A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Dupilumab in Adult Patients With Bullous Pemphigoid
Phase: PHASE2
Conditions: Bullous Pemphigoid
Sponsor: Regeneron Pharmaceuticals

Regeneron Pharmaceuticals, Inc. 
Page 1 of 107 
CONFIDENTIAL 
NCT04206553
EudraCT: 2019-003520-20 
IND Number: 107969 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF DUPILUMAB IN 
ADULT PATIENTS WITH BULLOUS PEMPHIGOID 
Compound: 
Dupilumab 
Study Name: 
LIBERTY-BP ADEPT 
Clinical Phase: 
2/3 
Protocol Number: 
R668-BP-1902 
Protocol Version: 
R668-BP-1902 Amendment 3 
Amendment 3 Date of Issue: 
See appended electronic signature page 
Amendment 2 Date of Issue: 
22 Apr 2021 
Amendment 1 Date of Issue: 
11 Jun 2020 
Original Date of Issue:  
18 Oct 2019 
Medical /Study Director: 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity.  For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
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Clinical Study Protocol 
 
R668-BP-1902 Amendment 3 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 2 of 107 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 3 
The purpose of this amendment is to 
 
 
. None of the changes in this amendment will affect study conduct. 
The following table outlines the changes made to the protocol along with the corresponding 
rationale. 
Description of Change 
Brief Rationale 
Section Number and Name 
“Time to first use of rescue 
medication (up to week 36)” has 
been added as a new key secondary 
endpoint for efficacy. 
Assessing the time to first use of 
rescue medication is clinically 
important, as it permits evaluation 
of efficacy in delaying the need for 
use of rescue medications (eg, oral 
corticosteroids/ other 
immunosuppressive medications). 
Participants are permitted to use 
rescue medications during the 
study to manage disease worsening 
(eg, loss of control or relapses). 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Key Secondary 
Efficacy Endpoints 
Two secondary endpoints for 
efficacy have been clarified as 
follows (amended text is 
underlined): 
• 
“Proportion of patients who do 
not achieve control of disease 
activity, who relapse after 
achieving control of disease 
activity, or do not achieve 
complete remission (up to 
week 36) (Note: control of 
disease activity is defined 
when new lesions cease to 
form and existing lesions begin 
to heal)” 
• 
“Proportion of patients who do 
not achieve control of disease 
activity, who relapse after 
achieving control of disease 
activity, or do not achieve 
Disease control, complete 
remission, and relapses are 
assessed during the study as 
measures of disease activity. The 
endpoints have been clarified to 
include complete remission to 
provide a comprehensive view of 
disease activity.  
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.3 Other Secondary 
Endpoints 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section Number and Name 
complete remission (up to 
week 52)” 
Missing data handling methods 
have been further clarified for the 
primary and secondary efficacy 
analyses.  
 
Missing data handling methods are 
clarified 
 
 
 
 
 
  
 
Clinical Protocol Synopsis: 
Statistical Plan 
Section 6.2 Planned Interim 
Analysis 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Table 3 Summary of Primary 
Estimand for Primary Endpoint 
Table 4 Summary of Primary 
Estimand for Key Secondary 
Endpoint (Binary) 
Table 5 Summary of Primary 
Estimand for Key Secondary 
Endpoint (Continuous) 
In the case of use of rescue 
treatment as an intercurrent event 
for continuous endpoints, the 
imputation strategy is further 
elaborated.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The purpose of this strategy is to 
try to accurately capture disease 
worsening at week 36 as 
possible. Bullous pemphigoid is 
known to flare.  All patients will 
have received steroids at the 
beginning of the study with the 
intended effect of disease 
improvement.  If a patient has a 
flare of disease requiring rescue 
medications, the intent is to 
accurately capture it. 
Clinical Protocol Synopsis: 
Statistical Plan 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Table 5 Summary of Primary 
Estimand for Key Secondary 
Endpoint (Continuous) 
Administrative change to the 
Medical/Study Director name 
To accurately reflect the name and 
title of the current Medical/Study 
Director 
Title Page 
Minor editorial corrections and 
clarifications. 
For clarification. 
Throughout the protocol. 
 
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Page 4 of 107 
 
CONFIDENTIAL 
Amendment 2 
Overall Rationale for Amendment 2: The primary purpose of this protocol amendment is to reduce 
study burden for patients from protocol-required invasive procedures and to provide flexibility for 
the visit options (eg, telemedicine) in view of the COVID-19 pandemic; to update patient 
eligibility requirements; and to add estimand for the statistical analyses of primary and key 
secondary efficacy endpoints. The following table outlines the changes made to the protocol and 
the rationale.  
Description of Change 
Brief Rationale 
Section Number and Name 
Clarified inclusion criterion for the 
serological evidence necessary for a 
diagnosis of bullous pemphigoid (BP) to 
allow for either a positive BP180 or 
BP230 serology result, or a positive 
indirect immunofluorescence (utilizing a 
peripheral blood specimen) result, and to 
expand the window for use of results 
from a historical biopsy from 3 months 
to 6 months.  
To provide flexibility 
for eligibility criteria 
while ensuring 
appropriate patients 
qualify for the study.  
Clinical Study Protocol Synopsis: Target 
Population 
Section 6.1 Study Description and 
Duration 
Section 7.2.1 Inclusion Criteria, 
criterion #2 
Section 9.1.1.1 Table 1 Schedule of 
Events Footnotes, footnotes #18 and 27 
(previously #19 and 29) 
Section 9.2.1 Procedures Performed Only 
at the Screening/Baseline Visit 
Updated exclusion criteria: 
• The washout period for systemic 
corticosteroids (prednisone or 
prednisolone equivalent) was 
changed from 2 weeks to at least 
7 days 
• To clarify reference to systemic 
antihistamine use to require a stable 
dose of antihistamine use for at least 
7 days prior to the baseline visit. 
Patients on a stable dose of systemic 
antihistamine for at least 7 days prior 
to baseline may enter study; however, 
the dose of these medications should 
remain unchanged for the duration of 
the study. Exclusion criterion related 
to use of topical antihistamines was 
removed. 
• The washout period for antibiotics 
directed at the treatment of BP was 
changed from 2 weeks to at least 
7 days. 
• The washout period for nicotinamide 
directed at the treatment of BP was 
changed from 2 weeks to at least 
7 days. 
• Patients previously treated with an 
IL-5 inhibitor such as benralizumab 
or mepolizumab may be entered after 
a washout period of 5 half-lives (if 
To clarify eligibility 
requirements while 
ensuring appropriately 
symptomatic patients 
are eligible. 
Clinical Study Protocol Synopsis: Study 
Design 
Section 6.1 Study Description and 
Duration 
Section 7.2.2 Exclusion Criteria, 
criteria #4, 5, 6, 7, 8, and 10 
Section 8.10.1 Prohibited Medications and 
Procedures 
 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section Number and Name 
known) or 16 weeks prior to the 
baseline visit, whichever is longer. 
The following changes were made: 
• 
Changed the required biomarker 
and exploratory 
sample 
collection timing and removed the 
requirement for 
 
 
 
. Updated exploratory 
objectives to remove/revise 
objectives related to 
 
 samples. 
• 
Changed the requirement for skin 
biopsies after visit 1 (screening 
visit) to select study sites only. 
To minimize study 
burden for patients of 
invasive procedures. 
Clinical Study Protocol Synopsis: 
Objectives 
Section 2.3 Exploratory Objectives 
Table 1: Schedule of Events (Screening, 
Baseline, and Double-Blind Treatment 
Period) 
Table 2: Schedule of Events (Follow-up 
Period, Unscheduled Visit, Unscheduled 
Visit for BP Relapse, and Early 
Termination Visit) 
Section 9.1.1.1 Table 1 Schedule of 
Events Footnotes, footnotes #1 and 26 
(previously #27), previous footnote #28 
deleted 
Section 9.1.1.2 Table 2 Schedule of 
Events Footnotes, footnotes #1 and 17 
(previously #18), previous footnote #19 
deleted) 
Section 9.2.6.1 Exploratory Research 
Updated Schedule of Events: 
• To allow telemedicine visits for study 
visits 5 through 9.  
• Changed visits 12 and 16 from 
in-person visits to phone visits. 
• Added row for Karnofsky 
performance status at visit 1 
• Patients may self-administer study 
drug beginning at week 6. 
• Added that a healthcare provider (eg, 
visiting nurse) could perform the 
injection of study medication if 
patient (or caregiver) did not wish to 
self-administer.  
• Removed PK and biomarker blood 
draws at weeks 24 and 44.  
• Removed monitoring of patients at 
study site for 30 minutes post-study 
drug administration. 
• Updated footnotes and 
cross-references to footnotes 
accordingly. 
To minimize study 
burden for patients and 
to provide study visit 
options 
(eg, telemedicine 
visits) in view of the 
COVID-19 pandemic. 
Clinical Study Protocol Synopsis: Study 
Design 
Section 6.1 Study Description and 
Duration 
Table 1: Schedule of Events (Screening, 
Baseline, and Double-Blind Treatment 
Period) 
Table 2: Schedule of Events (Follow-up 
Period, Unscheduled Visit, Unscheduled 
Visit for BP Relapse, and Early 
Termination Visit) 
Section 9.1.1.1 Table 1 Schedule of 
Events Footnotes, footnotes #1a, 2, 9, and 
17 (previously #18); deleted prior footnote 
#7 
Section 9.1.1.2 Table 2 Schedule of 
Events Footnotes, footnote #14 
(previously #15), deleted prior footnote #6 
Section 9.2.3.1 Vital Signs 
Added assessment for BP flare during 
phone visits and added unscheduled 
visits for BP relapse. 
To evaluate potential 
disease worsening. 
Table 1: Schedule of Events (Screening, 
Baseline, and Double-Blind Treatment 
Period) 
Table 2: Schedule of Events (Follow-up 
Period, Unscheduled Visit, Unscheduled 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section Number and Name 
Visit for BP Relapse, and Early 
Termination Visit) 
Section 9.1.1.1 Table 1 Schedule of 
Events Footnotes, footnote #29 (new 
footnote) 
Section 9.1.1.2 Table 2 Schedule of 
Events Footnotes, footnotes #3 and 18 
(new footnote) 
Section 9.1.3.1 Unscheduled Visit for BP 
Relapse (new section) 
Section 9.2.2.14 Assessment of Bullous 
Pemphigoid Flare (new section) 
Increased number of study sites from 
approximately 30 to approximately 
40 sites. 
To ensure the targeted 
number of patients is 
enrolled. 
Clinical Study Protocol Synopsis: Site 
Location(s), Sample Size 
Section 7.1 Number of Patients Planned 
Updated prohibited medications: 
• Clarified prohibited medications that 
may be used as rescue treatment and 
whether or not use results in 
discontinuation of study drug. 
• Clarified that initiation, 
discontinuation, or change in dosing 
regimen of systemic antihistamines 
after the baseline visit is prohibited. 
• Added that changes to treatments 
known to cause or exacerbate BP 
should be made in consultation with 
the medical monitor. 
To ensure the use of 
rescue medications are 
appropriately 
accounted for in the 
endpoint analysis. 
Section 8.10.1 Prohibited Medications and 
Procedures 
Section 7.2.2 Exclusion Criteria, 
criteria #5 and 6 
 
Updated the risks-benefits associated 
with dupilumab and removed the 
30-minute post-dose monitoring for 
hypersensitivity reactions 
To provide more 
current information.  
Section 3.3.1 Risk-Benefit of Dupilumab 
for Patients with Bullous Pemphigoid 
Added that 
 
 may be used for 
exploratory biomarker research. 
To allow for 
exploratory research. 
Section 9.2.6.1 Exploratory Research 
Patients from study sites in Japan will 
not be stratified. 
Approximately 10% 
(~10 patients) will be 
randomized from 
Japan. Given the small 
number of patients 
from Japan, using 
 strata may result in 
an imbalance of 
patients across strata. 
Clinical Study Protocol Synopsis, Study 
Design 
Section 6.1 Study Description and 
Duration 
Section 8.6 Method of Treatment 
Assignment 
Added primary estimand of interest and 
intercurrent event(s) strategy, and added 
missing data-handling methods for 
primary and key secondary efficacy 
endpoints. 
 
. Removed 
To implement a 
concept estimand in 
the primary analysis 
approaches for the 
primary and key 
secondary efficacy 
Clinical Study Protocol Synopsis, 
Statistical Plan 
Section 11 Statistical Plan 
Section 11.3.1 Efficacy Analysis Sets 
Section 11.4 Statistical Methods 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section Number and Name 
per-protocol set (PPS) from protocol. 
Removed statements regarding updating 
the statistical analysis plan (SAP). 
Updated summaries of patient 
disposition and adverse events (AEs). 
endpoints based on 
International Council 
for Harmonisation 
(ICH) E9 (R1). 
For clarification, 
consistency, and 
completeness. 
Section 11.4.1 Patient Disposition 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Table 3: Summary of Primary Estimand 
for Primary Endpoint (new table) 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Table 4: Summary of Primary Estimand 
for Key Secondary Endpoint (Binary) 
(new table) 
Table 5: Summary of Primary Estimand 
for Key Secondary Endpoint (Continuous) 
(new table)  
Section 11.4.3.3 Subgroup Analysis 
Section 11.4.5.1 Adverse Events 
Minor editorial corrections and 
clarification. 
For clarification. 
Throughout the protocol. 
 
Amendment 1 
The purpose of this protocol amendment is to address regulatory authority feedback regarding 
study design. The number of patients to be enrolled in the study has been increased. The duration 
of the double-blind treatment period has been extended. Additional exclusion criteria have been 
incorporated. Other minor changes were made for clarification and to protect patient safety and 
data integrity during the COVID-19 pandemic. The following table outlines the changes made to 
the protocol and the rationale.  
 
Description of Change 
Rationale 
Section Changed 
Increased the duration of the 
double-blind treatment period from 
36 weeks to 52 weeks and added 
visits/procedures at weeks 38 
(phone visit), 40 (phone visit), 42 
(phone visit), 44, 46 (phone visit), 
48 (phone visit), 50 (phone visit), 
and 52. 
 
To comply with the 
request of a regulatory 
authority. 
Clinical Study Protocol Synopsis: Study 
Design, Study Duration, Endpoints 
Section 3.2.1 Rationale for Study Design 
Section 4.1.3 Other Secondary Endpoints 
Section 4.1.4 Exploratory Endpoints 
Section 6.1 Study Description and Duration 
Figure 1: Study Flow Diagram 
Table 1: Schedule of Events (Screening, 
Baseline, and Double-Blind Treatment Period) 
Table 2: Schedule of Events (Follow-up Period, 
Unscheduled Visits, and Early Termination 
Visit) 
Section 9.1.1.1 Table 1 Schedule of Events 
Footnotes, #10, #25, #27 
Section 11.4.3.2 Secondary Efficacy Analysis 
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CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Section 11.4.5.1 Adverse Events 
New secondary endpoints were 
added at week 52. 
These new secondary 
endpoints correspond to 
the new double-blind 
treatment period, which 
was increased from 
36 weeks to 52 weeks. 
Clinical Study Protocol Synopsis: Endpoints 
Section 4.1.3 Other Secondary Endpoints 
 
 
 
 
 
 
 
 
 
 
To comply with the 
request of a regulatory 
authority. 
Clinical Study Protocol Synopsis: Site 
Location(s), Population, Statistical Plan 
Section 7.1 Number of Patients Planned 
Section 8.6 Method of Treatment Assignment 
Section 11.2 Justification of Sample Size 
Section 11.4 Statistical Methods 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy Analysis 
Section 11.4.4 Control of Multiplicity 
Increased the screening period 
from 14 days to 35 days. 
To ensure inclusion is 
documented for 
histological and 
serological confirmation 
of bullous pemphigoid 
(BP) prior to 
randomization and to 
ensure appropriate 
medication washout for 
exclusion criteria. 
Clinical Study Protocol Synopsis: Study Design 
Section 6.1 Study Description and Duration 
Figure 1: Study Flow Diagram 
Table 1: Schedule of Events (Screening, 
Baseline, and Double-Blind Treatment Period) 
Added new exclusion criteria and 
clarified existing criteria. 
To comply with the 
request of a regulatory 
authority and for 
clarification. 
Section 7.2.2 Exclusion Criteria, #8 , #23 , #24  
Added an additional prohibited 
medication to the prohibited 
medication list and clarified 
restrictions regarding receiving live 
virus vaccines during the study. 
To comply with the 
request of a regulatory 
authority 
Section 8.10.1 Prohibited Medications and 
Procedures 
Added 
 
 
 
 
 for early 
termination (ET) visits, where 
these assessments were previously 
inadvertently omitted. 
For clarification. 
Table 2: Schedule of Events (Follow-up Period, 
Unscheduled Visits, and Early Termination 
Visit) 
 
Provided updated clinical evidence 
to support investigating dupilumab 
as a possible efficacious and 
well-tolerated treatment for BP. 
To align with updated 
clinical data. 
Section 1 Introduction 
Section 3.2.1 Rationale for Study Design 
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CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Section 3.3.1 Risk-Benefit of Dupilumab for 
Patients with Bullous Pemphigoid 
Section 19 References 
Added language to clarify general 
changes in study conduct in the 
context of the COVID-19 
pandemic. 
To address guidance 
from the US and EU 
regarding the conduct of 
clinical trials during the 
COVID-19 pandemic. 
Section 3.3 Risk-Benefit 
Section 9.1 Schedule of Events 
Section 11 Statistical Plan 
Minor clarifications and editorial 
corrections. 
For clarification and 
consistency. 
Throughout the protocol. 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABQOL 
Autoimmune bullous disease quality of life 
AD 
Atopic dermatitis  
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BP 
Bullous pemphigoid 
BPDAI 
Bullous Pemphigoid Disease Area Index 
BSA 
Body Surface Area  
 
 
 
 
CI 
Confidence interval 
 
 
CRF/eCRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRSwNP 
Chronic rhinosinusitis with nasal polyposis 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EDTA 
Ethylenediamine tetraacetic acid 
EoE 
Eosinophilic esophagitis 
 
 
EQVAS 
EQ visual analogue scale 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
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CONFIDENTIAL 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
 
 
IgG 
Immunoglobulin G 
 
 
IL-4 
Interleukin 4 
IL-13 
Interleukin 13 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
NRS 
Numerical rating score 
OCS 
Oral corticosteroids 
 
 
 
 
PCSV 
Potentially clinically significant value 
 
 
 
 
PK 
Pharmacokinetic 
PT 
Preferred term 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
 
 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
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CONFIDENTIAL 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOCF 
Worst observation carried forward 
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CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................19 
1. 
INTRODUCTION ......................................................................................................27 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
2.3. 
Exploratory Objectives ...............................................................................................29 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................30 
3.1. 
Hypotheses ..................................................................................................................30 
3.2. 
Rationale .....................................................................................................................30 
3.2.1. 
Rationale for Study Design .........................................................................................30 
3.2.2. 
Rationale for Dose Selection ......................................................................................31 
3.3. 
Risk-Benefit ................................................................................................................31 
3.3.1. 
Risk-Benefit of Dupilumab for Patients with Bullous Pemphigoid ...........................32 
4. 
ENDPOINTS ..............................................................................................................34 
4.1. 
Primary and Secondary Endpoints..............................................................................34 
4.1.1. 
Primary Endpoint ........................................................................................................34 
4.1.2. 
Key Secondary Efficacy Endpoints ............................................................................34 
4.1.3. 
Other Secondary Endpoints ........................................................................................34 
4.1.4. 
Exploratory Endpoints ................................................................................................36 
5. 
STUDY VARIABLES................................................................................................38 
5.1. 
Demographic and Baseline Characteristics ................................................................38 
5.2. 
Efficacy Variables ......................................................................................................38 
5.3. 
Safety Variables ..........................................................................................................38 
5.4. 
Pharmacokinetic Variables .........................................................................................38 
5.5. 
Immunogenicity Variables ..........................................................................................38 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................38 
6. 
STUDY DESIGN .......................................................................................................40 
6.1. 
Study Description and Duration .................................................................................40 
6.1.1. 
End of Study Definition ..............................................................................................44 
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6.2. 
Planned Interim Analysis ............................................................................................44 
6.3. 
Study Committees .......................................................................................................44 
6.3.1. 
Independent Data Monitoring Committee ..................................................................44 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............45 
7.1. 
Number of Patients Planned .......................................................................................45 
7.2. 
Study Population .........................................................................................................45 
7.2.1. 
Inclusion Criteria ........................................................................................................45 
7.2.2. 
Exclusion Criteria .......................................................................................................46 
7.3. 
Premature Withdrawal from the Study .......................................................................49 
7.4. 
Replacement of Patients .............................................................................................50 
8. 
STUDY TREATMENTS............................................................................................51 
8.1. 
Investigational and Reference Treatments ..................................................................51 
8.2. 
Background Treatment ...............................................................................................51 
8.3. 
Rescue Treatments ......................................................................................................52 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................53 
8.4.1. 
Dose Modification ......................................................................................................53 
8.4.2. 
Study Drug Discontinuation .......................................................................................53 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................53 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................54 
8.5. 
Management of Acute Reactions ................................................................................54 
8.5.1. 
Acute Injection Reactions ...........................................................................................54 
8.5.1.1. 
Systemic Injection Reactions ......................................................................................54 
8.5.1.2. 
Local Injection Site Reactions ....................................................................................55 
8.6. 
Method of Treatment Assignment ..............................................................................55 
8.7. 
Blinding ......................................................................................................................55 
8.8. 
Emergency Unblinding ...............................................................................................55 
8.9. 
Treatment Logistics and Accountability .....................................................................56 
8.9.1. 
Supply and Disposition of Treatments .......................................................................56 
8.9.2. 
Treatment Accountability ...........................................................................................56 
8.9.3. 
Treatment Compliance ................................................................................................56 
8.10. 
Concomitant Medications and Procedures .................................................................57 
8.10.1. 
Prohibited Medications and Procedures .....................................................................57 
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8.10.1.1. 
Adverse Events Requiring the Use of Systemic Corticosteroids ................................58 
8.10.2. 
Permitted Medications ................................................................................................58 
8.10.3. 
Glucocorticoid-Induced Osteopenia/Osteoporosis Prevention and Treatment ...........58 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................59 
9.1. 
Schedule of Events .....................................................................................................59 
9.1.1. 
Footnotes for the Schedule of Events Tables .............................................................69 
9.1.1.1. 
Table 1 Schedule of Events Footnotes ........................................................................69 
9.1.1.2. 
Table 2 Schedule of Events Footnotes ........................................................................71 
9.1.2. 
Early Termination Visit ..............................................................................................72 
9.1.3. 
Unscheduled Visits .....................................................................................................72 
9.1.3.1. 
Unscheduled Visits for BP Relapse ............................................................................72 
9.2. 
Study Procedures ........................................................................................................72 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................73 
9.2.2. 
Efficacy Procedures ....................................................................................................73 
9.2.2.1. 
Body Surface Area ......................................................................................................73 
9.2.2.2. 
Pruritus Numerical Rating Scale ................................................................................73 
9.2.2.3. 
Skin Pain Numerical Rating Scale ..............................................................................73 
9.2.2.4. 
Sleep Numerical Rating Scale ....................................................................................73 
9.2.2.5. 
Bullous Pemphigoid Disease Area Index Activity Score ...........................................74 
9.2.2.6. 
Bullous Pemphigoid Disease Area Index Pruritus......................................................74 
9.2.2.7. 
Patient Global Assessment of Disease Severity .........................................................74 
9.2.2.8. 
Patient Global Assessment of Treatment ....................................................................74 
9.2.2.9. 
Patient-Assessed 
 .......................................................................................74 
9.2.2.10. 
Autoimmune Bullous Disease Quality of Life ...........................................................75 
9.2.2.11. 
Blister and Urticaria/Eczematous Plaque Count .........................................................75 
9.2.2.12. 
Bullous Pemphigoid Clinical Assessment ..................................................................75 
9.2.2.13. 
Bullous Pemphigoid Area Photographs ......................................................................76 
9.2.2.14. 
Assessment of Bullous Pemphigoid Flare ..................................................................76 
9.2.3. 
Safety Procedures .......................................................................................................76 
9.2.3.1. 
Vital Signs ..................................................................................................................76 
9.2.3.2. 
Body Weight and Height ............................................................................................76 
9.2.3.3. 
Physical Examination .................................................................................................76 
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9.2.3.4. 
Electrocardiogram .......................................................................................................77 
9.2.3.5. 
Laboratory Testing ......................................................................................................77 
9.2.4. 
Drug Concentration and Measurements .....................................................................78 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................79 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................79 
9.2.6.1. 
Exploratory Research ..................................................................................................80 
9.2.7. 
Future Biomedical Research (Optional) .....................................................................80 
9.2.7.1. 
 Analysis (Optional) ......................................................................80 
10. 
SAFETY EVALUATION AND REPORTING .........................................................82 
10.1. 
Recording and Reporting Adverse Events ..................................................................82 
10.1.1. 
General Guidelines .....................................................................................................82 
10.1.2. 
Reporting Procedure ...................................................................................................83 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................83 
10.2. 
Definitions ..................................................................................................................84 
10.2.1. 
Adverse Event .............................................................................................................84 
10.2.2. 
Serious Adverse Event ................................................................................................84 
10.2.3. 
Adverse Events of Special Interest .............................................................................84 
10.2.4. 
Severity .......................................................................................................................85 
10.2.5. 
Causality .....................................................................................................................85 
10.3. 
Safety Monitoring .......................................................................................................86 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................87 
11. 
STATISTICAL PLAN................................................................................................88 
11.1. 
Statistical Hypothesis ..................................................................................................88 
11.2. 
Justification of Sample Size........................................................................................88 
11.3. 
Analysis Sets ...............................................................................................................88 
11.3.1. 
Efficacy Analysis Sets ................................................................................................88 
11.3.2. 
Safety Analysis Set .....................................................................................................89 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................89 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................89 
11.4. 
Statistical Methods ......................................................................................................89 
11.4.1. 
Patient Disposition ......................................................................................................90 
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11.4.2. 
Demography and Baseline Characteristics .................................................................90 
11.4.3. 
Efficacy Analyses .......................................................................................................90 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................90 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................91 
11.4.3.3. 
Subgroup Analysis ......................................................................................................93 
11.4.4. 
Control of Multiplicity ................................................................................................93 
11.4.5. 
Safety Analysis ...........................................................................................................93 
11.4.5.1. 
Adverse Events ...........................................................................................................94 
11.4.5.2. 
Other Safety ................................................................................................................94 
11.4.5.3. 
Treatment Exposure ....................................................................................................95 
11.4.5.4. 
Treatment Compliance ................................................................................................95 
11.4.6. 
Pharmacokinetics ........................................................................................................95 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................95 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................96 
11.5. 
Statistical Considerations Surrounding the Premature Termination of a Study .........96 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................97 
12.1. 
Data Management and Electronic Systems ................................................................97 
12.1.1. 
Data Management .......................................................................................................97 
12.1.2. 
Electronic Systems ......................................................................................................97 
12.2. 
Study Monitoring ........................................................................................................97 
12.2.1. 
Monitoring of Study Sites ...........................................................................................97 
12.2.2. 
Source Document Requirements ................................................................................98 
12.2.3. 
Case Report Form Requirements ................................................................................98 
12.3. 
Audits and Inspections ................................................................................................98 
12.4. 
Study Documentation .................................................................................................99 
12.4.1. 
Certification of Accuracy of Data ...............................................................................99 
12.4.2. 
Retention of Records ..................................................................................................99 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................100 
13.1. 
Good Clinical Practice Statement .............................................................................100 
13.2. 
Informed Consent .....................................................................................................100 
13.3. 
Patients Confidentiality and Data Protection ............................................................100 
13.4. 
Institutional Review Board/Ethics Committee .........................................................101 
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13.5. 
Clinical Study Data Transparency ............................................................................101 
14. 
PROTOCOL AMENDMENTS ................................................................................102 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................103 
15.1. 
Premature Termination of the Study .........................................................................103 
15.2. 
Close-out of a Site ....................................................................................................103 
16. 
CONFIDENTIALITY ..............................................................................................103 
17. 
FINANCING AND INSURANCE ...........................................................................103 
18. 
PUBLICATION POLICY ........................................................................................103 
19. 
REFERENCES .........................................................................................................104 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................106 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................107 
 
LIST OF TABLES 
Table 1: 
Schedule of Events (Screening, Baseline, and Double-Blind Treatment 
Period) .........................................................................................................................60 
Table 2: 
Schedule of Events (Follow-up Period, Unscheduled Visit, Unscheduled 
Visit for BP Relapse, and Early Termination Visit) ...................................................67 
Table 3: 
Summary of Primary Estimand for Primary Endpoint ...............................................91 
Table 4: 
Summary of Primary Estimand for Key Secondary Endpoint (Binary) .....................91 
Table 5: 
Summary of Primary Estimand for Key Secondary Endpoint (Continuous) .............92 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................43 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
Title 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Efficacy and Safety of Dupilumab in Adult 
Patients with Bullous Pemphigoid 
Site Location(s) 
Approximately 40 sites globally 
Objective(s) 
Primary objective:  
• 
To demonstrate that dupilumab is superior to placebo in 
achieving sustained remission off oral corticosteroids (OCS) 
in patients with bullous pemphigoid (BP)  
Secondary objectives: 
• 
To evaluate the OCS-sparing effects of dupilumab in patients 
with BP 
• 
To evaluate the effect of dupilumab on itch in patients with 
BP 
• 
To evaluate the effects of dupilumab on health-related quality 
of life measures in patients with BP 
• 
To evaluate the effect of dupilumab on circulating BP180 and 
BP230 autoantibody titers 
• 
To assess the safety and tolerability of dupilumab 
administered to patients with BP 
• 
To characterize the trough concentrations of functional 
dupilumab over time following administration of dupilumab 
in patients with BP 
• 
To assess the immunogenicity of dupilumab in patients with 
BP over time 
 
• 
• 
• 
• 
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• 
Study Design 
This is a global, multicenter, randomized, double-blind, placebo-controlled, 
parallel group study to assess the efficacy, safety, tolerability, 
pharmacokinetics (PK), and immunogenicity of dupilumab in patients with 
BP.   
The study consists of a 35-day screening period, a 52-week double-blind 
treatment period, and a 12-week follow-up period. After patients provide 
informed consent, patients will be assessed for study eligibility at the 
screening visit. 
During the screening period, treatments for BP will be washed out, as 
applicable, according to eligibility requirements. 
At the baseline visit, eligible patients will be randomized to receive 
dupilumab or matching placebo. 
 
 
 
 
 In addition, 
all patients will start a standard regimen of OCS beginning at the baseline 
visit to obtain control of disease activity (note: control of disease activity is 
defined as when new lesions cease to form and existing lesions begin to 
heal). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
During the 52-week double-blind treatment period, patients will have study 
visits every 2 weeks until week 16 (some specified study visits may be 
conducted as telemedicine visits). After week 4, patients will have the 
option to self-administer study drug (or have a caregiver/healthcare provider 
[eg, visiting nurse] administer) during weeks in which no clinic visit is 
scheduled. Patients who do not want to self-inject may have the clinic staff 
administer all the study drug injections in the clinic. After week 16, patients 
will have in-clinic or phone visits as specified during the remainder of the 
52-week treatment period. Study drug will be administered subcutaneously 
(SC) q2w through week 50. 
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Following the 52-week double-blind treatment period, patients will have 
phone visits as specified and then return for an in-person follow-up visit at 
week 64 (end of study). 
Study Duration 
The duration of the study for a patient is approximately 64 weeks, excluding 
the screening period. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last 
study visit, withdraws from the study, or is lost to follow-up (ie, the study 
patient can no longer be contacted by the investigator).   
Population 
 
 
Sample Size: 
Approximately 98 patients will be enrolled at approximately 40 study sites. 
 
Target Population: 
The proposed study population is patients with BP. All patients must have 
documented clinical features of BP at the screening visit and confirmed 
diagnosis of BP based on histopathology, immunopathology, and serology 
by the baseline visit.  Diagnosis of BP based upon histopathology, 
immunopathology, and serologic testing performed at a local laboratory 
with results available within 6 months of the screening visit is acceptable to 
fulfill the criteria for diagnostic confirmation of BP. 
Bullous pemphigoid patients must also have moderate-to-severe disease at 
the screening and baseline visits defined by a BPDAI activity score ≥24; and 
a peak pruritus numerical rating score (NRS) for maximum itch intensity ≥4 
at baseline.  Patients are also required to have a minimum Karnofsky 
Performance Status Scale score of 50% at the screening visit. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab: (loading) dose of 
 administered SC, followed by 
 
administered SC q2w. 
 
Placebo 
 
Route/Schedule: 
Dupilumab-matching placebo (containing same formulation as dupilumab 
without active substance): loading dose administered SC, followed by 
SC q2w dosing. 
 
Background Treatment 
 
Dose/Route/Schedule: 
Prednisone/prednisolone  
In addition to dupilumab (or matching placebo), all patients will start on a 
standard regimen of OCS (prednisone or prednisolone) to obtain control of 
disease activity. 
 
 
 
 
 
 
 
 
 
 
 
 
. Control of disease 
activity is expected to occur by 2 weeks after randomization with the starting 
doses of OCS, but some patients may take longer; usually no longer than 4 
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weeks. For moderate BP patients who are not showing signs of disease 
control (eg, continued blister or urticarial plaque formation) 2 weeks after 
randomization (week 2), 
 
. Tapering of OCS will begin 
when there has been 2 weeks of sustained control of disease activity. 
 
 
 
 
 
 
 
. These patients should receive rescue 
treatment per investigator’s discretion. 
Patients will  undergo a protocol-defined OCS tapering regimen as long as 
they maintain control of disease activity. The OCS taper employed in this 
study uses a schedule typical for this disease which is as follows:  
 
• 
• 
• 
• 
 
 
 
• 
• 
• 
• 
• 
Endpoints 
 
 
Primary: 
 
The primary endpoint is the proportion of patients achieving sustained 
remission at week 36, defined as: 
• 
Achievement of complete remission and off OCS no later than 
week 16 after randomization (Note: complete remission is defined 
as absence of new lesions and epithelialization of old lesions), 
and 
• 
Absence of disease relapse from the time the patient has 
completed the OCS taper (no later than week 16 after 
randomization) to week 36 (Note: relapse is defined as the 
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appearance of 3 or more new lesions a month [blisters, 
eczematous lesions, or urticarial plaques] or at least 1 large 
[> 10 cm diameter] eczematous lesion or urticarial plaque that 
does not heal within 1 week), and 
• 
Absence of need for rescue therapy during the 36-week 
double-blind treatment period (Note: rescue therapy includes 
increase of OCS dose during the taper, re-initiation of OCS after 
completion of the OCS taper, or initiation of any BP-directed 
therapy). 
Secondary: 
Key secondary efficacy endpoints: 
• 
Total cumulative dose of OCS from baseline to week 36 
• 
Percent change in weekly average of daily peak pruritus NRS 
from baseline to week 36 
• 
Proportion of patients with improvement (reduction) of weekly 
average of daily peak pruritus NRS ≥4 from baseline to week 36 
• 
Percent change in BPDAI activity score from baseline to week 36 
• 
Time to first use of rescue medication (up to week 36) 
Other secondary efficacy endpoints: 
• 
Duration of complete remission while not requiring OCS (up to 
week 36) 
• 
Proportion of patients who do not achieve control of disease 
activity, who relapse after achieving control of disease activity, or 
do not achieve complete remission (up to week 36) (Note: control 
of disease activity is defined when new lesions cease to form and 
existing lesions begin to heal) 
• 
Proportion of patients who achieve a reduction in BPDAI activity 
score of at least 50%, 75%, and 90% from baseline to week 36 
• 
Change in autoimmune bullous disease quality of life (ABQOL) 
from baseline to week 36 
• 
Change from baseline to week 36 in percent body surface area 
(BSA) of BP involvement 
• 
Change in BP180 and BP230 autoantibody (Immunoglobulin G 
[IgG]) titers from baseline to week 36 
• 
Proportion of patients with sustained remission at week 52 
• 
Total cumulative dose of OCS from baseline to week 52 
• 
Duration of complete remission while not requiring OCS (up to 
week 52) 
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• 
Proportion of patients who do not achieve control of disease 
activity, who relapse after achieving control of disease activity, or 
do not achieve complete remission (up to week 52) 
• 
Percent change in weekly average of daily peak pruritus NRS 
from baseline to week 52 
• 
Proportion of patients with improvement (reduction) of weekly 
average of daily peak pruritus NRS ≥4 from baseline to week 52 
• 
Percent change in BPDAI activity score from baseline to week 52 
• 
Proportion of patients who achieve a reduction in BPDAI activity 
score of at least 50%, 75%, and 90% from baseline to week 52 
• 
Change in ABQOL from baseline to week 52 
• 
Change from baseline to week 52 in percent BSA of BP 
involvement 
• 
Change in BP180 and BP230 autoantibody (IgG) titers from 
baseline to week 52 
• 
Proportion of patients in complete remission and off OCS at 
week 16 
• 
Percent change in BPDAI activity score from baseline to week 16 
• 
Proportion of patients who achieve a reduction in BPDAI activity 
score of at least 50%, 75%, and 90% from baseline to week 16 
• 
Percent change in weekly average of daily peak pruritus NRS 
from baseline to week 16 
• 
Proportion of patients with improvement (reduction) of weekly 
average of daily peak pruritus NRS ≥4 from baseline to week 16 
Secondary endpoints for safety: 
• 
Incidence of treatment-emergent adverse events (TEAEs) from 
baseline through end of treatment (up to week 52) 
• 
Incidence of treatment-emergent serious adverse events (SAEs) 
from baseline through the end of treatment (up to week 52) 
• 
Incidence of adverse events of special interest (AESIs) from 
baseline through the end of treatment (up to week 52) 
• 
Incidence of TEAEs from baseline through end of study (up to 
week 64) 
• 
Incidence of treatment-emergent SAEs from baseline through the 
end of study (up to week 64) 
• 
Incidence of AESIs from baseline through the end of study (up to 
week 64) 
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Secondary endpoints for clinical pharmacology and immunogenicity: 
• 
Concentrations of functional dupilumab in serum at each 
scheduled sampling timepoint from baseline to end of study (up to 
week 64) 
• 
Incidence of treatment-emergent anti-drug antibody (ADA) 
responses and titer over time (up to week 64) 
Note: The safety, clinical pharmacology and immunogenicity endpoints 
will not be included in the testing hierarchy. 
Procedures and Assessments 
Efficacy will be assessed during the study at specified clinic visits using 
patient-reported assessments (including Pruritus, Pain, and Sleep Quality 
NRS [daily], 
, 
, BPDAI Pruritus, 
, ABQOL, 
BPDAI activity score, BSA, blister and urticaria/eczematous plaque count, 
and BP clinical assessment [includes disease relapses]). Photography will 
also be done at select sites. Safety will be assessed by vital signs, physical 
examinations, 12-lead electrocardiograms (ECG), and height and weight 
measurements. Patients will report all adverse events experienced from the 
time of signed informed consent until their last study visit.   
Statistical Plan 
The sample size calculation of the study is based on a comparison between 
dupilumab 
 q2w versus placebo with regard to the primary endpoint. 
 
 
 
 
 
   
The full analysis set (FAS) is defined as all randomized patients analyzed 
according to the treatment group allocated by randomization regardless of 
whether the treatment kit is used or not.  
All efficacy endpoints will be evaluated on the FAS, which will be 
considered to be the primary 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. 
For the time-to-event data, Kaplan-Meier curves and estimates, and median 
time along with 95% confidence interval (CI), will be provided. 
Unless otherwise specified, the baseline value is defined as the latest 
available valid value before the first dose of study drug. If any randomized 
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patients are not treated, the baseline will be the last value on or prior to the 
randomization. 
All statistical tests will be performed 2-sided with a type I error rate of 5% 
unless otherwise stated. 
Primary Efficacy Analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Secondary Efficacy Analysis: 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
The safety analysis will be based on the reported AEs, clinical laboratory 
evaluations, physical examination, vital signs, and 12-lead ECG. 
 
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1. 
INTRODUCTION 
Bullous pemphigoid (BP) is a rare, autoimmune subepidermal blistering disease with a clinical 
course that may last from months to years. The disease characteristically presents in the elderly 
(mean onset age of 80) with a prodromal, non-bullous phase which may progress over weeks to 
years to a generalized, pruritic bullous eruption. In the bullous phase, BP is characterized by large, 
tense, serous, or hemorrhagic bullae arising on erythematous, urticarial, or eczematous skin. 
Because of the intractable pruritus and the presence of bullous, eroded or impetiginized lesions, 
the disease often has a profound, negative impact on the quality of life (Kouris, 2016). The 
estimated mortality rate during the first year in the bullous phase of disease varies between 
10% and 40%, depending on the series (Bystryn, 2005) (Joly, 2005).  
Clinical findings and histological features suggest that a type 2 or T-helper type 2 (Th2) 
cell-mediated immune response plays a central role in the pathogenesis of BP. In support of the 
type 2-mediated response, elevated blood eosinophils, increased total serum 
 
 concentrations, and elevated serum and blister-fluid levels of different soluble, inflammatory 
Th2 cell-response mediators have been described in large cohorts of patients with BP 
(Cozzani, 2018).   
Currently, there are no approved pharmacologic treatments for BP in the United States. Systemic 
corticosteroids are approved for BP in some countries in the European Union. In Japan, human 
immunoglobulin is approved for the treatment of BP inadequately controlled by corticosteroids. 
While high doses of oral corticosteroids (OCS) (eg, doses of prednisone 
) 
have been considered the mainstay of treatment for many years, it has been clearly demonstrated 
that the prolonged use of high OCS doses are deleterious and directly responsible for a high rate 
of treatment side effects and contribute to the high mortality rate associated with this disease 
(Joly, 2002) (Joly, 2005) (Roujeau, 1998). Due to the toxicity of OCS in this elderly population, it 
is recommended that the cumulative dose of OCS be limited, and the high doses of OCS tapered 
expeditiously (eg, initial reduction of the OCS dose by one-third steps every 2 weeks) to the 
minimal effective dose of OCS that can control the disease (Venning, 2012). Moreover, to 
compensate for the high disease relapse rate (up to 80%) which occurs during OCS tapering, 
OCS-sparing immunosuppressive agents (eg, mycophenolate mofetil, methotrexate, rituximab) are 
frequently added (Joly, 2002) (Simon, 2019) (Venning, 2012) (Lamberts, 2018). However, these 
treatments have additional undesirable side effects, such as increased risk of infections and others 
(eg, myelosuppression and gastrointestinal toxicity for mycophenolate mofetil, myelosuppression 
and hepatotoxicity for methotrexate, and potentially fatal infusion-related reactions and severe 
mucocutaneous reactions for rituximab) (Joly, 2002) (Simon, 2019) (Venning, 2012). 
Highly potent topical corticosteroids (eg, clobetasol propionate 0.05% cream) have been 
demonstrated to be effective for BP and may be safer than high doses of OCS (Joly, 2009) 
(Joly, 2002). Despite their efficacy, highly potent topical corticosteroids can result in cutaneous 
atrophy, striae, and folliculitis. Long-term application of highly potent topical corticosteroids is 
also not recommended for sensitive skin areas (eg, face, groin, axillae) or for application over a 
large body surface area, which may result in substantial systemic absorption with a resultant side 
effect profile similar to that of systemic corticosteroids. Therefore, there exists a significant unmet 
medical need for an effective treatment that has a favorable safety profile for long-term use for the 
treatment of BP. 
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Dupilumab is a targeted immunomodulatory agent selectively inhibiting the type 2 inflammatory 
pathway, and therefore may potentially provide therapeutic benefit as an OCS-sparing agent in 
patients with BP. Dupilumab may also avoid the significant side effects typically associated with 
the use of broad immunosuppressants and may even be more preferable in many patients than the 
prolonged use of highly potent topical corticosteroids. Blocking interleukin 4 (IL-4) receptor alpha 
(IL-4Rα) with dupilumab inhibits IL-4 and interleukin 13 (IL-13) type-2 cellular and cytokine-
induced responses, including release of pro-inflammatory cytokines, chemokines, 
, and 
infiltration by mast cells and eosinophils responsible for tissue damage. In clinical studies, a 
significant decrease in IgE, eotaxin-3, and 
 in 
circulation and/or tissue RNA expression has been demonstrated after dupilumab treatment across 
several clinical indications (atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis 
[CRSwNP], and eosinophilic esophagitis [EoE]).   
Bullous pemphigoid shares pathophysiological pathways with these type 2 inflammatory diseases 
mediated by key type 2 cytokines, IL-4 and IL-13; therefore, dupilumab has the potential to be an 
effective treatment with a favorable safety profile for long-term use for BP. The preliminary 
clinical evidence to support the hypothesis for efficacy of dupilumab in the treatment of BP is 
derived from a case series of clinically significant improvement in the majority of patients (Abdat, 
2020). In a retrospective case series study conducted at 5 centers, 13 patients with a confirmed 
diagnosis of BP were treated with dupilumab 300 mg (after an initial loading dose of 600 mg) SC. 
In this study, 92.3% (12/13) patients achieved either disease clearance or a clinical improvement 
after treatment with dupilumab. Additionally, 76.9% (10/13) patients experienced resolution of 
their bullae and residual pruritis. Dupilumab was well tolerated with no dupilumab-related adverse 
events. This case series provides further clinical support for dupilumab as a possible efficacious 
and well tolerated treatment for BP (Abdat, 2020). 
The current multicenter, randomized, double-blind, placebo-controlled, parallel-group study is 
designed to investigate the efficacy and safety of dupilumab in patients with BP. It is anticipated 
that patients with BP treated with dupilumab may achieve sustained clinical remission while being 
able to taper expeditiously off their background OCS, thus potentially curtailing the side effects of 
chronic OCS use in this vulnerable elderly population.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to demonstrate that dupilumab is superior to placebo in 
achieving sustained remission off OCS in patients with BP. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the OCS-sparing effects of dupilumab in patients with BP 
• To evaluate the effect of dupilumab on itch in patients with BP 
• To evaluate the effects of dupilumab on health-related quality of life measures in 
patients with BP 
• To evaluate the effect of dupilumab in circulating BP180 and BP230 autoantibody titers 
• To assess the safety and tolerability of dupilumab administered to patients with BP 
• To characterize the trough concentrations of functional dupilumab over time following 
administration of dupilumab in patients with BP 
• To assess the immunogenicity of dupilumab in patients with BP over time 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• 
• 
• 
• 
• 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Dupilumab is efficacious in the treatment of patients with moderate-to-severe BP. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study is designed to investigate the efficacy and safety of dupilumab in patients with 
moderate-to-severe BP. A double-blinded, randomized, placebo-controlled design is chosen to 
minimize bias in data collection and interpretation. The presence of a placebo arm is appropriate 
for the objectives of this study since it will provide the most robust assessment of the efficacy and 
safety of dupilumab. There will be a 52-week, double-blind treatment period and a 12-week 
follow-up period. 
All patients will start on day 1/baseline dupilumab (or matched placebo) and receive a standard 
regimen of OCS (prednisone or prednisolone) to obtain control of disease activity (Joly 2002) 
(Murrell, 2012) (Venning, 2012). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 (Joly, 2002). 
Per the “Definitions and outcome measures for bullous pemphigoid: recommendations by an 
international panel of experts,” control of disease activity occurs when new lesions (eg, blisters, 
urticarial plaques) cease to form and existing lesions begin to heal (eg, show signs of 
epithelialization) (Murrell, 2012). Patients will therefore be maintained on their assigned treatment 
level of OCS until they have achieved control of disease activity. Control of disease activity is 
expected to occur by 2 weeks after randomization with the aforementioned background doses of 
OCS, but some patients may take longer, usually no longer than 4 weeks (Joly, 2002) (Simon, 
2019). 
Although the majority (~95%) of moderate BP patients achieve control of disease activity on 
0.5 mg/kg/day of prednisone (or prednisolone), a few may require higher doses (Joly, 2002). For 
moderate BP patients who are not showing signs of disease control (eg, continued blister or 
urticarial plaque formation) 2 weeks after randomization (week 2), the dose of OCS may be 
increased to 
 of prednisone (or prednisolone). Doses higher than 
 
of prednisone have not been shown to be more effective in BP in achieving control of disease and 
have been associated with increased mortality and side effects (Kirtschig, 2010). Patients requiring 
doses greater than 
 of prednisone (or prednisolone) in achieving control of disease 
activity, 
, will be 
considered treatment failures. These patients should receive rescue treatment per investigator’s 
discretion and will be requested to complete the study visits and per-protocol assessments for the 
duration 
of 
the 
study. 
If 
patients 
are 
rescued 
with 
a 
systemic 
immunosuppressive/immunomodulating agent (including but not limited to omalizumab, 
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rituximab, mycophenolate-mofetil, azathioprine, and methotrexate), they will be discontinued 
from study drug. 
It is recommended that tapering of OCS should begin when there has been 2 weeks of sustained 
control of disease activity. This coincides with the “end of the consolidation phase” which is 
defined as the time at which there has been control of disease activity for a minimum of 2 weeks 
and when tapering of OCS should begin (Murrell, 2012). Oral corticosteroid tapering may 
therefore start at week 4 or up to week 6 depending on when initial control of disease activity was 
achieved (eg, if initial control of disease activity occurred at week 4, OCS tapering should begin 
at week 6).  
Patients will  undergo a protocol-defined OCS tapering regimen as long as they maintain control 
of disease activity. The OCS taper employed in this study uses a schedule typical for this disease 
which allows for patients to be off OCS by week 16 (or sooner), as described in Section 8.2. 
Following the period in which OCS are completely tapered off, there will be a remission period of 
at least 36 weeks where patients will be assessed for relapses off OCS. This study provides the 
opportunity to investigate long-term efficacy/effectiveness and safety over the 52-week treatment 
period. The duration of the 12-week follow-up period is based on the time expected for drug levels 
to reach zero (below the lower limit of quantification) in most patients after the last dose of 
dupilumab. 
3.2.2. 
Rationale for Dose Selection 
The dose regimen of dupilumab selected for this study is an initial (loading) dose of 
 
administered subcutaneously (SC), followed by 
 administered SC q2w. Dupilumab 
 q2w has proven to be effective and has shown to have a favorable safety profile in adult 
patients with moderate-to-severe atopic dermatitis (AD, another skin disease), moderate-to-severe 
asthma, and in CRSwNP. In addition, dupilumab 
 q2w was demonstrated to have a 
significant steroid-sparing effect while significantly reducing exacerbations and improving lung 
function in a population of severe corticosteroid-dependent asthmatic patients. Based on the case 
studies and the demonstrated efficacy of dupilumab at this dose in other type 2 inflammatory 
diseases, the selected dose is considered appropriate for investigation in patients with BP. 
Furthermore, the selected dosing regimen is 
 
 
. 
Furthermore, for AD, a loading dose was administered to more rapidly achieve effective drug 
concentrations, thereby allowing a rapid PD response as demonstrated by improvement in pruritus, 
a hallmark of AD. Similarly, as pruritus is a core symptom of BP, and to achieve effective drug 
concentrations more rapidly, a loading dose is selected for this study. 
3.3. 
Risk-Benefit 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any patients in this study until 
the impact of the COVID-19 pandemic is deemed manageable and no longer interferes with the 
conduct of trials at individual sites, and patients can safely participate in this study. Until then, the 
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sponsor plans to obtain approvals from health authorities/ethics committees to enable initiation of 
study sites for this study, as allowed by local laws and regulations. 
3.3.1. 
Risk-Benefit of Dupilumab for Patients with Bullous Pemphigoid  
Benefits 
The underlying role of type 2 inflammation in BP bears striking similarities to the role of type 2 
inflammation in AD, asthma, EoE, and CRSwNP, conditions in which dupilumab has been 
demonstrated to have significant efficacy, leading to approved indications for AD, asthma, and 
CRSwNP. Specifically, similar to BP, the skin lesions of AD are characterized by increased 
expression of proinflammatory type 2 cytokines, such as IL-4, 
 
, and by skin infiltration of Th2 cells. Bullous pemphigoid 
also bears similarities to EoE, which is characterized by eosinophil, mast cell, and Th2 cell 
infiltration and an increase in expression of type 2 cytokines and chemokines (eg, IL-4, IL-13, 
eotaxin-3). 
Current standard of care in BP includes the use of topical and systemic corticosteroids, and other 
immunosuppressant therapies; however, these are associated with significant risks, particularly in 
an elderly population, and a more targeted therapy with an improved benefit/risk profile would be 
highly beneficial. Chronic use of broad immunosuppressants (eg, OCS) contributes to the high 
morbidity and mortality in patients with BP. 
The goals of a new therapy for BP are to suppress new lesion and blister development, to encourage 
lesion healing, and to achieve sustained disease remission with no disease flares. There is 
preliminary clinical evidence for the efficacy of dupilumab in the treatment of BP derived from a 
case series in which clinically significant improvement in disease activity was observed in patients 
who would otherwise have been very unlikely to improve (see Section 1). Given the biologic 
rationale and preliminary clinical evidence, it is anticipated that patients with BP treated with 
dupilumab may achieve sustained clinical remission while being able to taper expeditiously off 
their background OCS, thus potentially curtailing the side effects of chronic OCS use in this 
vulnerable elderly population. 
Risks 
Dupilumab has an extensive safety database. As of 28 March 2020, 10191 subjects were enrolled 
into the development program for dupilumab and are included in the safety population: 382 as 
healthy volunteers, 4405 from AD studies, 3614 from asthma studies, 782 from CRSwNP studies, 
232 from EoE studies, 103 from the grass allergy study, 145 from peanut allergy studies, 511 from 
the chronic obstructive pulmonary disease study, 5 from prurigo nodularis studies, and 12 from 
the chronic spontaneous urticaria study. The number of subjects exposed to dupilumab in clinical 
studies was 8720 (356 in healthy volunteer studies, 4052 in AD studies, 3263 in asthma studies, 
470 in CRSwNP studies, 166 in EoE studies, 52 in the grass allergy study, 96 in peanut allergy 
studies, 256 in the chronic obstructive pulmonary disease study, 3 in prurigo nodularis studies, and 
6 in the chronic spontaneous urticaria study).  
The identified adverse drug reactions are injection site reactions, serum sickness-like 
reaction/serum 
sickness, 
anaphylactic 
reaction, 
conjunctivitis, 
conjunctivitis 
allergic, 
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conjunctivitis bacterial, blepharitis, dry eyes, eye pruritus, herpes simplex (primarily 
mucocutaneous in nature), and oral herpes. 
Overall, systemic hypersensitivity has been established as an important identified risk with 
dupilumab. As protein therapeutics, all monoclonal antibodies are potentially immunogenic. Rare, 
serious and systemic hypersensitivity reactions have been observed in the dupilumab program 
including serum sickness/serum sickness-like reaction in the adult AD clinical trials and 
anaphylaxis related to dupilumab in the adult asthma clinical trials. If a clinically significant 
systemic hypersensitivity event occurs, appropriate therapeutic intervention will be administered, 
and the patient will be discontinued from treatment.   
An important potential risk, eosinophilia associated with clinical symptoms, has been observed in 
the asthma clinical trials (a few cases of eosinophilic granulomatosis with polyangiitis and 
eosinophilic pneumonia) but not in AD clinical studies. 
Risk/Benefit Conclusion 
Long-term treatment with OCS and other immunosuppressives have a less favorable safety and 
tolerability profile than what has been observed with dupilumab. The safety data available to date, 
in conjunction with the risk monitoring and mitigation strategies in the study protocol, and the 
clinical benefit of dupilumab demonstrated in multiple type 2 indications (AD, asthma, CRSwNP) 
and case reports and series in BP so far, support a favorable benefit-risk profile for dupilumab.  
A risk-benefit statement with respect to the overall clinical development program is provided in 
the investigator brochure. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint is the proportion of patients achieving sustained remission at week 36, 
defined as:  
• Achievement of complete remission and off OCS no later than week 16 after 
randomization (Note: complete remission is defined as absence of new lesions and 
epithelialization of old lesions), and  
• Absence of disease relapse from the time the patient has completed the OCS taper (no 
later than week 16 after randomization) to week 36 (Note: relapse is defined as the 
appearance of 3 or more new lesions a month (blisters, eczematous lesions, or urticarial 
plaques) or at least 1 large [>10 cm diameter] eczematous lesion or urticarial plaque 
that does not heal within 1 week), and 
• Absence of need for rescue therapy during the 36-week double-blind treatment period 
(Note: rescue therapy includes increase of OCS dose during the taper, re-initiation of 
OCS after completion of the OCS taper, or initiation of any BP-directed therapy). 
4.1.2. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• Total cumulative dose of OCS from baseline to week 36 
• Percent change in weekly average of daily peak pruritus numerical rating score (NRS) 
from baseline to week 36 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
pruritus NRS ≥4 from baseline to week 36 
• Percent change in BPDAI activity score from baseline to week 36 
• Time to first use of rescue medication (up to week 36) 
4.1.3. 
Other Secondary Endpoints 
Other secondary endpoints for efficacy: 
• Duration of complete remission while not requiring OCS (up to week 36) 
• Proportion of patients who do not achieve control of disease activity, who relapse 
after achieving control of disease activity, or do not achieve complete remission (up 
to week 36) (Note: control of disease activity is defined when new lesions cease to 
form and existing lesions begin to heal; see Section 9.2.2.12 for complete definitions) 
• Proportion of patients who achieve a reduction in BPDAI activity score of at least 
50%, 75%, and 90% from baseline to week 36 
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• Change in autoimmune bullous disease quality of life (ABQOL) from baseline to 
week 36 
• Change from baseline to week 36 in percent body surface area (BSA) of BP 
involvement 
• Change in BP180 and BP230 autoantibody (Immunoglobulin G [IgG]) titers from 
baseline to week 36 
• Proportion of patients with sustained remission at week 52 
• Total cumulative dose of OCS from baseline to week 52 
• Duration of complete remission while not requiring OCS (up to week 52) 
• Proportion of patients who do not achieve control of disease activity, who relapse 
after achieving control of disease activity, or do not achieve complete remission (up 
to week 52) 
• Percent change in weekly average of daily peak pruritus NRS from baseline to 
week 52 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
pruritus NRS ≥4 from baseline to week 52 
• Percent change in BPDAI activity score from baseline to week 52 
• Proportion of patients who achieve a reduction in BPDAI activity score of at least 
50%, 75%, and 90% from baseline to week 52 
• Change in ABQOL from baseline to week 52 
• Change from baseline to week 52 in percent BSA of BP involvement 
• Change in BP180 and BP230 autoantibody (IgG) titers from baseline to week 52 
• Proportion of patients in complete remission and off OCS at week 16 
• Percent change in BPDAI activity score from baseline to week 16 
• Proportion of patients who achieve a reduction in BPDAI activity score of at least 
50%, 75%, and 90% from baseline to week 16 
• Percent change in weekly average of daily peak pruritus NRS from baseline to week 
16 
• Proportion of patients with improvement (reduction) of weekly average of daily peak 
pruritus NRS ≥4 from baseline to week 16 
Other secondary endpoints for safety: 
• Incidence of treatment-emergent adverse events (TEAEs) from baseline through end 
of treatment (up to week 52) 
• Incidence of treatment-emergent serious adverse events (SAEs) from baseline 
through the end of treatment (up to week 52) 
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• Incidence of adverse events of special interest (AESIs) from baseline through the end 
of treatment (up to week 52) 
• Incidence of TEAEs from baseline through end of study (up to week 64) 
• Incidence of treatment-emergent SAEs from baseline through the end of study (up to 
week 64) 
• Incidence of AESIs from baseline through the end of study (up to week 64) 
Other secondary endpoints for clinical pharmacology and immunogenicity: 
• Concentrations of functional dupilumab in serum at each scheduled sampling time 
point from baseline to end of study (up to week 64) 
• Incidence of treatment-emergent anti-drug antibody (ADA) responses and titer over 
time (up to week 64) 
Note: The safety, clinical pharmacology and immunogenicity endpoints will not be included in the 
testing hierarchy. 
4.1.4. 
Exploratory Endpoints 
The exploratory endpoints are: 
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical history, and medication history for each patient.   
5.2. 
Efficacy Variables 
The efficacy variables include measurements or scores for individual patients for the following: 
BP clinical assessment (includes disease relapses), total cumulative dose of OCS, peak pruritus 
NRS, skin pain NRS, sleep quality NRS, BPDAI activity score, BPDAI pruritus, 
, BSA, 
blister and urticaria/eczematous plaque count, ABQOL, 
, 
 and BP180 and BP230 
autoantibody titers.   
5.3. 
Safety Variables 
The safety variables include recordings, measurements or laboratory test results for individual 
patients for the following: Adverse events, concentrations of functional dupilumab in serum, vital 
signs, physical examinations, electrocardiogram (ECG), hematology, blood chemistry, and 
urinalysis. 
5.4. 
Pharmacokinetic Variables 
The pharmacokinetic variable is the concentration of functional dupilumab at each time point. 
Samples in this study will be collected using a sparse sampling schedule. The sampling time points 
are specified in Table 1.   
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) status, and 
time point/visit. Samples in this study will be collected at the clinic visits specified in Table 1.   
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Pharmacodynamic and biomarker variables include biopsy and laboratory test results for 
individual patients for the following:  
 
 
  
 
 
 
 
 
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Serum anti-BP180 and anti-BP230 autoantibodies of the IgG subclass concentration: A 
serologic characteristic of BP is the presence of circulating autoantibodies in patient serum, which 
are mostly against BP180 (collagen XVII) and BP230 (hemidesmosomal proteins). NC16A, a 
non-collagenous stretch of the BP180 ectodomain, is the primary target of the pathogenic IgG 
antibodies. Autoantibodies from BP patients react with BP180, which leads to the degradation of 
the basement membrane, and this has been regarded as a central event in BP pathogenesis. IgG 
autoantibodies against BP180 are the ones first to be detected, followed by IgG autoantibodies 
against BP230. Concentrations of anti-BP180 and anti-BP230 are elevated during active disease 
and decrease with resolution of BP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a global, multicenter, randomized, double-blind, placebo-controlled, parallel group study 
to assess the efficacy, safety, tolerability, pharmacokinetics, and immunogenicity of dupilumab in 
patients with BP.   
The study consists of a 35-day screening period, a 52-week double-blind treatment period, and a 
12-week follow-up period. After patients provide informed consent, they will be assessed for study 
eligibility at the screening visit. 
Study participants are required to have characteristic clinical features of BP present at the screening 
visit (eg, urticarial, eczematous or erythematous plaques, bullae, pruritus). Patients are also 
required to have a minimum Karnofsky Performance Status Scale score of 50% at the screening 
visit. Patients with severe concomitant illness(es) at the screening visit that, in the investigator’s 
judgment, would adversely affect the patient’s participation in the study will be excluded.  
Study participants are required to have a confirmed diagnosis of BP based on histopathology, 
immunopathology, and serology at the baseline visit as described in Section 7.2.1. 
Patients must also have moderate-to-severe BP at the screening and baseline visits, as determined 
by a BPDAI activity score ≥24. Patients are also required to have a peak pruritus NRS for 
maximum itch intensity ≥4 at the baseline visit.   
During the screening period, treatments for BP will be washed out, as applicable, according to 
eligibility requirements (see Section 7.2.2). 
At the baseline visit, eligible patients will be randomized to receive dupilumab or matching 
placebo. Randomization will be stratified by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. In addition, 
all patients will receive a standard regimen of OCS (prednisone or prednisolone) beginning at the 
baseline visit to obtain control of disease activity (Joly, 2002) (Murrell, 2012) (Venning, 2012). 
 
 
 (Joly, 2002). 
Per the publication of “Definitions and Outcome Measures for Bullous Pemphigoid: 
Recommendations by an International Panel of Experts (Murrell, 2012),” control of disease 
activity occurs when new lesions (eg, blisters, urticarial plaques) cease to form and existing lesions 
begin to heal (eg, show signs of epithelialization) (Murrell, 2012). Patients will therefore be 
maintained on their assigned treatment level of OCS until they have achieved control of disease 
activity. Control of disease activity is expected to occur by 2 weeks after randomization with the 
aforementioned doses of OCS, but some patients may take longer, usually no longer than 4 weeks 
(Joly, 2002) (Simon, 2019).   
Although the majority (~95%) of moderate BP patients achieve control of disease activity on 
 of prednisone (or prednisolone), a few may require higher doses (Joly, 2002). For 
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moderate BP patients who are not showing signs of disease control (eg, continued blister or 
urticarial plaque formation) 2 weeks after randomization (week 2), the dose of OCS may be 
increased 
 of prednisone (or prednisolone). Doses higher than 
 
of prednisone have not been shown to be more effective in BP and have been associated with 
increased mortality and side effects (Kirtschig, 2010). Patients requiring doses greater than 
 
 will be considered treatment failures. These patients should receive rescue 
treatment per investigator’s discretion and will be requested to complete the study visits and 
per-protocol assessments for the duration of the study. 
After achieving sustained control of disease activity, patients will follow a protocol-defined OCS 
tapering regimen as long as they maintain control of disease activity. Tapering of OCS starts after 
2 weeks of sustained control of disease activity. This signifies the “end of the consolidation phase” 
which is defined as the time at which there has been sustained control of disease activity for a 
minimum of 2 weeks and when tapering of OCS should begin (Murrell, 2012). Oral corticosteroid 
tapering may therefore start at week 4 or up to week 6 depending on when initial control of disease 
activity is achieved (eg, if initial control of disease activity occurs at week 4, OCS tapering should 
begin at week 6).  
The OCS taper employed in this study uses a schedule typical for this disease (as described in 
Section 8.2) which allows for patients to be off OCS by week 16 (or sooner). 
 
 
 
 
 
 
 
  
Following this OCS taper period, there will be a remission period of at least 36 weeks where 
patients will be observed for relapses off OCS.  A relapse is defined as the appearance of 3 or more 
new lesions a month (blisters, eczematous lesions, or urticarial plaques) or at least 1 large (>10 cm 
diameter) eczematous lesion or urticarial plaque that does not heal within 1 week (Murrell, 2012).  
Patients who experience a relapse after completely tapering off OCS may be rescued, including 
with re-initiation of OCS. 
Unless permanently discontinued from the study, all patients will be requested to complete the 
scheduled study visits and assessments whether or not they complete study drug treatment, and 
whether or not they receive rescue treatment.   
During the 52-week double-blind treatment period, patients will have study visits every 2 weeks 
until week 16 (some specified study visits may be conducted as telemedicine visits [see Table 1]). 
After week 4, patients will have the option to self-administer study drug (or have a 
caregiver/healthcare provider [eg, visiting nurse] administer study drug) during weeks in which no 
clinic visit is scheduled. Patients who do not want to self-inject may have the clinic staff administer 
all the study drug injections in the clinic. After week 16, patients will have in-clinic or phone visits 
as specified during the remainder of the 52-week treatment period. Study drug will be administered 
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SC q2w through week 50. Following the 52-week double-blind treatment period, patients will have 
phone visits as specified and then return for an in-person follow-up visit at week 64 (end of study). 
Efficacy, safety, and laboratory assessments will be performed as specified in Table 1. Samples to 
measure dupilumab concentrations, assess immunogenicity, and for research purposes will be 
collected at specified time points throughout the study, as noted in Table 1. 
An overview of the study is provided in Figure 1.  
 
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Figure 1: 
Study Flow Diagram 
 
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6.1.1. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the 
investigator).   
6.2. 
Planned Interim Analysis 
No interim analysis is planned. An unblinded primary analysis may be performed once all patients 
in the study have completed the 36-week treatment period or discontinued from the study. If 
performed, the primary analysis will be considered the final analysis for the primary and secondary 
efficacy endpoints for week 36; safety and PK analyses up to week 36 will also be performed. No 
changes in the conduct of the study will be made and no need for alpha adjustment based on the 
primary analysis.   
A description of the statistical methods to be employed is in Section 11.4, and blinding 
implications are discussed in Section 8.7. 
6.3. 
Study Committees 
6.3.1. 
Independent Data Monitoring Committee 
Although the safety of dupilumab has been well established in a large number of clinical trials 
across multiple indications, this study represents the first study primarily conducted in elderly 
patients with a severe, potentially life-threatening disease. Therefore, an independent data 
monitoring committee (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 that will be blinded by treatment group; if requested, the DMC may have access to the 
treatment allocation code or any other requested data for the purposes of 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. 
All activities and responsibilities of the DMC are described in the DMC charter. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 98 patients (49 patients per arm) will be enrolled at approximately 40 global sites. 
7.2. 
Study Population 
The proposed study population is patients with BP. All patients must have documented clinical 
features of BP at the screening visit and histological and serological confirmation of BP by the 
baseline visit. Bullous pemphigoid patients must also have moderate-to-severe disease at the 
screening and baseline visits defined by a BPDAI activity score ≥24; and a peak pruritus NRS for 
maximum itch intensity ≥4 at baseline.  Patients are also required to have a minimum Karnofsky 
Performance Status Scale score of 50% at the screening visit. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Patients must have characteristic clinical features of BP (eg, urticarial or eczematous or 
erythematous plaques, bullae, pruritus) at the screening and baseline visits. 
2. Study participants are required to have a confirmed diagnosis of BP based on 
histopathology, immunopathology, and serology at the baseline visit.  Required for 
inclusion:  
a. Compatible histopathologic findings on a skin biopsy specimen supporting a diagnosis 
of BP (eg, a subepidermal blister with eosinophils within the cleft, a mixed cellular 
inflammatory infiltrate that includes eosinophils) AND 
b. Characteristic direct immunofluorescence findings on a skin biopsy specimen 
demonstrating linear IgG and/or C3 at the basement membrane zone AND 
c. At least 1 of the following serologic assessments (utilizing a peripheral blood 
specimen): 
i. 
Positive indirect immunofluorescence demonstrating IgG antibodies localizing to 
the roof (epidermal side) of split-skin substrate  
ii. 
Increased IgG serum antibody levels by immunoassay to BP antigens, BPAG1 
(230-kd, also known as BP230) and/or BPAG2 (180-kd, also known as BP180) 
NOTE: Histopathology, immunopathology, and serologic testing performed at a local 
laboratory with results available within 6 months of the screening visit that confirm the 
diagnosis of BP are acceptable to fulfill the above criteria for diagnostic confirmation of 
BP.  
3. BPDAI activity score ≥24 at baseline and screening visits. 
4. 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 
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ranges from 0 to 10) during the 7 days immediately preceding randomization. A minimum 
of 3 daily scores out of the 7 days is required to calculate the baseline average score.   
5. Male or female, age 18 to 90 at the screening visit (age 20 to 90 for sites in Japan) 
6. Karnofsky performance status score ≥50% at the screening visit. 
7. Willing and able to comply with clinic visits and study-related procedures. 
8. Willing and able to understand and complete study-related questionnaires. 
9. Willing and able to provide voluntary signed informed consent. 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Forms of pemphigoid other than classic BP (eg, Brunsting-Perry cicatricial pemphigoid, 
anti-p200 pemphigoid, epidermolysis bullosa acquisita, or BP with concomitant 
pemphigus vulgaris).  
2. Patients who are receiving treatments known to cause or exacerbate BP (eg, angiotensin 
converting enzyme inhibitors, penicillamine, furosemide, phenacetin, dipeptidyl 
peptidase 4 inhibitor) who have not been on a stable dose of these medications for at least 
4 weeks prior to the screening visit. 
3. Have ever received treatment with an IL-4 or IL-13 antagonist such as dupilumab, 
tralokinumab, or lebrikizumab.   
4. Treatment with systemic corticosteroids within 7 days before the baseline visit.  
5. Treatment with topical corticosteroids of medium potency or higher, topical calcineurin 
inhibitor, or topical crisaborole within 7 days before the baseline visit. 
6. Initiation, discontinuation, or change in the dosage regimen of systemic antihistamines 
within 7 days before the baseline visit. Patients on a stable dose of systemic antihistamines 
for at least 7 days prior to the baseline visit may be included in the study; however, the 
dose of these medications should remain unchanged for the duration of the study. 
7. Treatment with an antibiotic (such as doxycycline or dapsone) directed at the treatment of 
BP within 7 days before the baseline visit. 
8. Treatment with nicotinamide directed at the treatment of BP within 7 days prior to the 
baseline visit (note: use of multivitamins containing nicotinamide is allowed). 
9. Treatment 
with 
non-steroidal 
immunosuppressive/immunomodulating 
drug(s) 
(eg, mycophenolate mofetil, azathioprine, or methotrexate) within 4 weeks before the 
baseline visit. 
10. Treatment with BP-directed biologics as follows: 
a. Any cell-depleting agents including but not limited to rituximab: within 12 months 
before the baseline visit, or until lymphocyte and CD 19+ lymphocyte count returns to 
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b. Other biologics (such as IL-5 inhibitors benralizumab or mepolizumab): within 5 half-
lives (if known) or 16 weeks prior to the baseline visit, whichever is longer 
c.  Intravenous immunoglobulin within 16 weeks prior to the baseline visit. 
11. Treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit. 
12. Planned or anticipated use of any prohibited medications or procedures during study 
treatment. 
13. Any active infection requiring systemic treatment; patients with such infection must have 
their infection resolved at least 1 week before baseline to be eligible to enroll in the study. 
14. 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. 
15. 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’s judgment. 
16. History of human immunodeficiency virus (HIV) infection or positive HIV serology at 
screening. 
17. With a current diagnosis of hepatitis B viral infection at the time of screening as evidenced 
by 
a. Positive hepatitis B surface antigen (HBsAg) or  
b. Positive total hepatitis B core antibody (HBcAb) confirmed by positive hepatitis B 
virus (HBV) DNA. 
NOTE: Patients who have gained immunity for hepatitis B virus infection after vaccination 
(patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and HBcAb 
negative) or after natural infection (patients who are HBsAg negative, hepatitis B surface antibody 
[HBsAb] positive, and HBcAb positive) are eligible for the study. These patients will be allowed 
to enroll into the study, but will be followed using routine clinical and liver function tests. 
In case of results showing HBsAg negative, HBsAb negative, and HBcAb positive, an HBV DNA 
testing will be performed prior to randomization to rule out a false positivity and to confirm current 
infection. 
18. With a current diagnosis of hepatitis C viral infection at the time of screening as evidence 
by 
a. Positive hepatitis C virus (HCV) Ab AND 
b. Positive HCV RNA. 
19. On current treatment for hepatic disease including, but not limited to, acute or chronic 
hepatitis, cirrhosis, or hepatic failure, or has evidence of liver disease as indicated by 
persistent (confirmed by repeated tests ≥2 weeks apart) elevated transaminases (alanine 
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) more than 3 times the 
upper limit of normal (ULN) during the screening period. 
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20. Presence of any 1 or more of the following abnormalities in laboratory test results at 
screening: 
a. Platelet count ≤100×103/μL 
b. Neutrophil count ≤1.5×103/μL. 
21. Presence of skin comorbidities that may interfere with study assessments.  
22. History of malignancy within 5 years before the baseline visit, except completely treated 
in situ carcinoma of the cervix, or completely treated and resolved non-metastatic 
squamous or basal cell carcinoma of the skin. 
23. Known systemic hypersensitivity to dupilumab or the excipients of the drug product. 
24. Patients having a contraindication to systemic corticosteroids (eg, severe osteoporosis, 
adrenal insufficiency, Cushing’s disease) that, in the investigator’s judgment, would 
adversely affect the patient’s participation in the study. 
25. 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 (HbA1c ≥9%), patients with 
cardiovascular conditions (eg, stage III or IV cardiac failure according to the New York 
Heart Association classification), severe renal conditions (eg, patients on dialysis), 
debilitating neurological conditions (eg, demyelinating diseases), active major 
autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), 
other severe endocrinological, gastrointestinal, hepatobiliary, metabolic, pulmonary, or 
lymphatic diseases. The specific justification for patients excluded under this criterion will 
be noted in study documents. 
26. 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 trial, 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. 
27. History of alcohol or drug abuse within 2 years before the screening visit. 
28. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities. 
29. Pregnant or breastfeeding women or planning to become pregnant or breastfeed during the 
patient’s participation in this study. 
30. 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 12 weeks after the last dose. Highly effective contraceptive measures 
include:  
a. stable use of combined (estrogen- and progestogen-containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
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injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
b. intrauterine device; intrauterine hormone-releasing system 
c. bilateral tubal ligation 
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure). 
e. and/or sexual abstinence †, ‡. 
*Women of childbearing potential are defined as women who are fertile following 
menarche until becoming postmenopausal, unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence 
of a postmenopausal state. The above definitions are according to Clinical Trial 
Facilitation Group guidance. 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 
drugs. 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 amenorrhea method are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together. 
31. Patient is a member of the investigational team or his/her immediate family. 
7.3. 
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 has 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 the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.4.2. 
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7.4. 
Replacement of Patients 
Patients prematurely discontinued from study/study drug will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
Dupilumab: (loading) dose of 
 administered SC, followed by 
 administered SC q2w. 
Dupilumab-matching placebo (containing same formulation as dupilumab without active 
substance): loading dose administered SC, followed by SC q2w dosing. 
Instructions on dose preparation are provided in the pharmacy manual. 
8.2. 
Background Treatment 
All patients will receive a standard regimen of OCS (prednisone or prednisolone) on day 1/baseline 
visit to obtain control of disease (Joly, 2002) (Murrell, 2012) (Venning, 2012). Specifically, 
 
 
 (Joly, 2002).  
Per the “Definitions and outcome measures for bullous pemphigoid: Recommendations by an 
international panel of experts” (Murrell, 2012), control of disease activity occurs when new lesions 
(eg, blisters, urticarial plaques) cease to form and existing lesions begin to heal (eg, show signs of 
epithelialization). Patients will therefore be maintained on their assigned treatment level of OCS 
until they have achieved control of disease activity. Control of disease activity is expected to occur 
by 2 weeks after randomization with the aforementioned doses of OCS, but some patients may 
take longer, usually no longer than 4 weeks (Joly, 2002) (Simon, 2019).   
Although the majority (~95%) of moderate BP patients achieve control of disease activity on 
0.5 mg/kg/day of prednisone (or prednisolone), a few may require higher doses (Joly, 2002). For 
moderate BP patients who are not showing signs of disease control (eg, continued blister or 
urticarial plaque formation) 2 weeks after randomization (week 2), the dose of OCS may be 
increased to 
 of prednisone (or prednisolone).  
It is recommended that tapering of OCS should begin when there has been 2 weeks of sustained 
control of disease activity. This coincides with the “end of the consolidation phase” which is 
defined as the time at which there has been control of disease activity for a minimum of 2 weeks 
and when tapering of OCS should begin (Murrell, 2012). Oral corticosteroid tapering may 
therefore start at week 4 or up to week 6 depending on when initial control of disease activity is 
achieved (eg, if initial control of disease activity occurs at week 4, OCS tapering should begin at 
week 6).  
 
 
  
 
• 
 
• 
 
• 
  
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• 
 
 
 
• 
 
• 
 
• 
 
• 
  
• 
 
 
 
8.3. 
Rescue Treatments 
Patients requiring doses greater than 
 of prednisone (or prednisolone) and those 
who do not achieve control of disease activity by week 4 will be considered treatment failures. 
These patients should receive rescue treatment per investigator’s discretion. 
During the OCS taper period, 
 
 will be 
considered treatment failures, but will be allowed to increase the prednisone (or prednisolone) dose 
to the dose level where there was control of disease activity before resuming the predefined OCS 
tapering regimen (as described in Section 8.2). If a patient fails to 
 
, they should be considered for rescue.  
Following the OCS taper period, there will be a remission period of at least 36 weeks where 
patients will be observed for relapses off OCS.  
A relapse is defined as the appearance of 3 or more new lesions a month (blisters, eczematous 
lesions, or urticarial plaques) or at least 1 large (>10 cm diameter) eczematous lesion or urticarial 
plaque that does not heal within 1 week (Murrell, 2012).  
Patients who experience a relapse after completely tapering off OCS may also be rescued, 
including with re-initiation of OCS.  Rescue treatment may include treatment with high-potency 
topical corticosteroids, OCS (eg, increases of OCS doses during the taper regimen, or re-initiation 
of OCS after tapering completely off OCS), and systemic non-steroidal immunosuppressive drugs 
or immunomodulating biologics.  
If topical or oral corticosteroids are used as rescue treatments, patients may continue study 
treatment.  If a patient receives rescue treatment with a systemic non-steroidal immunosuppressive 
drug or immunomodulating biologic (including, but not limited to, omalizumab, rituximab, 
mycophenolate-mofetil, azathioprine, methotrexate), study treatment will be permanently 
discontinued immediately. 
Unless permanently discontinued from the study, all patients will be requested to complete the 
scheduled study visits and assessments, whether or not they complete study drug treatment and 
whether or not they receive rescue treatment.   
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8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
Dose modification of study drug for an individual patient is not allowed. 
8.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study. Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits 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 9.1.2. 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction (eg, Hy’s law is met (Guidance for Industry Drug 
Induced Liver Injury: Premarketing Clinical Evaluation FDA, 2009) 
• Patient withdraws consent 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with an immunomodulating biologic (eg, omalizumab, intravenous 
immunoglobulin [IVIG]) 
• Treatment with a systemic non-steroidal immunosuppressive drug (including but not 
limited to mycophenolate-mofetil, azathioprine, methotrexate)  
• Diagnosis of a malignancy during study other than non-melanoma skin cancer or 
carcinoma in situ of the cervix that can be treated with curative local surgery 
• Any infection that is opportunistic, such as tuberculosis and other infections whose 
nature or course may suggest an immunocompromised status 
• Severe laboratory abnormalities assessed as related to study drug*: 
− Neutrophil count ≤0.5 × 103/µL 
− Platelet count ≤50 × 103/µL 
− ALT and/or AST values >3x × ULN with total bilirubin >2x × ULN, excluding 
confirmed Gilbert’s Syndrome 
− Confirmed AST and/or ALT >5x × ULN (for more than 2 weeks) 
*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 
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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). 
• Treatment with a live attenuated vaccine (refer to Section 8.10.1) 
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. 
If a patient requires a prohibited medication at any time during the study, the principal investigator 
should contact the Regeneron Pharmaceuticals, Inc. medical monitor (except for illness requiring 
prompt treatment). 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• Clinically important laboratory abnormalities, such as: 
− ALT or AST >3x × ULN 
− Neutrophil count <1.5 × 103/μL but >0.5 × 103/μL 
− Platelet count ≤100 × 103/μL but >50 × 103/μL 
• Helminth infection not responding to antihelminth therapy 
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. 
8.5. 
Management of Acute Reactions  
8.5.1. 
Acute Injection Reactions 
8.5.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as adverse events (AEs) (as defined in 
Section 10.2.1) and graded using the grading scales as instructed in Section 10.2.4. 
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
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8.5.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.6. 
Method of Treatment Assignment  
Approximately 98 patients will be randomized in a 1:1 ratio to receive either a loading dose of 
 SC followed by 
 dupilumab every 2 weeks (q2w), or a matching placebo loading 
dose and SC placebo injections q2w, according to a central randomization scheme provided by an 
interactive voice response system (IVRS)/interactive web response system (IWRS) to the 
designated study pharmacist (or qualified designee). Randomization will be stratified by 
 
 
 
 
. All patients will receive a standard regimen of OCS (prednisone or 
prednisolone) on day 1/baseline visit to obtain control of disease. 
 
 
 
 
8.7. 
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. In order to 
maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody, drug concentration results, and biomarker results (eg, 
 will not be 
communicated to the sites, and the sponsor’s blinded operational team will not have access to 
results associated with patient identification until after the database is locked. 
8.8. 
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) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment. Study drug will be discontinued for patients whose 
treatment has been unblinded/unmasked (Section 8.4.2)  
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− 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 
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investigator for the site will unblind/unmask the patient. Unblinding is performed 
using the IVRS/IWRS which will notify Regeneron.   
− 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 and when a treatment decision is contingent on knowing the patient’s treatment 
assignment. 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. 
8.9. 
Treatment Logistics and Accountability 
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 
; storage instructions will be 
provided in the pharmacy manual. 
8.9.1. 
Supply and Disposition of Treatments  
Study drug will be shipped 
 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 can be destroyed on site after sponsor 
approval or returned to the sponsor/designee. 
8.9.2. 
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 medication 
• 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. 
8.9.3. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
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8.10. 
Concomitant Medications and Procedures  
Any treatment administered from the time of informed consent to the final study will be recorded. 
This includes medications that were started before the study and are ongoing during the study.  
8.10.1. 
Prohibited Medications and Procedures  
Treatment with the following concomitant medications is prohibited during the study:   
• Topical corticosteroids 
• Topical calcineurin inhibitors 
• Topical crisaborole 
• Treatment with immunomodulating biologics (eg, omalizumab, rituximab, IVIG) 
• Treatment with a systemic non-steroidal immunosuppressive drug (including but not 
limited to mycophenolate-mofetil, azathioprine, methotrexate) 
• Treatment with any BP-directed therapy, which includes dapsone or tetracycline class 
of antibiotics (unless being used to treat an infection suspected or known to be sensitive 
to dapsone or tetracycline class of antibiotics) 
• Initiation, discontinuation, or change in the dosages of treatments known to cause or 
exacerbate BP (eg, angiotensin-converting enzyme inhibitors, penicillamine, 
furosemide, phenacetin, dipeptidyl peptidase 4 inhibitor) must be discussed with the 
medical monitor. 
• Initiation, discontinuation, or change in the dosage regimen of systemic antihistamines 
after baseline 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with nicotinamide directed at the treatment of BP (note: use of multivitamins 
containing nicotinamide is allowed) 
• Initial treatment with a live (attenuated) vaccine: 
Chickenpox (varicella) 
FluMist® (influenza) 
Intranasal (influenza) 
Measles (rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (vaccinia) 
Yellow fever 
Bacille Calmette-Guerin 
Rotavirus 
Varicella zoster (shingles) (use 
of Zostavax® is prohibited as it is 
live attenuated; use of Shingrix® 
is allowed as it is non-live)   
 
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Note: If rescue consists of topical agents (eg, high-potency topical corticosteroids), patients may 
continue study treatment (see Section 8.3). If a patient receives rescue treatment with a systemic 
non-steroidal immunosuppressive drug or immunomodulating biologic (including, but not limited 
to, omalizumab, rituximab, mycophenolate-mofetil, azathioprine, methotrexate), study treatment 
will be permanently discontinued immediately. 
The following concomitant procedures are prohibited during study treatment: 
• Major elective surgical procedures 
8.10.1.1. Adverse Events Requiring the Use of Systemic Corticosteroids 
If the patient develops an AE for a condition not related to BP that requires a corticosteroid dose 
modification (eg, increase or decrease of current concomitant oral prednisone or equivalent), or 
the introduction of a new oral or systemic steroid medication, the sponsor must be notified at the 
time of the steroid dose modification to verify that the patient can continue to participate in the 
study. Furthermore, the dosage modification and AE must be recorded on the patient electronic 
case report form (eCRF). Intranasal, inhaled, and ophthalmic corticosteroids as per label are 
permitted, as needed throughout the course of the study. 
8.10.2. 
Permitted Medications 
Other than the prohibited medications listed in Section 8.10.1, treatment with concomitant 
medications are permitted during the study. Medications used to treat chronic disease such as 
diabetes, hypertension, and asthma are also permitted. Treatment with drugs, including biologics 
that do not have an immunosuppressive/immunomodulating effect and are not intended for the 
treatment of BP are permitted (eg, Praluent). If there is any question regarding whether a 
concomitant medication may be used during the study, the study site should contact the medical 
monitor. 
8.10.3. 
Glucocorticoid-Induced Osteopenia/Osteoporosis Prevention and Treatment 
Oral calcium, 25-hydroxy vitamin D supplementation, and bisphosphonate therapy 
(eg, alendronate 70 mg weekly or zoledronate 4 mg annually) for the prevention or treatment of 
glucocorticoid-induced osteoporosis are permitted. The doses and treatment duration should 
comply with local practice or clinical guidelines at the discretion of the investigator. 
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CONFIDENTIAL 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1 and Table 2. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct 
and 
oversight 
may 
require 
implementation 
of 
temporary 
or 
alternative 
mechanisms. Examples of such mechanisms may include, but are not limited to, any of the 
following:  phone contact, virtual visits, telemedicine visits, online meetings, non-invasive remote 
monitoring devices, use of local clinic or laboratory locations, and home visits by skilled staff. 
Additionally, no waivers to deviate from protocol enrollment criteria due to COVID-19 will be 
granted. All temporary mechanisms utilized, and deviations from planned study procedures in 
response to COVID-19, are to be documented as being related to COVID-19 and will remain in 
effect only for the duration of the public health emergency. 
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CONFIDENTIAL 
Table 1: 
Schedule of Events (Screening, Baseline, and Double-Blind Treatment Period) 
Study Period 
Screening3,4  
Double-Blind Treatment Period    
Study Milestone 
 
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
In-Clinic Visit (V)1 or 
Phone Visit (PV)2 
V1 
V2 
V3 
V4 
V51a 
V61a 
V71a 
V81a 
V91a 
V10 PV11 PV12 PV13 V14 PV15 PV16 PV17 V18 PV19 V20 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 W12 W14 W16 W18 
W20 W22 W24 
W26 W28 W30 W32 W34 W36 
Study Day (D) 
D-35 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 D113 D127 D141 D155 D169 D183 D197 D211 D225 D239 D253 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/ Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient e-Diary Training 
(Pruritus, Pain, and 
Sleep Quality NRS 
Assessments)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Patient e-Diary 
Data6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
Study Drug and/or 
Background Treatment 
(OCS) Administration/ 
Dispensing7,8,9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Accountability10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
Injection 
Training/Observation11 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Patient 
Dosing Diary (ies)7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
Collect Patient Dosing 
Diary (ies)12 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
Concomitant 
Meds/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Period 
Screening3,4  
Double-Blind Treatment Period    
Study Milestone 
 
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
In-Clinic Visit (V)1 or 
Phone Visit (PV)2 
V1 
V2 
V3 
V4 
V51a 
V61a 
V71a 
V81a 
V91a 
V10 PV11 PV12 PV13 V14 PV15 PV16 PV17 V18 PV19 V20 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 W12 W14 W16 W18 
W20 W22 W24 
W26 W28 W30 W32 W34 W36 
Study Day (D) 
D-35 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 D113 D127 D141 D155 D169 D183 D197 D211 D225 D239 D253 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Efficacy13,14 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pruritus, Pain, and Sleep 
Quality NRS (daily)15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPDAI Pruritus 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
ABQOL 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
BPDAI Activity Score, 
BSA, Blister and 
Urticaria/Eczematous 
Plaque Count, BP 
Clinical Assessment 
(includes disease 
relapses)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
Photograph BP Area 
(select sites)16 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Assessment of BP 
Flare29 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
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Study Period 
Screening3,4  
Double-Blind Treatment Period    
Study Milestone 
 
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
In-Clinic Visit (V)1 or 
Phone Visit (PV)2 
V1 
V2 
V3 
V4 
V51a 
V61a 
V71a 
V81a 
V91a 
V10 PV11 PV12 PV13 V14 PV15 PV16 PV17 V18 PV19 V20 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 W12 W14 W16 W18 
W20 W22 W24 
W26 W28 W30 W32 W34 W36 
Study Day (D) 
D-35 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 D113 D127 D141 D155 D169 D183 D197 D211 D225 D239 D253 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Skin Biopsies for BP 
Diagnosis (Histology, 
Immunofluorescence)18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serologies (HIV Ab, 
HBsAg, HBsAb, 
HBcAb19, HCV Ab20, 
HBV DNA21, 
HCV RNA22, TB test23) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (if needed to 
confirm menopausal 
status)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
(WOCBP only)24 
Serum 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
Urinalysis 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
PK and 
Immunogenicity 
Samples25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional Dupilumab 
PK Sample 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Anti-dupilumab 
Antibody Sample 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Biomarker Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Study Period 
Screening3,4  
Double-Blind Treatment Period    
Study Milestone 
 
BL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
In-Clinic Visit (V)1 or 
Phone Visit (PV)2 
V1 
V2 
V3 
V4 
V51a 
V61a 
V71a 
V81a 
V91a 
V10 PV11 PV12 PV13 V14 PV15 PV16 PV17 V18 PV19 V20 
Week (W) 
- 
- 
W2 
W4 
W6 
W8 
W10 W12 W14 W16 W18 
W20 W22 W24 
W26 W28 W30 W32 W34 W36 
Study Day (D) 
D-35 to  
D-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D99 D113 D127 D141 D155 D169 D183 D197 D211 D225 D239 D253 
Visit Window in Days 
- 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
BP180, BP230 
Autoantibodies 
X27 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Optional FBR Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Plasma 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Study Period 
Double-Blind Treatment Period    
  
 
Study Milestone 
EOT 
In-Clinic Visit (V) 1 or 
Phone Visit (PV) 2 
PV21 
PV22 
PV23 
V24 
PV25 
PV26 
PV27 
V28 
Week (W) 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
Study Day (D) 
D267 
D281 
D295 
D309 
D323 
D337 
D351 
D365 
Visit Window in Days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Treatment 
 
 
 
 
 
 
 
 
Review Patient e-Diary 
Data6 
 
 
 
X 
 
 
 
X 
Study Drug and/or 
Background Treatment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
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Study Period 
Double-Blind Treatment Period    
  
 
Study Milestone 
EOT 
In-Clinic Visit (V) 1 or 
Phone Visit (PV) 2 
PV21 
PV22 
PV23 
V24 
PV25 
PV26 
PV27 
V28 
Week (W) 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
Study Day (D) 
D267 
D281 
D295 
D309 
D323 
D337 
D351 
D365 
Visit Window in Days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
(OCS) Administration/ 
Dispensing7,8,9 
Accountability10 
 
 
 
X 
 
 
 
X 
Administer Patient 
Dosing Diary (ies)7 
 
 
 
X 
 
 
 
 
Collect Patient Dosing 
Diary (ies)12 
 
 
 
X 
 
 
 
X 
Concomitant 
Meds/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy13,14 
 
 
 
 
 
 
 
 
Pruritus, Pain, and Sleep 
Quality NRS (daily)15 
X 
X 
X 
X 
X 
X 
X 
X 
BPDAI Pruritus 
 
 
 
X 
 
 
 
X 
ABQOL 
 
 
 
 
 
 
 
X 
BPDAI Activity Score, 
BSA, Blister and 
Urticaria/Eczematous 
Plaque Count, BP 
Clinical Assessment 
(includes disease 
relapses)  
 
 
 
X 
 
 
 
X 
Photograph BP Area 
(select sites)16 
 
 
 
 
 
 
 
X 
Assessment of BP Flare29 
X 
X 
X 
 
X 
X 
X 
 
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Study Period 
Double-Blind Treatment Period    
  
 
Study Milestone 
EOT 
In-Clinic Visit (V) 1 or 
Phone Visit (PV) 2 
PV21 
PV22 
PV23 
V24 
PV25 
PV26 
PV27 
V28 
Week (W) 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
Study Day (D) 
D267 
D281 
D295 
D309 
D323 
D337 
D351 
D365 
Visit Window in Days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Safety 
 
 
 
 
 
 
 
 
Vital Signs17 
 
 
 
X 
 
 
 
X 
Physical Exam 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
X 
Weight 
 
 
 
 
 
 
 
X 
Height 
 
 
 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory testing 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
 
 
 
 
 
 
 
X 
Pregnancy Test (WOCBP 
only)24 
 
Urine 
 
Urine 
 
Urine 
 
Urine 
Urinalysis 
 
 
 
 
 
 
 
X 
PK and 
Immunogenicity 
Samples25 
 
 
 
 
 
 
 
 
Functional Dupilumab 
PK Sample 
 
 
 
 
 
 
 
X 
Anti-Dupilumab 
Antibody Sample 
 
 
 
 
 
 
 
X 
Biomarker Samples 
 
 
 
 
 
 
 
 
BP180, BP230 
Autoantibodies 
 
 
 
 
 
 
 
X 
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CONFIDENTIAL 
Study Period 
Double-Blind Treatment Period    
  
 
Study Milestone 
EOT 
In-Clinic Visit (V) 1 or 
Phone Visit (PV) 2 
PV21 
PV22 
PV23 
V24 
PV25 
PV26 
PV27 
V28 
Week (W) 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
Study Day (D) 
D267 
D281 
D295 
D309 
D323 
D337 
D351 
D365 
Visit Window in Days 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Optional FBR Samples 
 
 
 
 
 
 
 
 
Serum 
 
 
 
 
 
 
 
X 
Plasma 
 
 
 
 
 
 
 
X 
ABQOL: Autoimmune bullous disease quality of life; BP: Bullous pemphigoid; BPDAI: Bullous Pemphigoid Disease Area Index; BSA: Body surface area; 
; FBR: Future biomedical research; FSH: Follicle-stimulating hormone; HBV: Hepatitis B virus; HBcAb: 
Hepatitis B core antibody; HBsAb: Hepatitis B surface antibody; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C virus; HIV: Human immunodeficiency 
virus; ICH: immunohistochemistry; NRS: Numerical rating score; OCS: oral corticosteroids; 
 
; PK: Pharmacokinetic; 
 
; TB: Tuberculosis; WOCBP: women of childbearing potential. 
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CONFIDENTIAL 
Table 2: 
Schedule of Events (Follow-up Period, Unscheduled Visit, Unscheduled Visit 
for BP Relapse, and Early Termination Visit) 
Study period 
Follow-up Period    
Unscheduled 
Visit  
(if applicable)3 
Unscheduled 
Visit for BP 
Relapse (if 
applicable)3 
Early 
Termination 
Visit 
(if applicable)4 
Study milestone 
  
  
 EOS 
In-Clinic Visit (V)1 or Phone 
Visit (PV)2 
PV29 
PV30 
V31 
Week (W) 
W56 
W60 
W64 
Study Day (D) 
D393 
D421 
D449 
Visit window in days 
±3 
±3 
±3 
Treatment 
 
 
 
 
 
 
Review Patient e-Diary Data5 
 
 
X 
X 
X 
X 
Study Drug and/or Background 
Treatment (OCS) 
Administration/Dispensing7 
 
 
 
X 
X (only if 
needed) 
 
Accountability8 
 
 
 
X 
X 
X 
Administer Patient Dosing Diary 
(ies)6 
 
 
 
X 
X 
 
Collect Patient Dosing Diary 
(ies)9 
 
 
 
X 
X 
X 
Concomitant Meds/Procedures 
X 
X 
X 
X 
X 
X 
Efficacy10,11 
 
 
 
 
 
 
Pruritus, Pain, and Sleep Quality 
NRS (daily)12 
X 
X 
X 
X 
X 
X 
BPDAI Pruritus 
 
 
X 
X 
X 
X 
ABQOL 
 
 
X 
X 
 
X 
BPDAI Activity Score, BSA, 
Blister and Urticaria/Eczematous 
Plaque Count, BP Clinical 
Assessment (includes disease 
relapses)  
 
 
X 
X 
X 
X 
Photograph BP Area (select 
sites)13 
 
 
X 
 
X 
X 
Assessment of BP Flare18 
X 
X 
 
 
 
 
Safety 
 
 
 
 
 
 
Vital Signs14 
 
 
X 
X 
X 
X 
Physical Exam 
 
 
X 
X 
 
X 
ECG 
 
 
X 
X 
 
X 
Weight 
 
 
X 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Laboratory testing 
 
 
 
 
 
 
Hematology, Chemistry 
 
 
X 
X 
 
X 
Pregnancy Test  
(WOCBP only)15 
 
 
Urine 
Urine 
 
Urine 
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Study period 
Follow-up Period    
Unscheduled 
Visit  
(if applicable)3 
Unscheduled 
Visit for BP 
Relapse (if 
applicable)3 
Early 
Termination 
Visit 
(if applicable)4 
Study milestone 
  
  
 EOS 
In-Clinic Visit (V)1 or Phone 
Visit (PV)2 
PV29 
PV30 
V31 
Week (W) 
W56 
W60 
W64 
Study Day (D) 
D393 
D421 
D449 
Visit window in days 
±3 
±3 
±3 
Urinalysis 
 
 
X 
X 
 
X 
PK and Immunogenicity 
Samples16 
 
 
 
 
 
 
Functional Dupilumab PK Sample 
 
 
X 
X 
X 
X 
Anti-dupilumab Antibody Sample 
 
 
X 
X 
X 
X 
Biomarker Samples 
 
 
 
 
 
 
BP180, BP230 Autoantibodies 
 
 
X 
X 
X 
X 
Optional FBR Samples 
 
 
 
 
 
 
Serum 
 
 
X 
 
 
 
Plasma 
 
 
X 
 
 
 
ABQOL: Autoimmune bullous disease quality of life; BP: Bullous pemphigoid; BPDAI: Bullous Pemphigoid Disease 
Area Index; BSA: Body surface area; 
; FBR: Future 
biomedical research; 
; NRS: Numerical rating score; OCS: oral corticosteroids; 
 
 
; PK: Pharmacokinetic; 
; 
WOCBP: women of childbearing potential. 
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9.1.1. 
Footnotes for the Schedule of Events Tables 
9.1.1.1. 
Table 1 Schedule of Events Footnotes 
1. Assessments/procedures should be conducted in the following order: patient-reported 
outcomes, investigator assessments, safety and laboratory assessments (including sample 
collection for ADA, pharmacokinetics [PK], biomarkers [including 
 at select 
study sites only], 
), and then administration of study drug.   
a. Visits 5 through 9 may be conducted as in-clinic or telemedicine visits. All 
telemedicine visits must include the BPDAI Activity Score, BSA, Blister and 
Urticaria/Eczematous Plaque Count, and BP Clinical Assessment (including disease 
relapses as assessed by the investigator) performed via video during the visit for a 
virtual assessment by the investigator with support from a healthcare provider (eg, 
visiting nurse) present with the patient. If a telemedicine visit is conducted, 
Accountability and Collecting Dosing Diaries are to be performed at the next in-clinic 
visit. Study drug and background treatment (OCS) dispensation should occur, if 
necessary, at these visits. 
2. The site will contact the patient by telephone to conduct these visits. The patient, caregiver, 
or healthcare provider (eg, visiting nurse) may administer study drug on these days. 
Patients who receive study drug outside the study center will complete a dosing diary to 
document compliance with study drug administration and to document any related issues.   
3. 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 diagnostic 
criteria. 
4. During the screening period, treatments for BP will be washed out, as applicable, according 
to eligibility requirements (see Section 7.2.2).  
5. Patients will receive training on completion of e-diary to record completion of assessment 
of Pruritus, Pain, and Sleep Quality NRS scales. 
6. Study site staff will check patient data collected on the e-diary.   
7. Study site staff will counsel patients on completing the dosing diary(ies) at each visit.  
8. Starting at baseline visit, prednisone (or prednisolone) tablets will be dispensed to the 
patient in sufficient quantities until their next clinic visit. Patients will be counseled on 
documenting their daily prednisone (or prednisolone) dose in their dosing diary. Patients 
will return the remaining dispensed medication at each clinic visit. Refer to Section 8.2 
(Background Treatments) for OCS dosing. 
9. Starting at week 6, for patients who choose to self-administer study drug, counsel patient 
on proper dosing diary completion/reporting of each dose of study drug that is administered 
outside of the clinic. Study drug (s) will be administered biweekly, either in the clinic or 
outside the clinic (self-administration or administration by a caregiver or healthcare 
provider [eg, visiting nurse]). An unscheduled visit may be used for in-clinic injections. 
Study drug will be administered through week 50. 
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10. Patients will return the original kit box for the prefilled syringe at each clinic visit.  
11. Patients or caregivers will be trained on how to administer study drug under the observation 
of site staff to ensure correct administration technique is used. This will enable 
administration at home in between clinic visits. 
12. Study site staff will review and check compliance each time the patient dosing diary(ies) 
are collected. 
13. Questionnaires will be completed before any other assessments or invasive procedures 
(blood draws, study drug injection, etc.). 
14. 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). 
15. Pruritus, Pain, and Sleep Quality NRS will be completed daily via electronic questionnaire 
(e-diary). Reporting of these data begins on visit 1 (screening). 
16. Select sites only - photograph BP area. 
17. Vital signs (heart rate, blood pressure, respiration rate, and body temperature) should be 
taken pre-dose. 
18. Biopsy for histology and direct immunofluorescence to be performed during screening 
unless a ≤6-month-old biopsy report (from the screening visit) for histology and direct 
immunofluorescence is available. Histopathology, immunopathology, and serological 
confirmation of BP performed at a local laboratory with results available within 6 months 
of the screening visit is acceptable.  
19. In case of results showing HBsAg negative, HBsAb negative, and HBcAb positive, HBV 
DNA testing will be performed prior to randomization to rule out a false positivity and to 
confirm current infection. 
20. In case of results showing positive Hep C Ab, HCV RNA testing will be performed to rule 
out a false positivity and to confirm current infection. 
21. Will only be performed in patients whose serology results show HBsAg negative, HBsAb 
negative and HBcAb positive. 
22. Will only be performed in patients whose serology results show positive Hep C Ab. 
23. Tuberculosis testing will be performed on a country-by-country basis, according to local 
guidelines if required by regulatory authorities or ethics boards. 
24. Not required if postmenopausal status confirmed at screening. After visit 1, monthly urine 
pregnancy tests are required for WOCBP.  
25. Blood samples for both PK and ADA will be collected before the administration of study 
drug.  Pharmacokinetic samples will be collected for the determination of dupilumab 
concentration and ADA samples for the immunogenicity assessment of dupilumab. In the 
event of suspected SAEs, such as anaphylaxis or hypersensitivity, unscheduled additional 
PK and ADA samples may be collected at or near the event. 
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26. 
 
 
 
 
27. Serological confirmation of BP for diagnostic criteria performed through a local laboratory 
within 6 months of the screening visit is acceptable (see inclusion criterion #2 in 
Section 7.2.1). 
28. 
 
 
 
 
29. If a BP flare (defined as worsening of disease) is suspected during a phone visit, then the 
patient should be assessed in person by the investigator at an unscheduled visit for a 
BP relapse (Table 2).  
9.1.1.2. 
Table 2 Schedule of Events Footnotes 
1. Assessments/procedures should be conducted in the following order: patient-reported 
outcomes, investigator assessments, safety and laboratory assessments (including sample 
collection for ADA, pharmacokinetics [PK], biomarkers [including 
 at select 
study sites only],
), and then administration of study drug.  
2. The site will contact the patient by telephone to conduct these visits.   
3. Unscheduled visits may be necessary to repeat testing following abnormal laboratory 
results, for follow-up of AEs, or for other reason (eg, before a rescue medication/procedure 
is used), as warranted. The assessments and procedures performed during an unscheduled 
visit will depend upon the reason for the visit. During an unscheduled visit, any of the study 
procedures noted may be performed, but not all are required. If the unscheduled visit is due 
to an AE, collect samples for PK and ADA analysis. An unscheduled visit may also be 
used for those patients who choose in-clinic administration of study drug. If a BP flare is 
suspected during a phone visit, then the patient is to return for assessments and procedures 
specified in Table 2 for an unscheduled visit for BP relapse. 
4. Patients who are withdrawn from the study will be asked to return to the clinic for early 
termination assessments. 
5. Study site staff will check patient data collected on the e-diary.    
6. Study site staff will counsel patients on completing the dosing diary(ies) at each visit. 
7. If applicable, prednisone (or prednisolone) tablets will be dispensed to the patient in 
sufficient quantities until their next clinic visit. Patients will return the remaining dispensed 
medication at each clinic visit. 
8. Patients will return the original kit box for the prefilled syringe at each clinic visit.  
9. Study site staff will review and check compliance each time the patient dosing diary (ies) 
are collected. 
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10. Questionnaires will be completed before any other assessments or invasive procedures 
(blood draws, study drug injection, etc.). 
11. 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). 
12. Pruritus, Pain, and Sleep Quality NRS will be completed daily via electronic questionnaire 
(e-diary).  
13. Select sites only - photograph BP area. 
14. Vital signs (heart rate, blood pressure, respiration rate, and body temperature) should be 
taken pre-dose. 
15. Not required if postmenopausal status confirmed at screening. 
16. In the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional PK and 
ADA samples may be collected at or near the event. 
17. 
 
 
18. If a BP flare (defined as worsening of disease) is suspected during a phone visit, then the 
patient should be assessed in person by the investigator at a scheduled visit or at an 
unscheduled visit for BP relapse. 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for an early 
termination visit consisting of the early termination assessments described in Table 2. 
9.1.3. 
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, as warranted. 
9.1.3.1. 
Unscheduled Visits for BP Relapse 
These visits allow for an assessment for BP relapse after week 16 when a BP flare (worsening of 
disease) has been reported by a patient during the phone visits which start at week 18. If a BP flare 
is suspected during these phone visits, then the patient must return for assessments and procedures 
specified in Table 2 for an unscheduled visit for BP relapse. 
9.2. 
Study Procedures 
Assessments/procedures at the clinic visit should be performed in the following order:  
1. Patient-reported outcomes  
2. Investigator assessments (performed only by adequately trained and qualified investigators 
or sub-investigators; it is recommended that the same investigator or sub-investigator 
perform all the evaluations for a given patient throughout the entire study period)  
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3. Safety and laboratory assessments (including sample collection for ADA, PK, biomarker, 
and optional 
). 
4. Administration of study drug  
9.2.1. 
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: Inclusion/exclusion criteria, medical history, 
demographics, and patient e-diary training (Pruritus, Pain, and Sleep Quality NRS assessments). 
A biopsy and assessments for diagnosis of BP based on histopathology, immunopathology, and 
serology will be performed during screening for the BP diagnostic criteria unless a ≤6-month-old 
biopsy report (from the screening visit) for histology and direct immunofluorescence is available 
(see Section 7.2.1 Inclusion Criteria, Inclusion Criterion #2.  
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Body Surface Area 
Body surface area affected by BP 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 1 and Table 2. The BSA assessment tool is provided in the study reference 
manual/site binder or file. 
9.2.2.2. 
Pruritus Numerical Rating Scale 
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. Patients will be instructed on using the patient diary 
to record their Pruritus NRS score at the screening and baseline visits. Patients will complete the 
rating scale DAILY according to the time points in Table 1 and Table 2. Clinical sites will check 
and remind patients to complete the diary at each visit. 
9.2.2.3. 
Skin Pain Numerical Rating Scale 
Skin pain will be measured using a validated skin pain NRS. This is an 11-point scale (0 to 10) in 
which 0 indicates no pain while 10 indicates worst pain possible. Clinical sites will check and 
remind the patient to complete the scale according to the time points in Table 1 and Table 2. 
Patients will be instructed on using the scale to record their skin pain score at the screening visit. 
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. 
9.2.2.4. 
Sleep Numerical Rating Scale 
Sleep quality will be measured using a validated sleep quality NRS. This is an 11-point scale 
(0 to 10) in which 0 indicates worst possible sleep while 10 indicates best possible sleep. The 
patients will be asked to select the number that best describes the quality of their sleep during the 
previous night. 
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Clinical sites will check and remind the patients to complete the scale according to the time points 
in Table 1 and Table 2. Patients will be instructed on using the scale to record their sleep quality 
score at the screening visit. Clinical sites will check patient data collected using an e-diary. 
9.2.2.5. 
Bullous Pemphigoid Disease Area Index Activity Score 
The BPDAI activity score is a well-developed and validated instrument in BP patients 
(Wijayanti, 2017). The total BPDAI activity score is the arithmetic sum of 3 subcomponents: 
cutaneous blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions. Scores 
can range from 0 to 360 for BPDAI total activity (maximum 240 for total skin activity and 120 for 
mucosal activity), with higher scores indicating greater disease activity. The minimal clinically 
important difference (MCID) in the BPDAI activity score is 4 points for assessing clinical 
improvement and 3 points for deterioration. Patients will undergo this assessment at time points 
according to Table 1 and Table 2. 
9.2.2.6. 
Bullous Pemphigoid Disease Area Index Pruritus 
A separate subjective component of the BPDAI, BPDAI Pruritus, is used to assess pruritus. The 
intensity of pruritus is subjectively graded using a visual analog scale where 0 represents no itch 
and 10 represents maximal itching. Patient mark an “x” to indicate severity of itching in the past 
24 hours, in the past week, and in the past month, producing a total score out of 30. In cases where 
the patient was unable to reliably complete the grading (due to impaired mental functioning), 
pruritus was inferred from the degree of excoriations, also scored out of 30. However, for this 
study, patients should be the only ones completing this assessment. Patients will undergo this 
assessment at time points according to Table 1 and Table 2. 
9.2.2.7. 
Patient Global Assessment of Disease Severity 
Patients will rate their overall wellbeing based on a 5-point scale. Patients will be asked: “Overall, 
how would you rate your bullous pemphigoid symptoms right now?” Response choices are: “No 
symptoms”, “Mild Symptoms”, “Moderate Symptoms”, “Severe Symptoms”, “Very Severe 
Symptoms”. Patients will undergo this assessment at time points according to Table 1 and Table 2. 
The assessment tool is provided in the study reference manual. 
9.2.2.8. 
Patient Global Assessment of Treatment 
Patients will rate their satisfaction with the study treatment based on a 5-point scale. Patients will 
be asked: “Compared to before you started the study, how would you rate your bullous pemphigoid 
symptoms now?” Response choices are: “Much Better”, “A Little Better”, “No Difference”, “A 
Little Worse”, “Much Worse”. Patients will undergo this assessment at time points according to 
Table 1 and Table 2.  
The assessment tool is provided in the study reference manual. 
9.2.2.9. 
Patient-Assessed 
 
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9.2.2.10. Autoimmune Bullous Disease Quality of Life 
ABQOL has been shown to have good validity and reliability (Sebaratnam, 2013). This 
questionnaire consists of 17 items, which encompass physical burden of the disease, psychiatric 
effects, and effects on daily life functioning. Each question ranges from 0 to 3 points, with higher 
scores indicating poorer quality of life. The maximum ABQOL score is 51. Patients will undergo 
this assessment at time points according to Table 1 and Table 2. 
9.2.2.11. Blister and Urticaria/Eczematous Plaque Count 
The number of blisters (or erosions) and urticarial/eczematous lesions will be collected for each 
anatomical location (eg, head, neck, chest). Patients will undergo this assessment at time points 
according to Table 1 and Table 2. 
9.2.2.12. Bullous Pemphigoid Clinical Assessment 
The investigator will be required for completing the overall evaluation of BP clinical activity, 
which may include the following: 
• Control of disease activity (Note: Control of disease activity is defined as when new 
lesions [eg, blisters, urticarial plaques] cease to form and existing lesions begin to 
heal [eg, show signs of epithelialization]). Initial control of disease is obtained when 
there have been no new lesions and lesions have begun to heal for at least 24 hours. 
• Achievement of complete remission (Note: complete remission is defined as absence 
of new lesions and epithelialization of old lesions). 
• Assessment of adherence to the protocol-defined prednisone taper regimen (see 
Section 8.2). 
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• Assessment of disease relapse (Note: Relapse is defined as the appearance of 3 or more 
new lesions a month [blisters, eczematous lesions, or urticarial plaques] or at least 1 
large [>10 cm diameter] eczematous lesion or urticarial plaque that does not heal within 
1 week) 
• Need for rescue therapy (see Section 8.3). 
Evaluation of the above should be based on the signs of BP, which include the presence (or 
absence) of blisters, erosions, urticarial and eczematous plaques. Once a lesion has been 
epithelialized, the lesion should no longer be considered a blister or erosion. Further, the presence 
of scarring or post-inflammatory hyperpigmentation or hypopigmentation should not be 
considered as active disease. 
To ensure consistency of assessments, the same investigator or sub-investigator should perform 
all the evaluations for a given patient throughout the entire study period. Patients will undergo this 
assessment at time points according to Table 1 and Table 2. 
9.2.2.13. Bullous Pemphigoid Area Photographs 
At select study sites, photographs will be taken of a representative area of BP involvement. 
Subsequent photographs of the same area will be taken at time points according to Table 1 and 
Table 2. 
Instructions for taking the photographs are provided in the photography reference manual. 
9.2.2.14. Assessment of Bullous Pemphigoid Flare 
During phone visits, patients will be asked to report any worsening of their disease. If worsening 
of a patient’s disease is suspected, the patient should return to the clinic for an unscheduled visit 
for BP relapse (Table 2).  At this visit, the assessments and procedures specified in Table 2 should 
be performed. 
9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiration rate, and body temperature will be 
collected pre-dose at each clinic visit, as noted in Table 1 and Table 2. Heart rate and blood 
pressure will be measured with the patient in a sitting position after the patient has rested 
comfortably for at least 5 minutes. 
9.2.3.2. 
Body Weight and Height 
Body weight will be measured at time points according to Table 1 and Table 2. Height will be 
measured according to Table 1. 
9.2.3.3. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1 and 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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9.2.3.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 1 and Table 2. Heart 
rate will be recorded from the ventricular rate and the PR, QRS, and QT intervals will be recorded. 
The ECG strips or reports will be retained with the source. 
9.2.3.5. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Detailed instructions for blood sample collection are in the laboratory manual provided 
to study sites. 
Samples for laboratory testing will be collected at visits according to Table 1 and Table 2. Tests 
will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
Potassium 
Creatinine 
Total cholesterol2 
Chloride 
Blood urea nitrogen 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase3 
Glucose 
Alkaline phosphatase 
Hemoglobin A1c 
Albumin 
Lactate dehydrogenase 
hs-CRP 
1 Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN.  
2 Low-density lipoprotein and high-density lipoprotein 
3 CPK isoenzymes will be measured when CPK >5× the ULN  
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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 according to Table 1 and Table 2.  
The following additional laboratory tests will be performed at screening: HIV; HBsAg; HBsAb; 
HBcAb; HBV DNA (only in patients who are HBsAg negative, HBsAb negative, and HBcAb 
positive); hepatitis C antibody; HCV RNA (only in patients who are HCV Ab positive); 
tuberculosis (will be performed on a country-by-country basis according to local guidelines if 
required by regulatory authorities or ethics boards). 
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 medication 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 10.1.1. 
9.2.4. 
Drug Concentration and Measurements 
Samples for measuring functional dupilumab concentrations will be collected at visits listed in 
Table 1 and Table 2.  
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9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1 and Table 2. 
Samples positive in the ADA assay will be analyzed for the presence of neutralizing antibody in 
the NAb assay. 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore how dupilumab may modify the 
underlying disease process in BP. Biomarker samples will be collected at time points according to 
Table 1 and Table 2. Biomarker measurements will be performed to determine effects on relevant 
physiological and pathogenic processes.  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
Serum anti-BP180 and anti-BP230 autoantibodies of the IgG subclass concentration 
measurement 
Serum anti-BP180 and anti-BP230 IgG increase during BP disease flares are markers of disease 
activity. The concentration of anti-BP180 and anti-BP230 IgG are measured at screening as part 
of the inclusion criteria and monitored during the treatment period in the study, as described in 
Table 1 and Table 2. 
 
 
 
 
 
 
 
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9.2.6.1. 
Exploratory Research 
Research samples (
) will be collected for exploratory research related to 
immunology of BP. Samples may also be used to evaluate the effects of dupilumab on the 
inflammatory profile in circulation, as measured by serum and plasma chemokines/cytokines 
 
 
 
 
 
The list may be altered or expanded as it is recognized that more relevant or novel biomarkers may 
be discovered during the course of this study. Banked research plasma samples (serum/plasma), 
as well as any unused samples for study-related research (including 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 the scope of research described above. After 15 years, any residual samples will be 
destroyed. Results of these exploratory analyses will not be reported in the clinical study report. 
Residual tissue block from the screening punch biopsies (if performed) may be used for 
exploratory biomarker research, including 
 analysis. 
Skin biopsies collection (at select study sites only): Punch biopsies will be collected from the 
affected areas of BP lesions. The skin biopsies may be used to evaluate 
 
 
 
 
 
9.2.7. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR.  Additional 
samples will be collected for FBR.  Residual 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 (or for a shorter time period if required per regional laws and regulations).  The samples may 
be utilized for FBR that may or may not be directly related to the study, including being used as 
reference samples and assay development or validation.  The results of these future biomedical 
research analyses will not be presented in the CSR. 
9.2.7.1. 
 Analysis (Optional) 
Patients who agree to participate in the 
 sub-study will be required to consent to this 
optional sub-study before collection of the samples. 
 
 
 
 
 
 
. 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 
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involving the 
 analyses which the sponsor is unable to comply with, samples 
will not be collected at those sites.   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research findings from the optional 
 sub-study will not be disclosed to the patient or 
principal investigator, even if these findings have implications for a patient’s health and 
management. 
 results from this sub-study are for research purposes only and not for 
medical diagnosis or for 
. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period, from the time of signing the informed consent form (ICF) to the end of the study. Medical 
conditions that existed or were diagnosed prior to the signing of the informed consent will be 
recorded as part of medical history. Abnormal laboratory values and vital signs observed at the 
time of informed consent should also be recorded as medical history. Any subsequent 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 should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature. The investigator should follow up on SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation, lead to dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE. Pre-planned (prior to signing the ICF) 
procedures, treatments requiring hospitalization for pre-existing conditions that do not worsen in 
severity, and admission for palliative or social care should not be reported as SAEs (see 
Section 10.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of study) that the investigator 
assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.   
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10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable: blinded) study drug. For SAEs and 
AESIs, a detailed narrative summarizing the course of the event including its evaluation, treatment, 
and outcome should be provided on the AE CRF. Specific or estimated dates of event onset, 
treatment, and resolution should be included when available. Medical history, concomitant 
medications, and laboratory data that are relevant to the event should also be summarized in the 
narrative. For fatal events, the narrative should state whether an autopsy was or will be performed, 
and include the results if available. Information not available at the time of the initial report must 
be documented in a follow-up report. Source documents (including hospital or medical records, 
diagnostic reports, etc.) will be summarized in the narrative on the AE CRF and retained at the 
study center, and available upon request.   
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• AESIs; serious and nonserious: Adverse events of special interest for this study include 
the following:   
1. Anaphylactic reactions  
2. Systemic hypersensitivity reactions  
3. Helminthic infections 
4. Any severe type of conjunctivitis or blepharitis 
5. Keratitis  
6. Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms 
• 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 12 weeks 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.  
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10.2. 
Definitions 
10.2.1. 
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 
(ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
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 a hospital admission (any duration) or an 
emergency room visit 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.  
10.2.3. 
Adverse Events of Special Interest 
An AESI; serious or non-serious is one of scientific and medical interest 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.   
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10.2.4. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild: Does not interfere in a significant manner with the patient’s 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. 
Injection Site Reactions 
The severity of injection site reactions 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 
10.2.5. 
Causality 
The investigator must provide causality assessment as to whether or not there is a reasonable 
possibility that the drug caused the AE, based on evidence or facts, his/her clinical judgment, and 
the following definitions. The causality assessment must be made based on the available 
information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs. time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
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• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications), or 
other external factors. 
Causality to the study conduct (protocol-specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol-specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol-specified 
procedure, or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications), or other external factors. 
10.3. 
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; 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. 
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10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, Ethics Committees 
(ECs)/Institutional Review Board (IRBs), and the participating investigators of any SUSARs 
(Suspected Unexpected Serious Adverse Reactions) occurring in other study centers or other 
studies of the active study drug (dupilumab), as appropriate per local reporting requirements. In 
addition, the sponsor and/or CRO will comply with any additional local safety reporting 
requirements. All notifications to investigators will contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (dupilumab) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure that is effective for expedited safety reporting.  
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and ECs/IRBs as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study.  
Data collected through the implementation of new CRFs regarding the impact of the COVID-19 
pandemic on the patients will be summarized (eg, discontinuation due to COVID-19). Handling 
missing data due to COVID-19 pandemic and any additional analyses and methods required to 
investigate the impact of COVID-19 on the efficacy (eg, missing data due to COVID-19) and 
safety will be detailed in the SAP. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
The primary analyses of the study will compare the treatment effect of dupilumab 
 q2w 
against placebo on the proportion of patients achieving sustained remission at week 36 as defined 
in Section 4.1.1. The following hypothesis of the primary endpoint will be tested:   
• Null hypothesis (H0): pp = pd, ie, the proportion of patients achieving sustained 
remission at week 36 is the same between the dupilumab group (pd) and the placebo 
group (pp) 
• Alternative hypothesis (H1): pp ≠ pd, ie, the proportion of patients achieving sustained 
remission at week 36 is different between the dupilumab group (pd) and the placebo 
group (pp) 
11.2. 
Justification of Sample Size 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) is defined as all randomized patients analyzed according to the 
treatment group allocated by randomization regardless of whether the treatment kit is used or not.  
All efficacy endpoints will be evaluated on the FAS, which will be considered as the primary 
analysis set.  
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11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who have 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. 
In addition:  
• For patients who receive any dose of active study drug(dupilumab) during the trial, 
the treatment group allocation for as-treated analysis will be the dupilumab group. 
11.3.3. 
Pharmacokinetic Analysis Sets 
 The PK analysis set includes all randomized patients who have received any study drug and who 
had at least 1 non-missing drug concentration result following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any study drug and had at least 
1 non-missing ADA result following the first dose.  
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or have at least 1 non-missing result in the NAb assay following the first dose. 
Patients who are ADA negative are set to negative in the NAb analysis set. 
11.4. 
Statistical Methods 
For continuous variables, the following information will be provided: the number of patients 
reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, and 
maximum. Continuous variables will be described by visit and as change from baseline, if 
applicable. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
For the time-to-event data, Kaplan-Meier curves and estimates, and median time along with 95% 
confidence interval (CI), will be provided. 
Unless otherwise specified, the baseline value is defined as the latest available valid value before 
the first dose of study drug. If any randomized patients are not treated, the baseline will be the last 
value on or prior to the randomization. 
All statistical tests will be performed 2-sided with a type I error rate of 5% unless otherwise stated. 
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11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who have signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• The total number of patients who completed week 36 and week 52, respectively 
• The total number of patients who took rescue medications 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
 
 
 
  
 
 
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11.4.3.2. Secondary Efficacy Analysis 
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11.4.3.3. Subgroup Analysis 
 
 
 
 
11.4.4. 
Control of Multiplicity 
 
 
   
11.4.5. 
Safety Analysis 
All safety analyses will be performed on the SAF and the summary of safety results will be 
presented by treatment group. The safety analysis will be based on the reported AEs, clinical 
laboratory evaluations, physical examination, vital signs, and 12-lead ECG. 
Thresholds for treatment-emergent potentially clinically significant values (PCSVs) in laboratory 
variables and vital signs are defined as abnormal values considered medically important by the 
sponsor based on a review of the literature. Treatment-emergent PCSV is any PCSV developed or 
worsened in severity compared to the baseline during the treatment period. 
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11.4.5.1. Adverse Events 
Definitions 
Treatment-emergent adverse events are AEs that developed or worsened in severity compared to 
the baseline during the treatment and follow-up period. 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 pre-treatment AE and TEAE are defined in the following 3 observation periods: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of study drug. Pre-treatment signs and symptoms (pre-treatment AEs) are AEs 
that developed or worsened in severity during the pre-treatment period. 
• The on-treatment period during the 52-week treatment period are AEs with onset after 
the first dose up to the week 52 visit date (study day 365 if the week 52 visit date is 
missing) or early termination visit, whichever is earlier. TEAEs that have an onset 
during the 52-week treatment period and continue afterwards into the follow-up period 
will be counted only once as TEAEs during the 52-week treatment period. 
• The post-treatment period (follow-up period) is AEs with onset after the week 52 visit 
date up to the end of study 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment and follow-up periods. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by system organ 
class (SOC) and preferred term (PT) 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• TEAEs leading to permanent treatment discontinuation, 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. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
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Number and percentage of patients with a treatment-emergent 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 post-randomization time point will be 
summarized for each clinical laboratory test for all patients and separately for patients in whom 
the PCSV criterion was normal or missing at baseline.  
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. The criteria for treatment-emergent PCSV 
will be defined in the SAP. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.5.3. Treatment Exposure  
The duration of exposure during the study will be presented by treatment group and calculated as: 
• last dose date – first dose date + 14 days, regardless of unplanned intermittent 
discontinuations. 
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, standard deviation, minimums, Q1, medians, Q3, and 
maximums. A summary of the number of doses by treatment group will be provided. 
11.4.5.4. Treatment Compliance 
The compliance with study treatment will be calculated as follows: 
• Treatment Compliance = (Number of study drug injections during exposure 
period)/(Number of planned study drug 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. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
No formal statistical analysis will be performed. Trough functional dupilumab concentration in 
serum (Ctrough time point) will be summarized at each time point using descriptive statistics. The 
data may be combined with data from other adult dupilumab studies (eg, AD) for analysis using 
population methods. Any population PK analysis will be reported separately.  
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11.4.7. 
Analysis of Immunogenicity Data  
Immunogenicity will be characterized by ADA, titer, and NAb responses observed:  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers, 
and NAb positivity presented by patient, time point, and dose cohort/group will be provided. 
Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and 
percent of patients (%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.5. 
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 15.1. 
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12. 
QUALITY CONTROL AND 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 described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
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). 
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) will be done using 
internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) system. 
12.1.2. 
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 
• Digital archive system for photographs 
12.2. 
Study Monitoring 
12.2.1. 
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. This study will use the principles of risk-based 
monitoring (ICH). This means that the number of visits for any given site may vary based on site 
risk indicators. 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. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and is 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
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. The investigator must ensure the accuracy, completeness, and 
timeliness of the data reported to the sponsor in the CRFs. 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. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided.  
12.3. 
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.  
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12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of patient 
final CRFs/eCRFs that will be provided to the sponsor. 
12.4.2. 
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.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
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, the Japanese GCP, and 
applicable regulatory requirements. 
13.2. 
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. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in the 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, or if there 
are significant changes to the study procedures, 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. 
13.3. 
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. 
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13.4. 
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. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Where required per local legislation, regulatory authority approval 
will also be sought.  
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Regeneron Pharmaceuticals, Inc. 
Page 103 of 107 
 
CONFIDENTIAL 
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
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. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
REFERENCES 
Abdat R, Waldman RA, de Bedout V, Czernik A, McLeod M, King B, et al. Dupilumab as a Novel 
Therapy for Bullous Pemphigoid: A Multicenter Case Series. J Am Acad Dermatol 2020. 
 
Bystryn JC, Rudolph JL. Why is the mortality of bullous pemphigoid greater in Europe than in the 
US? J Invest Dermatol 2005; 124(3):xx-xxi. 
 
Cozzani E, Di Zenzo G, Cioni M, Javor S, Altieri M, Anselmi L, et al. Is gliclazide a new 
antidiabetic drug implicated in the pathogenesis of ocular mucous membrane pemphigoid? Eur J 
Dermatol 2018; 28(3):396-7. 
 
Dopp R, Schmidt E, Chimanovitch I, Leverkus M, Brocker EB, Zillikens D. IgG4 and IgE are the 
major immunoglobulins targeting the NC16A domain of BP180 in Bullous pemphigoid: serum 
levels of these immunoglobulins reflect disease activity. J Am Acad Dermatol 2000; 42(4):577-
83. 
 
Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation FDA. 2009. 
US Department of Health and Human Services Food and Drug Administration. 
 
Gunther C, Carballido-Perrig N, Kopp T, Carballido JM, Pfeiffer C. CCL18 is expressed in 
patients with bullous pemphigoid and parallels disease course. Br J Dermatol 2009; 160(4):747-
55. 
 
Ishiura N, Fujimoto M, Watanabe R, Nakashima H, Kuwano Y, Yazawa N, et al. Serum levels of 
IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol 
Sci 2008; 49(2):153-61. 
 
Iwata Y, Komura K, Kodera M, Usuda T, Yokoyama Y, Hara T, et al. Correlation of IgE 
autoantibody to BP180 with a severe form of bullous pemphigoid. Arch Dermatol 2008; 
144(1):41-8. 
 
Joly P, Benichou J, Lok C, Hellot MF, Saiag P, Tancrede-Bohin E, et al. Prediction of survival for 
patients with bullous pemphigoid: a prospective study. Arch Dermatol 2005; 141(6):691-8. 
 
Joly P, Roujeau JC, Benichou J, Delaporte E, D'Incan M, Dreno B, et al. A comparison of two 
regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a 
multicenter randomized study. J Invest Dermatol 2009; 129(7):1681-7. 
 
Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, et al. A comparison of oral and 
topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002; 346(5):321-7. 
 
Kakinuma T, Wakugawa M, Nakamura K, Hino H, Matsushima K, Tamaki K. High level of 
thymus and activation-regulated chemokine in blister fluid and sera of patients with bullous 
pemphigoid. Br J Dermatol 2003; 148(2):203-10. 
 
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Kirtschig G, Middleton P, Bennett C, Murrell DF, Wojnarowska F, Khumalo NP. Interventions 
for bullous pemphigoid. Cochrane Database Syst Rev 2010; 10):Cd002292. 
 
Kouris A, Platsidaki E, Christodoulou C, Armyra K, Korkoliakou P, Stefanaki C, et al. Quality of 
life, depression, anxiety and loneliness in patients with bullous pemphigoid. A case control study. 
An Bras Dermatol 2016; 91(5):601-3. 
 
Lamberts A, Euverman HI, Terra JB, Jonkman MF, Horvath B. Effectiveness and Safety of 
Rituximab in Recalcitrant Pemphigoid Diseases. Front Immunol 2018; 9(248. 
 
Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, et al. Definitions and 
outcome measures for bullous pemphigoid: recommendations by an international panel of experts. 
J Am Acad Dermatol 2012; 66(3):479-85. 
 
Roujeau JC, Lok C, Bastuji-Garin S, Mhalla S, Enginger V, Bernard P. High risk of death in elderly 
patients with extensive bullous pemphigoid. Arch Dermatol 1998; 134(4):465-9. 
 
Sebaratnam DF, Hanna AM, Chee SN, Frew JW, Venugopal SS, Daniel BS, et al. Development 
of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease 
Quality of Life questionnaire. JAMA Dermatol 2013; 149(10):1186-91. 
 
Simon D, Yousefi S, Cazzaniga S, Burgler C, Radonjic S, Houriet C, et al. Mepolizumab failed to 
affect bullous pemphigoid: a randomized, placebo-controlled, double-blind phase 2 pilot study. 
Allergy 2019. 
 
Venning VA, Taghipour K, Mohd Mustapa MF, Highet AS, Kirtschig G. British Association of 
Dermatologists' guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 2012; 
167(6):1200-14. 
 
Wijayanti A, Zhao CY, Boettiger D, Chiang YZ, Ishii N, Hashimoto T, et al. The Reliability, 
Validity and Responsiveness of Two Disease Scores (BPDAI and ABSIS) for Bullous 
Pemphigoid: Which One to Use? Acta Derm Venereol 2017; 97(1):24-31. 
 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Efficacy and Safety of Dupilumab in Adult Patients with 
Bullous Pemphigoid 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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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Efficacy and Safety of Dupilumab in Adult 
Patients with Bullous Pemphigoid 
Protocol Number: 
R668-BP-1902  
Protocol Version: 
R668-BP-1902 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 Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00337156-1.0 Approved - 04 Mar 2024 GMT-5:00

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                                        VV-RIM-00337156-1.0 Approved - 04 Mar 2024 GMT-5:00