal expression 
and regulation of interleukin-33 during homeostasis and inflammation:  strong species 
differences.  J Invest Dermatol 2015;135(7):1771–80. 
Tamagawa-Mineoka R, Okuzawa Y, Masuda K, Katoh N.  Increased serum levels of interleukin 
33 in patients with atopic dermatitis.  J Am Acad Dermatol 2014;70(5):882-8. 
Williams MR, Nakatzuji T, Gallo RL.  Staphylococcus aureus:  master manipulator of the skin.  
Cell Host Microbe 2017;22(5):579-81. 
Zigmond AS, Snaith RP.  The hospital anxiety and depression scale.  Acta Psychiatr Scand 
1983;67(6):361-70. 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Dose-Ranging Study Investigating the Efficacy, Safety, and Pharmacokinetic 
Profiles of REGN3500 Administered to Adult Patients with Moderate-to-Severe Atopic Dermatitis 
and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
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APPENDIX 1: INVESTIGATOR’S GLOBAL ASSESSMENT (IGA) SCALE 
 
Please refer to the instructions below and place a checkmark next to the appropriate score below: 
 
_____    0   Clear 
_____    1   Almost Clear 
_____    2   Mild Disease 
_____    3   Moderate Disease 
_____    4   Severe Disease 
 
 
______________________________________________________ 
 
____________________ 
 
_______________ 
 
Print Name (First/Last) of Investigator Completing Assessment 
 
Signature 
 
 
 
Date 
 
 
Instructions: 
The Investigator’s Global Assessment is a static 5-point measure of disease severity based on an overall assessment of the skin lesions. 
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IGA:  Disease Severity Scale and Definitions of the scoring: 
Score 
Investigator’s Global Assessment (IGA)  
Standard Definitions 
Investigator’s Global Assessment (IGA): 
Proposed Morphological Descriptors 
0 = Clear           
No inflammatory signs of atopic dermatitis 
No inflammatory signs of atopic dermatitis 
1 = Almost clear 
Just perceptible erythema, and just perceptible 
papulation/infiltration  
Barely perceptible erythema and/or minimal lesion elevation 
(papulation/infiltration) 
2 = Mild disease 
Mild erythema and mild papulation/infiltration  
  
Visibly detectable, light pink erythema and very slight 
elevation (papulation/infiltration) 
3 = Moderate disease 
Moderate erythema and moderate 
papulation/infiltration   
Dull red, clearly distinguishable erythema; clearly perceptible 
elevation (papulation/infiltration), but not extensive 
4 = Severe disease 
Severe erythema and severe papulation/infiltration  
  
Deep/dark red erythema; marked and extensive elevation 
(papulation/infiltration) 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Dose-Ranging Study Investigating the Efficacy, Safety, and Pharmacokinetic Profiles of 
REGN3500 Administered to Adult Patients with Moderate-to-Severe Atopic Dermatitis 
Protocol Number: 
R3500-AD-1805  
Protocol Version: 
R3500-AD-1805 Amendment 3 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
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Signature Page for VV-RIM-00067457 v1.0
Signature Page for VV-RIM-00067457 v1.0 Approved
ESig Approval
00
ESig Approval
2019 15:47:39 GMT+0000
ESig Approval
9 17:25:06 GMT+0000
ESig Approval
2019 17:29:02 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
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Document’s type 
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Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL V1.0 
Clinical Study Protocol Title: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Dose-Ranging Study Investigating the Efficacy, Safety, and 
Pharmacokinetic Profiles of REGN3500 Administered to Adult Patients with Moderate-to-
Severe Atopic Dermatitis 
Compound: 
REGN3500 
Protocol Number: 
R3500-AD-1805 
Clinical Phase:  
Phase 2b 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Original Statistical Analysis Plan / June 15, 2020 
VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00
 NCT03738423


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 2 of 58 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatistician  (
) 
 
 
See appended electronic signature page 
Study Medical Director 
(
) 
 
 
See appended electronic signature page 
Head of BDM or designee 
(
) 
 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Other Objectives ...........................................................................................................9 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ..................................9 
1.2.5. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................12 
2.3. 
Study Plan ...................................................................................................................12 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
The Full Analysis Set (FAS) .......................................................................................14 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................14 
3.3. 
Pharmacokinetic Analysis Set (PKAS) ......................................................................15 
3.4. 
The Immunogenicity Analysis Set..............................................................................15 
4. 
ANALYSIS VARIABLES .........................................................................................16 
4.1. 
Demographic and Baseline Characteristics ................................................................16 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Prior / Concomitant Medication .................................................................................16 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................17 
4.5. 
Efficacy Variable ........................................................................................................18 
4.5.1. 
Primary Efficacy Variable ..........................................................................................18 
4.5.2. 
Secondary Efficacy Variables .....................................................................................18 
4.5.3. 
Other Efficacy Variables ............................................................................................19 
4.6. 
Safety Variables ..........................................................................................................20 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................20 
4.6.2. 
Adverse Events of Special Interest .............................................................................21 
4.6.3. 
Laboratory Safety Variables .......................................................................................22 
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Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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4.6.4. 
Vital Signs ..................................................................................................................23 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................23 
4.6.6. 
Physical Examination Variables .................................................................................23 
4.6.7. 
Other Safety Variables ................................................................................................23 
4.7. 
Pharmacokinetic Variables .........................................................................................23 
4.8. 
Immunogenicity Variables ..........................................................................................24 
4.9. 
Pharmacodynamic and Biomarker Variables .............................................................25 
5. 
STATISTICAL METHODS .......................................................................................26 
5.1. 
Demographics and Baseline Characteristics ...............................................................26 
5.2. 
Medical and AD History .............................................................................................26 
5.3. 
Prior/concomitant Medications and Procedures .........................................................26 
5.4. 
Rescue/Prohibited Medications and Procedures .........................................................27 
5.5. 
Subject Disposition .....................................................................................................27 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................28 
5.6.1. 
Measurement of Compliance ......................................................................................28 
5.6.2. 
Treatment Exposure and Observation Period .............................................................28 
5.7. 
Analyses of Efficacy Variables ..................................................................................28 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................29 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................29 
5.7.3. 
Adjustment for Multiple Comparison .........................................................................29 
5.8. 
Analysis of Safety Data ..............................................................................................29 
5.8.1. 
Adverse Events ...........................................................................................................30 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................31 
5.8.3. 
Analysis of Clinical Laboratory Measurements .........................................................31 
5.8.4. 
Analysis of Vital Signs ...............................................................................................31 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................32 
5.8.6. 
Physical Exams ...........................................................................................................32 
5.8.7. 
Ophthalmological exams ............................................................................................32 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................32 
5.10. 
Analysis of Immunogenicity Data ..............................................................................32 
5.10.1. 
Analysis of ADA Data ................................................................................................32 
5.11. 
Association of Immunogenicity with Exposure & Safety ..........................................33 
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Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
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5.11.1. 
Immunogenicity and Exposure ...................................................................................33 
5.11.2. 
Immunogenicity and Safety ........................................................................................33 
5.12. 
Analysis of Biomarker Data .......................................................................................34 
6. 
DATA CONVENTIONS ............................................................................................35 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................35 
6.2. 
General Data Handling Convention ............................................................................35 
6.3. 
Data Handling Convention for Missing Data .............................................................35 
6.4. 
Visit Windows ............................................................................................................37 
7. 
INTERIM ANALYSIS ...............................................................................................40 
8. 
SOFTWARE ...............................................................................................................41 
9. 
REFERENCES ...........................................................................................................42 
10. 
APPENDIX.................................................................................................................43 
10.1. 
Summary of Statistical Analyses ................................................................................43 
10.2. 
Schedule of Time and Events .....................................................................................45 
10.3. 
Criteria for Treatment-Emergent Potentially Clinically Significant Values 
(PCSV) for REGN3500 AD studies in Adults ...........................................................50 
10.4. 
Search Criteria for TEAE of Special Interest .............................................................55 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................45 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................11 
 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AD 
 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGOT) 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST (SGPT) 
Aspartate aminotransferase 
BAS 
Biomarker analysis set 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
DFI 
Dermatitis Family Index 
EASI 
Eczema area and severity index 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
GISS 
Global Individual Signs Score 
HADS 
Hospital Anxiety and Depression Scale 
HLT 
High Level Term 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
IGA 
Investigator global assessment 
IL 
Interleukin 
IgE 
Immunoglobulin E 
LDH 
Lactate dehydrogenase  
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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PKAS 
Pharmacokinetic analysis set 
POEM 
Patient Oriented Eczema Measure 
PT 
Preferred term 
Q2W 
Once every 2 weeks 
Q4W 
Once every 4 weeks 
Q8W 
Once every 8 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCORAD 
SCORing atopic dermatitis 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
TARC 
Thymus and activation-regulated chemokine 
TCI 
Topical calcineurin inhibitors 
TCS 
Topical corticosteroids 
TEAE 
Treatment emergent adverse event 
 
 
 
 
 
 
 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to pre-specify the statistical approaches for 
the analysis of study data prior to database lock. The SAP is intended to be a comprehensive and 
detailed description of the strategy and statistical methods to be used in the analysis of data for 
R3500-AD-1805 study.  
1.1. 
Background/Rationale 
Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by intense 
pruritus (ie, itchiness), xerosis (skin dryness), and eczematous lesions whose features include 
erythema, infiltration/papulation, oozing with crusting, excoriations, and lichenification. Severe 
disease can be extremely disabling due to several factors: major psychological problems, 
significant sleep loss, and impaired quality of life (QOL) that lead to a high socioeconomic cost. 
The pathophysiology of AD is influenced by a complex interplay between inflammation, 
environmental factors, genetics, and skin barrier dysfunction. Both the disturbances in epidermal 
barrier function and hyperactive immune response are associated with changes in the skin 
microbiome. 
For patients with moderate-to-severe AD, topical therapies have limited efficacy, and systemic 
treatments are associated with substantial toxic effects.  
Interleukin-33 is released by damaged epithelial tissue cells in response to insults such as allergens, 
viruses, or injuries. Interleukin-33 signaling activates multiple downstream inflammatory 
pathways, resulting in effects characteristic of both Type 1 and Type 2 inflammation. Experimental 
evidence suggest a role for IL-33 in pathogenesis of AD. 
REGN3500 (also referred to as SAR440340) is a human IgG4P mAb that binds IL-33 with 
subnanomolar affinity and thereby inhibits IL-33 signaling. Preclinical murine lung models 
suggest that treatment with REGN3500 and dupilumab display additive effects, further 
suppressing pathways associated with allergic inflammation or target pathways not affected by 
either monotherapy. These additive effects suggest that REGN3500 plus dupilumab combination 
treatment may provide additional benefits in patients with AD. REGN3500 has been studied in 
3 phase 1 clinical studies evaluating the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of REGN3500 in healthy volunteers and in patients with asthma, as well 
as in phase 2 studies in patients with AD, asthma, and COPD, alone and in combination with 
dupilumab 
This trial is a 5-arm, placebo-controlled, double-blind, randomized, parallel-group, dose ranging  
(phase 2b) study over a 16-week treatment period followed by a 20-week safety follow-up period 
in approximately 300 adult patients with moderate-to-severe AD. The five treatment groups are:  
• REGN3500 300 mg Q2W 
• REGN3500 300 mg Q4W 
• REGN3500 100 mg Q4W 
• REGN3500 30 mg Q8W  
• Placebo Q2W  
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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The administrative looks on study R3500-AD--l798 (Efficacy and Safety of REGN3500 
Monotherapy and Combination of REGN3500 Plus Dupilumab in Adult Patients With Moderate-
to-Severe Atopic Dermatitis) were conducted to make strategic decisions on the clinical 
development program for REGN3500 by an unblinded management team not involved with the 
conduct of the study. The first administrative look was based on data cutoff on 18Nov2019 and 
the second on 24Jan2020. The data analyses indicated the lack of efficacy of REGN3500 in 
patients with moderate to severe atopic dermatitis when compared to placebo.  Safety information 
currently available from this study did not suggest safety concerns related to REGN3500.  As a 
result of lack of efficacy of REGN3500 from study R3500-AD-1798, Regeneron Pharmaceuticals, 
Inc and Sanofi have discontinued the REGN3500 atopic dermatitis program, and terminated the 
ongoing AD studies earlier than planned (R3500-AD-1798 and R3500-AD-1805).  Therefore, all 
analyses of these 2 studies will be descriptive; no hypothesis testing will be performed.  However, 
clinical development of REGN3500 for the treatment of other diseases remains ongoing. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to assess the efficacy of REGN3500 monotherapy in AD, as 
well as understand the dose-response relationship, compared with placebo treatment, in adult 
patients with moderate-to-severe AD. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To assess the safety and tolerability of subcutaneous (SC) doses of REGN3500 
monotherapy in adult patients with moderate-to-severe AD 
• To assess the PK of REGN3500 in adult patients with moderate-to-severe AD 
• To assess the immunogenicity of REGN3500 in adult patients with moderat-to-severe 
AD 
1.2.3. 
Other Objectives 
The exploratory objectives of the study are to assess the effects of REGN3500 monotherapy on 
skin and blood biomarkers of inflammation, QOL, and patient-reported measures of pain and sleep 
quality in comparison with placebo. 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The current active protocol for countries other than Japan is the protocol amendment 3 and the one 
for Japan is the protocol amendment 2. As mentioned on Section 1.1 , due to lack of efficacy of 
REGN3500 in this study, Regeneron Pharmaceuticals, Inc and Sanofi have discontinued the 
REGN3500 atopic dermatitis program and terminated both ongoing AD studies earlier than 
planned (R3500-AD-1798 and R3500-AD-1805).  Due to the decision, not all planned patients 
were enrolled in the study. For patients who were already enrolled, investigators were instructed 
to discontinue the study drugs and transition these patients into post- treatment follow-up period 
for safety assessments. As a result, a large amount of data remained uncollected as not all enrolled 
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Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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patients completed all planned study visits and study procedures for the assessments of efficacy, 
ADA, and biomarker endpoints. Only the abbreviated clinical study report will be reported. 
Therefore, the following will be removed: 
• the analyses using ANCOVA model for both the primary analysis and sensitivity 
analysis in the primary endpoint (ie, percent change in EASI score), secondary 
endpoints (ie, absolute change in EASI score, absolute change and percent change in 
pruritus NRS) and other endpoints (ie, absolute change and percent change in pain NRS 
and sleep quality NRS) 
• the analysis using Cochran-Mantel-Haenszel test for both the primary analysis and 
sensitivity analysis in the binary secondary endpoints (ie, IGA score of 0 or 1, EASI-
50, EASI-75, EASI-90, and improvement in pruritus NRS ≥4)  
• the multiple imputation and last observation carried forward methods for the missing 
data imputation in efficacy endpoints 
• the imputation of missing data to non-responder except that the data is set to missing 
due to rescue treatment 
• the analyses on association between ADA and efficacy endpoints.  
• the analysis on the endpoints of BSA, SCORAD, HADS, DLQI, POEM, and GISS. 
• the pharmacodynamic analysis set for biomarker analysis. 
One change is that the biomarkers will be analyzed based on the full analysis set. 
1.2.5. 
Revision History for SAP Amendments 
None. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging 
study investigating the efficacy, safety, and PK profiles of REGN3500 administered to adult 
patients with moderate-to-severe AD. Eligible patients must have a documented history of 
inadequate response or intolerance to treatment with topical AD medications.   This study is 
intended to provide information regarding 4 different REGN3500 monotherapy dosing regimens. 
Each REGN3500 dosing regimen will be compared with placebo to enable robust assessment of 
efficacy and safety. 
The study duration is up to 41 weeks, including an up to 5-week (ie, 35 days) screening period, 
16-week double-blind treatment period, and 20-week post-treatment follow-up period. 
Approximately 300 subjects (60 subjects per treatment group) will be recruited and randomized 
from approximately 60 sites. Approximately 10% of patients are planned to be enrolled in Japan; 
and that the Japanese patients will be randomized in 2 cohorts:  a sentinel cohort of 15 patients and 
a second cohort of 15 patients.  The randomization scheme and procedure of the Japanese patients 
will be the same as the rest of the patients. Independent Data Monitoring Committee will review 
of safety data from the first 15 Japanese patients when the 15th patient completes the Day 15 visit.  
Figure 1: 
Study Flow Diagram 
 
D: day; EASI:  Eczema Area and Severity Index; EOS:  end-of-study; EOT:  end-of-treatment; Q2W: every 2 weeks; 
Q4W: every 4 weeks; Q8W: every 8 weeks; R:  randomization; W: week 
On 12 February 2020, the Sponsor decided to stop the study. At that time, 129 subjects had been 
randomized including 6 Japanese patients. The sponsor instructed the investigators to transition all 
patients in the treatment phase to the twenty-week safety-follow-up period. These patients will 
stop the treatment and finish the end of treatment assessments before entering into the follow-up 
period. All patients who were in the screening period, but had not received study investigational 
medicinal product (IMP), will be screen failed for the reason of sponsor decision to discontinue 
study. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
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2.2. 
Sample Size and Power Considerations 
For the primary endpoint, the enrollment of 60 patients per treatment group will provide 96% 
power to detect a 35% difference between the most efficacious REGN3500 SC dose and the 
placebo group with respect to percent change in EASI score from baseline to week 16, assuming 
the common standard deviation (SD) is 50%, with a 2-sided test at the 0.05 significance level.  The 
50% SD along with the 35% difference in the mean percent were estimated based on results from 
two phase 3 dupilumab AD studies (R668-AD-1334 and R668-AD-1416). 
The above calculation is for the full enrollment. However, the number of randomized patients is 
129 in 5 arms including 6 Japanese patients because the Sponsors decided to stop the study 
prematurely due to the lack of efficacy in REGN3500 based on AD-1798 interim look data. 
2.3. 
Study Plan 
After providing informed consent, patients will be assessed for study eligibility at the screening 
visit.  Patients will undergo screening within 5 weeks (ie, 35 days) prior to randomization.  During 
the screening period, treatments for AD will be washed out, as applicable, according to eligibility 
requirements.  Patients may be re-screened once if they fail the screening evaluation for reasons 
related to incidental transitory conditions (eg, medication use, concomitant illness, medical 
condition), unless the reason for the screen failure is related to failing the disease severity inclusion 
criteria. 
Patients will be required to apply moisturizers (bland emollients) at least twice daily for at least 
the 7 consecutive days immediately before randomization (ie, baseline/randomization visit would 
be the eighth day) and throughout the study. However, to allow adequate assessment of skin 
dryness, moisturizers should not be applied on any area(s) of lesional or non-lesional skin 
designated for such assessments for at least 8 hours before each clinic visit. 
Patients who continue to meet eligibility criteria will undergo day 1/baseline assessments and will 
be randomized in a 1:1:1:1:1 ratio to 1 of 5 treatment regimens (REGN3500 300 mg SC Q2W, 
REGN3500 300 mg SC Q4W, REGN3500 100 mg SC Q4W, REGN3500 30 mg SC Q8W, or 
placebo SC Q2WREGN3500 300 mg SC Q2W, REGN3500 300 mg SC Q4W, REGN3500 
100 mg SC Q4W, REGN3500 30 mg SC Q8W, or placebo SC Q2W REGN3500 300 mg SC Q2W, 
REGN3500 300 mg SC Q4W, REGN3500 100 mg SC Q4W, REGN3500 30 mg SC Q8W, or 
placebo SC Q2W) during the 16-week double-blind treatment period followed by a 20-week post-
treatment follow-up period.  
Randomization will be stratified by baseline disease severity (moderate [IGA=3] vs. severe 
[IGA=4] AD). It is planned that at least approximately 50% of patients randomized will have an 
IGA score of 4. To ensure enrollment according to intended distribution of disease severity, alerts 
will be built into the interactive voice response system/interactive web response system 
(IVRS/IWRS) to limit enrolling patients with an IGA score <4. 
Patients will remain at the study site for a minimum of 30 minutes after administration of study 
drug, and the monitoring period may be extended up to 2 hours as per country-specific 
requirements. During the 16-week treatment period, patients will have study visits every other 
week. The end-of-treatment (EOT) visit will occur at week 16, which is 2 weeks after the last dose 
of study drug. The primary endpoint will be determined at week 16. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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Post-treatment follow-up visits will occur every 4 weeks from week 20 through week 36. The 
duration of the 20-week post-treatment follow up period is based on the time expected for 
REGN3500 drug levels to reach zero (below the lower limit of quantification) in most patients 
after the last dose of REGN3500. The end of study (EOS) visit will occur at week 36.Efficacy will 
be assessed using various outcome measures of severity and extent of AD (EASI, SCORAD, IGA, 
GISS, BSA), patient-reported symptoms (PRO) measures of symptoms (Pruritus NRS, Pain NRS, 
Sleep Quality NRS, outcome Patient Oriented Eczema Measure [POEM]), mood  (Hospital 
Anxiety and Depression Scale [HADS]), and QOL (Dermatology Life Quality Index [DLQI]).  
Safety and tolerability will be monitored by clinical assessment of adverse events (AEs) and by 
repeated measurements of clinical evaluation including vital signs (body temperature and sitting 
blood pressure, pulse, and respiration rate), physical examinations, eye examinations, 12-lead 
electrocardiograms (ECGs), and laboratory assessment including standard hematology, chemistry, 
and urinalysis. 
Blood samples for the determination of functional REGN3500 and ADA in serum will be 
collected. Serum and plasma samples will also be collected for analysis of additional biomarkers, 
including total IL-33, thymus and activation-regulated chemokine (CCL17; TARC), total IgE, 
high-sensitivity C-reactive protein (hs-CRP), and serum amyloid A (SAA). Following the initial 
dose of study drug administered SC on day 1, study treatment will be administered SC through 
week 14. The last study treatment will be administered at week 14. If medically necessary (ie, to 
control intolerable AD symptoms), patients may receive rescue treatment for AD (eg, systemic 
and topical corticosteroids) at the discretion of the investigator.  
The study event table is presented in Section 10.2. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population will be used for all 
statistical analysis as specified below: 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients; it is based on the treatment allocated 
(as randomized).  Efficacy endpoints will be analyzed using the FAS. 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
The actual treatment group as treated is defined by the following rules: 
• For a patient randomized to receive REGN3500, if the patient received all placebo 
injections, the actual treatment will be assigned as placebo. 
• For a patient randomized to receive REGN3500, if the patient received at least one 
REGN3500 injection as planned, the actual treatment will be same as the planned 
treatment. 
• For patients randomized to receive matching placebo for REGN3500 but accidentally 
received REGN3500 once injection, the actual treatment will be assigned as 
REGN3500. 
The safety analysis will be performed separately for the treatment period, follow-up period and 
overall study period as defined below. 
Treatment period: from the date of the first dose of study drug to the date of the end of treatment 
which is defined as: 
• the date of Week 16 visit (or study day 113 starting from the first dose of study drug if 
the date of the Week 16 visit is unavailable for those patients who completed the 
16 week)  
• the date of early termination visit, for those patients who did not complete the Week 16 
visit 
• 12Feb2020 for the patients who were early terminated from the treatment per Sponsor’s 
decision to stop the study on 12Feb2020 and Week 16 visit or early termination visit is 
unavailable.  
Follow-up period: from the date of the end  of the treatmentto the date of the end of study visit  
Overall study period: from the date of the first dose of study drug to the date of the end of study 
visit 
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Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
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For the analyses of follow-up period, only a subset of SAF will be included, which is defined as 
the patients who entered the follow-up period and had at least one visit during the follow-up period. 
3.3. 
Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set includes all randomized patients who received any study drug and who had at 
least one non-missing study drug concentration result following the first dose of study drug. 
Patients will be analyzed according to the treatment actually received.  
3.4. 
The Immunogenicity Analysis Set  
The ADA analysis set (AAS) includes all patients who received any study drug and had at least 1 
non-missing ADA result in REGN3500 ADA assay, after the first dose of the study drug. Patients 
will be analyzed according to the treatment actually received.  
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Regeneron Pharmaceuticals, Inc. 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The baseline value is defined as the last available value prior to the first dose of study drug, unless 
otherwise specified. For patients randomized but not treated, the baseline value is the last available 
value up to randomization. 
The following demographic and baseline characteristics variables will be summarized: 
• Demographic variables: Age at screening with grouping (year; ≥18-<40, ≥40-<65, ≥65-
<75), sex, ethnicity with grouping (Hispanic or Latino, Not-Hispanic or Latino), race 
with grouping (White, Black, Asian, Other), region, country, baseline weight with 
grouping (kg, <70; ≥70-<100,  ≥100), height (m), and BMI (kg/m2; <15, ≥15-<25, ≥25-
<30, ≥30), patients with inadequate response to topicals (Yes/No) with the reasons for 
patients who are “No” for  inadequate response to topicals. 
• Baseline characteristics: Duration of AD disease with grouping (year; < median 
duration, ≥ median duration), Pruritus numerical rating scale (NRS) for maximum or 
average itch intensity, Pruritus categorical scale, Investigator’s Global Assessment 
(IGA) score, Eczema Area and Severity Index (EASI) score, SCORing Atopic 
Dermatitis (SCORAD) score, Body Surface Area (BSA) Involvement of Atopic 
Dermatitis, Patient Oriented Eczema Measure (POEM), Dermatology Life Quality 
Index (DLQI), Global Individual Signs Score (GISS), Hospital Anxiety and Depression 
Scale (HADS), history of eye/conjuntivial discorder (such as conjunctivitis, blepharitis 
or keratitis), and findings of ophthalmogical exam at Baseline.  
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of the Medical 
Dictionary for Regulatory Activities (MedDRA) at the coding CRO. Information on conditions 
related to AD includes diagnosis of AD and AD treatment history, asthma, allergic conjunctivitis, 
allergic rhinitis, chronic rhinosinusitis, nasal polyps, eosinophilic esophagitis, food allergy, hives 
and other allergies due to medications, animals, plants, mold, etc. will be collected.  
4.3. 
Prior / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
(EOS) visit. Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 
4 (chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary at the coding CRO. Patients will be counted once in all ATC categories linked to the 
medication. 
Procedures will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA at the 
coding CRO. 
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Prior medications/procedures: medications taken or procedures performed prior to the first dose 
of study drug. 
Concomitant medications/procedures: medications taken or procedures performed following the 
first dose of study drug through the EOS visit.   
The prior systemic corticosteroid, immunosuppresent, phototherapy use and concomitant topical 
steroid eye drops or cyclosporine eye drops will be adjudicated by the clinical study director and 
the adjudication procedure will be documented before database lock. 
4.4. 
Rescue Medication/or Prohibited Medication During Study  
Prohibited concomitant medications: Treatment with the following concomitant medications is 
prohibited during the study: 
• Treatment with a live (attenuated) vaccine 
• Treatment with an investigational drug (other than REGN3500) 
• Treatment with immunomodulating biologics 
• Treatment with systemic nonsteroidal immunosuppressant (may be used as rescue) 
• Treatment with systemic corticosteroids (may be used as rescue) 
• Treatment with TCS or TCI (may be used as rescue in which study drug will not be 
discontinued) 
• Treatment with topical crisabarole (may be used as rescue in which study drug will 
not be discontinued) 
• Initiation of treatment of AD with prescription moisturizers 
Prohibited concomitant procedures: The following concomitant procedures are prohibited during 
study participation: 
• Major elective surgical procedures 
• Phototherapy (UVA, UVB, nbUVB, high dose UVA and PUVA) 
• Tanning in a bed/booth 
Rescue treatments (both medications and procedures): If medically necessary (ie, to control 
intolerable AD symptoms), study patients may receive rescue treatment for AD at the discretion 
of the investigator. If a patient receives rescue treatment with systemic corticosteroids or non-
steroidal systemic immunosuppressive drugs, study treatment will be permanently discontinued 
immediately. If rescue treatment consists of topical medications, the patient can continue study 
drug treatment.  
Unless permanently discontinued from the study or discontinued from study due to sponsor’s 
decision of stopping the study, all patients will complete the scheduled study visits and assessments 
whether or not they complete study treatment and whether or not they receive rescue treatment for 
AD. Investigators should make every attempt to conduct efficacy and safety assessments (eg, 
disease severity scores, safety labs) immediately before administering any rescue treatment. An 
unscheduled visit may be used for this purpose, if necessary. 
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Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency and the potential 
impact of the use of the prohibited medication or procedure. The rescue treatments will be 
adjudicated by the clinical study director and the adjudication procedure will be documented. 
4.5. 
Efficacy Variable 
All endpoints will be collected at time points according to Table 1. 
4.5.1. 
Primary Efficacy Variable 
The primary efficacy variable in the study is the percent change in EASI score from baseline to 
week 16.  
Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin, 2001). The EASI score calculation is based upon the Physician’s 
Assessment of Individual Signs [erythema (E), induration/papulation (I), excoriation (X), and 
lichenification (L)], where each sign is scored as 0 = Absent, 1 = Mild, 2 = Moderate, or 3 = Severe, 
and also upon the Area Score [based on the % (BSA) affected] where 0 = 0% BSA, 1 = 1-9% BSA, 
2 = 10-29% BSA, 3 = 30-49% BSA, 4 = 50-69% BSA, 5 = 70-89% BSA, 6 = 90-100% BSA. 
For each of major section of the body (head, upper extremities, trunk and lower extremities), EASI 
score = (E+I+X+L) x Area Score. The total EASI score is the weighted total of the section EASI 
using the weights. For patients of age >=8 years, the weights are 10% = head, 20% = upper 
extremities, 30% = trunk, 40% = lower extremities. For patients of age <8 years, the weights are 
20% = head, 20% = upper extremities, 30% = trunk, 30% = lower extremities.  The minimum 
possible EASI score is 0 and the maximum possible EASI score is 72 where a higher score 
indicates increased extent and severity of atopic dermatitis. The EASI score of each sign (E, I, X 
and L) can be calculated in a similar way, for example, the EASI score of erythema = weighted 
sum of E x Area Score at each section. 
4.5.2. 
Secondary Efficacy Variables 
The secondary efficacy variables include: 
• Proportion of patients achieving EASI-50 (≥50% improvement from baseline) at week 16 
• Proportion of patients achieving EASI-75 (≥75%  improvement from baseline) at week 16 
• Proportion of patients achieving EASI-90 (≥50%  improvement from baseline) at week 16 
• Absolute change in EASI score from baseline to week 16 
• Proportion of patients with both an IGA score of 0 or 1 (on a 5-point scale) and a reduction 
from baseline of ≥2 points at week 16 
• Change (absolute and percent) from baseline to week 16 in weekly average of daily peak 
Pruritus Numerical Rating Scale (NRS) 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
Pruritus NRS ≥4 from baseline at week 16 
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Investigator’s Global Assessment (IGA) 
The IGA is a static 5-point assessment instrument to rate AD disease severity globally in clinical 
studies. The ratings (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe) are an 
overall assessment of AD skin lesions based on erythema and papulation/infiltration.  
Pruritus Numeric Rating Scale (NRS) 
The Pruritus NRS is a simple assessment tool that patients will use to report the intensity of their 
pruritus (itch) using an electronic questionnaire (e-diary).   
At screening, patients will be instructed on using the e-diary to record the worst intensity of their 
itch/pruritus, using a scale from 0 to 10, where 0 is no itch and 10 is the worst itch imaginable. 
Patients will complete the rating scale twice every day, morning and evening reports, through the 
entire study (screening, treatment, and follow-up periods). Clinical sites will check patient data 
collected using an e-diary for protocol compliance and remind patients to complete their e-diary 
throughout the study. 
The daily peak pruritus NRS score is the worse one between the morning and evening scores of 
the day. 
The baseline Pruritus NRS score will be determined based on the average of daily NRS scores 
during the 7 days immediately preceding randomization (i.e. study day -7 to day -1). A minimum 
of 4 daily scores out the 7 days is required to calculate the baseline average score.  
For post-baseline Pruritus NRS score, the weekly average is calculated as the prorated average of 
the reported daily NRS within the week. For example, if there are 3 scores in a week, the 
prorated average = (score1 + score2 + score3)/3.  
The weekly worst score is calculated by taking the worst score within the week.  
The endpoint “Proportion of patients with improvement (reduction) of peak daily Pruritus NRS ≥4 
from baseline to week 16” will be based on the weekly average of daily peak Pruritus NRS score.  
Body Surface Area (BSA) Involvement of Atopic Dermatitis 
Body surface area affected by AD will be assessed for each section of the body (the possible 
highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper 
limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as the sum of all the 
percentages combined. . 
4.5.3. 
Other Efficacy Variables 
Other efficacy variables include: 
• Change (absolute and percent) from baseline to week 16 in weekly average of daily 
Peak Pain NRS 
• Change (absolute and percent) from baseline to week 16 in weekly average of daily 
Sleep Quality NRS 
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Peak Pain Numeric Rating Scale (NRS) 
The Peak Pain NRS is a simple assessment tool that patients will use to report the intensity of their 
pain during a 24-hour recall period using an electronic questionnaire. Patients will be asked to 
answer the following question on a scale from 0 (no pain) to 10 (worst pain possible): 
For the question below, think about all the areas of your skin with eczema. 
“How would you rate your skin pain at its worst in the previous 24 hours?” 
Patients will be instructed on using an electronic questionnaire to record their Peak Pain NRS score 
at the screening visit. Patients will complete the rating scale DAILY through the entire study 
(screening, treatment, and follow-up periods). 
The daily peak pain NRS score and weely average for post-baseline pain NRS score are 
calculated using the same algorithm for daily peak, and weekly average of pruritus NRS score.   
Sleeping Quality Numeric Rating Scale (NRS) 
The Sleep Quality NRS is a simple assessment tool that patients will use to report the quality of 
their sleep during a 24-hour recall period using an electronic questionnaire. Patients will be asked 
the following question on a scale of 0 (best possible sleep) to 10 (worst possible sleep) upon 
awakening for the day: 
“Select the number that best describes the quality of your sleep last night.” 
Patients will be instructed on using an electronic questionnaire to record their Sleep Quality NRS 
score at the screening visit. Patients will complete the rating scale DAILY through the entire study 
(screening, treatment, and follow-up periods).  
The baseline sleeping quality NRS score will be determined based on the average of daily NRS 
scores during the 7 days immediately preceding randomization (i.e. study day -7 to day -1). A 
minimum of 4 daily scores out the 7 days is required to calculate the baseline average score.  
For post-baseline sleeping quality NRS score, the weekly average is calculated as the prorated 
average of the reported daily NRS within the week. For example, if there are 3 scores in a week, 
the prorated average = (score1 + score2 + score3)/3.  
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
“Preferred Term (PT)”, “High Level Term (HLT)” and associated primary “System Organ Class 
(SOC)” according to the Medical Dictionary for Regulatory Activities (MedDRA) latest version  
available.  
An Adverse Event is any untoward medical occurrence in a patient administered a study drug 
which may or may not have a causal relationship with the study drug.  Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease 
which is temporally associated with the use of a study drug, whether or not considered related to 
the study drug. 
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AEs also include: any worsening (i.e. any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug; 
abnormal laboratory findings considered by the investigator to be clinically significant; and any 
untoward medical occurrence. 
The criteria for determining whether an abnormal laboratory, vital sign or ECG finding should be 
reported as an AE are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• Test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy 
A Serious Adverse Event is any untoward medical occurrence that at any dose results in death; 
is life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; 
results in persistent or significant disability/ incapacity; is a congenital anomaly/ birth defect; or is 
an important medical event.  
The pre-treatment AEs are AEs that developed or worsened in severity during pre-treatment period 
defined as the period from the patient providing informed consent upto the first dose of study drug.  
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in severity compared to 
the baseline during the treatment emergent period defined as the period from the administration of 
first study dose to the EOS visit.  As only the worsening pre-existing AEs and new AEs reported 
during the treatment and follow-up period will be collected in the study, all AEs collected during 
the treatment and follow-up period are considered as TEAEs.   
The skin infection TEAEs will be identified based on blinded adjudication of all reported TEAEs 
under the two primary system organ classes (SOCs): SOC = “Infection and infestations” or SOC 
= “Skin and subcutaneous tissue disorders”. Blinded adjudication will be done and finalized by 
the study medical monitor before database lock. 
4.6.2. 
Adverse Events of Special Interest 
In this study, the adverse event of special interest (AESI) category includes: 
• Anaphylactic reactions or acute allergic reactions that require immediate treatment 
• Severe ISRs that last longer than 24 hours 
• Mycosis fungoides or other forms of cutaneous T-cell lymphoma 
• Any severe infection; any infection requiring treatment with parenteral 
antibiotics/anti-viral/anti-fungal agent; any infection requiring treatment with oral 
antibiotic/anti-viral/anti-fungal for longer than 2 weeks; any clinical endoparasitosis; 
any opportunistic infection  
• Conjunctivitis (any type or etiology), keratitis, or blepharitis (only events that are 
either severe or serious or lasting ≥4 weeks will be reported as AESIs) 
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• Significant ALT elevation 
a. ALT >3×ULN associated with total bilirubin >2×ULN; or  
b. ALT >5×ULN in patients with baseline ALT ≤2×ULN; or  
c. ALT >8×ULN if baseline ALT >2×ULN 
The search criteria for AESIs are provided in Section 10.4.  
4.6.3. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  
Samples for laboratory testing will be collected according to visit schedule (Table 1). Tests will 
include 
 Serum Chemistry 
Sodium 
Total protein, serum 
Total  and indirect bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
AST 
Uric acid 
Calcium 
ALT 
CPK 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
* Low-density lipoprotein and high-density lipoprotein 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
 
Clarity 
Blood 
Hyaline and other casts 
 
pH 
Bilirubin 
Bacteria 
 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
 
Ketones 
Nitrite 
Crystals 
 
Protein 
WBC 
Yeast  
 
Other Laboratory Tests 
Serum and urine pregnancy testing will be performed for all female patients of childbearing 
potential at time points according to Table 1. The following tests will be performed at screening: 
HIV, HBsAg, HBsAb, HBcAb, hepatitis C antibody, and tuberculosis. 
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4.6.4. 
Vital Signs 
The following vital signs parameters will be collected: 
• Respiratory rate (bpm) 
• Pulse (beats/min) 
• Sitting systolic and diastolic blood pressures (mmHg) 
• Body temperature (oC) 
Vital signs (sitting blood pressure, pulse, and respiration rate) will be collected predose and 
30 (±10) minutes postdose. In addition, body temperature should be taken predose. See Table 1 
for assessment time points.  
4.6.5. 
12-Lead Electrocardiography (ECG) 
Standard 12-Lead ECG parameters include: Ventricular HR, PR interval, QRS interval, corrected 
QT interval (QTc Fridericia [QTcF] = QT/[RR0.33] and QTc Bazett [QTcB]=QT/[RR0.5]), ECG 
status: normal, abnormal not clinical significant or abnormal clinical significant. See Table 1 for 
assessment time points. 
4.6.6. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal. A thorough 
and complete physical examination will be performed at time points according to visit schedule 
(Table 1). 
Any abnormal findings during the screening period are recorded as medical history. Any 
abnormal findings during post-screening period are recorded as adverse events. 
4.6.7. 
Other Safety Variables 
Body weight and height will be measured at time points according to Table 1. 
Ophthalmological exams: Patients who have a history of certain eye disorders (conjunctivitis, 
blepharitis, or keratitis) within the last 12 months of the screening visit will be referred during 
screening to an ophthalmologist (preferably with expertise in treating Cornea and External Eye 
Disease [‘front-of-the-eye’] subspecialty expert). Patients who experience AESIs related to eye 
disorders will also be referred to an ophthalmologist (preferably with expertise in treating patients 
or Cornea and External Eye Disease [‘front-of-the-eye’] subspecialty expert). Further evaluation 
of these AESIs will be performed including any additional tests, if applicable, as per the discretion 
of the ophthalmologist. 
4.7. 
Pharmacokinetic Variables 
Samples for measurement of functional REGN3500 or total IL-33 (REGN3500 target) will be 
collected at visits listed in Table 1.  
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4.8. 
Immunogenicity Variables 
The immunogenicity variables are anti-drug antibody (ADA) status and titer at each time-
point/visit. Serum samples for anti-REGN3500 antibody bioanalysis will be collected at time 
points according to visit schedule (Table 1).  In the event a patient sample is positive in the 
REGN3500 ADA assay at week 16 or the first time point analyzed, the week 4 PK sample may be 
analyzed in the ADA assay. 
Immunogenicity will be characterized by ADA responses and titers observed in patients in the  
ADA analysis set. ADA responses and titer categories are defined as follows: 
• ADA Negative, defined as ADA negative response in the REGN3500 ADA assay at all 
time points, regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the assay 
at baseline with all post first dose ADA results negative, OR a positive response at 
baseline with all post first dose ADA responses less than 9-fold for anti-REGN3500 
antibody assay over baseline titer levels 
• Treatment-emergent response, defined as a positive response in the ADA assay post 
first dose when baseline results are negative or missing.  The treatment-emergent 
responses will be further characterized as Persistent, Indeterminate or Transient 
−  Persistent Response - Treatment emergent ADA positive response with two or 
more consecutive ADA positive sampling time points separated by at least 16-week 
period, for anti-REGN3500 antibody assays, with no ADA negative samples in 
between  
− Indeterminate Response - as a treatment-emergent response with only the last 
collected sample positive in the ADA assay 
− Transient Response - a treatment emergent ADA positive assay response that is not 
considered persistent or indeterminate. 
• Treatment-boosted response, defined as a positive response in the ADA assay post first 
dose that is greater than or equal to 9-fold for anti-REGN3500 antibody assay over 
baseline titer levels, when baseline results are positive 
• Titer categories  (Maximum titer values) 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000)   
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4.9. 
Pharmacodynamic and Biomarker Variables 
Biomarkers to be analyzed in this study are:  
• TARC  
• Total serum IgE  
•  hsCRP 
• Serum amyloid A (SAA) 
• Lactate dehydrogenase (LDH) [which will be measured as part of the blood 
chemistry] 
Serum samples for measurements of biomarkers to study the PD activity of study treatments in 
AD patients will be collected at time points according to Table 1. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, first quartile (Q1), third quartile 
(Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
All data will be summarized by treatment group.  
The safety data collected during the COVID-19 pandemic will be analyzed separately for the 
impacted patients, if applicable. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics variables (see Section 4.1) will be summarized by 
treatment group for FAS. Listing of demographics and baseline characteristics will be presented.  
5.2. 
Medical and AD History 
Medical history will be summarized by primary SOC and PT for each treatment group for SAF. 
The table will be sorted by decreasing frequency of SOC followed by PT based on the overall 
incidence across treatment groups. Medical history will be listed. 
Information on conditions related to AD includes diagnosis of AD and AD treatment history, 
asthma, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, eosinophilic 
esophagitis, food allergy hives and other allergies due to medications, animals, plants, mold, etc 
History of eye/conjuntivial discorder will also be summarized. 
5.3. 
Prior/concomitant Medications and Procedures  
Number and proportion of patients taking prior/concomitant medications will be summarized by 
treatment group for SAF, sorted by decreasing frequency of ATC Level 2 and ATC level 4 based 
on the incidence in the REGN3500 treatment group. Patients will be counted only once for each 
medication class (ATC level 2 and 4) linked to the medication. The prior systemic corticosteroid, 
immunosuppresent, phototherapy use and the concomitant topical steroid eye drops or 
cyclosporine eye drops will be summarized similarly. 
Number and proportion of patients undergoing a prior/concomitant procedure(s) will be 
summarized, sorted by decreasing frequency of SOC and PT based on the incidence in the 
REGN3500 treatment group. Patients will be counted only once for each SOC and PT linked to 
the procedure. 
The compliance of moisturizers (emollients) used from 7 days before the baseline visit to end of 
study, which is defined as the (number of days moisturizers used during the period) / (number of 
days within the period) x 100%, will be summarized by treatment group.  
Descriptive statistics or listings will be provided for the prior and concomitant medications and 
procedures for the patients impacted by COVID-19 pandemic as well as for three periods (pre-, 
during-, post-COVID-19 periods), if applicable. 
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5.4. 
Rescue/Prohibited Medications and Procedures 
Rescue/prohibited medication and procedures will be summarized by treatment group for SAF and 
FAS, separately. Number and proportion of patients taking medications and rescue medications 
will be summarized, sorted by decreasing frequency of ATC level 2 and ATC level 4 based on the 
incidence in the REGN3500 treatment group. Patients will be counted only once for each 
medication class (ATC level 2 and 4) linked to the medication.  
Number and proportion of patients undergoing prohibited procedures and rescue procedures will 
be summarized, sorted by decreasing frequency of SOC and PT based on the incidence in the 
REGN3500 treatment group. Patients will be counted only once for each SOC and PT linked to 
the procedure. 
Prohibited medications will be listed. 
Descriptive statistics or listings will be provided for the rescue medications for the patients 
impacted by COVID-19 pandemic as well as for three periods (pre-, during-, post-COVID-19 
periods), if applicable. 
5.5. 
Subject Disposition 
The following summaries will be provided: 
• The total number of screened patients 
• The total number of randomized patients: received a randomization number 
• The total number of patients in each analysis set by visit and overall 
• The total numbers of patients who completed the study treatment and who 
discontinued the study treatment with the reason of discontinuation 
• The total numbers of patients who completed the study and who discontinued the 
study with the reason of discontinuation (including COVID-19 related reasons) 
• The total number of patients who entered follow-up period  
The following listings will be provided: 
• Listing of patient disposition including: date of randomization, date of the last visit, 
received dose, completed study treatment or discontinued, completed study or discontinued  
• A listing of patients randomized but not treated, and patients randomized but not treated as 
randomized 
• A listing of patients prematurely discontinued from the treatment or from the study, along 
with reasons for discontinuation 
• A summary table and a listing of protocol deviations will be provided.  
• The listing of the protocol deviations for the prohibited treatments will be provided. 
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5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Compliance with study treatment will be calculated for REGN3500 injection by treatment group 
as follows: 
Treatment Compliance =  
(Number of study drug injections during exposure period)/(Number of planned study drug 
injections taken during exposure period) x 100% 
Summary of study drug administration will include the number of study drug doses administered 
and treatment compliance. The treatment compliance will be presented by the following specific 
ranges for each treatment group: <80%, and ≥80%. 
Listing of dose administration: including date/time, study day, number of injections, locations of 
injections, dosing information, and whether or not the total dose is administered for each dose will 
be presented. 
5.6.2. 
Treatment Exposure and Observation Period 
The duration of treatment exposure during the study in days is calculated as: 
 (Date of last study drug injection – date of first study drug injection) + x days , where x days are 
7, 14, 28, 56 days for QW, Q2W, Q4W, and Q8W, respectively. 
The calculations are regardless of temporary dosing interruption. The duration of exposure during 
the study will be summarized by treatment group using number of patients, means, SD, minimums, 
Q1, medians, Q3 and maximums. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories and cumulatively by these categories as well: ≥ 15 days, ≥ 
29 days, ≥ 43 days, ≥ 57 days, ≥ 71 days, ≥ 85 days, ≥ 99 days, and ≥ 113 days. 
The duration of observation period during the study in days is calculated as: 
(Date of the last visit – date of the first study drug injection) +1. 
The number (%) of patients with observation periods will be presented by specific time periods. 
The time periods of interest are specified as: < 15 days, ≥ 15 days, ≥ 29 days, ≥43 days, ≥ 57 days, 
≥ 71 days, ≥ 85 days, ≥99 days, ≥113 days, ≥141 days, ≥169 days,  ≥197 days, ≥225 days and 
≥253 days. Since the Sponsor stopped the study, it is possible that no patient reaches some time 
categories.If so, these categories will not be reported. 
5.7. 
Analyses of Efficacy Variables 
All efficacy variables will be summarized by descriptive statistics by treatment groups and visits 
during the treatment period. 
The analyses of efficacy variables are described in subsections below and summarized in 
Section 10.1.  
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Since the Sponsor stopped the study prematurely, many patients did not reach week 16 when the 
study was terminated. The last assessments of such patients will be re-mapped to the next 
scheduled visits in general. Details have been documented in Section 6.4. 
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary efficacy variable, the percent change in EASI score from baseline to week 16, will be 
summarized by treatment groups and visits using descriptive statistics. The results will be tabulated 
based on the following cases. 
1. Observed values regardless of rescue treatment use 
2. Observed values and the data will be censored after the rescue treatment is used 
The primary efficacy data, regardless of whether the patient remains on study treatment or 
discontinues the study treatment but remains in the study, will be used for analysis. Specifically, 
if a patient stays in the study until the end of the study planned placebo-controlled treatment period, 
all efficacy data collected up to the study planned end of treatment visit will be included in the 
primary analysis, regardless of whether the patient is on treatment or not. 
5.7.2. 
Analysis of Secondary Efficacy Variables 
All secondary endpoints will be evaluated on the FAS.  
The binary secondary efficacy endpoints will be analyzed using descriptive statistics by treatment 
groups and visits. The results will be tabulated based on the following cases. 
1. Observed values regardless of rescue treatment use. 
2. Observed values and the data will be censored after the rescue treatment is used. Patients 
with missing value due to rescue treatment will be counted as non-responder . 
The continuous secondary efficacy variables will be analyzed using the same approach as that used 
for the analysis of the primary endpoint. 
Similar to the primary endpoint, the secondary efficacy data, regardless of whether the patient 
remains on study treatment or discontinues the study treatment but remains in the study, will be 
used for analysis. 
5.7.3. 
Adjustment for Multiple Comparison 
There will be no control for multiplicity for this study. 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF and presented for each 
treatment group. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs and 12-lead ECG).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.3. 
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The summary of safety results will be presented for each treatment group. 
Descriptive statistics or listings will be provided for the safety endpoints for the patients impacted 
by COVID-19 pandemic as well as for three periods (pre-, during-, post-COVID-19 periods), if 
applicable. 
5.8.1. 
Adverse Events  
Listing of TEAEs, serious TEAEs, and TEAEs resulting in death and study drug discontinuation 
will be generated. 
Numbers and proportions of patients reporting TEAEs will be summarized for treatment period 
and follow-up  period, sorted by alphabetical order of SOC and decreasing frequency of PT 
based on the incidence in the REGN3500 treatment group. 
Summaries of TEAEs will include: 
• TEAEs 
− TEAEs by SOC/PT 
− TEAEs by SOC/HLT/PT 
− TEAEs by PT 
− Common TEAEs by SOC/PT (incidence with PT ≥5%) 
− TEAEs related to study drug as assessed by the investigator by SOC/PT  
− TEAEs related to study procedure as assessed by the investigator by SOC/PT 
− TEAEs by severity by SOC/PT 
− Severe TEAEs by SOC/PT 
− Severe TEAEs related to study drug as assessed by the investigator by SOC/PT  
− Severe TEAEs related to study procedure as assessed by the investigator by 
SOC/PT 
− Common non-serious TEAEs by SOC/PT (incidence with PT ≥5%) 
− TEAE per 100 patient years by SOC/PT during treatmen period only 
• Serious TEAEs by SOC/PT 
− Serious TEAEs by SOC/PT 
− Serious TEAEs by SOC/HLT/PT 
− Serious TEAEs related to study drug as assessed by the investigator by SOC/PT  
− Serious TEAEs related to study drug as assessed by the investigator by SOC/PT  
• TEAEs leading to permanent discontinuation from study treatment by SOC/PT 
• Serious TEAE per 100 patient years by SOC/PT during treatmen period only 
• Death by SOC/PT 
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• Skin infection TEAEs by SOC and PT 
5.8.2. 
Analysis of Adverse Events of Special Interest 
The adverse events of special interest (AESI) will be summarized by AESI category 
(see Section 10.4 ) and by high level term and PT. 
5.8.3. 
Analysis of Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units and US conventional units. Summaries of laboratory 
variables for overall study period, treatment period and follow-up period will include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• Descritive statistics of blood eosinophils and change and percent change from 
baseline by visit 
• The number (n) and percentage (%) of patients with treatment-emergent PCSVs  
• The number (n) and percentage (%) of patients with treatment-emergent PCSVs for 
patients without PCSVs in corresponding category at baseline  
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listing of all laboratory parameters normal range, abnormal flag and treatment-emergent PCSV 
by patient and visit will be provided. 
5.8.4. 
Analysis of Vital Signs 
Summaries of vital sign variables for the overall study period, treatment period and follow-up 
period will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of patients with treatment-emergent PCSV  
• The number (n) and percentage (%) of patients with treatment-emergent PCSVs for 
patients without PCSVs in corresponding category at baseline  
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listings of vital sign will be provided with flags indicating the treatment-emergent PCSVs. 
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5.8.5. 
Analysis of 12-Lead ECG 
Summaries of 12-lead ECG parameters by the overall study period, treatment group for treatment 
period and follow-up period will include: 
• Each ECG parameter and change from baseline 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV  
• The number (n) and percentage (%) of patients with treatment-emergent PCSVs for 
patients without PCSVs at baseline in corresponding category  
• ECG status (i.e. normal, abnormal) summarized by a shift table 
Listings of ECG will be provided with flags indicating PCSVs. 
5.8.6. 
Physical Exams 
The number (n) and percentage (%) of patients with abnormal physical exams will be summarized 
at baseline, end of treatment period and end of study by treatment group. 
5.8.7. 
Ophthalmological exams 
The findings from the ophthalmological exams will be summarized and listed.   
5.9. 
Analysis of Pharmacokinetic Data 
No formal statistical analysis will be performed. Concentrations of functional REGN3500 and total 
IL-33 (REGN3500 target) in serum will be summarized at each time point by treatment group 
using descriptive statistics. The data may be combined with data from other studies, as applicable, 
for analysis using population methods. Any population PK analysis will be reported separately.  
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data  
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics in the ADA analysis set.  
The following analysis will be provided based on AAS: 
• Number (n) and percent (%) of ADA-negative patients (pre-exisiting 
immunoreactivity and ADA negative at all timepoints) in the respective ADA assay 
by treatment groups 
• Number (n) and percent (%) of ADA positive patients (treatment-emergent and 
treatment-boosted responses) by treatment groups and ADA titer categories 
• Number (n) and percent (%) of treatment-emergent ADA-positive patients by 
treatment group and ADA titer categories 
a. Number (n) and percent (%) of persistent treatment-emergent ADA-positive patients 
b. Number (n) and percent (%) of indeterminate treatment-emergent ADA-positive 
patients 
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c. Number (n) and percent (%) of transient treatment-emergent ADA-positive patients 
• Number (n) and percent (%) of treatment-boosted ADA-positive patients by treatment 
groups and ADA titer categories 
• Listing of all ADA titer levels will be provided for patients with pre-existing, 
treatment-emergent and treatment-boosted ADA responses 
5.11. 
Association of Immunogenicity with Exposure & Safety 
5.11.1. 
Immunogenicity and Exposure 
Potential association between ADA variables and systemic exposure to study treatment 
(REGN3500) will be explored by treatment group. Plots of study drug concentration may be 
provided for analyzing the potential impact of ADA response status and titer on corresponding 
drug concentration.  
5.11.2. 
Immunogenicity and Safety 
Association between ADA and safety event may be explored with a primary focus on the 
following events during the TEAE period:  
• 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
The above mentioned safety analyses will be conducted using the following ADA response 
categories: 
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response, 
• ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points 
• Patients with persistent treatment-emergent ADA response 
• Maximum post-baseline titer level in treatment emergent or treatment boosted ADA 
positive patients:  
− Low (titer < 1,000) 
− Moderate (1.000 ≤ titer ≤10,000) 
− High (titer > 10,000) 
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5.12. 
Analysis of Biomarker Data 
Descriptive statistics for the observed values, change from baseline and percent change from 
baseline values by treatment and visit will be provided for the following biomarker variables based 
on FAS analysis set: 
• TARC  
• total serum IgE  
• hsCRP 
• Serum amyloid A (SAA) 
• Lactate dehydrogenase (LDH)  
Serum total IgE and LDH are established clinical assays; the upper limit of normal (ULN) from 
the central lab reference range will determine the threshold for normal vs. elevated status.  
Summary tables with normal/elevated status for serum total IgE and LDH at baseline and each 
post-baseline visit (until end-of-study) will be provided by treatment group.  
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6. 
DATA CONVENTIONS 
The analysis conventions that are described in this section will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the first administration of study drug.  
If any randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization. The baseline of worst itch scale is defined in Section 4.5.2. 
The following rules specify the determination of baseline by both date/time information: 
• For the AE, lab, PK and ADA data, both date and time of the measurement will be used 
to determine baseline by comparing with the first injection date and time. 
• For other data except AE, lab, PK or ADA, only date of the measurement will be used 
to determine baseline by comparing with the first injection date. 
For the rescreened patients, all data from the same patient will be used to derive baseline regardless 
if the data is from the screen-failure subject ID or enrolled subject ID. 
6.2. 
General Data Handling Convention  
For the laboratory safety variables data, if the data below the lower limit of quantification (LLOQ) 
/ limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used for quantitative 
analyses. For data above the upper limit of quantification (ULOQ) / limit of linearity, the upper 
limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month) then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
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If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use end of follow 
up date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 31 
December as the day and month. If this leads to a date after end of study follow up date, use the 
end of follow up date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’. 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before inform consent date. Imputation flag 
is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However in 
order to simplify the programming flow, the imputation is proposed to in line with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
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If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’. 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use end of follow up date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the end of follow up 
date instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of follow up date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.4. 
Visit Windows 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ECG, ADA) will 
be summarized by the study scheduled visits described in the study protocol and SAP “Schedule 
of Events”. The analysis visit windows will be exhaustive so that all available values obtained 
from unscheduled visits and early termination (ET) visit have the potential to be summarized. No 
analysis visit windows will be applied for the study scheduled visits.  
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The following analysis visit windows will be used to map the unscheduled visits: 
Visit 
Target Day 
Analysis 
Time 
Window 
Based on Study Day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 2 
15 
[2, 21] 
Week 4 
29 
[22, 36] 
Week 6 
43 
[37, 50] 
Week 8 
57 
[51, 64] 
Week 10 
71 
[65, 78] 
Week 12 
85 
[79, 92] 
Week 14 
99 
[93, 106] 
Week 16 
113 
[107, 127] 
 
 
Analysis Time Window Based 
on Days Relative to Treatment 
Period End Date** 
Week 20 
28 
[1, 42] 
Week 24 
56 
[43, 70] 
Week 28 
84 
[71, 98] 
Week 32 
112 
[99, 126] 
Week 36  
140 
>=127 
*study day is calculated relative to the date of first study drug injection. 
** Days relative to treatment period end date =visit date –the treatment period end date. 
If the early termination (ET) occurs during the treatment period, it will be mapped to next 
scheduled visit during the period. Similarly, it occurs during the follow-up period, it will be 
mapped to the next scheduled visit during the follow-up period: 
For patients who discontinued from the treatment due to the sponsor’s decision to stop study, the 
Week 16 will be mapped to the patients’ next scheduled visit. 
In general, the following order will be used to select the record for analysis at given visit: 
1. Scheduled visit  
2. Early termination (ET) if scheduled visit not available  
3. Unscheduled visit if both scheduled visit and ET are not available 
For the multiple measurements of the same test in the same window, the following rules will be 
used to pick up the analysis value: 
• If multiple valid values of a variable within an analysis visit window, the closest from 
the target study day will be selected.  
• If the difference is a tie, the value after the targeted study day will be used.  
• If multiple available values of a variable exist within a same day, then the first value of 
the day will be selected. 
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Both scheduled and unscheduled measurements will be considered for determining 
abnormal/PCSV values from laboratory, vital sign or ECG as well as the baseline values.  
For the daily collected ePRO data, the analysis visit windows will be implemented following the 
procedure below: 
Step 1: Derive the study day or days relative to the treatment period end date,  
If diary date ≥ 1st injection date and ≤ the treatment period end date, then diary study day=diary 
date – 1st injection date +1.  
If diary date < 1st injection date,  diary study day=diary date – 1st injection date. 
If diary date > the treatment period end date, days relative to treatment period end date = diary 
date -treatment period end date. 
Step 2: Windows for treatment period are defined as diary study day -7 to -1 = BL,  1 to 7 = week 
1, 8 to 14 = week 2, etc, with 7 days interval between visit windows. Similarly, windows for 
follow-up period are defined as days relative to treatment period end date 1 to 7 = week 17, 8 to 
14 = week 18, etc, with 7 days interval between visit windows. 
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7. 
INTERIM ANALYSIS 
No interim with alpha spending is planned.  
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber Ml. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol 
2001;10(1):11-8. 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Parameter(s) 
Endpoints  
Primary Statistical Method 
Supportive/Sen
sitivity 
Statistical 
Method 
Subgroup 
Analysis 
Eczema Area and Severity 
Index (EASI) 
• % change from baseline 
• Change from baseline 
• EASI 75 
• EASI 50 
• EASI 90 
Descriptive Statistics 
No 
No 
Investigator’s Global 
Assessment (IGA) 
IGA 0 to 1 responder 
Descriptive Statistics  
No  
No 
Weekly average of daily 
peak Pruritus NRS 
• Percent change and absolute 
change from baseline  
• Proportion with ≥4 
improvement from baseline 
 
Descriptive Statistics  
No 
No 
Weekly average of daily 
Pain NRS 
Percent change and absolute 
change from baseline  
Descriptive Statistics 
No 
No 
Weekly average of daily 
Sleep Quality NRS 
Percent change and absolute 
change from baseline  
Descriptive Statistics 
No 
No 
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Safety Analyses: 
Endpoint 
Analysis Populations 
Statistical Method 
Supportive Analysis 
Subgroup Analysis 
Other Analyses 
Adverse Events 
SAF 
Descriptive statistics  
No 
No 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
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10.2. 
Schedule of Time and Events 
Table 1: 
Schedule of Events 
 
Screenin
g 
Period13, 
14 
Double-Blind Treatment Period 
Follow-Up Period 
 
 
In-clinic Visit (V) 
Study Procedure1 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
EOT 
V10 
V11 
V12 
V13 
V14 
EOS 
V15 
Un-
sch16 
ET 
19 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
W32 
W36 
- 
- 
Day (D) 
D−35 to 
D−1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
D225 
D253 
- 
- 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
- 
Screening/Baseline:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ocular History8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient e-diary Training 
(Pruritus, Pain, and 
Sleep Quality NRS 
Assessments and 
Emollient Use)2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review patient e-diary 
data 
 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
Administration/ 
Dispensing/ 
Accountability3 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Concomitant Meds/ 
Procedures 
X14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus, Pain, and Sleep 
Quality NRS (daily)4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-reported HADS, 
DLQI, POEM5,6 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
EASI, IGA, GISS, 
SCORAD, BSA5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 46 of 58 
 
Screenin
g 
Period13, 
14 
Double-Blind Treatment Period 
Follow-Up Period 
 
 
In-clinic Visit (V) 
Study Procedure1 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
EOT 
V10 
V11 
V12 
V13 
V14 
EOS 
V15 
Un-
sch16 
ET 
19 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
W32 
W36 
- 
- 
Day (D) 
D−35 to 
D−1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
D225 
D253 
- 
- 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
- 
Safety:1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
ECG 
X 
  
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmological Exam8 
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
X17  
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
X 
Laboratory Testing:1,11  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serologies (HIV Ab, 
HBsAg, HBcAb, 
HCV Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB QuantiFERON 
Testing 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (confirm 
menopausal status)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(WOCBP only)10 
Serum 
Urine 
 
Urin
e 
 
Uri-
ne 
 
Urin
e 
 
Ser-
um 
Urin
e 
Urin
e 
Urin
e 
Urin
e 
Ser-
um 
Uri-
ne 
Ser-
um 
Urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PK and ADA Samples:,1, 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum REGN3500 
Concentration (PK) 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X18 
X 
Anti-REGN3500 
Antibody (ADA)20 
 
X 
 
  
 
 
 
 
 
X 
 
 
 
 
X 
X18 
X 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 47 of 58 
 
Screenin
g 
Period13, 
14 
Double-Blind Treatment Period 
Follow-Up Period 
 
 
In-clinic Visit (V) 
Study Procedure1 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
EOT 
V10 
V11 
V12 
V13 
V14 
EOS 
V15 
Un-
sch16 
ET 
19 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
W28 
W32 
W36 
- 
- 
Day (D) 
D−35 to 
D−1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 
D113 
D141 
D169 
D197 
D225 
D253 
- 
- 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
- 
Biomarkers:1, 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hs-CRP, SAA 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
TARC 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Total IgE 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Total IL-33 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X  
X 
FBR Samples 
(serum/plasma) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Genomics Sample:1, 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood DNA12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood RNA12 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
ADA:  anti-drug antibody; BSA:  body surface area; D:  day; DLQI:  Dermatology Life Quality Index; EASI:  Eczema Area and Severity Index; 
ECG:  electrocardiogram; e-diary:  electronic patient diary; EOS:  end-of-study; EOT:  end-of-treatment; ET:  early termination; FBR:  Future Biomedical 
Research; FSH:  follicle-stimulating hormone; GISS:  Global Individual Signs Score; HADS:  Hospital Anxiety and Depression Scale; HBcAb:  hepatitis B core 
antibody; HBsAg:  hepatitis B surface antigen; HCV Ab:  hepatitis C virus antibody; HIV Ab:  human immunodeficiency virus antibody; 
hs-CRP:  high-sensitivity C-reactive protein; ICF:  informed consent form; IGA:  Investigator’s Global Assessment; IgE:  immunoglobulin E; IL:  interleukin; 
Meds:  medications; NRS:  Numerical Rating Scale; PK:  pharmacokinetic; POEM:  Patient Oriented Eczema Measure; SAA:  serum amyloid A; 
SCORAD:  SCORing Atopic Dermatitis; TARC:  thymus and activation-regulated chemokine (CCL17); V:  visit; Unsch:  unscheduled visit; W:  week; 
WOCBP:  women of childbearing potential. 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 48 of 58 
Footnotes for the Schedule of Events Table 
1. Assessments/procedures should be conducted in the following order:  patient reported outcomes, investigator assessments, safety 
and laboratory assessments (including sample collection for ADA, PK, biomarkers, DNA, and RNA), and then administration 
of study drug.   
2. Training of patients regarding completion of e-diary to record (1) completion of assessment of Pruritus, Pain, and Sleep Quality 
NRS scales and (2) emollient usage. 
3. All patients will receive Q2W SC injections.  For the REGN3500 300 mg SC Q4W group, REGN3500 100 mg SC Q4W group, 
and REGN3500 30 mg SC Q8W group, in order to maintain the blinding, there will be SC injection(s) of placebo in between 
REGN3500 doses so the injection frequency will match the other 2 groups (REGN3500 300 mg SC Q2W and placebo SC Q2W) 
(see randomization and dosing regimen in Section 7.1 Table 1 in the protocol amendment 3).  Patients will be closely monitored 
at the study site at visits 2 through 9 (day 1 through week 14) for a minimum of 30 minutes after the administration of study 
drug, and the monitoring period may be extended up to 2 hours as per country specific requirements.  In addition to the predose 
assessments, patients will be assessed for adverse events (AEs) at 30 minutes (±10 minutes) postdose or until the end of the 
monitoring period (if applicable). 
4. Pruritus, Pain, and Sleep Quality NRS will be completed daily via electronic questionnaire (e-diary).  Reporting of these data 
begins the evening of visit 1 (screening). 
5. Questionnaires will be completed before any other assessments or invasive procedures (blood draws, study drug injection, etc). 
6. The questionnaires will be administered only to the subset of patients who speak fluently the language in which the questionnaire 
is presented (based on availability of validated translations in participating countries). 
7. Vital signs (sitting blood pressure, pulse, and respiratory rate) should be taken predose and 30 minutes (±10 minutes) postdose.  
In addition, body temperature should be taken predose.  
8. Ophthalmological exams at screening are limited to those patients who have a history of certain eye disorders (conjunctivitis, 
blepharitis or keratitis) within the last 12 months. Exams must be performed by an ophthalmologist (preferably with expertise in 
Cornea and External Eye Disease [‘front-of-the-eye’] subspecialty expert). Further evaluation will be performed including any 
additional tests, if applicable, as per the discretion of the ophthalmologist.  
9. Tuberculosis QuantiFERON testing at screening will be performed. 
10. Not required if postmenopausal status confirmed at screening. 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 49 of 58 
11. Blood samples collected before the administration of study drug.  Pharmacokinetic samples will be collected for the 
determination of REGN3500 concentration and ADA samples for the immunogenicity assessment of REGN3500.  In the event 
of suspected SAEs, such as anaphylaxis or hypersensitivity, additional PK and ADA samples may be collected at or near the 
event.  At the visits where ADA samples are to be taken, the sample should be collected with the PK sample. Japanese sentinel 
cohort has Day 2, 4, and 8 PK sample collections. 
12. One whole blood sample to extract DNA for pharmacogenomics analyses should be collected on day 1/baseline (visit 2), but can 
be collected at any visit.  Whole blood samples for RNA extraction should be collected according to time points in Table 1. 
13. Patients may be re-screened once if they fail the screening evaluation for reasons related to incidental transitory conditions (eg, 
medication use, concomitant illness, medical condition), unless the reason for the screen failure is related to failing the disease 
severity inclusion criteria. 
14. During the screening period, treatments for AD will be washed out, as applicable, according to eligibility requirements (see 
Section 6.2 in the protocol amendment 3). 
15. Clinical sites will check patient data collected on the e-diary.  Baseline peak Pruritus NRS score for maximum itch intensity will 
be determined based on the average of daily NRS scores for maximum itch intensity during the 7 days immediately preceding 
randomization.  A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average score.  For patients 
who do not have at least 4 daily scores reported during the 7 days immediately preceding the planned randomization date, 
randomization should be postponed until this requirement is met, but without exceeding the 35-day maximum duration for 
screening.  Patients are also required to have applied a stable dose of topical bland emollient (moisturizer) at least twice daily 
for at least the 7 consecutive days immediately before randomization (ie, baseline/randomization visit would be the eighth day). 
16. Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason (eg, before a rescue medication/procedure is used), as warranted. 
17. Patients who experience adverse events of special interest (AESIs) related to eye disorders (refer to Section 9.4.3 in the protocol 
amendment 3) must be referred to an ophthalmologist (preferably with expertise in Cornea and External Eye Disease [‘front-of-
the-eye’] subspecialty expert). Further evaluation of these AEs will be performed including any additional tests, if applicable, as 
per the discretion of the ophthalmologist.  
18. If the unscheduled visit was due to an AE, collect samples for PK and ADA analysis. 
19. Patients who are withdrawn from the study will be asked to return to the clinic for ET assessments. 
20. In the event a patient sample is positive in the REGN3500 ADA assay at week 16 or the first time point analyzed, the week 4 
PK sample may be analyzed in the ADA assay. 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 50 of 58 
10.3. 
Criteria for Treatment-Emergent Potentially Clinically Significant Values (PCSV) for REGN3500 
AD studies in Adults 
Parameter 
Treatment Emergent PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple levels are optional for phase 2/3 
studies. If it is desirable to get the distribution across the different PCSV 
levels, additional shift table on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline may be provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple levels are optional for phase 2/3 
studies. If it is desirable to get the distribution across the different PCSV 
levels, additional shift table on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline may be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Total Bilirubin* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
* At least one level is required, multiple levels are optional for phase 2/3 
studies. If it is desirable to get the distribution of significant level, 
additional shift table on ≤1.5, >1.5 to ≤2.0 and > 2.0 category for baseline 
vs. post baseline may be provided 
Conjugated 
Bilirubin 
 (Direct Bilirubin >35% Total Bilirubin and Total Bilirubin 
>1.5 ULN) and (Direct Bilirubin ≤35%  Total Bilirubin 
or  Total Bilirubin ≤1.5 ULN) at baseline 
 
Conjugated bilirubin dosed on a case-by-case basis. 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 51 of 58 
Parameter 
Treatment Emergent PCSV 
Comments 
(ALT or AST) 
and Total 
Bilirubin 
((ALT>3 ULN or AST>3 ULN) and TBILI>2 ULN) and  
baseline ((ALT <=3 ULN and AST<=3 ULN) or  
TBILI <=2 ULN) 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple levels are optional for phase 2/3 
studies. If it is desirable to get the distribution of significant level, 
additional shift table on ≤3, >3 to ≤10, and > 10 category for baseline vs. 
post baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) and baseline < 150 μmol/L 
>=30% change from baseline and <100% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at baseline 
<120 μmol/L and >= 120 μmol/L at baseline 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline 
Two independent criteria 
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 mmol/L  
≥160 mmol/L and baseline <160 mmol/L  
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 52 of 58 
Parameter 
Treatment Emergent PCSV 
Comments 
Total Cholesterol ≥7.74 mmol/L and < 7.74 mmol/L at baseline 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at baseline 
Threshold for therapeutic intervention. 
Glucose 
Hypoglycaemia 
 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and (>3.9 mmol/L or >=LLN) 
 at baseline 
 
≥11.1 mmol/L (unfasted); 
 ≥7 mmol/L (fasted) and < 11.1 mmol/L (unfasted);  
<7 mmol/L (fasted) at baseline 
 
ADA May 2005. 
 
 
ADA Jan 2008. 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided)  
and 
<=2 ULN or <=10 mg/L (if ULN not provided) at baseline 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at baseline  
(Non-Black);  
<2.0 Giga/L and >=2.0 Giga/L at baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L at baseline 
Increase in WBC: not relevant. 
 
 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at baseline for all races 
 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and (<=0.5 Giga/L or <= ULN at 
baseline) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 53 of 58 
Parameter 
Treatment Emergent PCSV 
Comments 
Hemoglobin 
≤115 g/L and > 115 g/L at baseline for male; 
 ≤95 g/L and> 95 g/L at baseline for Female. 
 
≥185 g/L and <185 g/L at baseline for Male; 
≥165 g/L and < 165 g/L at baseline for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
 
Criteria based upon decrease from baseline are more relevant than based 
on absolute value. Other categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v and > 0.37 v/v at baseline for Male; ≤0.32 v/v and > 
0.32 v/v at baseline forFemale 
≥0.55 v/v and < 0.55 v/v at baseline for Male; ≥0.5 v/v and < 
0.5 v/v at baseline for Female 
Two Criteria are independent 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for particular drug development, the analysis 
is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L and >=100 Giga/L at baseline 
≥700 Giga/L and < 700 Giga/L at baseline 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
Two independent criteria 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
Pulse 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) except STANDING. 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 54 of 58 
Parameter 
Treatment Emergent PCSV 
Comments 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
 
PR 
≥220 ms and increase from baseline ≥20 ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
Borderline: 
431-450 ms and < 431ms at baseline  
for Male;  
451-470 ms and < 451 ms at baseline  
for Female  
Prolonged:  
>450 to <500 ms and <= 450 ms at baseline  
for Male;  
 >470 to <500 ms and <= 470 ms at baseline  
for Female 
 ≥500 ms and < 500 ms at baseline 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
 
 
 
*QTc prolonged and QTc>60 ms are the PCSV to be identified in individual 
subject/patient listings. 
 
5 independent criteria 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 55 of 58 
10.4. 
Search Criteria for TEAE of Special Interest 
The search criteria are meant to assist the process of identification of TEAE of Special Interest.  However, since these criteria might not 
be exhaustive in some cases or may not be specific in other cases. Hence an additional blinded review of all PTs in the database may be 
performed by the Medical monitor, based on medical judgement, to identify any TEAE of Special Interest/TEAE Syndrome that might 
have been missed by the criteria or to identify any TEAE that may have been inaccurately assigned as AESI by the algorithmic search.  
AESI 
Search Criteria 
Anaphylactic reactions  
 
For SMQ “anaphylactic reaction” An algorithmic approach will be used. A case must 
include either:  
1. A narrow term (a term from Category A);  
2. Patient with both a term from Category B AND a term from Category C;  
3. Patient with a term from Category D AND { a term from Category B -  OR a term from 
Category C } 
For bullets 2 and 3, the search terms that are included under the SMQ for a particular event 
need to have the same start date (for e.g. if search shows cough (category B term) occurring 
at day 3 and urticaria (category C term) occurring at day 7, this event is not adjudicated as 
anaphylactic reaction as this is inconsistent with the clinical presentation of anaphylaxis as 
an acute event with simultaneous involvement of 2 or more body systems. 
Note:  manual adjudication of relevant PTs will be required by the study medical monitor, 
before database lock 
Conjunctivitis (any type or 
etiology), keratitis, or blepharitis 
(only events that are either severe or 
serious or lasting ≥4 weeks will be 
reported as AESIs) 
broad CMQ conjunctivitis (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, 
Conjunctivitis viral, Atopic keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye 
pruritus, Lacrimation increased, Eye discharge, Foreign body sensation in eyes, Photophobia, 
Ocular hyperaemia, Conjunctival hyperaemia, Xerophthalmia) 
Blepharitis PTs (Blepharitis, blepharitis allergic) 
AND 
Serious AE= “Yes” OR Severity= “severe” OR lasting ≥4 weeks  
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 56 of 58 
Note: manual adjudication of relevant PTs will be required by the study medical monitor, 
before database lock. 
Keratitis 
Any of the following PTs: 
• Keratitis 
• Allergic keratitis 
• Ulcerative keratitis 
• Atopic keratoconjunctivitis 
• Herpes ophthalmic  
• Ophthalmic herpes simplex  
Note: manual adjudication of relevant PTs will be required by the study medical monitor, 
before database lock. 
Severe ISRs that last longer than 24 
hours 
- HLT = Injection site reactions 
- Severity = “severe” or Serious AE =”Yes” 
- AE duration ≥1 day 
Mycosis fungoides or other forms of 
cutaneous T-cell lymphoma 
-HLT = Mycoses fungoides 
-OR LLT = Sezary syndrome 
-OR LLT = Cutaneous T-cell lymphoma 
-OR PT = Cutaneous T-cell dyscrasia 
Any severe infection 
-SOC = Infections and infestations 
-Severity = “severe” OR Serious AE= “Yes” 
Any infection requiring treatment 
with parenteral antibiotics 
SOC = Infections and infestations 
- Action taken for AE = “medication” 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 57 of 58 
- ConMed: ATC3= “Antiinfectives” during the TEAE course (between start and stop dates), 
Route = IV, IM 
Any infection requiring treatment 
with oral antibiotic/anti-viral/anti-
fungal for longer than 2 weeks 
-SOC = Infections and infestations 
-Action taken for AE = “medication” 
-Check CM: ATC3=” BETA-LACTAM ANTIBACTERIALS, PENICILLINS” OR 
“OTHER ANTIBACTERIALS” during the TEAE course (between start and stop dates), 
Route = PO and Treatment duration >14 days 
Any clinical endoparasitosis 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infections 
Any opportunistic infectiona 
a:The definition of opportunistic 
infections is referring to the recent 
consensus guidance for 
opportunistic infections in the 
setting of biologic therapy ( K L 
Winthrop  et al, 2015) 
The following HLTs plus PTs 
-HLT = Pneumocystis infections 
-HLT* = Fungal infections NEC 
-HLT* = Pseudallescheria infections 
-HLT = Herpes viral infections 
-HLT = Paracoccidioides infections 
-HLT = Sporothrix infections 
-HLT = Cryptosporidia infections 
-HLT* = Trypanosomal infections 
-HLT* = Campylobacter infections 
-HLT* = Shigella infections 
-HLT* = Vibrio infections 
Plus the following PTs  
-Polyomavirus-associated nephropathy 
-BK virus infection 
-Cytomegalovirus infection 
-Post transplant lymphoproliferative disorder 
-Progressive multifocal leukoencephalopathy 
-*Bartonellosis 
-Blastomycosis 
-Toxoplasmosis 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3500-AD-1805 
Statistical Analysis Plan 
 
Date: June 15, 2020 
 
CONFIDENTIAL 
Page 58 of 58 
-Coccidioidomycosis 
-Histoplasmosis 
-*Aspergillus infection 
-Systemic candida 
-Oropharyngeal candidiasis 
-Cryptococcosis 
-Listeriosis 
-Tuberculosis 
-Nocardiosis 
-Mycobacterial infection 
-*Salmonellosis 
-*Hepatitis B 
-Herpes zoster 
-*Strongyloidiasis 
-Microsporidia infection 
-Visceral leishmaniasis 
-*Hepatitis C 
Note: *Blinded manual adjudication of relevant PTs under each of HLTs listed above will be 
required by the study medical monitor,  before database locks 
Significant ALT elevation 
ALT >3×ULN associated with total 
bilirubin >2×ULN; or  
ALT >5×ULN in patients with 
baseline ALT ≤2×ULN; or  
ALT >8×ULN if baseline ALT 
>2×ULN 
Algorithm is to first search adverse event PT term = “Alanine aminotransferase increased” 
and the event must meet the following: ALT>3*ULN associated with total bilirubin>2*ULN 
or ALT>5*ULN with baseline ALT≤2*ULN or  
ALT>8*ULN if baseline ALT>2*ULN 
 
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00


Signature Page for VV-RIM-00114774 v1.0
Signature Page for VV-RIM-00114774 v1.0 Approved
ESig Approval
00
ESig Approval
00
ESig Approval
-2020 12:50:19 GMT+0000
                                        VV-RIM-00114774-1.0 Approved - 18 Jun 2020 GMT-5:00