Clinical trial NCT04791319
Conditions: Dermatitis, Atopic
Sponsor: Janssen Research & Development, LLC
Start date: 2021-05-03; Completion date: 2022-03-31
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of bermekimab in participants with moderate to severe atopic dermatitis (AD).

Detailed description:

Arms: arm 1: Participants will receive subcutaneous (SC) placebo once a week (qw) through Week 15. At Week 16, participants will crossover to receive SC bermekimab Dose 2 qw through Week 31. arm 2: Participant will receive SC bermekimab Dose 1 qw from Week 0 through Week 31. arm 3: Participants will receive SC bermekimab Dose 2 qw from Week 0 through Week 15. At Week 16, participants who achieve an eczema area and severity index (EASI)-75 response (responders) will be rerandomized either to continue to receive bermekimab Dose 2 qw, or to receive bermekimab Dose 1 qw, through Week 31 and participants who do not achieve an EASI-75 response (non responders) will continue to receive bermekimab Dose 2 qw through Week 31. arm 4: Participants will receive a loading dose of SC dupilumab Dose 1 at Week 0, SC placebo every two week (q2w) from Week 1 through Week 15 and then dupilumab Dose 2 q2w from Week 2 through Week 14. At Week 16, participants who achieve EASI-75 response (dupilumab responders) will continue on dupilumab Dose 2 q2w through Week 30 and placebo q2w from Week 17 through Week 31. Participants who do not achieve an EASI-75 response (dupilumab non-responders) will receive placebo qw from Week 16 through Week 18 (washout period) and bermekimab Dose 2 qw from Week 19 through Week 31.
Interventions: intervention 1: Placebo intervention 2: Bermekimab intervention 3: Dupilumab
Intervention descriptions: intervention 1: Placebo will be administered subcutaneously. intervention 2: Bermekimab will be administered subcutaneously. intervention 3: Dupilumab will be administered subcutaneously.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 02 June 2021
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 2b, Multicenter, Randomized, Placebo- and Active-comparator-controlled, 
Double-blind Study to Evaluate the Safety and Efficacy of Bermekimab (JNJ-77474462) 
for the Treatment of Participants with Moderate to Severe Atopic Dermatitis
GENESIS
A Study of Bermekimab (JNJ-77474462) in the Treatment of Participants with 
Moderate to Severe Atopic Dermatitis
Protocol 77474462ADM2001; Phase 2b
Amendment 1
JNJ-77474462  (bermekimab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Numbers:
IND:
112459
EudraCT NUMBER:
2020-002587-31         
Status:
Approved
Date:
02 June 2021
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-54593, 2.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04791319


JNJ-77474462 (bermekimab)
Clinical Protocol 77474462ADM2001 Amendment 1
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Status: Approved,  Date: 02 June 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
02 June 2021
Original Protocol
12 November 2020
Amendment 1 (02 June 2021)
Overall Rationale for the Amendment: Clarifications to the protocol have been implemented to provide 
guidance regarding the use of rescue therapy, correct the calculation error in Total Volume of Blood sample 
to be collected, and include additional safety measures related to 12-lead ECG (triplicate). Additional 
changes are also listed in the amendment table below. 
Section Number
and Name
Description of Change
Brief Rationale
1.3, Schedule of 
Activities; 8.2.3, 
Electrocardiograms
In Table 1, added Physical examination assessment 
at screening and removed assessment at Week 0. In 
Table 1, added Vital sign assessment at screening 
and added 12-lead ECG (triplicate) assessment at 
Week 16.
In Section 8.2.3 (Electrocardiograms), added 
Week 16 timepoint to align with the Schedule of 
Activities (SoA) (Table 1). 
Added Physical examination 
assessment at screening to evaluate  
eligibility.
Added Vital sign and 12-lead ECG 
(triplicate) at Week 16 to monitor 
changes while on study 
intervention. 
2.3.2, Dupilumab
Added details regarding hypersensitivity and 
eosinophilic conditions. 
To provide details regarding 
hypersensitivity and eosinophilic 
conditions.
5.1, Inclusion 
Criteria; 5.3, 
Lifestyle 
Considerations
Criterion #10 was modified and the following text 
was removed: and/or ultraviolet [UV] therapy.
Criterion #11 was modified to note that the 
participant agrees not to receive a live virus or live 
bacterial vaccination during the study, and for 
90 days after the last administration. 
In Section 5.3, Criterion #7 was revised to 
participants must not receive a live virus or 
bacterial vaccination during the study and for 
90 days after the last administration. 
Ultraviolet therapy text was 
removed because the washout 
period of phototherapy is specified 
in exclusion criterion #21.
The study protocol criterion was 
amended to note that the participant 
agrees not to receive a live virus or
bacterial vaccination for 90 days to 
align with the Bermekimab 
Investigator’s Brochure guidance 
on the use of  live virus or live 
bacterial vaccination.
5.3, Lifestyle 
Considerations; 
6.8.6, Vaccinations 
(including 
COVID-19)
Added COVID-19 vaccinations to lifestyle 
considerations and concomitant therapy. 
To provide guidance regarding 
locally approved vaccinations 
(including emergency 
use-authorized COVID-19 
vaccine).
6.8.1, Rescue 
Medication
Provided guidance that an IGA assessment will be 
required prior to starting rescue therapy. 
Removed language that hydrocortisone 2.5% 
ointment may be given to the participants for 
rescue treatment. Clarified that any topical 
corticosteroids and topical calcineurin inhibitors 
are allowed as rescue medication.
To provide guidance on the use of 
topical corticosteroids and topical 
calcineurin inhibitors as rescue 
medications during the study.


JNJ-77474462 (bermekimab)
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Status: Approved,  Date: 02 June 2021
Section Number
and Name
Description of Change
Brief Rationale
Removed the following sentence from the last 
paragraph: No more than 2 rounds of rescue 
therapy may be used by a participant and these 
rounds must be separated by at least 1 week.
6.8.4, Prohibited 
Therapy
Added the following clarifying text to topical 
calcineurin inhibitors: “except for rescue therapy”. 
Added text to clarify both systemic and topical 
JAK inhibitors are prohibited in the study. 
To allow topical calcineurin 
inhibitors as rescue medications.
Topical JAK therapies are available 
in some countries.
7.1, Discontinuation 
of Study 
Intervention
From the 4th bullet point, removed restrictive 
clinical details regarding hypersensitivity 
assessment.
From the 5th bullet point, removed “occurring 1 to 
14 days” after study intervention because this was 
considered a restrictive time frame. 
The revised sentences allow the 
investigator to perform clinical 
assessment without restrictive 
details/time frame.
8, Study 
Assessments and 
Procedures
In Table 3, the TB testing sample with a Volume 
per Sample (mL) was updated to 4 mL and the 
Approximate Total Volume of Blood (mL) was 
updated to 4 mL.
In Table 3, the Serum Biomarker with a Volume 
per Sample (mL) was updated to 8.5 mL and No. 
of Samples per Participant was updated to 9. The 
Approximate Total Volume of Blood (mL) was 
updated to 76.5 mL.
In Table 3, updated the Approximate Total Volume 
to 344 mL. Updated total blood volume in the 
paragraph above Table 3.
The tube size for TB collection 
changed. 
Corrected calculation error in Total 
Volume of Blood (mL) in the 
previous version of the protocol. 
8.2.7, Injection-site 
Reactions
Added guidance regarding monitoring for 
injection-site reactions after study intervention 
administration. 
Added for clarification.
8.3.1, Time Period 
and Frequency for 
Collecting Adverse 
Event and Serious 
Adverse Event 
Information
A definition was provided to clarify what 
constitutes a possible Hy’s Law case.
Added for clarification.
10.3, Appendix 3: 
Contraceptive 
Guidance
Minor updates to the appendix.
Minor edits were made to align 
with the sponsor’s most current 
template. 
10.4, Appendix 4: 
Hepatitis B Virus 
(HBV) Screening 
with HBV DNA 
Testing 
Added Japan specific guidance regarding surface 
antigen (HBsAg), core antibody (anti-HBc), and/or 
surface antibody (anti-HBs) monitoring. 
To provide guidance and 
evaluations to be obtained in the 
setting of specific patterns of 
hepatitis B virus test abnormalities.
10.5.1, Appendix 5: 
Regulatory, Ethical, 
and Study Oversight 
Considerations
Added text regarding the use of a “Protocol 
Clarification Communication”.
The sponsor’s template was 
updated to include potential use of 
a “Protocol Clarification 
Communication”. 
10.20, Appendix 20: 
Clinical Laboratory 
Tests 
Added a Clinical Chemistry footnote description 
about liver abnormalities that cross-references 
A Clinical Chemistry footnote was 
added to align with the sponsor’s 
most current template.


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Status: Approved,  Date: 02 June 2021
Section Number
and Name
Description of Change
Brief Rationale
Appendix 21. Potential Hy’s Law case description 
was added (cross-reference to Section 8.3.1).
10.21, Appendix 21: 
Liver Safety: 
Suggested Actions 
and Follow-up 
Assessments
The following new subsections were added: 
10.21.1, Stopping Algorithm; 10.21.2, Follow-up 
Assessments; and 10.21.2.1, Phase 2 Liver 
Chemistry Stopping Criteria and Follow-up 
Assessments.
The sponsor’s template was 
updated to provide guidance and 
evaluations to be obtained in the 
setting of specific patterns of liver 
enzymes abnormalities. 
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted.


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Status: Approved,  Date: 02 June 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1.
PROTOCOL SUMMARY ..................................................................................................................... 9
1.1.
Synopsis........................................................................................................................................... 9
1.2.
Schema .......................................................................................................................................... 14
1.3.
Schedules of Activities ................................................................................................................... 14
2.
INTRODUCTION................................................................................................................................ 20
2.1.
Study Rationale.............................................................................................................................. 20
2.2.
Background .................................................................................................................................... 21
2.2.1.
Comparator/Active Reference Arm............................................................................................. 23
2.3.
Benefit-Risk Assessment ............................................................................................................... 23
2.3.1.
Bermekimab................................................................................................................................ 23
2.3.2.
Dupilumab................................................................................................................................... 24
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 24
4.
STUDY DESIGN ................................................................................................................................ 26
4.1.
Overall Design................................................................................................................................ 26
4.2.
Scientific Rationale for Study Design............................................................................................. 27
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 28
4.3.
Justification for Dose...................................................................................................................... 28
4.4.
End of Study Definition................................................................................................................... 29
5.
STUDY POPULATION ...................................................................................................................... 29
5.1.
Inclusion Criteria ............................................................................................................................ 30
5.2.
Exclusion Criteria ........................................................................................................................... 34
5.3.
Lifestyle Considerations................................................................................................................. 38
5.4.
Screen Failures .............................................................................................................................. 39
5.5.
Criteria for Temporarily Delaying Administration of Study Intervention ......................................... 39
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 39
6.1.
Study Intervention(s) Administered................................................................................................ 39
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 41
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 42
6.4.
Study Intervention Compliance...................................................................................................... 44
6.5.
Dose Modification........................................................................................................................... 44
6.6.
Continued Access to Study Intervention After the End of the Study ............................................. 44
6.7.
Treatment of Overdose .................................................................................................................. 44
6.8.
Concomitant Therapy..................................................................................................................... 45
6.8.1.
Rescue Medication ..................................................................................................................... 45
6.8.2.
Atopic Dermatitis Management .................................................................................................. 46
6.8.3.
Required Treatment.................................................................................................................... 46
6.8.4.
Prohibited Therapy ..................................................................................................................... 46
6.8.5.
Drugs Metabolized by Cytochrome P450................................................................................... 47
6.8.6.
Vaccinations (including COVID-19)............................................................................................ 47
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 47
7.1.
Discontinuation of Study Intervention ............................................................................................ 47
7.1.1.
Liver Chemistry Stopping Criteria............................................................................................... 49
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 49
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 49


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7.3.
Lost to Follow-up............................................................................................................................ 50
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 51
8.1.
Efficacy Assessments .................................................................................................................... 53
8.1.1.
Eczema Area and Severity Index ............................................................................................... 53
8.1.2.
Validated Investigator Global Assessment for Atopic Dermatitis ............................................... 53
8.1.3.
Severity Scoring of Atopic Dermatitis ......................................................................................... 53
8.1.4.
Hand Dermatitis Investigator Global Assessment ...................................................................... 54
8.1.5.
Patient-Reported Dermatology Life Quality Index ...................................................................... 54
8.1.6.
Patient-Oriented Eczema Measure ............................................................................................ 54
8.1.7.
Patient Global Impression of Severity ........................................................................................ 55
8.1.8.
Patient-Reported Outcomes Measurement Information System-29........................................... 55
8.1.9.
Eczema Skin Pain and Itch Numeric Rating Scale..................................................................... 55
8.1.10.
Atopic Dermatitis Itch Scale........................................................................................................ 55
8.1.11.
Digital Actigraphy........................................................................................................................ 56
8.1.12.
Remote Endpoint Assessment Using Total Body Photography ................................................. 56
8.2.
Safety Assessments....................................................................................................................... 56
8.2.1.
Physical Examinations................................................................................................................ 57
8.2.2.
Vital Signs................................................................................................................................... 57
8.2.3.
Electrocardiograms..................................................................................................................... 57
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 57
8.2.5.
Concomitant Medication ............................................................................................................. 58
8.2.6.
Allergic Reactions ....................................................................................................................... 58
8.2.7.
Injection-site Reactions............................................................................................................... 58
8.2.8.
Tuberculosis Evaluation(s) ......................................................................................................... 59
8.2.8.1.
Initial Tuberculosis Evaluation................................................................................................. 59
8.2.8.2.
Ongoing Tuberculosis Evaluation............................................................................................ 59
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 60
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 61
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 62
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 62
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated 
Events......................................................................................................................................... 62
8.3.5.
Pregnancy................................................................................................................................... 63
8.3.6.
Adverse Events of Special Interest............................................................................................. 63
8.4.
Pharmacokinetics and Immunogenicity ......................................................................................... 63
8.5.
Pharmacogenomics ....................................................................................................................... 64
8.6.
Biomarkers ..................................................................................................................................... 64
8.6.1.
Skin Biomarkers.......................................................................................................................... 65
8.6.2.
Serum Biomarkers...................................................................................................................... 65
8.6.3.
Flow Cytometry Analysis ............................................................................................................ 65
8.6.4.
Gene Expression Analysis in Whole Blood ................................................................................ 66
8.7.
Health Economics .......................................................................................................................... 66
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 66
9.1.
Statistical Hypotheses.................................................................................................................... 66
9.2.
Sample Size Determination ........................................................................................................... 66
9.3.
Populations for Analysis Sets ........................................................................................................ 68
9.4.
Statistical Analyses ........................................................................................................................ 68
9.4.1.
General Considerations.............................................................................................................. 68
9.4.2.
Primary Endpoint ........................................................................................................................ 69
9.4.3.
Secondary Endpoints.................................................................................................................. 70
9.4.4.
Exploratory Endpoints................................................................................................................. 71
9.4.5.
Safety Analyses .......................................................................................................................... 72
9.4.6.
Other Analyses ........................................................................................................................... 74
9.5.
Interim Analysis.............................................................................................................................. 75
9.6.
Data Monitoring Committee ........................................................................................................... 75


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Status: Approved,  Date: 02 June 2021
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 76
10.1.
Appendix 1: Abbreviations ............................................................................................................. 76
10.2.
Appendix 2: Tuberculin Skin Testing ............................................................................................. 78
10.3.
Appendix 3: Contraceptive Guidance ............................................................................................ 80
10.4.
Appendix 4: Hepatitis B Virus (HBV) Screening with HBV DNA Testing....................................... 83
10.5.
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations......................................... 84
10.5.1.
Regulatory and Ethical Considerations ...................................................................................... 84
10.5.2.
Financial Disclosure.................................................................................................................... 87
10.5.3.
Informed Consent Process ......................................................................................................... 88
10.5.4.
Data Protection ........................................................................................................................... 89
10.5.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 89
10.5.6.
Committees Structure................................................................................................................. 90
10.5.7.
Publication Policy/Dissemination of Clinical Study Data ............................................................ 90
10.5.8.
Data Quality Assurance.............................................................................................................. 91
10.5.9.
Case Report Form Completion................................................................................................... 91
10.5.10.
Source Documents ..................................................................................................................... 92
10.5.11.
Monitoring ................................................................................................................................... 93
10.5.12.
On-Site Audits............................................................................................................................. 93
10.5.13.
Record Retention........................................................................................................................ 94
10.5.14.
Study and Site Start and Closure ............................................................................................... 94
10.6.
Appendix 6: Guidance on Study Conduct during the COVID-19 Pandemic.................................. 96
10.7.
Appendix 7: Eczema Area and Severity Index .............................................................................. 98
10.8.
Appendix 8: Validated Investigator Global Assessment for Atopic Dermatitis............................... 99
10.9.
Appendix 9: Severity Scoring of Atopic Dermatitis ...................................................................... 100
10.10.
Appendix 10: Hand Dermatitis Investigator Global Assessment ................................................. 101
10.11.
Appendix 11: Patient-Reported Dermatology Life Quality Index ................................................. 102
10.12.
Appendix 12: Patient-Oriented Eczema Measure........................................................................ 103
10.13.
Appendix 13: Patient Global Impression of Severity.................................................................... 105
10.14.
Appendix 14: Patient-Reported Outcomes Measurement Information System-29...................... 106
10.15.
Appendix 15: Eczema Skin Pain and Itch Numeric Rating Scale................................................ 109
10.16.
Appendix 16: Atopic Dermatitis Itch Scale................................................................................... 110
10.17.
Appendix 17: Digital Actigraphy................................................................................................... 112
10.18.
Appendix 18: Remote Endpoint Assessment Using Total Body Photography ............................ 113
10.19.
Appendix 19: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting............................................................................................................................... 114
10.19.1.
Adverse Event Definitions and Classifications ......................................................................... 114
10.19.2.
Attribution Definitions................................................................................................................ 115
10.19.3.
Severity Criteria ........................................................................................................................ 115
10.19.4.
Special Reporting Situations .................................................................................................... 115
10.19.5.
Procedures ............................................................................................................................... 116
10.19.6.
Product Quality Complaint Handling......................................................................................... 117
10.19.7.
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 118
10.20.
Appendix 20: Clinical Laboratory Tests ....................................................................................... 119
10.21.
Appendix 21: Liver Safety: Suggested Actions and Follow-up Assessments.............................. 120
10.21.1.
Stopping Algorithm ................................................................................................................... 120
10.21.2.
Follow-up Assessments............................................................................................................ 120
10.21.2.1.
Phase 2 Liver Chemistry Stopping Criteria and Follow-up Assessments ............................. 120
10.22.
Appendix 21: Protocol Amendment History ................................................................................. 124
11.
REFERENCES................................................................................................................................. 125
INVESTIGATOR AGREEMENT ............................................................................................................... 127


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LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Schedule of Activities From Screening through Week 16 ........................................................ 15
Table 2:
Schedule of Activities From Week 17 through Week 36 .......................................................... 18
Table 3:
Volume of Blood to be Collected From Each Participant.......................................................... 52
Table 4:
Power to Detect a Treatment Difference in EASI-75 at Week 16............................................. 67
Table 5:
Confidence Interval for the Treatment Difference in EASI-75 at Week 16............................... 68
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 14


JNJ-77474462 (bermekimab)
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Status: Approved,  Date: 02 June 2021
1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol number: 77474462ADM2001
A Phase 2b, Multicenter, Randomized, Placebo- and Active-comparator-controlled, Double-blind Study to 
Evaluate the Safety and Efficacy of Bermekimab (JNJ-77474462) for the Treatment of Participants with 
Moderate to Severe Atopic Dermatitis
JNJ-77474462 (bermekimab) is a recombinant human immunoglobulin G1 kappa monoclonal antibody 
(mAb) that binds with high affinity and selectivity for human interleukin-1 alpha (IL-1α) and is an effective 
blocker of IL-1α biological activity. IL-1α is a key mediator of sterile inflammatory responses.  Skin is a 
significant reservoir of preformed IL-1α, and it has been postulated that IL-1α may play a role in the 
pathophysiology of multiple inflammatory skin disorders, including atopic dermatitis (AD).
Bermekimab has been investigated in dermatologic clinical studies and in other indications. Two Phase 2 
studies (1 in AD and 1 in hidradenitis suppurativa) are currently ongoing. 
Bermekimab was initially developed by XBiotech, Inc and is currently being developed by Janssen 
Research and Development, LLC (sponsor).
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the efficacy of bermekimab in 
participants with moderate to severe AD

Proportion of participants with Eczema Area 
and Severity Index-75 (EASI-75, ≥75% 
improvement from baseline) at Week 16
Secondary

To characterize additional assessments of 
efficacy for bermekimab in participants with 
moderate to severe AD

Proportion of participants with both validated 
Investigator Global Assessment for Atopic 
Dermatitis (vIGA-AD) of 0 or 1 and a 
reduction from baseline of ≥2 points at 
Week 16

Proportion of participants with improvement 
(reduction) of eczema-related itch numeric 
rating scale (NRS) ≥4 from baseline to 
Week 16 among participants with a baseline 
itch value ≥4

Proportion of participants with EASI-90 at 
Week 16

To evaluate the efficacy of bermekimab
relative to dupilumab in participants with 
moderate to severe AD

Proportion of participants with EASI-75 at 
Week 16

Proportion of participants with EASI-90 at 
Week 16

Proportion of participants with both vIGA-AD 
of 0 or 1 (on a 5-point scale) and a reduction 
from baseline of ≥2 points at Week 16


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Objectives
Endpoints

Proportion of participants with improvement 
(reduction) of eczema-related itch NRS ≥4 
from baseline to Week 16 among participants 
with a baseline itch value ≥4

To assess the safety and tolerability of 
bermekimab in participants with moderate to 
severe AD

Number/proportion 
of 
participants 
with 
treatment-emergent adverse events (AEs)

Number/proportion 
of 
participants 
with 
treatment-emergent serious adverse events 
(SAEs)

To evaluate the pharmacokinetics (PK) and 
immunogenicity of bermekimab in adult 
participants with moderate to severe AD

Bermekimab concentration over time

The incidence of antibodies to bermekimab
Exploratory

To 
further 
characterize 
efficacy 
of 
bermekimab in participants with moderate to 
severe AD

Improvement from baseline to Week 16 in 
Severity 
Scoring 
of 
Atopic 
Dermatitis 
(SCORAD)

Change from baseline to Week 16 in 
Dermatology Life Quality Index (DLQI)

Improvement from baseline to Week 16 in 
Patient-Oriented Eczema Measure (POEM)

Improvement from baseline to Week 8 in 
eczema-related itch NRS

Improvement from baseline to Week 8 in 
eczema-related pain NRS

Improvement from baseline to Week 16 in 
eczema-related pain NRS

Improvement from baseline to Week 16 in itch 
as measured by the Atopic Dermatitis Itch 
Scale (ADIS)

Proportions of participants with a Patient 
Global Impression of Severity (PGIS) score of 
1 (none) or 2 (mild) at Week 16

Change from baseline to Week 16 in Patient-
Reported Outcomes Measurement Information 
System (PROMIS)-29 total score and sub-
scores

Hand 
Dermatitis
Investigator 
Global 
Assessment (IGA) at Week 16

To assess the impact of treatment with 
bermekimab on selected biomarkers

Changes in cellular and molecular biomarkers 
in skin and blood from baseline


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Hypothesis
The hypothesis for this study is that bermekimab treatment is superior to placebo as assessed by the 
proportion of participants achieving an EASI-75 (≥75% improvement from baseline) at Week 16.
OVERALL DESIGN
This is a randomized, double-blind, placebo- and active-comparator-controlled, multicenter, interventional 
study to assess the efficacy, safety, PK, and immunogenicity of subcutaneous (SC) administered 
bermekimab for the treatment of moderate to severe AD in adult participants. The participant population 
will be comprised of men and women ≥18 years of age, with AD that is moderate to severe, and has been 
present for at least 1 year before the first administration of study intervention, as determined by the 
investigator through patient interview and/or review of the medical history. Participants must also have a 
history of inadequate response to treatment for AD with topical medications or for whom topical treatments 
are otherwise medically inadvisable, an EASI score ≥16, an IGA score ≥3, and an involved percent body 
surface area (BSA) ≥10% at both screening and at baseline. Participants must agree to apply moisturizers 
at least once daily for at least 7 days before randomization and continue the treatment throughout the study.
Two planned database locks (DBLs) will occur when all participants complete the Week 16 visit and at 
Week 36 (end of study).
The end of study is considered as the last visit for the last participant in the study.
An independent, external data monitoring committee (DMC), whose members are not directly involved in 
the conduct of study 77474462ADM2001, will review unblinded safety data to ensure the safety of the 
participants enrolled in this study.
NUMBER OF PARTICIPANTS
Approximately 200 participants are targeted for enrollment in Study 77474462ADM2001.
INTERVENTION GROUPS AND DURATION
Group 1: Placebo

Participants will receive 2 placebo SC administrations weekly from Week 0 through Week 15.

At Week 16, participants will crossover to receive 2 bermekimab 350 mg SC administrations weekly 
through Week 31.
Group 2: Bermekimab 350 mg SC every week (qw)

Participants will receive 1 bermekimab 350 mg SC administration and 1 placebo SC administration at 
Week 0 and every week thereafter through Week 31.
Group 3: Bermekimab 700 mg SC qw

Participants will receive 2 bermekimab 350 mg SC administrations at Week 0 and every week 
thereafter through Week 15. 

At Week 16, participants who achieve an EASI-75 response will be rerandomized in a 1:1 ratio either 
to continue to receive 2 bermekimab 350 mg SC administrations weekly, or to receive 1 bermekimab 
350 mg SC administration and 1 placebo SC administration weekly, through Week 31.

At Week 16, participants who do not achieve an EASI-75 response will continue to receive 
2 bermekimab 350 mg SC administrations weekly through Week 31.


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Group 4: Comparator/Reference Arm (Dupilumab) 

Participants will receive 2 dupilumab 300 mg SC administrations at Week 0. Participants will receive 
2 placebo SC administrations every 2 weeks (q2w) beginning at Week 1 through Week 15. Participants 
will receive 1 dupilumab 300 mg SC administration and 1 placebo SC administration q2w beginning 
at Week 2 through Week 14. 

Participants who achieve an EASI-75 response at Week 16 will continue on 1 dupilumab 300 mg SC 
administration and 1 placebo SC administration q2w from Week 16 through Week 30, and 2 placebo 
SC administrations q2w from Week 17 to 31.

At Week 16, participants who do not achieve an EASI-75 response will receive 2 placebo SC 
administrations weekly at Weeks 16 through 18 (ie, washout period), and 2 bermekimab 350 mg SC 
administrations weekly from Week 19 through Week 31.
Description of Interventions
Bermekimab will be supplied as a sterile liquid formulation of 350 mg (175 mg/mL) of bermekimab in a 
prefilled syringe (PFS) with an injectable volume of 2.0 mL. Bermekimab will be manufactured and 
provided under the responsibility of the sponsor. Refer to the Investigator’s Brochure for a list of excipients.
Commercially available dupilumab will be provided by the sponsor as a sterile liquid formulation of 300 mg 
(150 mg/mL) in a PFS with an injectable volume of 2.0 mL. 
Placebo will be provided by the sponsor.
EFFICACY EVALUATIONS
Efficacy assessments (EASI, vIGA-AD™, percent BSA involvement, SCORAD, and Hand Dermatitis
IGA) and patient-reported outcome (PRO) measures (DLQI, POEM, PGIS, PROMIS-29, Eczema Skin Pain 
and Itch NRS, and ADIS) will be performed at visits according to the Schedules of Activities. Serum 
samples for PK, immunogenicity, and biomarker analyses will be collected at the timepoints shown in the 
Schedules of Activities. Digital actigraphy and evaluation of EASI and SCORAD endpoints from digital 
photographs will be completed from a subgroup of participants who consent to these optional substudies at 
selected sites.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Venous blood samples will be collected for the measurement of serum bermekimab concentrations and 
detection of antibodies to bermekimab at the time points presented in the Schedule of Activities. Serum 
samples will also be collected at the final visit from participants who terminate study participation early.
BIOMARKER EVALUATIONS
Biomarker samples will be collected to evaluate the pharmacodynamics (PD) and mechanism of action of 
bermekimab or help to explain interindividual variability in clinical outcomes or may help to identify 
population subgroups that respond differently to the intervention.
PHARMACOGENOMIC (DNA) EVALUATIONS
A whole blood sample will be collected for pharmacogenomic research in participants who consent 
separately to this optional part of the study (where local regulations permit). Genotyping or sequencing 
techniques will be used to assess variation in the filaggrin (FLG) gene, a risk factor for AD, and 
interleukin-1 alpha gene (IL1A), the target of bermekimab. Additionally, genome-wide genotyping or 
sequencing will be used to assess variation genome-wide. Participants will have the option to participate in 
1 or both of these studies. 


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SAFETY EVALUATIONS
Safety evaluations conducted at each study visit will include the assessment of AEs (at the visit and those 
occurring between evaluation visits), a tuberculosis evaluation and other infection assessment, clinical 
laboratory blood tests (complete blood count and serum chemistries), physical examinations, vital sign 
measurements, concomitant medication review, and observations for injection-site reactions and/or allergic 
reactions.
STATISTICAL METHODS
Sample Size Determination
This study is designed to enroll approximately 200 participants in order to have sufficient power to detect 
a difference between the bermekimab groups and the placebo group for the primary endpoint of the 
proportion of participants achieving EASI-75 at Week 16. The sample size was also chosen to have 
adequate confidence level for the difference between the bermekimab 700 mg group and the dupilumab 
group.
The EASI-75 response rate in the bermekimab 400 mg qw group was approximately 35% at Week 16 and 
70% at Week 7 from the placebo-controlled study (77474462ADM2002) and the open-label study
(2018-PT044), respectively. The EASI-75 response rates at Week 16 were 15% and 12% with placebo and 
51% and 44% with dupilumab, respectively, in the two Phase 3 trials of dupilumab versus placebo in the 
treatment of adult participants with moderate to severe AD.
The EASI-75 response at Week 16 are assumed to be 15% for placebo, 45% to 50% for dupilumab, and 
50% to 70% for the bermekimab 350 mg and 700 mg treatment groups, respectively. Based on these 
assumptions, approximately 200 participants are planned to be randomized in a 1:1:2:2 ratio to the placebo 
(n=33), bermekimab 350 mg (n=33), bermekimab 700 mg (n=67), or dupilumab (n=67) treatment groups. 
These sample sizes provide the study with at least 88% power to detect a treatment difference between the 
bermekimab treatment groups and the placebo group in EASI-75 at Week 16 based on a 2-sample Z-test at 
a Type I error rate of 0.05 (2-sided). These sample sizes also provide at least 88% power to detect a 
treatment difference between the dupilumab and placebo treatment group in EASI-75 at Week 16 at a 
2-sided significance level of 0.05.
Efficacy Analyses
All randomized participants who received at least 1 dose of study intervention will be included in the 
efficacy analyses. Participants will be analyzed according to the treatment group to which they were 
randomized, regardless of the treatment they actually received.
The treatment comparisons for binary endpoints will be performed using a Cochran-Mantel-Haenszel 
(CMH) test stratified by baseline EASI severity or Fisher’s exact test in the case of rare events. The 
differences in binary endpoints between groups and the corresponding CIs will be presented. For continuous 
efficacy endpoints, treatment comparisons will be performed using a Mixed-Effect Model Repeated 
Measure (MMRM) model. The MMRM will include treatment, visit, baseline EASI severity, baseline 
score, baseline score by visit interaction, baseline EASI severity by visit interaction, and the treatment-by-
visit interaction, if applicable. The Least Square mean (LSmean) estimates and their corresponding 95% 
confidence interval (CI) will be provided at each time point. In addition, the estimates of LSmean difference 
and 95% CIs between treatment groups will be provided.
In general, all statistical testing will be performed at a significance level of 0.05 (2-sided) unless otherwise 
specified. Nominal p-values will be displayed for all treatment comparisons.


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Safety Analyses
Safety data, including but not limited to, AEs, SAEs, infections, serious infections, mortality, changes in 
laboratory assessments, and changes in vital signs will be summarized. Treatment-emergent AEs will be 
summarized by treatment group and Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class and preferred terms.
1.2.
Schema
Figure 1:
Schematic Overview of the Study
1.3.
Schedules of Activities 
Two Schedules of Activities (SoA) are presented below, the first for the study period from 
screening through Week 16 (Table 1) and the second from Week 17 through Week 36 (Table 2). 






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Table 1:
Schedule of Activities From Screening through Week 16
  Period
Screeninga
(−28 Days to 
−7 Days)
Blinded, Placebo-controlled Periodm
Weekb
0
1
2
3t
4
5t
6
7t
8
9t
10
11t
12
13t
14
15t
16
Abbreviations: ADIS = Atopic Dermatitis Itch Scale; DLQI = Dermatological Life Quality Index; EASI = Eczema Area and Severity Index; ECG= electrocardiogram; HIV = human 
immunodeficiency virus; ICF = informed consent; IGA = Investigator Global Assessment; NRS = numeric rating scale; PBMC= peripheral blood mononuclear cells; PGIS = 
Patient Global Impression of Severity; POEM = Patient-Oriented Eczema Measure; PROMIS-29 = Patient-Reported Outcomes Measurement Information System-29; RNA = 
ribonucleic acid; SCORAD = Severity Scoring of Atopic Dermatitis; TB = tuberculosis; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis.
Footnotes:
a.
The screening visit should occur no more than 28 days prior to and no less than 7 days before the Week 0 (baseline) visit.
b.
Study visit dates in Weeks 1 through 32 must be calculated from the first study intervention administration visit in Week 0. Visit and study intervention administrations 
should occur within ±3 days of scheduled visit.
c.
All study procedures and evaluations are to be completed before study intervention is administered except where otherwise indicated.
d.
Must be signed before first study-related activity. Separate informed consents are required for participants who chose to participate in the optional pharmacogenomic 
research, biomarkers, actigraphy, and total body photography substudies.
e.
Study intervention administrations must occur no less than 4 days apart.
f.
Women of childbearing potential must have a negative urine pregnancy test result before randomization and before receiving study intervention at all study intervention 
administration visits. This assessment can be performed any other time during the study visit including prior to PRO collection.
g.
The optional total body photography for remote efficacy evaluations will be completed for a limited number of participants at some sites.
h.
All PROs should be collected during the study visit prior to all other assessments, unless otherwise specified.
i.
These assessments should be completed daily beginning at the screening visit.
j.
The optional actigraphy substudy will be completed for a limited number of participants at some sites.
k.
All participants will undergo QuantiFERON®-TB (or T-SPOT® for sites in Japan) testing. If the QuantiFERON®-TB test is not approved/registered in the country in which 
this protocol is being conducted or the tuberculin skin test is mandated by local health authorities, a negative tuberculin skin test result is also required. In Ukraine, while the 
QuantiFERON®-TB test is not approved/registered, it is accepted, and a tuberculin skin test is not required.
l.
For all visits where study intervention will be administrated, all blood samples should be collected prior to study intervention administration for evaluation of serum 
concentration of bermekimab and/or antibodies to bermekimab.
m.
Participants who discontinue study intervention but do not terminate study participation are strongly encouraged to return for all protocol-specified procedures and 
evaluations for approximately 5 weeks following the last dose of study intervention. The procedures and evaluations listed for the Early Termination visit in Table 2 should 
also be performed approximately 5 weeks after the last dose of study intervention. Participants who terminate study participation early should complete the procedures and 
evaluations listed for the Early Termination visit in Table 2 approximately 5 weeks after their last administration of study intervention.  
n.
A venous blood sample for population PK analysis will be collected from all participants at an additional study site visit and must occur on a random day between Week 2 
and Week 12. This visit must not occur on the same day as the scheduled Week 4, Week 8, or Week 12 visits and cannot be collected within 24 hours (either prior to or 
after) of the actual time of study intervention administration at Week 4, Week 8, or Week 12.
o.
Blood sample will be taken pre-dose
p.
The whole blood (pharmacogenomics) sample is optional and should be collected at the specified time point; however, if necessary, it may be collected at a later time point 
without constituting a protocol deviation.
q.
Participation is optional.
r.
Biopsy and tape strip samples to be collected pre-dose. At Week 0, lesional and non-lesional skin samples will be collected. At later timepoints, lesional skin samples will 
be collected.
s.
Skin swab will be collected before skin biopsy and/or tape stripping. Two swabs will be collected – one from the lesional skin from where skin biopsy will be taken and the 
second one from the adjacent non-lesional skin. 
t.
At Weeks 3, 5, 7, 9, 11, 13, and 15 there may be an option for a home health nurse visit instead of a site visit where feasible in the sponsor’s opinion.






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2.
INTRODUCTION
JNJ-77474462 (bermekimab) is a recombinant human immunoglobulin G1 kappa monoclonal 
antibody (mAb) that binds with high affinity and selectivity for human interleukin-1 alpha (IL-1α)
and is an effective blocker of IL-1α biological activity. IL-1α is a key mediator of sterile 
inflammatory responses. Skin is a significant reservoir of preformed IL-1α, and it has been 
postulated that IL-1α may play a role in the pathophysiology of multiple inflammatory skin 
disorders, including atopic dermatitis (AD).
Fourteen clinical studies to date have been conducted using bermekimab, including 12 completed 
studies in a wide range of therapeutic areas, and two Phase 2 studies currently ongoing, 1 in AD 
and 1 in hidradenitis suppurativa (HS). Bermekimab has been administered intravenously (IV) at 
doses ranging from 0.25 mg/kg to 7.5 mg/kg and subcutaneously (SC) at doses from 100 mg to 
800 mg.
For the most comprehensive nonclinical and clinical information regarding bermekimab, refer to 
the latest version of the Investigator's Brochure (IB) for bermekimab.
The term “study intervention” throughout the protocol, refers to bermekimab, dupilumab, or 
placebo as defined in Section 6.1, Study Interventions Administered. 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1.
Study Rationale
This is a Phase 2 randomized, placebo- and active-comparator-controlled, multicenter study to 
assess the safety and efficacy of bermekimab in adult participants with moderate to severe AD
using a placebo control and an active reference arm (DUPIXENT® [dupilumab]) by means of:

Assessment of the efficacy of bermekimab through Week 16.

Evaluating the longer-term efficacy resulting from the SC dose regimens of bermekimab 
through 32 weeks.

Evaluating the efficacy of bermekimab relative to dupilumab

Evaluating safety and tolerability data for bermekimab in these AD participants.
In addition, this study will evaluate the pharmacokinetics (PK), immunogenicity, and 
pharmacodynamics (PD) of bermekimab therapy in participants with AD.
The scientific rationale in support of the study as well as relevant background information on 
nonclinical and clinical studies of bermekimab are summarized in Section 2.2.
An overview of the protocol design and supportive rationale is described in Section 4.


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2.2.
Background
Atopic dermatitis is an inflammatory skin disease that has been reported to affect up to 20% of the 
adult population. Chronic eczema in AD and associated pruritus can be a significant cause of 
morbidity and can impact quality of life. Disease pathogenesis is complex but ultimately converges 
on a pathological inflammatory process that disrupts the protective barrier function of the skin.
Interleukin-1⍺plays a key role in the pathophysiology of a wide range of inflammatory skin 
disorders (Bou-Dargham 2017). Keratinocytes are a major reservoir of IL-1⍺and may be a key 
source of inflammatory stimulus in AD. Skin barrier defect and dysbiosis in AD stimulates 
keratinocytes to secrete chemokines and innate cytokines such as IL-1α, resulting in leukocyte 
infiltration and trafficking into skin to sustain chronic inflammation in AD. IL-1⍺is a key inducer 
of matrix metalloproteinases activity which could be directly involved in the epithelial barrier 
breakdown in AD (Han 2005). In addition, IL-1⍺, rather than IL-1β, was determined to be the 
primary driving force for inducing chronic skin inflammation (Archer 2019). The study included 
mice with epidermal birth defects and showed that keratinocytes, which constitute approximately 
90% of skin cells, secrete aberrant stores of intracellular IL-1⍺in response to skin injury (eg,
scratching), leading to chronic skin inflammation. Atopic dermatitis is strongly associated with 
epidermal barrier defects, most commonly caused by mutated copies of the filaggrin gene
(McAleer 2013). Filaggrin deficiencies are associated with changes in the composition of bacteria 
living on the skin of AD patients (Clausen 2017), whereby bacteria can colonize and infect the 
skin with greater success thereby exacerbating aberrant IL-1⍺secretion (Kezic 2012). In addition 
to being a driver of inflammation, IL-1α has been shown to induce pain mediator substance P 
secretion by neurons (Skoff 2009). Neutralizing IL-1⍺activity resolved chronic skin inflammation 
in the study by Skoff and strongly supported IL-1⍺as a key target for treating AD, along with 
other inflammatory skin diseases.
Endogenous anti-IL-1α antibodies are present in 5% to 28% of the general population
(Gallay 1991; Miossec 2002; Saurat 1991; Suzuki 1991). No negative correlations with disease 
have been noted for these individuals. To the contrary, the presence of natural anti-IL-1α 
antibodies has been associated with favorable outcomes, both with respect to rheumatoid arthritis 
and ischemic heart disease. Animal studies also indicate that IL-1α loss or antagonism does not 
result in harm. Moreover, the well-tolerated use of other approved biological agents that employ 
alternative strategies to block IL-1 activity suggest that bermekimab targeting of IL-1α represents 
a safe treatment approach. 
Bermekimab is a human monoclonal antibody, that binds the cytokine IL-1α with high affinity and 
is an effective blocker of IL-1 α biological activity. IL-1 α is a key mediator of sterile inflammatory 
responses and has been implicated in the pathology of advanced cancer, cardiovascular disease, 
and rheumatologic disease. Clinical evidence generated to date suggests that targeting IL-1 α may 
be an effective treatment in undermining the inflammatory process that drives a wide array of 
diseases, including dermatologic conditions.
In previous dermatology studies, bermekimab demonstrated therapeutic activity and a 
well-tolerated safety profile.


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Nonclinical Studies
A comprehensive overview of the nonclinical development program for bermekimab is available 
in Section 3 of the latest version of the bermekimab IB.
This section provides a summary of the sponsor's assessment of how the overall nonclinical data 
support the safety of the proposed dosing for bermekimab in this Phase 2 program in AD. 
Bermekimab binds with high affinity and specificity to human IL-1α with a dissociation rate 
constant (KD) of 0.14 nM. No binding to human IL-1β or interleukin-1 receptor antagonist 
(IL-1Ra) was detected up to the highest concentrations tested. In addition, bermekimab was shown 
to effectively neutralize the ability of human IL-1α to induce endothelial cell expression of 
adhesion molecules and fibroblast expression of interleukin-6 (IL-6). Bermekimab was bound by 
cynomolgus monkey IL-1α with a KD of 3 nM and did not bind with mouse, rat, or pig IL-1α at 
the highest concentrations tested.
A 1-month repeat intraperitoneal dose mouse study tested bermekimab up to 3 doses of 
312 mg/kg/week. No treatment-related adverse effects were observed.
Clinical Studies
Results from a Phase 2, open-label, dose escalation study of bermekimab in participants with 
moderate to severe AD showed that bermekimab appeared to be safe, well tolerated, and active at 
reducing the severity of AD, including reducing itch and pain (study 2018-PT044, NCT03496974). 
Thirty-eight patients across 9 clinical sites in 2 treatment groups received 1 of 2 SC doses: a low 
(200 mg, n=10) or high (400 mg, n=28) dose of bermekimab once weekly for either a 4 or 8-week 
treatment regimen, respectively. Safety was assessed by pre- and post-treatment measurements of 
vital signs, clinical laboratory assessments (blood chemistry, urinalysis, hematology), allergic 
reaction monitoring, and adverse event monitoring. Efficacy was assessed by change in Eczema 
Area and Severity Index (EASI), IGA, Numerical Rating Scale, Severity Scoring of Atopic 
Dermatitis (SCORAD), Patient-Oriented Eczema Measure (POEM), Dermatological Life Quality 
Index (DLQI), and Global Individual Signs Score from baseline to visit 9. The primary measure 
of efficacy was the EASI. In the study, 39% of participants in the 400 mg dose group achieved a 
75% improvement in EASI score (EASI-75) after 4 weeks of therapy and 75% achieved EASI-75 
at Week 8. An IGA score of 0 (clear) or 1 (minimal) and a ≥2-point decrease from baseline IGA 
at Week 7 was achieved by 25% of participants in the 400 mg dose group. In addition, 61% of 
participants in the 400 mg dose group achieved a 4-point or greater improvement in the Pruritus 
Numerical Rating Scale for overall itch; and 75% achieved a 4-point or greater improvement by 
Week 8. Furthermore, 80% of participants in the 400 mg dose group achieved a 4-point or greater 
improvement in the Numerical Rating Scale for pain by Week 8. 
Preliminary internal company data from a Phase 2 study, 77474462ADM2002 (NCT04021862), 
have recently become available and were used to support decisions about the dose regimens and 
design of this study. Study 77474462ADM2002 is a double-blind, placebo-controlled study of 
bermekimab in adult participants with moderate to severe AD. The primary endpoint of this study


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is the percentage of patients achieving EASI-75 (≥75% improvement from baseline) at Week 16. 
Preliminary results from this study are discussed in Section 4.3.
In other clinical studies completed to date in AD and HS, bermekimab was well tolerated and 
demonstrated therapeutic activity. For the most comprehensive clinical information regarding 
bermekimab, refer to the latest version of the IB for bermekimab.
2.2.1.
Comparator/Active Reference Arm 
DUPIXENT® (dupilumab)]
Dupilumab (DUPIXENT, Regeneron Pharmaceuticals, Inc.) is a human monoclonal IgG4 
antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically 
binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab 
inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the 
Type II receptor.
Dupilumab was selected as the active reference arm for this study because it has demonstrated 
efficacy in patients with moderate to severe AD and serves as a useful efficacy benchmark. 
Dupilumab has been approved for treatment of moderate to severe AD in the adult and pediatric 
populations in the United States, Canada, the European Union, and the Asia-Pacific region.
For further information regarding dupilumab, refer to the current prescribing information. 
2.3.
Benefit-Risk Assessment
2.3.1.
Bermekimab
Based on the available data and the proposed safety measures discussed below, the risks of the 
dose regimens of bermekimab to be investigated in this protocol appear to be acceptable relative 
to the potential benefit.
Bermekimab has undergone previous clinical evaluation in diseases such as psoriasis, AD, HS, 
acne vulgaris, pyoderma gangrenosum, and cancer, as summarized in the latest version of the IB. 
The collective efficacy and safety results of the Phase 1 and Phase 2 clinical studies in healthy 
volunteers and patients in dermatologic indications have indicated a favorable benefit-risk profile 
for bermekimab. In addition, nonclinical evidence suggests that IL-1α may be an important
component for inducing chronic skin inflammation (Abdel-Razzak 1993, Murphy 2000).
Unblinded safety will be evaluated on an ongoing basis throughout this study by an independent 
external Data Monitoring Committee (DMC), in addition to the standard safety oversight 
performed by the sponsor. Details about the safety evaluations that will be utilized to continue or 
modify the protocol as the trial progresses are outlined in Section 9.6 and in the DMC charter.
The risks for bermekimab are infections, hypersensitivity reactions, and injection site reactions. 
More detailed information about the known and expected benefits and risks of bermekimab may 
be found in the IB.


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The safety plan for bermekimab includes monitoring of AEs and safety laboratory results, using 
sites adequately prepared for managing hypersensitivity reactions and patient education for 
recognizing signs of a serious hypersensitivity reaction such as anaphylaxis. In addition, 
participants will be screened for tuberculosis (TB) prior to study entry (Section 8.2.8.1) and receive 
regular ongoing evaluation (Section 8.2.8.2).
Taking into account the measures taken to minimize risk to participants of this study, the potential 
risks identified in association with bermekimab are justified by the anticipated benefits that may 
be afforded to participants with AD.
2.3.2.
Dupilumab
The benefit:risk profile of dupilumab was established in multiple Phase 3 studies, which were the 
basis of global approvals for dupilumab in the treatment of moderate to severe AD in adult and 
pediatric populations. Warnings and precautions for dupilumab include hypersensitivity (including 
anaphylactic reaction, angioedema and serum sickness), conjunctivitis and keratitis, worsening of 
eosinophilic conditions (such as eosinophilic pneumonia and vasculitis consistent with 
eosinophilic granulomatosis with polyangiitis), exercising caution with reduction of corticosteroid 
dosage, and worsening of pre-existing parasitic infections. More detailed information about the 
known and expected benefits and risks of dupilumab can be found in the dupilumab prescribing 
information.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the efficacy of bermekimab in 
participants with moderate to severe AD

Proportion of participants with EASI-75 
(≥75% 
improvement 
from 
baseline) 
at 
Week 16
Secondary

To characterize additional assessments of 
efficacy for bermekimab in participants with 
moderate to severe AD

Proportion of participants with both validated 
Investigator Global Assessment for Atopic 
Dermatitis (vIGA-AD) of 0 or 1 and a 
reduction from baseline of ≥2 points at 
Week 16

Proportion of participants with improvement 
(reduction) of eczema-related itch numeric 
rating scale (NRS) ≥4 from baseline to 
Week 16 among participants with a baseline 
itch value ≥4

Proportion of participants with EASI-90 at 
Week 16

To evaluate the efficacy of bermekimab
relative to dupilumab in participants with 
moderate to severe AD

Proportion of participants with EASI-75 at 
Week 16

Proportion of participants with EASI-90 at 
Week 16


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Objectives
Endpoints

Proportion of participants with both vIGA-AD 
of 0 or 1 (on a 5-point scale) and a reduction 
from baseline of ≥2 points at Week 16

Proportion of participants with improvement 
(reduction) of eczema-related itch NRS ≥4 
from baseline to Week 16 among participants 
with a baseline itch value ≥4

To assess the safety and tolerability of 
bermekimab in participants with moderate to 
severe AD

Number/proportion 
of 
participants 
with 
treatment-emergent adverse events (AEs)

Number/proportion 
of 
participants 
with 
treatment-emergent serious adverse events 
(SAEs)

To evaluate the PK and immunogenicity of 
bermekimab in adult participants with 
moderate to severe AD

Bermekimab concentration over time

The incidence of antibodies to bermekimab
Exploratory

To 
further 
characterize 
efficacy 
of 
bermekimab in participants with moderate to 
severe AD

Improvement from baseline to Week 16 in 
SCORAD

Change from baseline to Week 16 in DLQI

Improvement from baseline to Week 16 in 
POEM

Improvement from baseline to Week 8 in 
eczema-related itch NRS

Improvement from baseline to Week 8 in 
eczema-related pain NRS

Improvement from baseline to Week 16 in 
eczema-related pain NRS

Improvement from baseline to Week 16 in itch 
as measured by the Atopic Dermatitis Itch 
Scale (ADIS)

Proportions of participants with a Patient 
Global Impression of Severity (PGIS) score of 
1 (none) or 2 (mild) at Week 16

Change from baseline to Week 16 in Patient-
Reported Outcomes Measurement Information 
System(PROMIS)-29 total score and sub-
scores

Hand Dermatitis IGA at Week 16

To assess the impact of treatment with 
bermekimab on selected biomarkers

Changes in cellular and molecular biomarkers 
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Other secondary analyses are listed in Section 9.4.3. Additional exploratory endpoints are listed in 
Section 9.4.4. Refer to Section 8, Study Assessments and Procedures for evaluations related to 
endpoints.
HYPOTHESIS
The hypothesis for this study is that bermekimab treatment is superior to placebo as assessed by 
the proportion of participants achieving an EASI-75 (≥75% improvement from baseline) at 
Week 16.
4.
STUDY DESIGN
4.1.
Overall Design
This is a randomized, double-blind, placebo- and active-comparator-controlled, multicenter,
interventional study to assess the efficacy, safety, PK, and immunogenicity of SC administered 
bermekimab for the treatment of moderate to severe AD in adult participants. The participant 
population will comprise men and women who have had moderate to severe AD for at least 1 year.
A diagram of the study design (Figure 1) is provided in Section 1.2, Schema.
As depicted in Figure 1, approximately 200 participants who satisfy all inclusion and exclusion 
criteria will be randomly assigned in this study a 1:1:2:2 ratio to 1 of 4 treatment groups:
Group 1: Placebo
Participants will receive placebo weekly through Week 15. At Week 16, participants will crossover 
to receive bermekimab 700 mg weekly through Week 31.
Group 2: Bermekimab 350 mg SC every week (qw)
Participants will receive bermekimab 350 mg at Week 0 and every week thereafter through 
Week 31.
Group 3: Bermekimab 700 mg SC qw
Participants will receive bermekimab 700 mg at Week 0 and every week thereafter through 
Week 15. At Week 16, participants who achieve an EASI-75 response will be rerandomized in a 
1:1 ratio either to continue to receive bermekimab 700 mg weekly, or to receive bermekimab 
350 mg weekly, through Week 31. At Week 16, participants who do not achieve an EASI-75 
response will continue to receive bermekimab 700 mg weekly through Week 31.
Group 4: Comparator/Reference Arm (Dupilumab) 
Participants will receive a loading dose of dupilumab 600 mg at Week 0. Participants will 
receive dupilumab 300 mg every 2 weeks (q2w) beginning at Week 2 through Week 14. 
Participants who achieve an EASI-75 response at Week 16 will continue on dupilumab 300 mg 
q2w from Week 16 through Week 30. At Week 16, participants who do not achieve an EASI-75 
response (ie, dupilumab nonresponders) will receive placebo weekly at Weeks 16 through 18 (ie, 
washout period), and bermekimab 700 mg weekly from Week 19 through Week 31.


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Details on placebo SC administrations to maintain the blind are provided in Section 6.1.
A screening period will occur approximately 4 weeks before Week 0. All participants will enter 
the safety follow-up after Week 31 through Week 36. The total duration of study participation will 
be approximately 40 weeks.
Two planned database locks (DBLs) will occur when all participants complete the Week 16 visit
and at Week 36 (end of study). 
Efficacy assessments (EASI, vIGA-AD™, percent body surface area [BSA] involvement, 
SCORAD, and Hand Dermatitis IGA) and patient-reported outcome (PRO) measures (DLQI, 
POEM, PGIS, PROMIS-29, Eczema Skin Pain and Itch NRS, and ADIS) will be performed at 
visits according to the Schedules of Activities. Serum samples for PK, immunogenicity, and 
biomarker analyses will be collected at the timepoints shown in the Schedules of Activities
(Section 1.3). Digital actigraphy and evaluation of EASI and SCORAD endpoints from digital 
photographs will be completed from a subgroup of participants who consent to these optional 
substudies at selected sites.
An interim analysis of data through Week 16 is planned for this study when approximately 50% 
of participants have completed the Week 16 visit. An independent, internal committee will review 
the results of the interim analysis. In addition, an independent, external DMC will review 
unblinded safety data to ensure the safety of the participants enrolled in this study. Refer to 
Section 9.5 (Interim Analysis) and Section 9.6 (Data Monitoring Committee) for details.
4.2.
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active intervention. Dupilumab (DUPIXENT) is 
approved for the treatment of moderate to severe AD and was selected as a reference arm to 
benchmark bermekimab efficacy relative to dupilumab. 
During the crossover period after Week 16, participants who received 700 mg bermekimab and 
are EASI-75 responders at Week 16 will be rerandomized 1:1 to either bermekimab 700 mg or 
350 mg to explore the potential for a lower maintenance dosage of bermekimab. For the dupilumab 
group, EASI-75 nonresponders at Week 16 will receive bermekimab 700 mg to explore if 
dupilumab nonresponders can gain response after switching to bermekimab.
Randomization will be used to minimize bias in the assignment of participants to intervention
groups, to increase the likelihood that known and unknown participant attributes (eg, demographic 
and baseline characteristics) are evenly balanced across intervention groups, and to enhance the 
validity of statistical comparisons across intervention groups. Blinded intervention will be used to 
reduce potential bias during data collection and evaluation of clinical endpoints.


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DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in intervention distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to 
allow the identification of genetic factors that may influence the PK, PD, efficacy, or safety of 
bermekimab and to identify genetic factors associated with AD.
Biomarker samples will be collected to evaluate the mechanism of action of bermekimab or help 
to explain interindividual variability in clinical outcomes or may help to identify population 
subgroups that respond differently to an intervention. The goal of the biomarker analyses is to 
evaluate the PD of bermekimab and aid in evaluating the intervention-clinical response 
relationship. 
DNA and biomarker samples may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits, 
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected from each participant in each group (approximately 294 mL 
over approximately 37 weeks) is far less than the American Red Cross standard limit for whole blood 
donation (approximately 475 mL every 8 weeks) and is therefore considered an acceptable amount 
of blood to be collected over this time period. For more details regarding blood collection, see Blood 
Sample Collection in Section 8.
4.3.
Justification for Dose
Two bermekimab dose regimens were selected to be evaluated in this study: 350 mg SC qw and 
700 mg SC qw. These dose regimens were chosen based on bermekimab PK, efficacy, and safety 
data from a Phase 2 open-label study (2018-PT044, NCT03496974) and a Phase 2 
placebo-controlled study (77474462ADM2002, NCT04021862) in participants with AD.   
Results from the open-label study (2018-PT044) of bermekimab demonstrated clinically 
meaningful activity in participants with AD. In the 400 mg SC qw group, 71% of participants 
achieved at least 75% improvement in EASI at Week 7, while none of the participants achieved 
EASI-75 at Week 4 in the 200 mg qw group. The study results suggested a possible dose response 
for the 400 mg SC qw compared with the 200 mg SC qw group. Based on these findings, a Phase 2 
placebo-controlled study (77474462ADM2002) was conducted to further evaluate 400 mg SC qw 


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and 400 mg SC q2w. The Week 16 data from study 77474462ADM2002 showed significant effect 
of bermekimab 400 mg qw group relative to placebo (EASI-75: 34.5% vs. 13.8%, respectively),
while the 400 mg q2w group showed numerically higher EASI-75 response relative to placebo
(EASI-75: 24.1% vs 13.8%, respectively). Since 400 mg SC qw demonstrated meaningful clinical 
efficacy in these 2 AD studies, a similar dose regimen of 350 mg SC qw was selected to be 
evaluated in this Phase 2b study. The formulation for 350 mg SC (175 mg/mL in 2 mL) is less 
viscous compared to the formulation for 400 mg SC (200 mg/mL in 2 mL). Bermekimab 350 mg 
SC qw is expected to result in only slightly lower PK exposure compared to 400 mg SC qw. 
In order to expand the dose range for treatment with bermekimab, a higher dose regimen of 700 mg 
SC qw was also selected to be evaluated in this Ph2b study. The dose regimen of 700 mg SC qw 
will provide 2-fold higher exposure than 350 mg qw and thus may achieve better efficacy in AD. 
The weekly dosing frequency was selected based on bermekimab half-life (T1/2). Bermekimab T1/2
was estimated to be approximately 1 week so that weekly dosing is necessary in order to maintain 
adequate drug exposure over the entire dosing interval. 
Bermekimab was well tolerated in AD study 2018-PT044 (200 mg SC qw and 400 mg SC qw) 
with no safety concerns. In ongoing Phase 2 AD and HS studies, 101 participants in
77474462HDS2002 (NCT04019041) and 29 participants in 77474462ADM2002 were dosed with 
an 800 mg SC loading dose followed by 400 mg qw of bermekimab with no safety concerns 
identified. The highest dose of bermekimab studied was 7.5 mg/kg IV q2w in HS (10 participants;
Kanni 2018), also with no safety concerns. The 7.5 mg/kg IV dose is equivalent to 1,125 mg SC 
for a 90 kg (average body weight of HS patients) individual assuming a SC bioavailability of 60%. 
Overall, the 2 proposed dose regimens are expected to be efficacious and would provide an 
opportunity to explore the dose response and PK/PD relationships to enable optimal dose selection 
for subsequent clinical trials in moderate to severe AD. These 2 dose regimens are also considered 
to be safe in participants with moderate to severe AD. 
4.4.
End of Study Definition
End of Study Definition
The end of study is considered as the last visit for the last participant in the study. The final data 
from the study site will be sent to the sponsor (or designee) after completion of the final participant 
visit at that study site, in the time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed all 
scheduled study interventions through Week 31 and has completed all assessments at Week 36 of 
the safety follow-up period.
5.
STUDY POPULATION
A target sample size of 200 participants will be enrolled under the 77474462ADM2001 protocol.


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Screening for eligible participants will be performed within 4 weeks before administration of the 
study intervention. Refer to Section 5.4, Screen Failures for conditions under which the repeat of 
any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age and Sex
1.
Be 18 (or the legal age of consent in the jurisdiction in which the study is taking place) 
years of age and be a male or female.
Type of Participant and Disease Characteristics
2.
Be otherwise healthy on the basis of physical examination, medical history, vital signs, 
and 12-lead electrocardiograms (ECGs) performed at screening. Any abnormalities, must 
be consistent with the underlying illness in the study population and this determination 
must be recorded in the participant's source documents and initialed by the investigator.
3.
Have AD for at least 1 year (365 days) prior to the first administration of study 
intervention as determined by the investigator through participant interview and/or review 
of the medical history.
4.
Have a history of inadequate response to treatment for AD with topical medications or 
for whom topical treatments are otherwise medically inadvisable (eg, due to important 
side effects or safety risks).
5.
Be considered, in the opinion of the investigator, a suitable candidate for dupilumab 
(DUPIXENT®) therapy according to their country's approved DUPIXENT product 
labeling.
6.
Have an EASI score ≥16 at screening and at baseline.
7.
Have an IGA score ≥3 at screening and at baseline.
8.
Have an involved BSA ≥10% at screening and at baseline.


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9.
Have screening laboratory test results within the following parameters, if one or more of 
the laboratory parameters is out of range, a single retest of laboratory values is permitted:
a.
Hemoglobin ≥10 g/dL (SI: ≥100 g/L)
b.
White blood cells ≥3.5 x 103/μL (SI: ≥3.5 GI/L)
c.
Neutrophils ≥1.5 x 103/μL (SI: ≥1.5 GI/L)
d.
Platelets ≥100 x 103/μL (SI: ≥100 GI/L)
e.
Serum creatinine ≤1.5 mg/dL (SI: ≤137 μmol/L)
f.
Aspartate aminotransferase ≤2 × upper limit of normal (ULN)
g.
Alanine aminotransferase ≤2 × ULN
h.
Alkaline phosphatase ≤2 × ULN
10.
Criterion modified per Amendment 1. 
10.1 Agree to discontinue any topical medications/treatments/therapies (excluding 
non-prescription moisturizers, which are required for daily use per protocol, see 
Section 6.8.3) for AD within 1 week before the first administration of study intervention.
11.
Criterion modified per Amendment 1. 
11.1 Agree not to receive a live virus or live bacterial vaccination during the study, and 
for 90 days after the last administration of study intervention.
12.
Agree not to receive a Bacille Calmette-Guérin (BCG) vaccination during the study, and 
for 12 months after the last administration of study intervention.
TB screening
13.
Are considered eligible according to the following TB screening criteria:
a.
Have no history of latent or active TB before screening. An exception is made 
for participants who have a history of latent TB and:
o
are currently receiving treatment for latent TB,
OR
o
will initiate treatment for latent TB before the first administration of study 
intervention,
OR
o
have documentation of having completed appropriate treatment for latent 
TB within 5 years before the first dose of study intervention. It is the 
responsibility of the investigator to verify the adequacy of previous anti 
tuberculous treatment and provide appropriate documentation. Participants
with a history and documentation of having completed appropriate 


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treatment for latent TB more than 5 years before the first dose of study 
intervention are not eligible.
b.
Have no signs or symptoms suggestive of active TB upon medical history and/or 
physical examination.
c.
Have had no known recent close contact with a person with active TB or, if there 
has been such contact, will be referred to a physician specializing in TB to 
undergo additional evaluation and, if warranted, receive appropriate treatment 
for latent TB before the first administration of study intervention.
d.
Within 2 months before the first administration of study intervention, have a 
negative QuantiFERON®-TB (or T-SPOT® for sites in Japan) test result, or have 
a newly identified positive QuantiFERON®-TB (or T-SPOT® for sites in Japan) 
test result (see laboratory manual) in which active TB has been ruled out and for 
which appropriate treatment for latent TB has been initiated before the first 
administration of study intervention. Within 2 months before the first 
administration of study intervention, a negative tuberculin skin test, or a newly 
identified positive tuberculin skin test in which active TB has been ruled out and 
for which appropriate treatment for latent TB has been initiated before the first 
administration of study intervention, is additionally required if the 
QuantiFERON®-TB test is not approved/registered in that country or the 
tuberculin skin test is mandated by local health authorities.
NOTE: A negative tuberculin skin test result (see Appendix 2 [Section 10.2]) is 
additionally required if the QuantiFERON-TB® test is not approved/registered in the 
country in which this protocol is being conducted. In Ukraine, while the 
QuantiFERON-TB® test is not approved/registered, it is acceptable, and an additional 
tuberculin skin test is not required. The QuantiFERON-TB® (or T-SPOT® for sites in 
Japan) test and the tuberculin skin test are not required at screening for participants with 
a history of latent TB, if active TB has been ruled out, and if appropriate treatment has 
been initiated/completed as described above in Inclusion Criterion #13a
e.
Have a chest radiograph (both posterior-anterior and lateral views, or per country 
regulations where applicable), taken within 12 weeks before the first 
administration of study intervention and read by a radiologist or qualified 
pulmonologist, with no evidence of current, active TB or old, inactive TB. A 
chest CT scan is also acceptable if already available or obtained outside of the 
study protocol.
Contraceptive/Barrier Requirements 
14.
Before randomization, a woman must be (as defined in Appendix 3, Section 10.3, 
Contraceptive Guidance):
a.
Not of childbearing potential
b.
Of childbearing potential and practicing a highly effective method of 
contraception (failure rate of <1% per year when used consistently and correctly) 
and agrees to remain on a highly effective method while receiving study 
intervention and until 12 weeks after last dose - the end of relevant systemic 


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exposure. The investigator should evaluate the potential for contraceptive 
method failure (eg, noncompliance, recently initiated) in relationship to the first 
dose of study intervention. Examples of highly effective methods of 
contraception are located in Appendix 3, Section 10.3, Contraceptive Guidance.
NOTE: If a female participant’s childbearing potential changes after start of the study 
(eg, a woman who is not heterosexually active becomes active, a premenarchal woman 
experiences menarche), she must begin practicing a highly effective method of birth 
control, as described above.
15.
A woman of childbearing potential must have a negative urine pregnancy test (β-human 
chorionic gonadotropin [β-hCG]) at screening and at Week 0 prior to administration of 
study intervention.
16.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for at least 12 weeks after receiving the last 
administration of study intervention.
17.
A man who is sexually active with a woman of childbearing potential and who has not
had a vasectomy must agree to use a barrier method of birth control (eg, either a condom 
[with spermicidal foam/gel/film/cream/suppository if available in their locale] or a partner 
with an occlusive cap [diaphragm or cervical/vault caps] plus
spermicidal
foam/gel/film/cream/suppository if available in their locale), during the study and for at 
least 12 weeks after receiving the last administration of study intervention.
18.
All men must also agree to not donate sperm during the study and for at least 12 weeks 
after receiving the last administration of study intervention.
Informed Consent
19.
Must sign an ICF indicating that he or she understands the purpose of, and procedures 
required for, the study and is willing to participate in the study.
20.
Must sign a separate informed consent form if he or she agrees to provide an optional 
DNA sample for research (where local regulations permit). Refusal to give consent for 
the optional DNA research sample does not exclude a participant from participation in
the study.
21.
Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.


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5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
Medical Conditions
1.
Has a current diagnosis or signs or symptoms of severe, progressive, or uncontrolled 
renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, 
hematologic, rheumatologic, psychiatric, or metabolic disturbances.
2.
Has unstable cardiovascular disease, defined as a recent clinical deterioration (eg, 
unstable angina, rapid atrial fibrillation) in the last 3 months or a cardiac hospitalization 
within the last 3 months.
3.
Has as a history of lymphoproliferative disease, including lymphoma; a history of 
monoclonal gammopathy of undetermined significance; or signs and symptoms 
suggestive of possible lymphoproliferative disease, such as lymphadenopathy or 
splenomegaly.
4.
A history of malignancy within 5 years before screening (exceptions are squamous and 
basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy,
which is considered cured with no evidence of recurrence for at least 3 months prior to 
the first administration of study intervention and with minimal risk of recurrence).
5.
Has a history of chronic or recurrent infectious disease, including but not limited to 
chronic renal infection, chronic chest infection (eg, bronchiectasis), recurrent urinary 
tract infection (recurrent pyelonephritis or chronic nonremitting cystitis), fungal 
infection (mucocutaneous candidiasis), or open, draining, or infected skin wounds or 
ulcers.
6.
Has or has had a serious infection (eg, sepsis, pneumonia, or pyelonephritis), or has 
been hospitalized or received IV antibiotics for an infection during the 2 months before 
screening.
7.
Has or has had herpes zoster within the 2 months before screening.
8.
Has a history of an infected joint prosthesis or has received antibiotics for a suspected
infection of a joint prosthesis, if that prosthesis has not been removed or replaced.
9.
Has a history of being human immunodeficiency virus (HIV) antibody-positive, or tests 
positive for HIV at screening.
10.
Tests positive for hepatitis B virus (HBV) infection (see Appendix 4, [Section 10.4]) or 
who are seropositive for antibodies to hepatitis C virus (HCV) at screening.


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11.
During the 6 weeks prior to baseline, have had any of (a) confirmed SARS-CoV-2 
(Coronavirus Disease 2019; COVID-19) infection (test positive), OR (b) suspected 
SARS-CoV-2 infection (clinical features without documented test results), OR (c) close 
contact with a person with known or suspected SARS-CoV-2 infection.
An exception to this criterion maybe granted if a participant has a documented negative 
result for a validated SARS-CoV-2 test:
(i)
Obtained at least 2 weeks after conditions (a), (b), (c) above (timed from 
resolution of key clinical features if present, eg, fever, cough, dyspnea)
        AND
(ii)
with absence of ALL conditions (a), (b), (c) above during the period between 
the negative test result and the baseline study visit
NOTES on COVID-19-related exclusion:

The field of COVID-19-related testing (for presence of, and immunity to, the 
SARS-CoV-2 virus) is rapidly evolving. Additional testing may be performed as 
part of screening and/or during the study if deemed necessary by the investigator 
and in accordance with current regulations / guidance from authorities / standards 
of care.

Precaution: for those who may carry a higher risk for severe COVID-19 illness, 
follow guidance from local health authorities when weighing the potential benefits 
and risks of enrolling in the study, and during participation in the study.
12.
Has a history of latent or active granulomatous infection, including histoplasmosis or 
coccidioidomycosis, prior to screening. Participants with radiographic evidence of 
possible prior histoplasmosis or coccidioidomycosis will be excluded. Refer to 
Inclusion Criterion 13 for information regarding eligibility with a history of latent TB.
13.
Has a chest radiograph within 3 months before the first administration of study 
intervention that shows an abnormality suggestive of a malignancy or current active 
infection, including TB. A chest CT scan is also acceptable if already available or 
obtained outside of the study protocol.
14.
Has ever had a nontuberculous mycobacterial infection or opportunistic infection (eg, 
cytomegalovirus, pneumocystis, aspergillosis).
15.
Has 2 indeterminate (on repeat sampling) QuantiFERON®-TB test results.


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16.
Has had major surgery (eg, requiring general anesthesia and hospitalization) within 
8 weeks before screening, or has not fully recovered from such surgery, or has such 
surgery planned during the time the participant is expected to participate in the study.
NOTE: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
17.
Has a transplanted organ (with exception of a corneal transplant >3 months before the 
first administration of study intervention).
18.
Has known allergies, hypersensitivity, or intolerance to bermekimab or its excipients 
(refer to the IB) or to dupilumab or its excipients.
Prior/Concomitant Therapy
19.
Has previously received dupilumab. 
20.
Has received an immunomodulating biologic therapy within the previous 3 months of 
study intervention administration (including, but not limited to, anti-cytokine, anti-
complement antibodies, anti-Ig antibodies, etc).
21.
Has received phototherapy or any systemic medications/treatments that could affect AD 
or IGA evaluations within 4 weeks of the first administration of any study intervention.
22.
Initiation of treatment of AD with any prescription topicals including moisturizers 
during the screening period (see Section 6.8.4), or use of any prescription topical 
treatment for AD within 1 week of the baseline visit.
23.
Has received systemic immunosuppressant, immunomodulatory, or cytotoxic 
treatments (including, but not limited to, oral or injectable corticosteroids, cyclosporin, 
or methotrexate) that could affect AD or IGA evaluations within 4 weeks before the 
baseline visit, or any condition that, in the opinion of the investigator, is likely to require 
such treatment(s) during the first 4 weeks of study treatment
24.
Has ever received any IL-1 antagonist (eg, including but not limited to anakinra, 
rilonacept).
25.
Has received natalizumab, belimumab, or agents that modulate B cells or T cells (eg, 
rituximab, alemtuzumab, abatacept, or visilizumab) within 12 months of the first 
administration of study intervention.
26.
Has received any systemic immunosuppressants (eg, methotrexate [MTX], 
azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil,
tacrolimus) within 4 weeks of the first administration of study intervention.


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Prior/Concurrent Clinical Study Experience
27.
Has received any non-biologic investigational therapy within 30 days or 5 half-lives 
(whichever is longer) of any study intervention administration or is currently enrolled 
in another study using an investigational agent, device, or procedure
28.
Has received, or is expected to receive, any live virus or bacterial vaccination within 
12 weeks before the first administration of study intervention. 
29.
Has had a BCG vaccination within 12 months of screening.
30.
Has known intolerance or hypersensitivity to any biologic medication, or known 
allergies or clinically significant reactions to murine, chimeric, or human proteins, 
mAbs, or antibody fragments.
31.
Is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this 
study or within 12 weeks after the last dose of study intervention.
32.
Plans to father a child while enrolled in this study or within 12 weeks after the last dose 
of study intervention.
Other Exclusions
33.
Is known to have had a substance abuse (drug or alcohol) disorder within the previous 
12 months.
34.
Lives in an institution on court or authority order.
35.
Any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
36.
Is an employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as 
family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The 
required source documentation to support meeting the enrollment criteria are noted in Appendix 5
(Section 10.5, Regulatory, Ethical, and Study Oversight Considerations.


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5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation:
1.
A woman of childbearing potential who is heterosexually active must remain on a 
highly effective method of birth control (Inclusion Criterion 14) during the study and 
for at least 12 weeks after receiving the last administration of study intervention.
2.
A woman must agree not to donate eggs (ova, oocytes) during the study and for a period 
of at least 12 weeks following the last administration of study intervention (Inclusion 
Criterion 16). 
3.
A man who is sexually active with a female of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control (See 
Inclusion Criterion 17) during the study and for at least 12 weeks after receiving the last 
administration of study intervention.
4.
A man must agree to not donate sperm during the study and for at least 12 weeks after 
receiving the last administration of study intervention (Inclusion Criterion 18). 
5.
Participants must comply with restrictions on concomitant medications and therapies 
specified in the protocol (see Section 6.8, Concomitant Therapy for details).
6.
All patients are required to apply moisturizers at least once daily for at least 7 days 
before randomization and continue the treatment throughout the study (including the 
safety follow-up period; see Section 6.8.3, Required Treatment for details).
7.
Participants must not receive a live virus or bacterial vaccination during the study and 
for 90 days after the last administration of any study intervention (Inclusion 
Criterion 11). 
8.
Participants must not receive a BCG vaccination during the study and for 12 months
after the last administration of any study intervention (Inclusion Criterion 12). 
9.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria.
10.
It is recommended that participants are up-to-date on age-appropriate vaccinations prior 
to screening as per routine local medical guidelines. For study participants who received 
locally-approved (and including emergency use-authorized) COVID-19 vaccines 
recently prior to study entry, follow applicable local vaccine labelling, guidelines, and 
standards of care for patients receiving immune-targeted therapy when determining an 
appropriate interval between vaccination and study enrollment (see Section 6.8.6,
Vaccinations [including COVID-19]).


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5.4.
Screen Failures
If, during the screening phase, the subject has not met all inclusion criteria or met any exclusion 
criteria, or is unable or unwilling to adhere to the prohibitions and restrictions of the study, the 
subject is considered to be a screen failure and is not eligible to be randomized at that time.
Retesting of abnormal laboratory values that may lead to exclusion will be allowed once. Retesting 
can occur at an unscheduled visit during the specified screening period of 4 weeks.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 1 time. Rescreened participants will be assigned a new participant number, undergo the 
informed consent process, and then start a new screening period.
Completion of screening and randomization procedures within the specified screening window of 
approximately 4 weeks is required. No exceptions or waivers for screen failures are allowed. 
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
5.5.
Criteria for Temporarily Delaying Administration of Study Intervention
Guidelines for study intervention administration affected by the COVID-19 pandemic are found 
in Appendix 6 (Section 10.6).
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1.
Study Intervention(s) Administered
The study intervention presentation to be used in this study is a sterile liquid formulation of 350 mg 
(175 mg/mL) of bermekimab in a prefilled syringe (PFS) with an injectable volume of 2.0 mL. 
Bermekimab will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB for a list of excipients.
Commercially available dupilumab will be provided by the sponsor as a sterile liquid formulation 
of 300 mg (150 mg/mL) in a PFS with an injectable volume of 2.0 mL. 
Placebo will be provided by the sponsor.


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All participants will receive 2 SC injections at each visit every week from Week 0 through 
Week 31. Since 2 SC injections will be administered at each administration visit, each SC injection 
should be given at a different location of the body. 
Group 1: Placebo

Participants will receive 2 placebo SC administrations weekly from Week 0 through Week 15.

At Week 16, participants will crossover to receive 2 bermekimab 350 mg SC administrations 
weekly through Week 31.
Group 2: Bermekimab 350 mg SC qw

Participants will receive 1 bermekimab 350 mg SC administration and 1 placebo SC 
administration at Week 0 and every week thereafter through Week 31.
Group 3: Bermekimab 700 mg SC qw

Participants will receive 2 bermekimab 350 mg SC administrations at Week 0 and every week 
thereafter through Week 15. 

At Week 16, participants who achieve an EASI-75 response will be rerandomized in a 1:1 
ratio either to continue to receive 2 bermekimab 350 mg SC administrations weekly, or to 
receive 1 bermekimab 350 mg SC administration and 1 placebo SC administration weekly, 
through Week 31.

At Week 16, participants who do not achieve an EASI-75 response will continue to receive 
2 bermekimab 350 mg SC administrations weekly through Week 31.
Group 4: Comparator/Reference Arm (Dupilumab) 

Participants will receive 2 dupilumab 300 mg SC administrations at Week 0. Participants will 
receive 2 placebo SC administrations q2w beginning at Week 1 through Week 15. Participants 
will receive 1 dupilumab 300 mg SC administration and 1 placebo SC administration q2w 
beginning at Week 2 through Week 14. 

Participants who achieve an EASI-75 response at Week 16 will continue on 1 dupilumab 
300 mg SC administration and 1 placebo SC administration q2w from Week 16 through 
Week 30, and 2 placebo SC administrations q2w from Week 17 to 31.

At Week 16, participants who do not achieve an EASI-75 response will receive 2 placebo SC 
administrations weekly at Weeks 16 through 18 (ie, washout period), and 2 bermekimab 
350 mg SC administrations weekly from Week 19 through Week 31.
Study intervention administration must be captured in the source documents and the case report 
form (CRF). Study-site personnel will instruct participants on how to store study intervention for 
at-home use when feasible as indicated in the Schedule of Activities (SoA).
For details on rescue medications, refer to Section 6.8.1. For a definition of study intervention 
overdose, refer to Section 6.7, Treatment of Overdose.
Guidelines for study intervention administration affected by the COVID-19 pandemic are found 
in Appendix 6 (Section 10.6).


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6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Bermekimab (JNJ-77474462) must be stored at controlled temperatures ranging from 36°F to 46°F 
(2°C to 8°C) and protected from light. Placebo must be stored at controlled temperatures, as 
indicated on the product-specific labeling. 
Dupilumab must be stored as indicated on the product-specific labeling.
Refer to the Site Investigational Product Binder for additional guidance, including Instructions For 
Use, on study intervention preparation, handling, and storage.
Study intervention labels will contain information to meet the applicable regulatory requirements.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The study intervention administered to the 
participant must be documented on the intervention accountability form. All study intervention 
will be stored and disposed of according to the sponsor's instructions. Study-site personnel must 
not combine contents of the study intervention containers.
The dispensing of study intervention to the participant, and the return of study intervention from 
the participant (if applicable), must be documented on the intervention accountability form. 
Participants must be instructed to return all original containers, whether empty or containing study 
intervention.
If rescue medication or other medication is also supplied by the sponsor, inclusion of this 
medication on the intervention accountability form is required. The participants must return unused 
study intervention to the study site.
Study intervention must be handled in strict accordance with the protocol and the container label 
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study intervention, and study intervention returned by the 
participant, must be available for verification by the sponsor's study site monitor during on-site 
monitoring visits. The return to the sponsor of unused study intervention, or used returned study 
intervention for destruction, will be documented on the intervention return form. When the study 
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this 
must also be documented on the intervention return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. The study intervention boxes will be retained for 
inventory by the sponsor.


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Study intervention should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be 
supplied only to participants participating in the study. Returned study intervention must not be 
dispensed again, even to the same participant. Study intervention may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Dynamic central randomization will be implemented in this study. Participants will be randomly 
assigned to 1 of 4 intervention groups based on a minimization randomization algorithm 
implemented in the interactive web response system (IWRS) before the study under the 
supervision of the sponsor.
The randomization method will be a minimization procedure with biased-coin assignment, which 
minimizes the imbalance in the distribution of the number of participants across treatment groups 
within the levels of each individual stratification factor: investigational site and baseline EASI 
severity (<28, ≥28). Based on the algorithm, each participant will be assigned to the treatment 
group which will produce minimum total imbalance score with a high probability, where the total 
imbalance score is a weighted average of the imbalance scores for each stratification factor and 
for the whole study. The IWRS will assign a unique treatment code, which will dictate the 
treatment assignment and matching study drug for the participant. Approximately 200 participants 
with moderate to severe AD at Week 0 will be assigned to 1 of 4 treatment groups in a 1:1:2:2 
ratio, resulting in approximately 33 participants to the placebo or bermekimab 350 mg treatment 
group, and approximately 67 participants to the bermekimab 700 mg or dupilumab treatment 
group.
At Week 16, participants randomized to bermekimab 700 mg who are EASI-75 responders will be 
rerandomized using the IWRS either to bermekimab 700 mg or 350 mg in a 1:1 ratio. Participants 
will be assigned to treatments groups using permuted block randomization and the randomization 
will be stratified by EASI-90 response status (<90%, ≥90% improvement from baseline) at 
Week 16.
The requestor must use his or her own user identification and personal identification number when 
contacting the IWRS and will then give the relevant participant details to uniquely identify the 
participant.
Blinding
Active study intervention and placebo will be prepared by an unblinded pharmacist or an unblinded 
qualified member of the investigational staff. The volume of the placebo injections will match the 
volume of the active intervention injections within each group where placebo administration is 
required. Prepared doses will be covered to mask potential visual differences between the active 


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study intervention and placebo. The participants and other site staff members, including the 
investigator, will be blinded to study intervention allocation through study completion to reduce 
bias in the assessment of safety and tolerability data.
Sites must ensure that they have the ability to physically blind and/or separate the blinded 
participant from the unblinded administrator. A physical barrier must be used such that the study 
drug can be administered by the unblinded site personnel, and the participant and other site 
personnel remain blinded.
To ensure that no unintentional unblinding occurs during study intervention administration, at least 
one qualified site staff member will be designated to perform all SC injections of the 
investigational product. This unblinded administrator will have no other contact with the 
participant during the study and will not discuss the participant’s treatment with the participant, 
the investigator, or other site personnel at any time. The unblinded administrator(s) will be 
documented in the source documents at each dosing day.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Data that may potentially unblind the intervention assignment (ie, study intervention serum 
concentrations, antibodies to bermekimab, and intervention allocation) will be handled with 
special care to ensure that the integrity of the blind is maintained and the potential for bias is 
minimized. This can include making special provisions, such as segregating the data in question 
from view by the investigators, clinical team, or others as appropriate until the time of database 
lock and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. However, selected sponsor personnel will be unblinded for 
analysis after the Week 16 DBL has occurred. All site personnel and participants will remain 
blinded to the treatment assignments until the last participant completes Week 36 evaluations and 
the database has been locked.
The investigator may in an emergency determine the identity of the intervention by contacting the 
IWRS. While the responsibility to break the intervention code in emergency situations resides 
solely with the investigator, it is recommended that the investigator contact the sponsor or its 
designee if possible, to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In the 
event the blind is broken, the sponsor must be informed as soon as possible. The date and reason 
for the unblinding must be documented in the appropriate section of the eCRF and in the source 
document. The documentation received from the IWRS indicating the code break must be retained 
with the participant's source documents in a secure manner.


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Participants who have had their intervention assignment unblinded by the investigator will not be 
eligible to receive further study intervention but should continue complete evaluations specified 
in the SoA (Section 1.3).
For the planned interim analyses and the DMC, the randomization codes and the translation of 
randomization codes into intervention and control groups will be disclosed to those authorized and 
only for those participants included in the interim analysis.
6.4.
Study Intervention Compliance
Because study intervention will be administered at the investigational site for all randomized 
participants, intervention compliance will be ensured by site personnel. If study intervention is 
administered by a home health nurse, the sites will be instructed on modifications to ensure study 
intervention compliance. 
The investigator or designated study personnel will maintain a log of all study intervention 
dispensed and returned. Study intervention supplies will be inventoried and accounted for 
throughout the study. Details of each administration will be recorded in the eCRF, including date, 
body location and time of SC injection.
All visits and study intervention administrations should occur ±3 days of scheduled visit 
throughout the study. Study intervention administration should occur not within 4 days of the prior 
administration of study intervention.
Information regarding study intervention administrations that are administered outside of the 
scheduled windows or missed will be recorded. Source data will be reviewed and compared with 
the data entries on the eCRFs to ensure accuracy. Although it is understood that intervention may 
be interrupted for many reasons, compliance with the intervention schedule is strongly encouraged.
6.5.
Dose Modification
No treatment/dose adjustment will be permitted through the study.
6.6.
Continued Access to Study Intervention After the End of the Study
No long-term extension is provided in this Phase 2 study. Participants will be instructed that study 
intervention will not be made available to them after they have completed/discontinued study 
intervention and that they should return to their primary physician to discuss treatment options. 
6.7.
Treatment of Overdose
For this study, any dose of bermekimab or dupilumab greater than the highest dose at a single 
dosing visit will be considered an overdose. The sponsor does not recommend specific treatment 
for an overdose.
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.


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
Closely monitor the participant for AE/SAE and laboratory abnormalities.

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
6.8.
Concomitant Therapy
Prestudy therapies administered up to 30 days before first dose of study intervention must be 
recorded at screening. 
Concomitant therapies must be recorded throughout the study from Week 0 through Week 36 or 
continuing until 5 weeks after the last dose of study intervention. Concomitant therapies on 
randomized participants should also be recorded beyond that point only in conjunction with SAEs
that meet the criteria outlined in Serious Adverse Events in Section 8.3.1, Time Period and 
Frequency for Collecting Adverse Event and Serious Adverse Event Information.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation) different from the study 
intervention must be recorded in the CRF. If a medication is temporarily discontinued because of 
abnormal laboratory values, side effects, concurrent illness, or the performance of a procedure, the 
change and reason for it should be clearly documented in the participant’s medical records. 
Modification of an effective pre-existing therapy should not be made for the explicit purpose of 
entering a participant into the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.8.1.
Rescue Medication
In the event that a participant experiences any unacceptable or worsening symptoms of AD, 
investigators should first attempt to control symptoms in patients with moisturizers by increasing 
the frequency of use to at least twice a day and by reemphasizing other permitted skin care 
measures. However, if these measures are insufficient to control symptoms, investigators will have 
the option to treat with protocol-allowed rescue therapy (topical corticosteroid or topical 
calcineurin inhibitor). Investigators will be required to perform an IGA assessment prior to starting 
rescue treatment and initiate rescue treatment only in participants who either have an 
IGA score = 4, or have intolerable symptoms. Rescue therapy should not be initiated in the first 
2 weeks after randomization. The rationale for rescue must be documented in source.
Participants using rescue by topical therapy will continue to receive investigational product and 
use of rescue therapy will be documented in the eCRF.
If topical rescue therapy as stipulated above fails to control AD symptoms sufficiently, the 
investigator should consider discontinuing the patient from the study.


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6.8.2.
Atopic Dermatitis Management
Investigators should counsel participants on expected management of their condition prior to 
randomization into the study. Participants should practice sensitive skin care measures as part of 
management of AD. These measures include taking infrequent (at most once daily) and brief 
showers or baths, using warm water (not hot) as tolerated. Moisturizer is best applied immediately 
after showering or bathing. Participants should use fragrance-free cleansers and avoid antibacterial 
or deodorant soaps, which may be more irritating to the skin. Participants should launder clothes 
with fragrance-free detergent and avoid fabric softeners. Participants should try to avoid fabrics 
that may be more irritating to the skin, such as wool or synthetic fabrics. 
6.8.3.
Required Treatment
All participants are required to apply moisturizers at least once daily for at least 7 days before 
randomization and continue the treatment throughout the study (including the safety follow-up 
period). All types of non-prescription moisturizers are permitted, excluding any moisturizer that 
contains a corticosteroid.
6.8.4.
Prohibited Therapy
The following therapies will not be allowed during the course of the study.

Topical corticosteroids, except for rescue therapy (see Section 6.8.1, Rescue Medication)

Topical calcineurin inhibitors (eg, tacrolimus and pimecrolimus), except for rescue therapy 
(see Section 6.8.1, Rescue Medication) 

Topical PDE4 inhibitors (eg, crisaborole)

Allergen immunotherapy 

Phototherapy (including PUVA, UVB, tanning beds, and excimer laser)

Bleach baths

Systemic corticosteroids (PO, IV, or IM)

The use of systemic corticosteroids for treatment of indications other than AD is 
permitted, but should be limited to situations for which, in the opinion of the treating 
physician, there are no adequate alternatives. They should be used on a short-term basis, 
preferably for ≤2 weeks. Longer-term use of corticosteroids should be discussed with the 
medical monitor or designee and may require discontinuation of study drug. 

Other route of administration of corticosteroids including those inhaled, otic, ocular, 
nasal, or other routes of mucosal delivery of corticosteroids are allowed.

Any systemic therapy, investigational or commercial (approved or off label use), used for the 
treatment of AD or symptoms of AD (eg, use of dupilumab outside of this protocol)

Systemic and topical JAK inhibitors

Systemic immunomodulatory agents, including, but not limited to, MTX, azathioprine, 
cyclosporine, mycophenolate mofetil. and immunomodulatory biologic therapies (eg,
guselkumab, risankizumab, secukinumab) 


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
IL-1 inhibiting agents (eg, anakinra, rilonacept, canakinumab)

Live vaccines
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.8.5.
Drugs Metabolized by Cytochrome P450
In vitro studies have shown that IL-1 could impact cytochrome (CYP) enzyme expression and 
activities (Renton 2005; Abdel-Razzak 1993). As such, suppression of IL-1α by bermekimab, a 
cytokine modulator, may potentially alter the hepatic metabolism and clearance of drugs that are 
substrates for CYP enzymes (FDA Guidance 2020). Therefore, upon initiation or discontinuation 
of bermekimab in patients being treated with CYP substrates with a narrow therapeutic index, 
monitoring of the effect (eg, warfarin) or drug concentration (eg, theophylline) is recommended 
and the individual dose of the drug may be adjusted as needed.
6.8.6.
Vaccinations (including COVID-19)
When considering use of locally approved non-live vaccines (including emergency use authorized 
COVID-19 vaccines) in study participants, follow applicable local vaccine labelling, guidelines, 
and standards of care for patients receiving immune-targeted therapy.
For study participants receiving a locally-approved COVID-19 vaccine (including emergency use 
authorized), in order to help identify acute reactions potentially related to COVID-19 vaccine, it is 
recommended where possible that vaccine and study drug be administered on different days, 
separated by as large an interval as is practical within the protocol. 
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:

The participant withdraws consent to receive study intervention

The participant or their legally acceptable representative withdraws consent/assent for 
administration of study intervention.

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the participant to discontinue study intervention

The participant has a serious adverse reaction that is related to an injection including a 
hypersensitivity reaction. In general, discontinuation of study intervention administration 
must be considered for participants who develop a nonserious but severe injection-site 
reaction.

The participant has a reaction resulting in myalgia and/or arthralgia with fever and/or rash 
(suggestive of serum sickness and not representative of signs and symptoms of other 
recognized clinical syndromes) after an injection of study intervention. These may be 


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accompanied by other events including pruritus, facial, hand, or lip edema, dysphagia, 
urticaria, sore throat, and/or headache.

The participant becomes pregnant or plans a pregnancy during the study period. Refer to 
Appendix 3 (Section 10.3), Contraceptive Guidance. 

The initiation of protocol-prohibited medications, treatments, or interventions (outlined in 
Section 6.8, Concomitant Therapy) that have an impact on AD efficacy evaluations.

The participant has a malignancy including squamous cell skin cancer. Consideration may be 
given to allow participants, who develop ≤2 basal cell skin cancers and who are adequately 
treated with no evidence of residual disease, to continue to receive study intervention.

A systemic opportunistic infection.

A recurrent or chronic serious infection.

The participant is deemed ineligible according to the following TB screening criteria:

A diagnosis of active TB is made.

A participant has symptoms suggestive of active TB based on follow-up assessment 
questions and/or physical examination or has had recent close contact with a person with 
active TB and cannot or will not undergo additional evaluation.

A participant undergoing evaluation has a chest radiograph with evidence of current 
active TB and/or a positive QuantiFERON®-TB test result and/or 2 indeterminate 
QuantiFERON®-TB test results on repeat testing (refer to Section 8.2.8, Tuberculosis 
Evaluations) (and/or a positive tuberculin skin test result in countries in which the 
QuantiFERON®-TB test is not approved/registered or the tuberculin skin test is 
mandated by local health authorities).

A participant receiving treatment for latent TB discontinues this treatment prematurely 
or is noncompliant with the therapy.

The participant is unable to adhere to the study visit schedule or comply with protocol 
requirements.

The participant has his/her treatment assignment unblinded by the investigator.

Sponsor decision.
Participants who decide to discontinue study intervention administration for reasons other than 
those outlined above must be interviewed by the investigator to determine if a specific reason for 
discontinuing study intervention can be identified. Participants should be explicitly asked about 
the possible contribution of AEs to their decision to discontinue study intervention; investigators 
should confirm that any AE information elicited has been documented. If a participant elects to 
discontinue study intervention due to an AE, the event should be recorded as the reason for study 
intervention discontinuation, even if the investigator’s assessment is that the AE would not require 
study intervention discontinuation. The reason for study intervention discontinuation must be 
documented in the eCRF and in source documents. Study intervention assigned to a participant 
who discontinues may not be assigned to another participant.


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A participant will not be automatically withdrawn from the study if he or she must discontinue 
treatment before the end of the treatment regimen. Participants who discontinue study intervention 
but do not terminate study participation are strongly encouraged to return for all protocol-specified 
procedures and evaluations for approximately 5 weeks following the last dose of study 
intervention. The procedures and evaluations listed for the Early Termination Visit should also be 
performed approximately 5 weeks after the last dose of study intervention.
All procedures and evaluations must be conducted prior to a participant’s withdrawal of consent.
7.1.1.
Liver Chemistry Stopping Criteria
Stopping of study intervention for abnormal liver tests is required by the investigator when a 
participant meets one of the conditions outlined in Appendix 21 (Section 10.21) or in the presence 
of abnormal liver chemistries not meeting protocol-specified stopping rules if the investigator 
believes that it is in best interest of the participant.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
To ensure access for participant follow-up, study sites should try to obtain both primary and 
secondary telephone contact numbers from participants (eg, home, work, and mobile phones), as 
well as other contact information such as email addresses, and emphasize the importance of 
follow-up information to the participant, before randomization. For participants who withdraw 
from study participation, every effort should be made to conduct the Early Termination Visit 
assessments, as indicated in the SoA (Section 1.3). If the reason for withdrawal from the study is 
withdrawal of consent, then no additional assessments are allowed. 
Withdrawal of consent should be a very unusual occurrence in a clinical trial; the investigator 
should make every effort to maintain good participant relationships to avoid withdrawals of 
consent. For participants who truly request withdrawal of consent, it is recommended that the 
participant withdraw consent in writing; if the participant or the participant’s representative refuses 
to do so or is physically unavailable, the study-site should document the reason for the participant’s 
failure to withdraw consent in writing, sign the documentation, and maintain it with the 
participant’s source records. When a participant withdraws before completing the study, the reason 
for withdrawal is to be documented in the eCRF and in the source document. Study intervention 
assigned to the withdrawn participant may not be assigned to another participant. Participants who 
withdraw will not be replaced.
7.2.1.
Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the optional 
research samples:


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
The collected samples will be retained and used in accordance with the participant's original 
separate informed consent for optional research samples.

The participant may withdraw consent for optional research samples, in which case the 
samples will be destroyed, and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study site contact of withdrawal 
of consent for the optional research samples and to request sample destruction. The sponsor 
study site contact will, in turn, contact the biomarker representative to execute sample 
destruction. If requested, the investigator will receive written confirmation from the sponsor 
that the samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study. 
In such a case, the optional research samples will be destroyed. The sample destruction process 
will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Appendix 5 (Section 10.5), Regulatory, 
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they
are no longer needed for the clinical study. Details of the sample retention for research are 
presented in the main ICF and in the separate ICF for optional research samples.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit:

The study-site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, e-
mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods. These contact attempts should be documented in the participant’s 
medical records.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site.


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8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (Section 1.3) summarizes the frequency and timing of efficacy, PK, 
immunogenicity, biomarker, pharmacogenomic, and safety measurements applicable to this study.
It is strongly recommended that the same investigator perform the efficacy assessments at every 
visit.
During screening, each participant will be provided with an electronic device to enter PRO data. 
Study-site personnel will train the participants on how to use the electronic device (ePRO), 
including instructions to capture the data according to the study design and not to wait until the 
study-site visit to record information. Participants will be provided with written instructions on 
how to get 24-hour technical support, if needed, for operation of the ePRO device.
All visit-specific PRO assessments should be conducted/completed before any tests, procedures or 
other consultations, with the exception of a urine pregnancy test, to prevent influencing participant 
perceptions. Refer to the PRO completion guidelines for instructions on the administration of 
PROs.
Electrocardiograms should precede vital signs and both procedures should be completed prior to 
any invasive procedures. Vital signs should be recorded from the opposite arm from which blood 
samples are being taken.
All samples (including safety, efficacy, PK, and biomarkers) must be obtained after the PRO and 
ECG assessments but prior to study intervention administration. Blood collections for PK and 
biomarker assessments should be kept as close to the specified time as possible. Actual dates of 
all assessments will be recorded in the source documentation; in addition, times of all blood 
collections will be recorded in the source documentation (laboratory requisition form).
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participation in the study. Results of all pregnancy testing should be documented in the 
participants’ source documents.
Guidelines for handling of assessments affected by the COVID-19 pandemic are found in 
Appendix 6 (Section 10.6).
Blood Sample Collection
The total blood volume to be collected from each participant through Week 36 of the study will be 
approximately 344 mL (Table 3). In addition, repeat or unscheduled samples may be collected for 
safety reasons or for technical issues with the samples.


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Table 3:
Volume of Blood to be Collected From Each Participant
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Participant
Approximate
Total Volume 
of Blood (mL)a
Safety (including screening and post-intervention
assessments)
- Hematology
2.0
11
22
- Serum chemistry
2.5
11
27.5
- Serology (HIV, HBV, HCV)
10
1
10
- HBV DNA testingb
6
1
6
- TB testing
4
1
4
Pharmacokinetic/Immunogenicity samples
7.5
11
82.5
Population PK sample
4.0
1
4.0
Serum Biomarker samples
8.5
9
76.5
PBMC Biomarker sample
16
5
80
Gene expression samples
2.5
10
25
Pharmacogenomic samplec
6
1
6
Approximate Totald
344 mL
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Performed only in participants who test positive for core HBV antibody.
c. A blood sample will be collected only from participants who have consented to provide an optional DNA sample 
for research. 
d. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the SoA (Section 1.3) for the timing and frequency of all sample 
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided.
Study-Specific Materials
The investigator will be provided with the following supplies:

Protocol

Investigator’s Brochure for bermekimab

Country-specific package insert for dupilumab

Site Investigational Product Binder

Laboratory Manual

Laboratory Kits

IWRS Manual

Sample CRF

eCRF Completion Guidelines


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
ePRO equipment (tablet device questionnaires, completion instructions)

Patient Diary

Actigraphy devices and instruction for use manual (at participating sites)

Digital photographic equipment and instructions manual (at participating sites)

Participant Study Participation Card

Investigative Site File

Recruitment materials, as needed
8.1.
Efficacy Assessments
Investigator assessments and PROs of efficacy are included in this section.

The PRO instrument will be provided in the local language in accordance with local 
guidelines.

The PRO instrument must be available for regulators and for IRB/ERC submissions.

The PRO and AE data will not be reconciled with one another.
8.1.1.
Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin 2001). The EASI is a composite index with scores ranging from 0 to 
72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], 
scratching [excoriation], and lichenification) will each be assessed for severity by the investigator 
or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of AD involvement 
will be assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and 
converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 
2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). The 
EASI will be collected at time points according to the SoA. See Appendix 7 (Section 10.7) for a 
representative example of the index. 
8.1.2.
Validated Investigator Global Assessment for Atopic Dermatitis
The vIGA-AD™ developed by Eli Lilly and Company is an assessment instrument used in clinical 
studies to rate the severity of AD, based on a 5-point scale ranging from 0 (clear) to 4 (severe; 
Simpson 2020). The IGA score is selected using the morphological descriptors that best describe 
the overall appearance of the AD lesions at a given time point. The IGA score will be assessed at 
time points according to the SoA. See Appendix 8 (Section 10.8) for a representative example of 
the assessment. 
8.1.3.
Severity Scoring of Atopic Dermatitis
The SCORAD is a validated tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD. There are 3 components to the 
assessment: A = extent or affected body surface area, B = severity, and C = subjective symptoms. 
The extent of AD is assessed as a percentage of each defined body area, and reported as the sum 


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of all areas, with a maximum score of 100% (assigned as “A” in the overall SCORAD calculation). 
The severity of 6 specific symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin 
thickening/lichenification, dryness) is assessed using the following scale: none (0), mild (1), 
moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall 
SCORAD calculation). Subjective assessment of itch and sleeplessness is recorded for each 
symptom by the patient or relative on a visual analog scale, where 0 is no itch (or sleeplessness) 
and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20. This 
parameter is assigned as “C” in the overall SCORAD calculation. The SCORAD is calculated as: 
A/5 + 7B/2 + C where the maximum is 103.  
Body surface area affected by AD will be assessed for each section of the body (the possible 
highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper 
limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a percentage of all 
major body sections combined. Body surface area (BSA) will be extracted using SCORAD.
See Appendix 9 (Section 10.9) for a representative example of the assessment.
8.1.4.
Hand Dermatitis Investigator Global Assessment
The Hand Dermatitis IGA is a measurement of severity of dermatitis localized to the hands. The 
measurements include evaluation of 7 features, erythema, edema, scaling, vesiculation, erosion, 
lichenification (skin thickening), and fissuring, graded from clear to severe on a scale from 0 to 4. 
The investigator will complete the assessment at timepoints according to the SoA. See 
Appendix 10 (Section 10.10) for a representative example of the assessment.
8.1.5.
Patient-Reported Dermatology Life Quality Index
The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of the 
disease on a participant's quality of life (Finlay 1994). It is a 10-item questionnaire that assesses 
quality of life (QoL) over the past week and in addition to evaluating overall quality of life, can be 
used to assess 6 different aspects that may affect quality of life: symptoms and feelings, daily 
activities, leisure, work or school performance, personal relationships, and treatment. The total 
score ranges from 0 to 30 with a higher score indicating greater impact on QoL. See Appendix 11
(Section 10.11) for a representative example of the index.
8.1.6.
Patient-Oriented Eczema Measure
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults (Charman 2004). The format is a response to 7 items 
(dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency during 
the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = every day) 
with a scoring system of 0 to 28; the total score reflects disease-related morbidity and a higher 
score indicates greater severity. See Appendix 12 (Section 10.12) for a representative example of 
the questionnaire.


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8.1.7.
Patient Global Impression of Severity 
The PGIS of AD is a one-item questionnaire that measures participants’ perceived severity of AD. 
Participants will rate the severity of their AD using a 5-point scale ranging from “none” to “very 
severe”. PGIS will be used as an anchor to establish a clinical response criterion of other patient 
or physician reported outcomes for future reference. The questionnaire will be administered at time 
points according to the SoA. See Appendix 13 (Section 10.13) for a representative example of the 
questionnaire.
8.1.8.
Patient-Reported Outcomes Measurement Information System-29
The PROMIS-29 is a 29-item generic health-related quality of life survey, assessing each of the 
7 PROMIS domains (depression; anxiety; physical function; pain interference; fatigue; sleep 
disturbance; and ability to participate in social roles and activities) with 4 questions. The questions 
are ranked on a 5-point Likert Scale. There is also one 11-point rating scale for pain intensity
(Cella 2010). Participants will undergo this assessment at time points according to the SoA. See 
Appendix 14 (Section 10.14) for a representative example of the questionnaire.
8.1.9.
Eczema Skin Pain and Itch Numeric Rating Scale 
The Eczema Skin Pain and Itch NRS is a 2-item patient-reported outcome developed by the 
sponsor that participants will use to rate the severity of their eczema-related skin pain and 
eczema-related itch daily. Participants will be asked the following questions:

Please rate the severity of your eczema-related skin pain at its worst in the past 24 hours.

Please rate the severity of your eczema-related itch at its worst in the past 24 hours.
Each item is on a 0 to 10 NRS ranging from 0 “none” to 10 “worst possible” and will be scored 
separately. Participants will complete the rating scale daily from the screening visit through the 
last study visit as detailed in the SoA. See Appendix 15 (Section 10.15) for a representative 
example of the scale.
8.1.10.
Atopic Dermatitis Itch Scale 
The ADIS will be used to assess pruritus (itching) among patients with AD, a condition commonly 
referred to as eczema. It will be evaluated by patient a twice-daily diary, in the morning and 
evening diary. The start-of-day item set consists of 4 items evaluating itching at the time of 
morning diary completion, the presence of itching at last night, itching at its worst at night, and 
the impact of itching on sleep at night. The end-of-day item set also consists of 4 items evaluating 
itching at the time of evening diary completion, the presence of itching during the day, itching at 
its worst during the day, and the amount of time the patient experienced eczema-related itching. 
The ADIS utilizes an 11-point scale which ranges from 0 (No itching at all) to 10 (Worst possible 
itching) with the presence of itching during the day or the evening (Yes/No).
Participants will complete the rating scale daily from the screening visit through the last study visit 
as detailed in the SoA. See Appendix 16 (Section 10.16) for a representative example of the scale.


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8.1.11.
Digital Actigraphy 
Clinical features of AD vary by age, duration, and severity but can include papules, vesicles, 
erythema, exudate, xerosis, scaling, and lichenification. However, the most defining and universal 
symptom of AD is pruritus. Pruritus or itch, defined as an unpleasant urge to scratch, is problematic 
for many reasons, particularly its negative impact on QoL. Despite the profoundly negative impact 
of pruritus on patients with AD, clinicians and researchers lack standardized and validated methods 
to objectively measure pruritus (Smith 2019). In addition, pruritus in AD patients leads to sleep 
disturbances, fatigue and altered physical activity patterns. A wrist actigraph is a portable device 
that uses a micro-accelerator to measure nocturnal wrist movement as a proxy for scratching 
activity that is correlated to itch in patients with AD (Price 2014). Furthermore, actigraphy has 
been used in several systemic autoimmune disease studies to document the differences in quality 
of the sleep and physical activity. 
The current study includes an optional substudy that will combine an ePRO and wearable 
actigraphy devices (worn by a limited number of participants at some clinical sites) with clinical 
and biomarker assessments to identify patterns or signatures that are indicative of clinical disease 
and potentially demonstrate clinical benefit of bermekimab in patients with AD. Details are 
provided in Appendix 17 (Section 10.17) and additional instructions about the actigraphy substudy 
are provided in the actigraphy manual. The results of these analyses will be presented in a separate 
report.
8.1.12.
Remote Endpoint Assessment Using Total Body Photography
Participation in clinical studies can be a burden on participants as well as investigators due to time 
constraints and the need to access a participating study site. Total body photography (TBP) has 
long been employed in dermatology for the process of “mole mapping,” ie, monitoring the 
development or change of nevi on the skin over time. As such a standardized photographic series 
has been established to capture the entirety of the skin surface for visual evaluation. As part of 
Study 77474462ADM2001, standard AD severity assessments (eg, EASI) will be completed using 
digital photographs and compared with results from in-person investigator assessments for a 
limited number of participants who consent to this optional substudy at some clinical sites. Details 
are provided in Appendix 18 (Section 10.18) and instructions for acquiring photographs and 
completing assessments are provided in the TBP manual. The results of these analyses will be 
presented in a separate report.
8.2.
Safety Assessments
Details regarding the independent Data Monitoring Committee are provided in Committees 
Structure in Appendix 5 (Section 10.5), Regulatory, Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 19
(Section 10.19, Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and 
Reporting.


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Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the SoA.
8.2.1.
Physical Examinations
Physical Examination
Physical examinations will be performed by the investigator or designated physician, nurse 
practitioner or physician assistant as specified in the SoA (Section 1.3). Any new, clinically 
significant finding (in the opinion of the investigator) must be captured as an AE. In addition, 
resolution of any abnormal findings during the study will be noted in the source document and in 
the eCRF.
Height and Weight
Height and weight will be measured as specified in the SoA (Section 1.3). Participants will be 
instructed to remove shoes and outdoor apparel and gear prior to these measurements.
8.2.2.
Vital Signs
Vital signs (including temperature, pulse/heart rate, respiratory rate, and blood pressure) will be 
obtained before prior to study intervention administration at visits specified in the SoA
(Section 1.3).
8.2.3.
Electrocardiograms
A triplicate 12-lead ECG will be performed during screening to serve as a baseline reference for 
comparison and at Week 16, should a cardiovascular related safety event occur. The 3 individual 
ECG tracings should be obtained as closely as possible in succession about 2 minutes apart. The 
full set of triplicates should be completed in about 5 minutes. 
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Appendix 20
(Section 10.20), Clinical Laboratory Tests. The investigator must review the laboratory results, 
document this review, and record any clinically relevant changes occurring during the study in the 
adverse event section of the CRF. The laboratory reports must be filed with the source documents.
The tests that will be performed by the central laboratory unless otherwise specified or approved 
by the medical monitor are specified in Appendix 20 (Section 10.20), Clinical Laboratory Tests.
Female participants of childbearing potential will undergo a urine pregnancy test at screening, 
before each study intervention administration, and at the Week 36 or early termination visit


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8.2.5.
Concomitant Medication
Concomitant medications will be reviewed at each visit and recorded in the source documents and 
eCRF.
8.2.6.
Allergic Reactions
Before any SC injection, appropriately trained personnel and medications must be available to treat 
allergic reactions, including anaphylaxis. All participants must be observed carefully for symptoms 
of an allergic reaction (eg, urticaria, itching, hives). If a mild or moderate allergic reaction is 
observed, acetaminophen, non-steroidal anti-inflammatory drugs, and/or diphenhydramine may be 
administered.
In the case of a severe allergic reaction (eg, anaphylaxis), IM or SC aqueous epinephrine, 
corticosteroids, respiratory assistance, and other proper resuscitative measures may be essential 
and must be available at the location where the injections are being administered.
Participants who experience serious adverse reactions related to an injection should be 
discontinued from further study intervention administrations.
Participants who experience reactions following an injection that result in bronchospasm, 
wheezing and/or dyspnea that requires ventilatory support, or that results in symptomatic 
hypotension with a decrease in systolic blood pressure of 30% from a participant’s baseline value 
blood or systolic blood pressure <90 mm Hg will not be permitted to receive additional study 
intervention (Sampson 2006).
Participants who experience reactions suggestive of serum sickness-like reactions (resulting in 
symptoms such as myalgia and/or arthralgia with fever and/or rash that are not representative of 
signs and symptoms of other recognized clinical syndromes) occurring 1 to 14 days after an 
injection of study intervention, should be discontinued from further study intervention 
administrations. Note that these symptoms may be accompanied by other events including pruritus, 
facial, hand, or lip edema, dysphagia, urticaria, sore throat, and/or headache.
8.2.7.
Injection-site Reactions
A study intervention injection-site reaction is any adverse reaction at an SC study intervention 
injection-site. The injection sites will be evaluated for reactions and any injection-site reactions 
will be recorded as an AE. Participants should be monitored for the occurrence of injection-site 
reactions for 30 minutes after the study intervention administration.


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8.2.8.
Tuberculosis Evaluation(s)
8.2.8.1.
Initial Tuberculosis Evaluation
Participants must undergo testing for TB (refer to Appendix 2 [Section 10.2]) and their medical 
history assessment must include specific questions about a history of TB or known occupational 
or other personal exposure to individuals with active TB. The participant should be asked about 
past testing for TB, including chest radiograph results and responses to tuberculin skin or other TB 
testing. Investigators have the option to use both the QuantiFERON-TB® (or T-SPOT® for sites in 
Japan) test and the tuberculin skin test to screen for latent TB if they believe, based on their 
judgment, that the use of both tests is clinically indicated to evaluate a participant who is high risk 
of having latent TB. If either the QuantiFERON-TB® (or T-SPOT® for sites in Japan) test or the 
tuberculin skin test is positive, the participant is considered to have latent TB infection for the 
purposes of eligibility for this study.
Participants with a negative QuantiFERON-TB® (or T-SPOT® for sites in Japan) test result (and a 
negative tuberculin skin test result in countries in which the QuantiFERON-TB® test is not 
approved/registered or the tuberculin skin is mandated by local health authorities) are eligible to 
continue with pre-randomization procedures. Participants with a newly identified positive 
QuantiFERON-TB® (or T-SPOT® for sites in Japan or tuberculin skin) test result must undergo an 
evaluation to rule out active TB and initiate appropriate treatment for latent TB. Appropriate 
treatment for latent TB is defined according to local country guidelines for immunocompromised 
patients. If no local country guidelines for immunocompromised patients exist, US guidelines 
should be followed, or the participant will be excluded from the study. 
A participant whose first QuantiFERON-TB® test result is indeterminate should have the test 
repeated. In the event that the second QuantiFERON-TB® test result is also indeterminate, the 
participant may be enrolled without treatment for latent TB if active TB is ruled out, their chest 
radiograph shows no abnormality suggestive of TB (active or old, inactive TB) and the participant 
has no additional risk factors for TB as determined by the investigator. For sites in Japan, a 
participant whose first T-SPOT® test result is borderline should have the test repeated. In the event 
that the second T-SPOT® (for sites in Japan) test result is also borderline, the participant may be 
enrolled without treatment for latent TB if active TB is ruled out, their chest radiograph shows no 
abnormality suggestive of TB (active or old, inactive TB) and the participant has no additional risk 
factors for TB as determined by the investigator. This determination must be promptly reported to 
the medical monitor or designee and recorded in the participant's source documents and initialed 
by the investigator.
8.2.8.2.
Ongoing Tuberculosis Evaluation
Early Detection of Active Tuberculosis
To aid in the early detection of TB reactivation or new TB infection during study participation, 
participants must be evaluated for signs and symptoms of active TB at scheduled visits (refer to 
the Schedule of Activities in Section 1.3). The following series of questions is suggested for use 
during the evaluation:


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
“Have you had a new cough of >14 days’ duration or a change in a chronic cough?”

“Have you had any of the following symptoms:

Persistent fever?

Unintentional weight loss?

Night sweats?”

“Have you had close contact with an individual with active TB?” (If there is uncertainty as to 
whether a contact should be considered “close,” a physician specializing in TB should be 
consulted.)
If the evaluation raises suspicion that a participant may have TB reactivation or new TB infection, 
an immediate and thorough investigation should be undertaken, including, where possible, 
consultation with a physician specializing in TB.
Investigators should be aware that TB reactivation in immunocompromised participants may 
present as disseminated disease or with extrapulmonary features. Participants with evidence of 
active TB should be referred for appropriate treatment.
Participants who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QuantiFERON®-TB (or T-SPOT® for sites 
in Japan) test, a repeat tuberculin skin test in countries in which the QuantiFERON®-TB test is not 
approved/registered or the tuberculin skin test is mandated by local health authorities, and, if 
possible, referral to a physician specializing in TB to determine the participant’s risk of developing 
active TB and whether treatment is warranted. Study intervention administration should be 
interrupted during the investigation. A positive QuantiFERON®-TB (or T-SPOT® for sites in 
Japan) test or tuberculin skin test result should be considered detection of latent TB. Participants 
with a newly identified positive QuantiFERON-TB® (or T-SPOT® for sites in Japan or tuberculin 
skin) test result must undergo an evaluation to rule out active TB and initiate appropriate treatment 
for latent TB. Appropriate treatment for latent TB is defined according to local country guidelines 
for immunocompromised patients. If no local country guidelines for immunocompromised 
patients exist, US guidelines should be followed, or the participant will be excluded from the study. 
If the QuantiFERON-TB® test result is indeterminate, the test should be repeated. For sites in 
Japan, a participant whose first T-SPOT® test result is borderline should have the test repeated. 
Participants should be encouraged to return for all subsequent scheduled study visits according to 
the protocol. Participants who discontinue treatment for latent TB prematurely or who are 
noncompliant with therapy must immediately discontinue further administration of study 
intervention and be encouraged to return for all subsequent scheduled study visits according to the 
Schedule of Activities (Section 1.3).
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including adverse 
events, serious adverse events, and product quality complaint (PQC), from clinical studies are 
crucial for the protection of participants, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 


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conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study.
Further details on adverse events, serious adverse events, and PQC can be found in Appendix 19
(Section 10.19), Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and 
Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include contact for follow-up of safety. 
Serious Adverse Events
All serious adverse events, as well as PQC, occurring during the study must be reported to the 
appropriate sponsor contact person by study-site personnel within 24 hours of their knowledge of 
the event.
Serious adverse events, including those spontaneously reported to the investigator within 12 weeks 
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
A possible Hy’s Law case is defined by the occurrence of alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) ≥ 3xULN together with total bilirubin ≥ 2xULN or international 
normalized ratio (INR) > 1.5 (if measured). Any possible Hy’s Law case is considered an important 
medical event and should be reported to the sponsor in an expedited manner using the Serious 
Adverse Event form, even before all other possible causes of liver injury have been excluded. 
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form and Safety Report Form of the CRF, which must be completed and reviewed 
by a physician from the study site and transmitted to the sponsor within 24 hours. The initial and 
follow-up reports of a serious adverse event should be transmitted electronically or by facsimile 
(fax). Telephone reporting should be the exception and the reporter should be asked to complete 
the appropriate form(s) first.


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8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire 
about adverse event occurrence. 
Solicited Adverse Events
Solicited adverse events are predefined local at the injection site and systemic events for which the 
participant is specifically questioned and which are noted by participants in their diary (see 
Section 8, Study Assessments and Procedures).
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the participant is not specifically 
questioned in the participant diary.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the adverse event, 
serious adverse event, or PQC as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Appendix 19 (Section 10.19), Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events and 
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory 
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR 
summary, unless otherwise specified. 
An anticipated event is an adverse event that commonly occurs in the study population independent 
of exposure to the drug under investigation. No anticipated events have been identified for this 
study.


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8.3.5.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using a serious adverse event reporting 
form. Any participant who becomes pregnant during the study must discontinue further study 
intervention (see Section 7.1, Discontinuation of Study Intervention).
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.3.6.
Adverse Events of Special Interest
Any newly identified malignancy or case of active TB occurring after the first study intervention 
administration(s) in participants participating in this clinical study must be reported by the 
investigator according to the procedures in Appendix 19 (Section 10.19). Investigators are also 
advised that active TB is considered a reportable disease in most countries. These events are to be 
considered serious only if they meet the definition of an SAE.
8.4.
Pharmacokinetics and Immunogenicity
Blood samples will be collected for the measurement of serum bermekimab concentrations and 
antibodies to bermekimab at the timepoints presented in the Schedules of Activities. 
At visits in which serum bermekimab concentration and/or antibodies to bermekimab will be 
evaluated, 1 venous blood sample of sufficient volume should be collected, and each serum sample 
should be divided into 3 aliquots: 1 for serum concentration of bermekimab and a back-up. Each 
serum sample will be divided into 3 aliquots: 1 for serum concentration of bermekimab, 1 for 
antibodies to bermekimab, and 1 back-up. 
Blood samples should also be collected at the final visit or at the Early Termination Visit from 
participants who are discontinued from intervention or withdrawn from the study.  Blood samples 
collected for serum bermekimab concentrations may also be used for exploratory biomarker 
analyses.
A random venous blood sample for population PK analysis will be collected from all participants 
on any day between Weeks 2 to 12, except on the days of the scheduled study visits. Additionally, 
this blood sample must be collected at least 24 hours prior to or after the actual time of study 
intervention administration. Each population PK serum sample will be divided into 2 aliquots: 1 
for serum concentration of bermekimab and a back-up.
The exact dates and times of blood sample collection must be recorded in the laboratory requisition 
form. See the laboratory manual for further information regarding collection, handling, and 
shipment of biological samples. Genetic analyses will not be performed on these serum samples. 
Participant confidentiality will be maintained.


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Pharmacokinetic Analytical Procedures
Serum samples will be analyzed to determine serum bermekimab concentrations using a validated, 
specific, and sensitive immunoassay method under the supervision of the sponsor. The sponsor, or 
its designee, under conditions in which the participants’ identity remains blinded, will assay these 
samples.
Immunogenicity Analytical Procedures
The detection and characterization of antibodies to bermekimab will be performed using a 
validated immunoassay method by or under the supervision of the sponsor. Serum samples will be 
screened for antibodies binding to bermekimab and the titer of confirmed positive samples will be 
reported. Antibodies to bermekimab may be further characterized and/or evaluated for their ability 
to neutralize the activity of bermekimab.
8.5.
Pharmacogenomics
Genetic variation can be an important contributory factor to interindividual differences in drug 
disposition and response and may also serve as a marker for disease susceptibility and prognosis. 
Here, pharmacogenomic research refers to the analysis of 1 or more candidate genes or of the 
analysis of markers throughout the genome in relation to bermekimab and AD clinical endpoints. 
The goal of the pharmacogenomic research component is to explore factors that may influence the 
PK, PD, efficacy, or tolerability of bermekimab and to evaluate genetic factors previously reported 
to be associated with AD or to identify new associations with disease. These DNA samples may 
be used to help address emerging issues and to enable the development of safer, more effective, 
and more precisely applied therapies.  
A whole blood sample will be collected for pharmacogenomic research in participants who consent 
separately to this optional part of the study (where local regulations permit). Genotyping or 
sequencing techniques will be used to assess variation in the filaggrin (FLG) gene, a risk factor for 
AD, and interleukin-1 alpha gene (IL1A), the target of bermekimab. Additionally, genome-wide 
genotyping or sequencing will be used to assess variation genome-wide. Participants will have the 
option to participate in 1 or both of these studies. 
8.6.
Biomarkers
Biomarker samples will be collected to evaluate the PD and mechanism of action of bermekimab 
or help to explain interindividual variability in clinical outcomes or may help to identify population 
subgroups that respond differently to the intervention. The goal of the biomarker analyses is to 
evaluate the PD of and aid in evaluating the intervention-clinical response relationship. 
Biomarker assessment will include the evaluation of relevant markers in serum, blood, and tape 
strips for all participants. Skin biopsies or skin swabs, or both, will also be collected in participants
that consent to this optional part of the study. The samples will be used to better understand the 
biology of AD; to provide biological assessment of the response of participants to treatment with 
bermekimab; to analyze differences between responders and nonresponders; and to determine if 
the markers can be used to classify participants as potential responders prior to treatment. Blood 


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samples will be separated into serum and PBMCs for biomarker analysis. Samples for serum 
biomarkers, flow cytometry and gene expression from blood will be collected at time points 
according to the SoA. Instructions for the collection and shipment of these samples are found in 
the Laboratory Reference Manual and Biopsy Collection Manual.
8.6.1.
Skin Biomarkers
Non-invasive skin sampling through tape stripping is mandatory and will be collected from all 
participants at time points specified in the SoA. At baseline, tape strips will be collected from both 
lesional and adjacent non-lesional areas; at Weeks 4, 16, and 32, only lesional areas will be 
sampled. Tape stripping allows for the measurement of gene expression as well as levels of 
proteins or other biomarkers in the stratum corneum.
Skin swabs on lesional and non-lesional skin will be collected from participants that consent to 
this part of the study at time points specified in the SoA. A skin swab will be collected to study 
the effects of intervention on microbiome composition on affected skin. 
Skin biopsy samples will be collected from participants that consent to this part of the study at 
time points specified in the SoA. At the baseline sampling time point, biopsy samples will be 
collected from both lesional and adjacent non-lesional areas; at Week 16 two lesional areas will 
be sampled. Gene expression analysis of skin biopsy samples will be performed to investigate 
differential gene expression during treatment compared with baseline to explore PD, mechanism 
of action, and differences in responders versus nonresponders. At Week 16, a whole biopsy will 
be dedicated for proteomic analysis. In addition, the tissue biopsies may be analyzed for 
histological readouts and immunohistochemistry to explore the effects of study intervention on 
cellular composition and PK/PD within skin tissue. 
Participants may consent to participate in either collection of skin biopsies or skin swabs (which 
is a less invasive collection method than a biopsy), or both of these methods for skin sampling.
8.6.2.
Serum Biomarkers
Serum samples will be collected from all participants at time points specified in the SoA. Potential 
circulating factors to be evaluated may include cytokines and other inflammatory markers (eg, 
CCL17/TARC), and other categories of biomarkers potentially associated with AD or related to 
the mechanism of action of bermekimab.
8.6.3.
Flow Cytometry Analysis
Whole blood samples will be collected from all participants at time points specified in the SoA, 
and peripheral blood mononuclear cells (PBMC) will be isolated. Flow cytometry analysis of 
blood cell samples will be utilized to monitor the effects of bermekimab on circulating immune 
cell populations. Cell surface markers such as, but not limited to, those for T cell subsets (eg, Th1, 
Th2), dendritic cells (DCs), and B cells will be assessed. 


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8.6.4.
Gene Expression Analysis in Whole Blood
Whole blood samples will be collected from all participants at time points specified in the SoA. 
Total RNA will be isolated and used for differential gene expression analyses to better understand 
the pathologic mechanisms involved in AD and to potentially identify a treatment response 
signature to bermekimab.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data.
8.7.
Health Economics
Health Economics parameters are not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data are outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1.
Statistical Hypotheses
The hypothesis for this study is that bermekimab treatment is superior to placebo as assessed by 
the proportion of participants achieving an EASI-75 (≥75% improvement from baseline) at 
Week 16. 
The null hypothesis to be tested to address the primary objective of this study is that there is no 
difference between any of the bermekimab doses (350 mg or 700 mg) and placebo treatment as 
measured by the proportion of participants achieving EASI-75 at Week 16.
9.2.
Sample Size Determination
This study is designed to enroll approximately 200 participants in order to have sufficient power 
to detect a difference between the bermekimab groups and the placebo group for the primary 
endpoint of the proportion of participants achieving EASI-75 at Week 16. The sample size was 
also chosen to have adequate confidence level for the difference between the bermekimab 700 mg 
group and the dupilumab group.
The EASI-75 response rate in the bermekimab 400 mg qw group was approximately 35% at 
Week 16 and 70% at Week 7 from the placebo-controlled study (77474462ADM2002) and the 
open-label study (2018-PT044), respectively. The EASI-75 response rates at Week 16 were 15% 
and 12% with placebo and 51% and 44% with dupilumab, respectively, in the two Phase 3 trials 


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of dupilumab versus placebo in the treatment of adult participants with moderate to severe AD 
(Simpson 2016). 
Therefore, based on the data from these studies, various assumptions to calculate sample size and 
power are shown in Table 4. The EASI-75 response at Week 16 are assumed to be 15% for placebo, 
45% to 50% for dupilumab, and 50% to 70% for the bermekimab 350 mg and 700 mg treatment 
groups, respectively. Based on these assumptions, approximately 200 participants are planned to 
be randomized in a 1:1:2:2 ratio to the placebo (n=33), bermekimab 350 mg (n=33), bermekimab 
700 mg (n=67), or dupilumab (n=67) treatment groups. These sample sizes provide the study with 
at least 88% power to detect a treatment difference between the bermekimab treatment groups and 
the placebo group in EASI-75 at Week 16 based on a 2-sample Z-test at a Type I error rate of 0.05 
(2-sided). These sample sizes also provide at least 88% power to detect a treatment difference 
between the dupilumab and placebo treatment group in EASI-75 at Week 16 at a 2-sided 
significance level of 0.05 (Table 4).
Table 4:
Power to Detect a Treatment Difference in EASI-75 at Week 16
Placebo
Treatment Group
Difference
Power
bermekimab 700 mg (n=67) vs placebo (n=33)
15%
50%
35%
95%
15%
60%
45%
>99%
15%
70%
55%
>99%
12%
50%
38%
98%
12%
60%
48%
>99%
12%
70%
58%
>99%
bermekimab 350 mg (n=33) vs placebo (n=33)
15%
50%
35%
88%
15%
55%
40%
94%
15%
50%
38%
93%
12%
55%
43%
97%
dupilumab (n=67) vs placebo (n=33)
15%
45%
30%
88%
15%
50%
35%
95%
15%
55%
40%
99%
12%
45%
33%
94%
12%
50%
38%
98%
12%
55%
43%
>99%
Note: The power calculation is based on two-sample Z-test (pooled variance) under the normal distribution 
approximation.
In addition, a sample size of 67 participants in each of the bermekimab 700 mg and dupilumab 
groups produce a 2-sided 80% confidence interval for the difference in 2 groups with a width of 


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22.9% when the assumed EASI-75 response is 60% and 50% in the bermekimab 700 mg and the 
dupilumab group, respectively. Assuming a EASI-75 response is 50% in both the bermekimab 
350 mg and dupilumab groups, a sample size of 33 participants in the 350 mg group and 
67 participants in the dupilumab group would provide a 2-sided 80% confidence interval of 
difference with a width of 27.3% (Table 5).
Table 5:
Confidence Interval for the Treatment Difference in EASI-75 at Week 16
EASI-75 
Response (P1)
EASI-75 
Response (P2)
Difference
(P1 − P2)
Width
Confidence 
Limit
Confidence
Level
bermekimab 700 mg (n=67; P1) vs dupilumab (n=67; P2)
60%
50%
10%
22.9%
(−1%, 21%)
80%
65%
50%
15%
21.6%
(4%, 26%)
80%
70%
50%
20%
21.2%
(9%, 31%)
80%
bermekimab 350 mg (n=33; P1) vs dupilumab (n=67; P2)
50%
50%
0%
27.3%
(−14%, 14%)
80%
55%
50%
5%
27.2%
(−9%, 19%)
80%
60%
50%
10%
26.9%
(−3%, 23%)
80%
bermekimab 700 mg (n=67; P1) vs bermekimab 350 mg (n=33; P2)
60%
50%
10%
27.1%
(−4%, 24%
80%
65%
50%
15%
26.8%
(2%, 28%)
80%
70%
50%
20%
26.5%
(7%, 33%)
80%
9.3.
Populations for Analysis Sets
For the efficacy analyses in this study, the full analysis set (FAS) will be used according to the 
participants’ assigned treatment to which they were randomized, regardless of the treatment they 
actually received. The FAS includes all randomized participants who receive at least one 
administration of study intervention. The FAS will be used for all primary and secondary efficacy 
analyses.
Safety analyses will include all participants who received at least 1 dose (complete or partial) of 
study intervention and participants will be analyzed based on the treatment they actually received, 
regardless of the treatment groups to which they were assigned.
Pharmacokinetics analyses for bermekimab will include participants who receive at least one 
complete dose of bermekimab and have at least one post-dose sample collection. Antibodies to 
bermekimab will be analyzed for participants who receive at least one dose of bermekimab and 
have at least one post-dose sample collection.
9.4.
Statistical Analyses
9.4.1.
General Considerations
Simple descriptive summary statistics, such as n, mean, standard deviation (SD), median, inter 
quantile range, minimum, and maximum for continuous variables, and counts and percentages for 
discrete variables will be used to summarize most data.


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The treatment comparisons for binary endpoints will be performed using a Cochran-Mantel-
Haenszel (CMH) test stratified by baseline EASI severity or Fisher’s exact test in the case of rare 
events. The differences in binary endpoints between groups and the corresponding CIs will be 
presented. For continuous efficacy endpoints, treatment comparisons will be performed using a 
Mixed-Effect Model Repeated Measure (MMRM) model. The MMRM will includes treatment, 
visit, baseline EASI severity, baseline score, baseline score by visit interaction, baseline EASI 
severity by visit interaction, and the treatment-by-visit interaction, if applicable. The Least Square 
mean (LSmean) estimates and their corresponding 95% confidence interval (CI) will be provided 
at each time point. In addition, the estimates of LSmean difference and 95% CIs between treatment 
groups will be provided.
In general, all statistical testing will be performed at a significance level of 0.05 (2-sided) unless 
otherwise specified. Nominal p-values will be displayed for all treatment comparisons.
9.4.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of participants with EASI-75 (≥75% improvement 
from baseline) at Week 16.
Primary Estimand: The primary estimand (ie, a precise definition of the primary targeted 
treatment effect) is defined by the following 5 attributes:

Population: adult participants with moderate to severe AD

Variable/endpoint: EASI-75 binary responder variable at Week 16, where participants are 
considered nonresponders if they experience any of the following intercurrent events post 
treatment initiation and prior to Week 16:

discontinuation of study intervention due to lack of efficacy or an AE of worsening of
AD

initiation of a protocol-prohibited medication or therapy during the study that could
improve AD

initiation of rescue medication for AD

Treatment:

Experimental: Bermekimab 350 mg, 700 mg

Control: Placebo 

Intercurrent Events: the composite strategy is used to address this trial intercurrent events; 
as reflected in the variable definition, a participant with any intercurrent event is not 
considered an EASI-75 responder after that event.

Population level summary: Difference in the proportions of participants achieving an 
EASI-75 response at Week 16 between the bermekimab and placebo treatment groups.
Primary Endpoint Analysis
In the primary efficacy analysis, data from all randomized participants who received at least 
1 administration of study intervention will be analyzed according to their assigned treatment 
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The primary endpoint will be analyzed at Week 16 based on the primary estimand and the number 
and proportion of participants who achieve an EASI-75 response at Week 16 will be summarized 
for each treatment group. To address the primary objective, a CMH chi-square statistic stratified 
by baseline EASI severity (less severe [EASI <28] or more severe [EASI ≥28]) at an alpha level 
of 0.05 will be used to compare each bermekimab group separately with placebo. The proportion 
difference between each bermekimab group and placebo group and its 2-sided 95% CI will be 
provided based on normal approximation with Mantel-Haenszel weights adjusting for baseline 
EASI severity.
The study would be considered as positive if any of the comparisons for primary endpoint analysis 
(bermekimab 700 mg vs placebo, and bermekimab 350 mg vs placebo) is less than or equal to 
p-value of 0.05. Therefore, an overall Type I error rate will be maintained at 0.1 or less for the 
primary endpoint analysis. 
In addition, the comparison between dupilumab and placebo for the primary endpoint will also be 
performed at a 2-sided significance level of 0.05. Nominal p-values will be reported.
For the analyses described above, participants with any intercurrent event before Week 16 will be 
considered as EASI-75 nonresponders at Week 16. In addition, participants who do not return for 
evaluation or have missing components of EASI will also be considered as nonresponders at 
Week 16.
To examine the robustness of the primary endpoint analysis, additional analyses of the primary 
endpoint will be conducted using different missing data approaches; these analyses will be 
described in the SAP. In addition, sensitivity analyses will be performed for the primary endpoint 
using the per-protocol population, which includes participants who are generally compliant with 
the protocol.
To evaluate the consistency of the efficacy, subgroup analysis of the primary endpoint will be 
performed.
9.4.3.
Secondary Endpoints
The major secondary analyses are:

The proportion of participants with both vIGA-AD 0 or 1 (on a 5-point scale) and a reduction 
from baseline of ≥2 points at Week 16 will be compared between each of the bermekimab 
groups and the placebo group.

Proportion of participants with improvement (reduction) of eczema-related itch NRS ≥4 from 
baseline to Week 16 among participants with a baseline itch value ≥4 will be compared 
between each of the bermekimab groups and the placebo group.

The proportion of participants with EASI-90 response at Week 16 will be compared between 
each of the bermekimab groups and the placebo group.


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
The difference in the EASI-75 response rate between each of the bermekimab treatment 
groups and the dupilumab treatment group and the corresponding 80% CIs will be calculated 
at Week 16.

The difference in the EASI-90 response rate between each of the bermekimab treatment 
groups and the dupilumab treatment group and the corresponding 80% CIs will be calculated 
at Week 16.

The difference and 2-sided 80% CIs in the proportion of participants with both vIGA-AD 
0 or 1 (on a 5-point scale) and a reduction from baseline of ≥2 points at Week 16 between 
each of the bermekimab groups and the dupilumab treatment group will be calculated.

The difference and 2-sided 80% CIs in the proportion of participants with improvement 
(reduction) of eczema-related itch NRS ≥4 from baseline to Week 16 among participants with 
a baseline itch value ≥4 will be calculated between each of the bermekimab groups and the 
dupilumab group.
Other secondary analyses include:

The improvement from baseline in EASI score at Week 16 will be compared between each of 
the bermekimab groups and the placebo group.

The percent improvement from baseline in EASI score at Week 16 will be compared between 
each of the bermekimab groups and the placebo group.

The improvement from baseline in eczema-related itch NRS at Week 16 will be compared 
between each of the bermekimab groups and the placebo group.
In addition, comparisons between dupilumab and placebo for the secondary endpoints will also be 
performed.
No adjustments for multiple comparisons will be made for the secondary endpoints.
9.4.4.
Exploratory Endpoints

The improvement from baseline in SCORAD at Week 16 will be compared between each of 
the bermekimab groups and the placebo group.

The change from baseline in DLQI at Week 16 will be compared between each of the 
bermekimab groups and the placebo group.

The improvement from baseline in POEM at Week 16 will be compared between each of the 
bermekimab groups and the placebo group.

The improvement from baseline in eczema-related itch NRS at Week 8 will be compared 
between each of the bermekimab groups and the placebo group.

The improvement from baseline in eczema-related pain NRS at Week 8 will be compared 
between each of the bermekimab groups and the placebo group.

The improvement from baseline in eczema-related pain NRS at Week 16 will be compared 
between each of the bermekimab groups and the placebo group.

The improvement from baseline in ADIS itch at Week 16 will be compared between each of 
the bermekimab groups and the placebo group.


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
The proportions of participants with a PGIS score of 1 (none) or 2 (mild) at Week 16 will be 
compared between each of the bermekimab groups and the placebo group. 

The change from baseline in PROMIS-29 total score and sub-scores at Week 16 will be 
compared between each of the bermekimab groups and the placebo group.

Hand Dermatitis IGA will be compared between each of the bermekimab groups and the 
placebo group. 

The improvement and percent improvement in EASI score will be summarized by treatment 
group over time. 

The proportion of participants who achieve EASI-50, EASI-75, EASI-90, and EASI-100 will 
be summarized by treatment group over time. The improvement from baseline and percent 
improvement from baseline in EASI total score will be summarized by treatment group over 
time.

The proportions of participants who achieve a vIGA-AD 0 or 1 and a reduction from baseline 
of ≥2 points over time will be summarized by treatment group.

The proportion of participants with improvement (reduction) of eczema-related itch NRS ≥4 
from baseline will be summarized by treatment group over time among participants with a 
baseline itch NRS value ≥4.

The improvement from baseline in eczema-related itch NRS will be summarized by treatment 
group over time.

The improvement from baseline in eczema-related pain NRS will be summarized by treatment 
group over time.

In addition, the EASI-50, EASI-75, EASI-90, EASI-100, vIGA-AD 0 or 1 and a reduction 
from baseline of ≥2 points after Week 16 will be summarized by different subpopulations (eg, 
dupilumab EASI-75 nonresponders, dupilumab EASI-75 responders, EASI-75 responders to 
bermekimab 700 mg, EASI-75 nonresponders to bermekimab 700 mg).  
Additional analyses through Week 36 will be specified in the SAP.
9.4.5.
Safety Analyses
Safety data, including but not limited to, AEs, SAEs, infections, serious infections, mortality, 
changes in laboratory assessments, and changes in vital signs will be summarized. 
Treatment-emergent AEs will be summarized by treatment group and Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred terms. Details will be specified 
in the SAP.
Safety Definition
Injection-Site Reactions
An injection-site reaction is any unfavorable or unintended sign that occurs at an injection-site and 
will be recorded as an AE. Detailed instructions for the evaluation of injection-site reactions are 
in the Trial Center File.


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Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
MedDRA. Treatment-emergent AEs are AEs with onset during the intervention period or that are 
a consequence of a pre-existing condition that has worsened since baseline. All treatment-emergent 
AEs will be included in the analysis. For each AE, the percentage of participants who experience 
at least 1 occurrence of the given event will be summarized by intervention group. In addition, 
comparisons between intervention groups will be provided if appropriate.
The following analyses will be used to assess the safety of participants in the study:

The incidence and type of AEs.

The incidence and type of SAEs.

The incidence and type of severe AEs.

The incidence and type of infections.

The incidence and type of reasonably related AEs as assessed by the investigator.

The incidence and type of injection-site reactions.

The incidence and type of AEs leading to discontinuation of study.
Listings of participants with SAEs, severe AEs, AEs leading to discontinuation of study 
intervention, and anaphylactic reaction/serum sickness reactions will also be provided. All safety 
analyses will be based on the population of participants who received at least 1 administration of 
study intervention; participants will be summarized by the intervention they received.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test (eg, hematology, clinical chemistry). 
Selected laboratory parameters will be summarized by treatment groups. Common Terminology 
Criteria (CTC) will be used to identify abnormal laboratory test results, and the incidence and 
severity of abnormal laboratory parameters (hematology and chemistry) will be summarized by 
treatment group.
In addition, a listing of participants with grade 2 or higher laboratory test results (based on the 
CTC criteria) will also be provided.
Vital Signs
Descriptive statistics of heart rate and blood pressure (systolic and diastolic) values and changes 
from baseline will be summarized.
Weight 
Descriptive statistics of changes from baseline will be summarized at selected scheduled time 
points.


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9.4.6.
Other Analyses
Pharmacokinetic Analyses 
The PK evaluable population is defined as all the participants who received at least 1 complete 
dose of bermekimab and had at least 1 valid blood sample drawn for PK analysis after their first 
dose of bermekimab.
Serum bermekimab concentrations will be summarized by visit and treatment group. Descriptive 
statistics will be calculated at each sampling timepoint. Concentrations below the lowest 
quantifiable concentration will be treated as zero in the summary statistics. All serum 
concentrations below the lowest quantifiable concentration or missing data will be labeled as such 
in the concentration database. Pharmacokinetic data may also be displayed graphically.
If feasible, population PK analysis of serum concentration-time data of bermekimab may be 
performed using nonlinear mixed-effects modeling. Data may be combined with those of other 
selected studies to support a relevant structural model. Available baseline participant 
characteristics (demographics, laboratory variables, race, etc) will be tested as potential covariates 
affecting PK parameters. The results of the population PK analysis will be presented in a separate 
report.
Pharmacokinetic/Pharmacodynamic Analyses 
If data permit, the relationships between serum bermekimab concentration and efficacy may be 
examined when appropriate. If a relationship is observed, a suitable PK/PD model may be 
developed to describe the exposure-response relationship and will be presented in a separate 
technical report.
Immunogenicity Analyses 
The incidence and titers of antibodies to bermekimab will be summarized for all participants who 
receive at least 1 dose of bermekimab and have appropriate samples for detection of antibodies to 
bermekimab (ie, participants with at least 1 sample obtained after their first dose of bermekimab).
A listing of participants who are positive for antibodies to bermekimab will be provided. The 
maximum titers of antibodies to bermekimab will be summarized for participants who are positive 
for antibodies to bermekimab.
The incidence of neutralizing antibodies (NAbs) to bermekimab will be summarized for 
participants who are positive for antibodies to bermekimab and have samples evaluable for NAbs 
to bermekimab.
Other immunogenicity analyses may be performed to further characterize the immune responses 
that are generated.


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Biomarker Analyses 
Planned biomarker analyses may be deferred if emerging study data show no likelihood of 
providing useful scientific information. Any biomarker samples received by the contract vendor 
or sponsor after the cutoff date will not be analyzed, and therefore, excluded from the biomarker 
analysis.
Changes in serum analytes obtained over time will be summarized by treatment group. 
Associations between baseline levels and changes from baseline in selected markers and response 
to treatment will be explored. The analyses will aim to identify biomarker relevant to treatment. 
Results of serum biomarker analyses will be reported in separate technical reports.
Additional analyses related to data collected using digital actigraphy are specified in the biomarker 
analysis plan and results will be reported in a separate technical report.
Pharmacogenomic Analyses 
DNA samples will be used for research related to bermekimab or AD. They may also be used to 
develop tests/assays related to bermekimab and AD. Pharmacogenomic research may consist of 
the analysis of one or more candidate genes or of the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate) in relation to bermekimab or AD clinical 
endpoints.
Results will be presented in a separate report.
9.5.
Interim Analysis
An interim analysis will be conducted prior to the Week 16 DBL when approximately 50% of 
participants have completed their Week 16 visit. The interim analysis will be used to inform the 
future development planning of bermekimab for AD based on the data accrued up to the interim 
analysis. No changes to the current study are planned. Details of the plan for the interim analysis 
will be specified in a separate interim analysis plan before the time at which the interim analysis 
is performed. An independent, internal committee will review the results of the interim analysis.
9.6.
Data Monitoring Committee
An independent, external DMC, whose members are not directly involved in the conduct of study 
77474462ADM2001, will review unblinded safety data to ensure the safety of the participants 
enrolled in this study. The committee will meet regularly to review unblinded safety data. After 
the review, the DMC will make recommendations to the study team regarding the conduct of the 
study. The DMC will consist of at least one clinical physician and one statistician, not involved in 
the conduct of the study. DMC responsibilities, authorities, and procedures will be documented in 
the DMC charter.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
AD
atopic dermatitis
ADIS
Atopic Dermatitis Itch Scale
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCG
Bacille Calmette-Guérin
BSA
Body Surface Area
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease 2019
CRF
case report form(s) (paper or electronic as appropriate for this study)
CTC
Common Terminology Criteria
CYP
cytochrome
DBL
database lock
DLQI
Dermatological Life Quality Index
DMC
Data Monitoring Committee
EASI
Eczema Area and Severity Index
ECG
electrocardiogram
FAS
full analysis set
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormonal replacement therapy
HS
hidradenitis suppurativa
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IGA
Investigator Global Assessment
IL-1α
interleukin-1 alpha
IP
Investigational Product
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
LSmean
Least Square mean
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-Effect Model Repeated Measure
MTX
methotrexate
NAbs
neutralizing antibodies
NRS
numeric rating scale
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamic(s)
PFS
prefilled syringe
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure
PQC
Product Quality Complaint
PRO
patient-reported outcome(s) 
PROMIS-29
Patient-Reported Outcomes Measurement Information System-29


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QoL
quality of life
qw
every week
q2w
every 2 weeks
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCORAD
Severity Scoring of Atopic Dermatitis
SD
standard deviation
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction 
TB
tuberculosis
TBP
Total body photography
ULN
upper limit of normal
vIGA-AD
validated Investigator Global Assessment for Atopic Dermatitis


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10.2.
Appendix 2: Tuberculin Skin Testing
Administering the Mantoux Tuberculin Skin Test
The Mantoux tuberculin skin test (CDC, 2000) is the standard method of identifying persons 
infected with Mycobacterium tuberculosis. Multiple puncture tests (Tine and Heaf) should not be 
used to determine whether a person is infected because the amount of tuberculin injected 
intradermally cannot be precisely controlled. Tuberculin skin testing is both safe and reliable 
throughout the course of pregnancy. The Mantoux tuberculin test is performed by placing an 
intradermal injection of 0.1 mL of tuberculin into the inner surface of the forearm. The test must 
be performed with tuberculin that has at least the same strength as either 5 tuberculin units (TU) 
of standard purified protein derivative (PPD)-S or 2 TU of PPD-RT 23, Statens Seruminstitut, as 
recommended by the World Health Organization. PPD strengths of 1 TU or 250 TU are not 
acceptable (Menzies, 2000). Using a disposable tuberculin syringe with the needle bevel facing 
upward, the injection should be made just beneath the surface of the skin. This should produce a 
discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter. To prevent needle-stick 
injuries, needles should not be recapped, purposely bent or broken, removed from disposable 
syringes, or otherwise manipulated by hand. After they are used, disposable needles and syringes 
should be placed in puncture-resistant containers for disposal. Institutional guidelines regarding 
universal precautions for infection control (eg, the use of gloves) should be followed. A trained 
health care worker, preferably the investigator, should read the reaction to the Mantoux test 48 to 
72 hours after the injection. Participants should never be allowed to read their own tuberculin skin 
test results. If a participant fails to show up for the scheduled reading, a positive reaction may still 
be measurable up to 1 week after testing. However, if a participant who fails to return within 72 
hours has a negative test, tuberculin testing should be repeated. The area of induration (palpable 
raised hardened area) around the site of injection is the reaction to tuberculin. For standardization, 
the diameter of the induration should be measured transversely (perpendicular) to the long axis of 
the forearm. Erythema (redness) should not be measured. All reactions should be recorded in 
millimeters, even those classified as negative.
Interpreting the Tuberculin Skin Test Results
In the US and many other countries, the most conservative definition of positivity for the tuberculin 
skin test is reserved for immunocompromised patients, and this definition is to be applied in this 
study to maximize the likelihood of detecting latent TB, even though the participants may not be 
immunocompromised at baseline.
In the US and Canada, an induration of 5 mm or greater in response to the intradermal tuberculin 
skin test is considered to be a positive result and evidence for either latent or active TB.
In countries outside the US and Canada, country-specific guidelines for immunocompromised 
patients should be consulted for the interpretation of tuberculin skin test results. If no local country 
guidelines for immunocompromised patients exist, US guidelines must be followed.


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Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable 
antituberculous treatment regimens for latent TB. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed.
References
Centers for Disease Control and Prevention. Core curriculum on tuberculosis: What the clinician should know 
(Fourth Edition). Atlanta, GA: Department of Health and Human Services; Centers for Disease Control and 
Prevention; National Center for HIV, STD, and TB Prevention; Division of Tuberculosis Elimination; 2000:25-86.
Menzies RI. Tuberculin skin testing. In: Reichman LB, Hershfield ES (eds). Tuberculosis, a comprehensive 
international approach. 2nd ed. New York, NY: Marcel Dekker, Inc; 2000:279-322.


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10.3.
Appendix 3: Contraceptive Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and 
Appendix 19 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required 
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if 
she wishes to continue HRT during the study.

permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.


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Examples of Contraceptives 
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT 
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)

Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(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 intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of 1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)


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a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).
Pregnancy During the Study
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor or designee by the study-site personnel within 24 hours of their knowledge 
of the event using the appropriate pregnancy notification form. Abnormal pregnancy outcomes 
(eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using the Serious Adverse Event Form. Any participant 
who becomes pregnant during the study must discontinue further study intervention. Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will 
be required.




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10.5.
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations
10.5.1.
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or 
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification 
communication (PCC) may be prepared. The PCC Document will be communicated to the 
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers 
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC 
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional 
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the 
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 


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situation and agree on an appropriate course of action. The data recorded in the CRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention 
to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
participant:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable


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
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the participants)

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda


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
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.5.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.


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10.5.3.
Informed Consent Process 
Each participant must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the participant can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Participants will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the participant will receive. Finally, they will be told that the investigator will 
maintain a participant identification register for the purposes of long-term follow-up if needed and 
that their records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the 
participant agrees to allow his or her study physician to recontact the participant for the purpose 
of obtaining consent for additional safety evaluations, and subsequent disease-related treatments, 
if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded by 
means of the participant's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
Participants will be asked for consent to provide optional samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the participant 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the participant.
Completion of screening and randomization procedures within the specified approximately 4-week 
window is required. If a participant is approaching the completion of that period, the medical 
monitor can be contacted to discuss eligibility.
If any delay leads to the expiration of time-specific assessments (eg, TB, chest radiograph), the 
participant will be considered a screen failure because he/she will not meet eligibility criteria, and 
the expired assessments (along with the non-time-specific laboratory tests) will have to be repeated 
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10.5.4.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The participant has the right to request through the investigator access to his or her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, biomarker, PK, and immunogenicity research is not conducted under standards 
appropriate for the return of data to participants. In addition, the sponsor cannot make decisions as 
to the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to participants or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
10.5.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand bermekimab, to understand atopic 
dermatitis, to understand differential intervention responders, and to develop tests/assays related 
to bermekimab and atopic dermatitis. The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).


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10.5.6.
Committees Structure
Data Monitoring Committee
Details regarding the DMC are presented in Section 9.6.
10.5.7.
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding bermekimab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker 
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and use 
this information only to accomplish this study and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of bermekimab, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of 
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. 
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 


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not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not 
be published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
10.5.8.
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRF for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. After upload of the data into the study database they will 
be verified for accuracy and consistency with the data sources. 
10.5.9.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable.  Study-specific data will be transmitted in a secure manner to the sponsor.


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Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
the eCRF in English. The CRF must be completed as soon as possible after a participant visit and 
the forms should be available for review at the next scheduled monitoring visit.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
10.5.10.
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study intervention administration information; and 
date of study completion and reason for early discontinuation of study intervention or withdrawal 
from the study, if applicable. 
The author of an entry in the source documents should be identifiable. Given that patient-reported 
outcomes (PROs) are reports of a patient's health condition that come directly from the patient, 
without interpretation by a clinician or anyone else, the responses to PRO measures entered by 
trial participants into source records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An electronic source (eSource) system may be utilized, which contains data traditionally 
maintained in a hospital or clinic record to document medical care (eg, electronic source 


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documents) as well as the clinical study-specific data fields as determined by the protocol. This 
data is electronically extracted for use by the sponsor. If eSource is utilized, references made to 
the CRF in the protocol include the eSource system, but information collected through eSource 
may not be limited to that found in the CRF.
10.5.11.
Monitoring
The sponsor designee will perform on-site monitoring visits as frequently as necessary. This will 
include blinded site monitors who will perform source data verification and review drug 
preparation and dispensation. The monitor will record dates of the visits in a study-site visit log 
that will be kept at the study-site, as allowed by local regulation. The first post-initiation visit will 
be made as soon as possible after enrollment has begun. At these visits, the monitor will compare 
the data entered into the eCRF (as defined in the monitoring guidelines) with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study-site, the method of 
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site.
10.5.12.
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its 
designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.


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10.5.13.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
10.5.14.
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines


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
Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development


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10.6.
Appendix 6: Guidance on Study Conduct during the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in-person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.  
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report. 
ADDITIONAL ELEMENTS, WHERE APPLICABLE: 

Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of patient care and study integrity. Certain 
measures, such as those listed below, may be necessary and should be instituted in accordance 
with applicable (including local) laws, regulations, guidelines, and procedures:

remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and patients for study procedures eg, those related to 
safety monitoring / efficacy evaluation / study drug storage and administration (including 
training where pertinent)


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
procurement of study drug by patients (or designee) or shipment of study drug from the 
study site directly to patients for at-home administration (including the potential for 
patient self-administration of study drug)

laboratory assessments using a suitably accredited local laboratory; for selected measures 
(eg, urine pregnancy), home testing may be employed

other procedures, eg, imaging, may be conducted at an appropriate facility

Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study 
should be documented with the prefix “COVID-19-related” in the CRF. 

other relevant study data elements impacted by the pandemic should also be documented 
/ labeled as “COVID-19-related” in CRFs and / or other study systems, as directed by 
detailed sponsor guidance. These may include missed / delayed / modified study visits / 
assessments / dosing, and instances where temporary measures such as those above are 
implemented. 

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study data 
and additional data analyses will be outlined in study SAP(s).  

Precaution: for those who may carry a higher risk for severe COVID-19 illness (eg, those aged 
over 65 years), follow guidance from local health authorities when weighing the potential 
benefits and risks of enrolling in the study, and during participation in the study. 


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10.7.
Appendix 7: Eczema Area and Severity Index
EASI Score Calculation: Assessment is performed on the indicated body regions, with each 
component (erythema, induration/papulation, excoriation, lichenification) graded on a scale of 0-
3 and summed. The component score is then multiplied by the area score corresponding to the 
degree of body area involvement, followed by the weighting factor for the particular body region. 
(diagram from francefoundation.com and table excerpted from Hanifin 2001)


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10.8.
Appendix 8: Validated Investigator Global Assessment for Atopic 
Dermatitis


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10.9.
Appendix 9: Severity Scoring of Atopic Dermatitis


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10.10. Appendix 10: Hand Dermatitis Investigator Global Assessment
4-Severe: Severe erythema (deep intense red color), scaling, vesiculation (with or without 
erosion), and/or edema (swelling). Prominent lichenification (thickening with accentuated 
normal skin markings) and/or deep fissuring (causing bleeding or severe pain).
3-Moderate: Moderate erythema (prominent redness), scaling, vesiculation, and/or edema. 
Palpable skin thickening and/or visible fissuring affecting multiple areas of the hand.
2-Mild: Faint but definite erythema, slight but definite flaking, scattered vesicles without 
erosion, and/or slight but definite swelling over limited areas of the hands. Slight but definite 
skin thickening and/or cracked skin affecting limited areas of the hands.
1-Almost Clear: Barely perceptible erythema, flaking, and/or swelling. Minimal vesicles. Barely 
perceptible skin thickening and/or minimal cracked skin over limited areas of the hands.
0-Clear: No erythema, scaling, vesiculation, edema, lichenifcation, or fissuring. Post-
inflammatory pigment alteration (either hyper- or hypopigmentation) may be present.


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10.11. Appendix 11: Patient-Reported Dermatology Life Quality Index


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10.12. Appendix 12: Patient-Oriented Eczema Measure


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10.13. Appendix 13: Patient Global Impression of Severity
Patient’s Global Impression of Severity (PGIS)
of Eczema
Overall, how would you rate the severity of your eczema currently?  (Please select one 
response)
1. None
2. Mild 
3. Moderate 
4. Severe 
5. Very Severe               


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10.14. Appendix 14: Patient-Reported Outcomes Measurement Information 
System-29 


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10.15. Appendix 15: Eczema Skin Pain and Itch Numeric Rating Scale
Eczema Skin Pain and Itch Numeric Rating Scale 
Individuals with eczema may experience skin pain and itch. Please indicate how severe your skin 
pain and itch were in the past 24 hours. Please select only one number for each item on the 0 to 
10 scale (0=none and 10=worst possible).
1. Please rate the severity of your eczema-related skin pain at its worst in the past 24 
hours.











0
1
2
3
4
5
6
7
8
9
10
  None
Worst 
possible
2. Please rate the severity of your eczema-related itch at its worst in the past 24 hours.











0
1
2
3
4
5
6
7
8
9
10
  None
   
Worst 
possible


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10.16. Appendix 16: Atopic Dermatitis Itch Scale 
Eczema Itching Severity Diary
[Morning Administration]
1. How would you rate your eczema-related itching right now?
0
1
2
3
4
5
6
7
8
9
10
No
Moderate
Worst
itching
itching
possible
at all
itching
2. Did you have any eczema-related itching last night? (since you last completed the diary)
 Yes
  No [End of morning administration]
3. At its worst, how would you rate your eczema-related itching last night?
0
1
2
3
4
5
6
7
8
9
10
No
Moderate
Worst
itching
itching
possible
at all
itching
4. To what extent did eczema-related itching impact your sleep last night?
No impact: itching did not affect sleep
Mild impact: a little difficulty falling or staying asleep due to itching
Moderate impact: a moderate amount of difficulty falling or staying 
asleep due to itching
Severe impact: a great deal of difficulty falling or staying asleep due to 
itching


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Eczema Itching Severity Diary
[Evening Administration]
1. How would you rate your eczema-related itching right now?
0
1
2
3
4
5
6
7
8
9
10
No
Moderate
Worst
itching
itching
possible
at all
itching
2. Did you have any eczema-related itching today? (since you last completed the diary)
 Yes
  No [End of evening administration]
3. At its worst, how would you rate your eczema-related itching today?
0
1
2
3
4
5
6
7
8
9
10
No
Moderate
Worst
itching
itching
possible
at all
itching
4. How much of the time did you experience eczema-related itching today?
A little of the time (less than 20% of the day)
Some of the time (20% to 40% of the day)
About half of the time (40% to 60% of the day)
Most of the time (60% to 80% of the day)
All or nearly all of the time (more than 80% of the day)


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10.17. Appendix 17: Digital Actigraphy 
Pruritus or itch is the most defining and universal symptom of AD. Pruritus is defined as an 
unpleasant urge to scratch and is problematic for many reasons, particularly its negative impact on 
quality of life (QoL). Despite the profoundly negative impact of pruritus on patients with AD, 
clinicians and researchers lack standardized and validated methods to objectively measure pruritus
(Smith 2019). In addition, pruritus in AD patients leads to sleep disturbances, fatigue and altered 
physical activity patterns. 
A wrist actigraph is a portable device that uses a micro-accelerator to measure nocturnal wrist 
movement as a proxy for scratching activity that is correlated to itch in patients with AD
(Price 2014). Furthermore, actigraphy has been used in several systemic autoimmune disease 
studies to document the differences in quality of the sleep and physical activity.
A recently published study presents an algorithm to detect nocturnal scratching events based on 
tri-axial wrist actigraphy data sampled at ≥20 Hz (Moreau 2018). The algorithm showed good 
performance with an F1 score of 0.68, sensitivity of 0.66, and precision of 0.71. The algorithm 
was trained on manually labeled scratching events from infrared video data collected from 
24 subjects (6 healthy controls and 18 AD patients). In this study, the published algorithm will be 
applied to actigraphy data collected on a subset of patients in order to assess treatment effects on 
nocturnal scratching. 
For the optional digital actigraphy assessments, a subgroup of participants across treatment arms 
from selected sites will be provided 2 wrist actigraphs from screening through Week 16. Study 
participants will be instructed to wear 2 devices (1 on each wrist) before going to sleep and wear 
one device on the non-dominant wrist during the day.
For analysis of results, scratching events will be quantified by night into 2 endpoints: normalized 
scratch duration (nightly scratch duration normalized by total sleep time) and normalized scratch 
rate (number of scratching events normalized by total sleep time). These nocturnal scratch 
endpoints will be correlated with self-reported itch, disease severity, and other efficacy 
assessments.


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10.18. Appendix 18: Remote Endpoint Assessment Using Total Body 
Photography
A previous study (Hughes 2019) has described the capture of digital images of subjects by site 
personnel, with subsequent analysis of the on-site investigator who also performed the in-person 
assessment. In addition, total body photography (TBP) has long been employed in dermatology 
for the process of “mole mapping,” ie, monitoring the development or change of nevi on the skin 
over time (Rice 2010, Truong 2016). As such a standardized photographic series has been 
established to capture the entirety of the skin surface for visual evaluation (Shriner 1990).
In the assessment of atopic dermatitis, the well-established and validated scoring systems of the 
Eczema Area and Severity Index (EASI; Appendix 7 [Section 10.7]) and Severity Scoring of
Atopic Dermatitis (SCORAD; Appendix 9 [Section 10.9]) are particularly well-suited for the use 
of photographic evaluation. Both scoring systems use regional component assessments (eg, arms, 
legs, chest, extremities) that correspond well to the photographic series proposed. Furthermore, 
the percentage of BSA involvement, itself a criterion for defining moderate to severe disease in 
AD, can be calculated separately (eg, rule of 9’s approximation) or extracted from the SCORAD 
system.
In this study, standard atopic dermatitis severity assessments captured and analyzed via digital 
photographs will be compared with in-person investigator assessments. In addition, comparisons 
at 3 time points and across the treatment groups in this study will allow assessment of the utility 
of digital photography in the measurement of treatment effects.
For the optional digital photographic assessments, a subgroup of participants across dose groups 
from selected sites will provide a series of digital total body photographs at the baseline, Week 8, 
and Week 16 visits. 
Participants will agree to take multiple series of total body photographs with assistance and with 
the provided device. Instructions and photographic guides will be provided to the participant. On 
the same day as a scheduled site visit, the participant will obtain the set of digital images. During 
the same visit, the investigator will also capture a corresponding set of images. Captured images 
will be transferred and stored in a secure manner. The site investigator (at some point after the 
Week 16 visit), will access the images for the subjects at their site and will assess the subjects’ 
severity according to the specified analyses. A central reader(s) will be selected to evaluate and 
score the images for all participants within the substudy.
For analysis of results, a comparison will be performed of the correlation of efficacy measures 
between the in-person site visit, site investigator assessment by images (including those captured 
by the participant and those captured by the site), and central reader assessment by images.


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10.19. Appendix 19: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.19.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a pharmaceutical (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the intervention. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non-investigational) product, whether or 
not related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse 
Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.


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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For bermekimab, the expectedness of an adverse event will 
be determined by whether or not it is listed in the IB. For dupilumab, the expectedness of an 
adverse event will be determined by whether or not it is listed in the package insert.
10.19.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following 
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the 
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.19.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
10.19.4.
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention


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
Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)

Exposure to a sponsor study intervention from breast-feeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
10.19.5.
Procedures
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon the participant's discontinuation from the study, must be followed until any of the following 
occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available


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
The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant’s participation in a study must be reported as a serious adverse event, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a participant in a study within 4 weeks of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
Information regarding serious adverse events will be transmitted to the sponsor using a serious 
adverse event reporting form and safety report form of the CRF, which must be completed and 
reviewed by a physician from the study site, and transmitted in a secure manner to the sponsor 
within 24 hours. The initial and follow-up reports of a serious adverse event should be transmitted 
in a secure manner electronically or by facsimile (fax). Telephone reporting should be the 
exception and the reporter should be asked to complete the appropriate form(s) first.
10.19.6.
Product Quality Complaint Handling
Definition
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or 
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or 
performance of a distributed product, including its labeling, drug delivery system, or package 
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it 
includes any technical complaints, defined as any complaint that indicates a potential quality issue 
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage 
or distribution of the product or the drug delivery system.
Timely, accurate, and complete reporting and analysis of PQC information from studies are crucial 
for the protection of participants, investigators, and the sponsor, and are mandated by regulatory 
agencies worldwide. The sponsor has established procedures in conformity with regulatory 


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requirements worldwide to ensure appropriate reporting of PQC information; all studies conducted 
by the sponsor or its affiliates will be conducted in accordance with those procedures
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
10.19.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.




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10.21. Appendix 21: Liver Safety: Suggested Actions and Follow-up 
Assessments 
10.21.1.
Stopping Algorithm
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are 
met.
10.21.2.
Follow-up Assessments
10.21.2.1.
Phase 2 Liver Chemistry Stopping Criteria and Follow-up 
Assessments
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate 
liver event etiology.


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Liver Chemistry Stopping Criteria
ALT/AST--
absolute
ALT or AST- 5xULN
ALT/AST-
Increase
If cannot monitor:
ALT or AST- 3 xULN and cannot be monitored weekly for 4 weeks
Or if able to monitor:
ALT or AST- 3xULN persists for 4 weeks
Total 
bilirubin1, 2
ALT or AST- 3xULN and total bilirubin 2xULN (or at least a doubling 
of direct bilirubin in known Gilbert’s syndrome)
INR2
ALT or AST- 3xULN and international normalized ratio (INR) >1.5, if 
INR measured
Symptomatic3
ALT or AST- 3xULN associated with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity
Suggested Actions, Monitoring and Follow-up Assessments
Actions
Follow-up Assessments
Immediately stop study intervention
Report the event to the sponsor within 
24 hours
Complete an SAE form
Perform follow-up assessments as described in 
the Follow Up Assessment column
Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return 
to baseline (see MONITORING)
MONITORING:
If ALP <2xULN, ALT or AST- 3xULN AND 
total bilirubin 2xULN (or at least a doubling 
of direct bilirubin in known Gilbert’s 
syndrome) or INR >1.5 (if measured): 
Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, total and direct bilirubin and 
INR) and perform liver event follow-up 
assessments within 24 hours
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline
A specialist or hepatology consultation is 
recommended
If ALT or AST- 3xULN AND total bilirubin 
<2xULN and INR 1.5: 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total and direct 
Viral hepatitis serology4
Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend
Obtain blood sample for 
pharmacokinetic (PK) within 1 week 
of the event of ALT or AST ≥3×ULN5
Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma-glutamyltransferase [GGT], 
glutamate dehydrogenase [GLDH], 
and serum albumin
Fractionate bilirubin
Obtain complete blood count with 
differential to assess eosinophilia
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the CRF as per 
CRF completion guidelines
Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, 
recreational drugs and other over-the-
counter medications)
Record alcohol use on the CRF as per 
CRF completion guidelines


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bilirubin and INR) and perform liver chemistry 
follow-up assessments within 24 to 72 hours
Monitor participant weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline
RESTART/RECHALLENGE
If liver event causality is determined to be 
“not related”, restart may be permitted 
upon written approval of the sponsor. See 
restart guidelines
If ALT or AST- 3xULN AND total 
bilirubin 2xULN or INR >1.5 (if 
measured) obtain the following in 
addition to the assessments listed above:
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins
Serum acetaminophen adduct assay, 
when available, to assess potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week
Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) and/or liver biopsy to 
evaluate liver disease; complete  CRF 
as per CRF completion guidelines
Liver biopsy may be considered and 
discussed with local specialist if 
available:
In participants when serology raises 
the possibility of autoimmune 
hepatitis (AIH)
In participants when suspected 
DILI progresses or fails to resolve 
on withdrawal of study intervention
In participants with acute or chronic 
atypical presentation
If liver biopsy conducted complete 
CRF as per CRF completion 
guidelines
1.Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention if ALT or AST 3xULN and total bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable 
urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
2.All events of ALT or AST- 3 xULN and total bilirubin 2xULN (or at least a doubling of direct bilirubin in 
known Gilbert’s syndrome), ALT or AST- 3 xULN and INR >1.5 (if measured) may indicate severe liver 
injury (possible ‘Hy’s Law’) and must be reported to sponsor in an expedited manner as an SAE. The INR 
stated threshold value will not apply to participants receiving anticoagulants.
3.New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
4.Includes: hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAB; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or 
monospot testing); and hepatitis E IgM antibody.


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5.PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior 
to the blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated, do not obtain a PK sample. Instructions 
for sample handling and shipping are in the laboratory manual.


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10.22. Appendix 21: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).


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11.
REFERENCES
Abdel-Razzak Z, Loyer P, Fautrel A, et al. Cytokines down-regulate expression of major cytochrome P-450 
enzymes in adult human hepatocytes in primary culture. Mol Pharmacol. 1993;44(4):707–715.
Archer NK, Jo J-H, Lee SK, et al. Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through 
keratinocyte IL-1α release. J Allergy Clin Immunol. 2019;143(4):1426-1443.
Bou-Dargham MJ, Khamis ZI, Cogneta AB, Sang QA. The role of interleukin-1 in inflammatory and malignant 
human skin diseases and the rationale for targeting interleukin-1 alpha. Med Res Rev. 2017;37(1):180-216.
Cella D, Riley W, Stone A, et al. Initial adult health item banks and first wave testing of the Patient-Reported 
Outcomes Measurement Information System (PROMISTM) network: 2005–2008. J Clin Epidemiol. 
2010;63(11):1179-1194.
Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and initial validation of a 
new tool for measuring atopic eczema severity from the patients’ perspective. Arch Dermatol. 2004;140(12):1513-
1519. 
Clausen ML, Edslev SM, Andersen PS, Clemmensen K, Krogfelt KA, Agner T. Staphylococcus aureus colonization 
in atopic eczema and its association with filaggrin gene mutations. Br J Dermatol. 2017;177(5):1394‐1400. 
FDA Guidance for Industry: Drug-Drug Interaction Assessment for Therapeutic Proteins (Draft Aug 2020). 
Available at: https://www.fda.gov/media/140909/download. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. 
Clin Experi Dermatol. 1994;19(3):210-216.
Gallay P, Mach JP, Carrel S. Characterization and detection of naturally occurring antibodies against IL-1α and IL-
1β in normal human plasma. Eur Cytokine Network. 1991;2(5):329-338.
Han Y-P, Downey S, Garner WL. Interleukin-1alpha-induced proteolytic activation of metalloproteinase-9 by 
human skin. Surgery. 2005;138(5):932-939.
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): 
assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001;10(1):11-18. 
Hughes MD, Aralis H, Bruhn KW, et al. A reliability study using network-oriented research assistant (NORA®) to 
evaluate the use of digital photographs in the assessment of atopic dermatitis. J Am Acad Dermatol. 2019;S0190-
9622(19):30150-30151.
Kanni T, Argyropoulou M, Spyridopoulos T, et al. MABp1 targeting IL-1α for moderate to severe hidradenitis 
suppurativa not eligible for adalimumab: a randomized study. J Invest Dermatol. 2018;138(4):795-801. 
Kezic S, O'Regan GM, Lutter R, et al. Filaggrin loss-of-function mutations are associated with enhanced expression 
of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin 
deficiency. J Allergy Clin Immunol. 2012;129(4):1031‐1039.
McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol.
2013;131(2):280-291.
Miossec P. Anti-interleukin 1α autoantibodies. Ann Rheum Dis. 2002;61(7):577-579.
Moreau A, Anderer P, Ross M, Cerny A, Almazan TH, Peterson B. Detection of nocturnal scratching movements in 
patients with atopic dermatitis using accelerometers and recurrent neural networks. IEEE J Biomed Health Inform. 
2018;22(4):1011-1018. 
Murphy JE, Robert C, Kupper TS. Interleukin-1 and cutaneous inflammation: a crucial link between innate and 
acquired immunity. J Invest Dermatol. 2000;114(3):602-608.
NCT03496974 ClinicalTrials.gov Identifier. Bermekimab. A Phase II study of bermekimab (MABp1) in patients 
with moderate to severe atopic dermatitis. Available at: https://clinicaltrials.gov/ct2/show/NCT03496974.
NCT04019041 ClinicalTrials.gov Identifier. Bermekimab. A study to evaluate the efficacy, safety and tolerability of 
bermekimab in patients with hidradenitis suppurativa. Available at: 
https://clinicaltrials.gov/ct2/show/NCT04019041.


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NCT04021862. ClinicalTrials.gov Identifier. Bermekimab. A Phase II, Randomized, Double-Blind, Placebo-
Controlled Study of Bermekimab in Patients With Moderate to Severe Atopic Dermatitis. Available at: 
https://clinicaltrials.gov/ct2/show/NCT04021862.
Price A, Cohen DE. Assessment of pruritus in patients with psoriasis and atopic dermatitis: subjective and objective 
tools. Dermatitis. 2014;25(6):334-244.
Renton KW. Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug 
Metab Toxicol. 2005;1(4):629-640.
Rice ZP, Weiss FJ, DeLong LK, Curiel-Lewandrowski C, Chen SC. Utilization and rationale for the implementation 
of total body (digital) photography as an adjunct screening measure for melanoma. Melanoma Res. 
2010;20(5):417-421. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of 
anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397.
Saurat JH, Schifferli J, Steiger G, Dayer JM, Didierjean L. Anti-IL-1α autoantibodies in humans: characterization, 
isotype distribution, and receptor-binding inhibition—higher frequency in Schnitzler’s syndrome (urticaria and 
macroglobulinemia). J Allergy Clin Immunol. 1991;88(2):244-256.
Shriner DL, Glowczwski J, Wagner RF. Techniques of full-scale colour total body photography: a useful tool in the
management of patients with the dysplastic naevus syndrome. J Dermatolog Treat. 1990;1:181-185.  
Simpson E, Bissonnette R, Eichenfield L, et al. The validated Investigator Global Assessment for Atopic Dermatitis 
(vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the 
severity of atopic dermatitis. J Am Acad Dermatol. 2020;83(3):839-846. 
Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab versus placebo in atopic 
dermatitis. N Engl J Med. 2016;375(24):2335-2348.
Skoff AM, Zhao C, Adler JE. Interleukin-1alpha regulates substance P expression and release in adult sensory 
neurons. Experimental Neurology. 2009;217(2):395-400.
Smith MP, Ly K, Thibodeaux Q, et al. Emerging methods to objectively assess pruritus in atopic dermatitis. 
Dermatol Ther (Heidelb). 2019;9(3):407-420. 
Suzuki H, Ayabe T, Kamimura J, Kashiwagi H. Anti- IL-1α autoantibodies in patients with rheumatic diseases and 
in healthy subjects. Clin Exp Immunol. 1991;85(3):407-412.
Truong A, Strazzulla L, March J, et al. Reduction in nevus biopsies in patients monitored by total body photography.
J Am Acad Dermatol. 2016;75(1):135-143. 


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research & Development 
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be 
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

SAP_001.pdf: 
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1
Status: Final, Date: 02 March 2022
Janssen Research & Development
Statistical Analysis Plan
Amendment 1
A Phase 2b, Multicenter, Randomized, Placebo- and Active-Comparator-Controlled, 
Double-blind Study to Evaluate the Safety and Efficacy of Bermekimab (JNJ-77474462) 
for the Treatment of Participants with Moderate to Severe Atopic Dermatitis
Protocol 77474462ADM2001; Phase 2b
JNJ-77474462  (bermekimab)
Status:
Final
Date:
02 March 2022
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-RIM-383804
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04791319


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 7
2.
STATISTICAL HYPOTHESES............................................................................................................ 9
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 9
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 11
5.
STATISTICAL ANALYSES............................................................................................................... 11
5.1.
General Considerations ................................................................................................................. 11
5.1.1.
Visit Windows ............................................................................................................................. 11
5.1.2.
Reference Date, Study Day and Relative Day ........................................................................... 11
5.2.
Participant Dispositions.................................................................................................................. 12
5.3.
Primary Endpoint Analysis ............................................................................................................. 13
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 13
5.3.2.
Estimand..................................................................................................................................... 13
5.3.2.1.
Primary Estimand (Estimand 1)............................................................................................... 14
5.3.2.2.
Treatment Policy Estimand (Estimand 2):............................................................................... 15
5.3.3.
Analysis Methods for Primary Estimand..................................................................................... 15
5.3.4.
Analysis for Supplementary Estimand........................................................................................ 16
5.4.
Secondary Endpoints Analysis ...................................................................................................... 16
5.4.1.
Multiplicity Adjustment for Testing Procedures .......................................................................... 16
5.4.2.
Key Secondary Endpoint(s)........................................................................................................ 16
5.4.2.1.
Definition of Endpoints............................................................................................................. 17
5.4.2.1.1.
Eczema Area and Severity Index......................................................................................... 17
5.4.2.1.2.
Validated Investigator Global Assessment for Atopic Dermatitis......................................... 17
5.4.2.1.3.
Eczema Skin Pain and Itch Numeric Rating Scale .............................................................. 17
5.4.2.2.
Estimands for Key Secondary Endpoints ................................................................................ 17
5.4.2.2.1.
Estimands 3-5 ...................................................................................................................... 17
5.4.2.2.2.
Estimands 6-9 ...................................................................................................................... 18
5.4.2.3.
Analysis Methods .................................................................................................................... 19
5.5.
Exploratory Efficacy Analyses........................................................................................................ 20
5.5.1.
Definition of Endpoints................................................................................................................ 20
5.5.1.1.
Eczema Area and Severity Index ............................................................................................ 20
5.5.1.2.
Eczema Skin Pain and Itch Numeric Rating Scale.................................................................. 20
5.5.1.3.
Validated Investigator Global Assessment for Atopic Dermatitis ............................................ 20
5.5.2.
Analysis Methods........................................................................................................................ 20
5.5.2.1.
Analyses for Binary and Continuous Endpoints ...................................................................... 21
5.5.2.1.1.
Analyses Related to EASI.................................................................................................... 23
5.5.2.1.2.
Analyses Related to NRS..................................................................................................... 23
5.5.2.1.3.
Analyses Related to vIGA-AD.............................................................................................. 24
5.6.
Safety Analyses ............................................................................................................................. 24
5.6.1.
Extent of Exposure ..................................................................................................................... 25
5.6.2.
Adverse Events........................................................................................................................... 25
5.6.3.
Additional Safety Assessments .................................................................................................. 26
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 26
5.6.3.2.
Vital Signs................................................................................................................................ 27


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5.6.3.3.
Electrocardiogram ................................................................................................................... 27
5.7.
Other Analyses............................................................................................................................... 27
5.7.1.
Pharmacokinetics ....................................................................................................................... 27
5.7.2.
Immunogenicity (Antibodies to Bermekimab)............................................................................. 29
5.7.3.
Biomarkers.................................................................................................................................. 30
5.7.4.
Definition of Subgroups .............................................................................................................. 30
5.8.
Interim Analyses............................................................................................................................. 31
5.9.
Data Monitoring Committee (DMC) or Other Review Board.......................................................... 32
6.
SUPPORTING DOCUMENTATION .................................................................................................. 33
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 33
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 34
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 35
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 36
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 37
6.6.
Appendix 6 Medical History ........................................................................................................... 38
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 39
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 40
6.9.
Appendix 9 Medications of Special Interest................................................................................... 41
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 42
7.
REFERENCES................................................................................................................................... 49


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VERSION HISTORY
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
Final
28 September 
2021
Not Applicable
Initial release
Amendment 1
02 March 2022
Updates were made to the 
primary estimand with respect to 
the strategy to handle COVID 
related (not infection) 
discontinuation and COVID-
related missing data for the 
primary and key secondary 
endpoints.
In addition, analyses for some 
exploratory endpoints were 
removed.
The IA futility criterion was met 
and the decision was made to 
terminate the study on 02
February 2022. The SAP has 
been updated with reduced 
efficacy and PK analyses.
Since COVID-19 can no longer 
be viewed as a temporary 
problem, all COVID-19 related 
reasons will be treated similarly 
to “Discontinuations of study 
intervention due to reasons other 
than lack of efficacy or 
worsening of AD” for which 
treatment policy strategy was 
used in the past. In addition, there 
is no or minimal occurrence of 
treatment discontinuation due to 
COVID related reason (not 
infection).  


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and
statistical methods for all planned analyses of efficacy, safety, pharmacokinetics (PK), and 
immunogenicity of bermekimab. This SAP incorporates all analyses through the Week 36 final 
database lock (DBL) for the study 77474462ADM2001.
1.1.
Objectives and Endpoints 
Objectives
Endpoints
Primary

To evaluate the efficacy of bermekimab 
in participants with moderate to severe 
AD

Proportion of participants with Eczema 
Area and Severity Index-75 (EASI-75, 
≥75% improvement from baseline) at 
Week 16
Secondary

To characterize additional assessments of 
efficacy for bermekimab in participants 
with moderate to severe AD

Proportion of participants with both 
validated Investigator Global Assessment 
for Atopic Dermatitis (vIGA-AD) of 0 or 1 
and a reduction from baseline of ≥2 points 
at Week 16

Proportion 
of 
participants 
with 
improvement 
(reduction) 
of 
eczema-
related itch numeric rating scale (NRS) ≥4 
from 
baseline 
to 
Week 16 
among 
participants with a baseline itch value ≥4

Proportion of participants with EASI-90 at 
Week 16. 

To evaluate the efficacy of bermekimab 
relative to dupilumab in participants with 
moderate to severe AD

Proportion of participants with EASI-75 at 
Week 16

Proportion of participants with EASI-90 at 
Week 16

Proportion of participants with both vIGA-
AD of 0 or 1 (on a 5-point scale) and a 
reduction from baseline of ≥2 points at 
Week 16

Proportion 
of 
participants 
with 
improvement 
(reduction) 
of 
eczema-
related itch NRS ≥4 from baseline to Week 
16 among participants with a baseline itch 
value ≥4

To assess the safety and tolerability of 
bermekimab 
in 
participants 
with 
moderate to severe AD

Number/proportion of participants with 
treatment-emergent adverse events (AEs)


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Objectives
Endpoints

Number/proportion of participants with 
treatment-emergent serious adverse events 
(SAEs)

To evaluate the pharmacokinetics (PK) 
and immunogenicity of bermekimab in 
adult participants with moderate to 
severe AD

Bermekimab concentration over time

The incidence of antibodies to bermekimab
Exploratory

To further characterize efficacy of 
bermekimab
in 
participants 
with 
moderate to severe AD

Improvement from baseline to Week 16 in 
Severity Scoring of Atopic Dermatitis 
(SCORAD)

Improvement from baseline to Week 16 in 
Dermatology Life Quality Index (DLQI)

Improvement from baseline to Week 16 in 
Patient-Oriented 
Eczema 
Measure 
(POEM)

Improvement from baseline to Week 8 in 
eczema-related itch NRS

Improvement from baseline to Week 8 in 
eczema-related pain NRS

Improvement from baseline to Week 16 in 
eczema-related pain NRS

Improvement from baseline to Week 16 in 
itch as measured by the Atopic Dermatitis 
Itch Scale (ADIS)

Proportions of participants with a Patient 
Global Impression of Severity (PGIS) 
score of 1 (none) or 2 (mild) at Week 16

Change from baseline to Week 16 in 
Patient-Reported Outcomes Measurement 
Information System (PROMIS)-29 total 
score and sub-scores

Hand 
Dermatitis 
Investigator 
Global 
Assessment (IGA) at Week 16. 

To assess the impact of treatment with 
bermekimab on selected biomarkers

Changes 
in 
cellular 
and 
molecular 
biomarkers in skin and blood from baseline


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1.2.
Study Design
This is a randomized, double-blind, placebo- and active-comparator-controlled, multicenter, 
interventional study to assess the efficacy, safety, PK and immunogenicity of subcutaneous (SC) 
administered bermekimab for the treatment of moderate to severe AD in adult participants. The 
participant population will be comprised of men and women ≥18 years of age, with AD that is 
moderate to severe, and has been present for at least 1 year before the first administration of study 
intervention, as determined by the investigator through patient interview and/or review of the 
medical history. Participants must also have a history of inadequate response to treatment for AD 
with topical medications or for whom topical treatments are otherwise medically inadvisable, an 
EASI score ≥16, an IGA score ≥3, and an involved percent body surface area (BSA) ≥10% at both 
screening and at baseline. Participants must agree to apply moisturizers at least once daily for at 
least 7 days before randomization and continue the treatment throughout the study.
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study


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As depicted in Figure 1, approximately 200 participants who satisfy all inclusion and exclusion 
criteria will be randomly assigned in this study in a 1:1:2:2 ratio to 1 of 4 intervention groups:
Group 1: Placebo
Participants will receive placebo weekly through Week 15. At Week 16, participants will crossover 
to receive bermekimab 700 mg weekly through Week 31.
Group 2: Bermekimab 350 mg SC qw
Participants will receive bermekimab 350 mg at Week 0 and every week thereafter through 
Week 31.
Group 3: Bermekimab 700 mg SC qw
Participants will receive bermekimab 700 mg at Week 0 and every week thereafter through 
Week 15. At Week 16, participants who achieve an EASI-75 response will be rerandomized in a 
1:1 ratio either to continue to receive bermekimab 700 mg weekly, or to receive bermekimab 
350 mg weekly, through Week 31. At Week 16, participants who do not achieve an EASI-75 
response will continue to receive bermekimab 700 mg weekly through Week 31.
Group 4: Comparator/Reference Arm (Dupilumab) 
Participants will receive a loading dose of dupilumab 600 mg at Week 0. Participants will 
receive dupilumab 300 mg q2w beginning at Week 2 through Week 14. Participants who achieve 
an EASI-75 response at Week 16 will continue on dupilumab 300 mg q2w from Week 16 through 
Week 30. At Week 16, participants who do not achieve an EASI-75 response (ie, dupilumab 
nonresponders) will receive placebo weekly at Weeks 16 through 18 (ie, washout period), and 
bermekimab 700 mg weekly from Week 19 through Week 31.
Details on placebo SC administrations to maintain the blind are provided in the protocol.
A screening period will occur approximately 4 weeks before Week 0. All participants will enter 
the safety follow-up after Week 31 through Week 36. The total duration of study participation will 
be approximately 40 weeks.
Two planned database locks (DBLs) will occur when all participants complete the Week 16 visit 
and at Week 36 (end of study). 
Efficacy assessments (EASI, vIGA-AD™, percent body surface area [BSA] involvement, 
SCORAD, and Hand Dermatitis IGA) and patient-reported outcome (PRO) measures (DLQI, 
POEM, PGIS, PROMIS-29, Eczema Skin Pain and Itch NRS, and ADIS) will be performed at 
visits according to the Schedules of Activities. Serum samples for PK, immunogenicity, and 
biomarker analyses will be collected at the timepoints shown in the protocol Schedules of 
Activities. Digital actigraphy and evaluation of EASI and SCORAD endpoints from digital 


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photographs will be completed from a subgroup of participants who consent to these optional 
substudies at selected sites. 
An interim analysis of data through Week 16 is planned for this study when approximately 50% 
of participants have completed the Week 16 visit. An independent, internal committee will review 
the results of the interim analysis. In addition, an independent, external DMC will review 
unblinded safety data to ensure the safety of the participants enrolled in this study.
2.
STATISTICAL HYPOTHESES
The hypothesis for this study is that bermekimab treatment is superior to placebo as assessed by 
the proportion of participants achieving EASI-75 (≥75% improvement from baseline) at Week 16.
The null hypothesis to be tested to address the primary objective of this study is that there is no 
difference between any of the bermekimab doses (350 mg or 700 mg) and placebo treatment based 
on the primary efficacy endpoint.
3.
SAMPLE SIZE DETERMINATION
Approximately 270 participants are planned to be screened with 200 participants randomized in 
order to have sufficient power to detect a difference between the bermekimab groups and the 
placebo group for the primary endpoint of the proportion of participants achieving EASI-75 at 
Week 16. The sample size was also chosen to have adequate confidence level for the treatment
difference between the bermekimab 700 mg group and the dupilumab group for the primary 
endpoint.
The EASI-75 response rate in the bermekimab 400 mg qw group was 35% at Week 16 and 70% 
at Week 7 from the placebo-controlled study (77474462ADM2002) and the open label study 
(2018-PT044), respectively. The EASI-75 response rates at Week 16 were 15% and 12% with 
placebo and 51% and 44% with dupilumab, respectively, in the two Phase 3 trials of dupilumab 
versus placebo in the treatment of adult participants with moderate to severe AD (Simpson 2016). 
Therefore, based on the data from these studies, various assumptions are used to calculate sample 
size and power as shown in Table . The EASI-75 responses at Week 16 are assumed to be 15% for 
placebo, 45% to 50% for dupilumab, and 50% to 70% for the bermekimab 350 mg and 700 mg 
intervention groups, respectively. Based on these assumptions, approximately 200 participants are 
planned to be randomized in a 1:1:2:2 ratio to the placebo (n=33), bermekimab 350 mg (n=33), 
bermekimab 700 mg (n=67), or dupilumab (n=67) intervention groups. These sample sizes provide 
the study with at least 88% power to detect a treatment difference between the bermekimab 
intervention groups and the placebo group in EASI-75 at Week 16 based on a 2-sample Z-test at a 
Type I error rate of 0.05 (2-sided). These sample sizes also provide at least 88% power to detect a 
treatment difference between the dupilumab and placebo intervention group in EASI-75 at Week 
16 at a 2-sided significance level of 0.05 (Table ).


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Table 1:
Power to detect a treatment difference in EASI-75 at Week 16
Placebo
Intervention group
Difference
Power
bermekimab 700 mg (n=67) vs placebo (n=33)
15%
50%
35%
95%
15%
60%
45%
>99%
15%
70%
55%
>99%
12%
50%
38%
98%
12%
60%
48%
>99%
12%
70%
58%
>99%
bermekimab 350 mg (n=33) vs placebo (n=33)
15%
50%
35%
88%
15%
55%
40%
94%
12%
50%
38%
93%
12%
55%
43%
97%
dupilumab (n=67) vs placebo (n=33)
15%
45%
30%
88%
15%
50%
35%
95%
15%
55%
40%
99%
12%
45%
33%
94%
12%
50%
38%
98%
12%
55%
43%
>99%
Note: The power calculation is based on two-sample Z-test (pooled variance) .
In addition, a sample size of 67 participants in each of the bermekimab 700 mg and dupilumab 
groups produce a two-sided 80% confidence interval for the difference in two groups with a width 
of 22.9% when the observed EASI-75 response is 60% and 50% in the bermekimab 700 mg and 
the dupilumab group, respectively. With an observed EASI-75 response rate of 50% in both the 
bermekimab 350 mg and dupilumab groups, a sample size of 33 participants in the 350 mg group 
and 67 participants in the dupilumab group would provide a two-sided 80% confidence interval of 
difference with a width of 27.3% (Table ).
Table 2:
Confidence interval for the treatment difference in EASI-75 at Week 16
EASI-75 
Response (P1)
EASI-75 
Response (P2)
Difference
(P1 − P2)
Width
Confidence 
Limit
Confidence
Level
bermekimab 700 mg (n=67; P1) vs dupilumab (n=67; P2)
60%
50%
10%
22.9%
(−1%, 21%)
80%
65%
50%
15%
21.6%
(4%, 26%)
80%
70%
50%
20%
21.2%
(9%, 31%)
80%
bermekimab 350 mg (n=33; P1) vs dupilumab (n=67; P2)
50%
50%
0%
27.3%
(−14%, 14%)
80%
55%
50%
5%
27.2%
(−9%, 19%)
80%
60%
50%
10%
26.9%
(−3%, 23%)
80%


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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The populations for analysis are defined in Table 3 below.
Table 3 Description of analysis sets used to analyze the data in the study
Analysis Sets
Description
Enrolled
All participants who sign the ICF
Randomized Analysis Set
The randomized analysis set includes all participants who were randomized at Week 
0 in the study.
Re-randomized Analysis 
Set
The re-randomized analysis set includes all participants who were randomized at 
Week 16 in the study.
Full Analysis Set (FAS)
The full analysis set (FAS) includes all participants who were randomized at Week 0 
and received at least 1 dose of study intervention.
Modified Full Analysis Set 
(mFAS)
The mFAS includes all FAS participants who could have reached a visit by the time 
of the decision was made to terminate the study on 02 February 2022.
projected visit (weeks) = (decision date of study termination – first dose date +1) /7
Participants will be excluded in the analysis after projected visit.
Safety
The safety analysis set includes all participants who received at least 1 dose of study 
intervention.
Pharmacokinetics Analysis 
Set
The PK analysis set is defined as participants who received at least 1 dose of 
bermekimab and have at least 1 valid blood sample drawn for PK analysis.
Immunogenicity Analysis 
Set
The immunogenicity analysis set is defined as all participants who received at least 1 
dose of bermekimab and who have at least 1 sample obtained after their first dose of 
bermekimab for the detection of antibodies to bermekimab.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
The statistical analyses will include all analyses from Week 0 through Week 16 and through Week 
36 (the final safety follow-up).
In general, baseline is defined as the last observation prior to or at the time of the first study agent 
administration, unless otherwise specified.
5.1.1.
Visit Windows
Nominal visits will be used for all by-visit analyses in the study. The study visits scheduled post 
randomization should occur at the times delineated in the Schedule of Activities.  The study visits 
should occur within ± 3 days of the scheduled visit throughout the study. 
5.1.2.
Reference Date, Study Day and Relative Day
The Reference Date is the date of the first study agent administration. If the date of the first study 
agent administration is missing or the first study agent administration is not done, then the 
bermekimab 700 mg (n=67; P1) vs bermekimab 350 mg (n=33; P2)
60%
50%
10%
27.1%
(−4%, 24%
80%
65%
50%
15%
26.8%
(2%, 28%)
80%
70%
50%
20%
26.5%
(7%, 33%)
80%


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Reference Date equals the corresponding visit date (eg, Week 0 visit date). If the corresponding 
visit date is also missing, then the Reference Date equals the randomization date. Study day is 
defined as the number of days from the study reference date to the event/visit date.  It will be 
calculated as follows: 

If the event/assessment occurs on or after the reference date, then study day = 
event/assessment date – reference date + 1.

If the event/assessment occurs before the reference date, then study day = 
event/assessment date – reference date.
Hence, the day of reference date is Study Day 1; the previous day is Study Day -1.
5.2.
Participant Dispositions
The number of screened participants will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall based on the randomized analysis set:

Participants randomized

Participants who received study intervention

Participants who completed the study

Participants who discontinued study intervention
–
Reasons for discontinuation of study intervention

Participants who terminated study prematurely
–
Reasons for termination of study
The above categories will include summaries over the placebo-controlled period (through Week 
16) and the entire study (through Week 36).
Listings of participants will be provided for the following categories:

Participants who discontinued study intervention

Participants who terminated study prematurely

Participants who were unblinded during the study period

Participants who were randomized but did not receive study intervention. Participants who 
were randomized with incorrect stratum.


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5.3.
Primary Endpoint Analysis
5.3.1.
Definition of Endpoint(s)
The primary efficacy endpoint is the proportion of patients achieving an EASI-75 response at 
Week 16. The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD. Four AD disease characteristics will be assessed for severity by the 
investigator or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of 
AD involvement will be assessed as a percentage by body area of head, trunk, arms, and legs and 
converted to a score of 0 to 6. 
For each region, severity score is the sum of intensity for each of four signs.

Severity score = Erythema + Edema/Papulation + Excoriation + lichenification intensity
For each body region, the total severity score is multiplied by the body area score for the same 
region, and then applied a multiplier that represents the proportion of the total body surface area 
contained in the body region assessed.

Head and neck: severity score x region score x 0.1 

Trunk: severity score x region score x 0.3

Upper extremities: severity score x region score x 0.2

Lower extremities: severity score x region score x 0.4 
Add up the total scores for each region to determine the final EASI score. The minimum EASI 
score is 0 and the maximum EASI score is 72.
EASI-100 responder is defined as a 100% improvement from baseline in EASI total score (EASI 
score=0).
EASI-90 responder is defined as at least a 90% improvement from baseline in EASI total score.
EASI-75 responder is defined as at least a 75% improvement from baseline in EASI total score.
EASI-50 responder is defined as at least a 50% improvement from baseline in EASI total score.
5.3.2.
Estimand
Primary Trial Objective: to evaluate the efficacy of bermekimab in participants with moderate 
to severe AD.
Estimand Scientific Question of interest: What is the proportion of participants considered to 
have benefited from bermekimab versus placebo assessed by the EASI-75 at Week 16, 
administered together with the protocol allowed background standard-of-care medication?


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5.3.2.1.
Primary Estimand (Estimand 1)
The primary estimand (i.e. a precise definition of the primary targeted treatment effect) is defined 
by the following 5 attributes:
Study intervention:

Bermekimab 350 mg, 700 mg SC qw through Week 15

Dupilumab 300 mg SC q2w through Week 14 with dupilumab 600 mg at Week 0

Placebo SC qw through Week 15
Population: adult participants with moderate to severe AD
Variable/endpoint:
Binary response variable, where a responder is defined as a participant 
achieving an EASI-75 response at Week 16. A participant with an intercurrent event in categories 
1-3 defined below will be considered as a non-responder.
Intercurrent Events (ICEs) and their corresponding strategies.
ICEs
Analysis Strategy for Addressing Intercurrent Events
1.
Discontinuation of study intervention due
to lack of efficacy, an AE of worsening of 
AD prior to Week 16
2.
Initiation of a protocol-prohibited
medication or therapy during the study
that could improve AD prior to Week 16
3.
Initiation of rescue medication for AD prior 
to Week 16
Composite Strategy: Participants with these intercurrent event are
considered as EASI-75 non-responders. The occurrence of these 
intercurrent event being captured in the variable definition.
4.
Discontinuation of study intervention or 
missed 4 or more administrations due to 
COVID-19 related reasons (excluding 
COVID-19 infection) prior to Week 16
Treatment Policy Observed data will be used regardless of the 
intercurrent event.
5.
Discontinuation of study intervention for
reasons other than ICEs 1 and 4 including 
COVID-19 infection prior to Week 16
Treatment Policy: Observed data will be used regardless of the 
intercurrent event.
Note: For participants experiencing multiple ICEs, ICEs in categories 2-3 will override ICEs 4 and 
5.
Population level summary: Difference in the proportions of participants achieving an EASI-75 
response at Week 16 between the bermekimab group and placebo group.
For ICEs 2 and 3, the protocol-prohibited medications/therapies and rescue medications include:


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Topical Therapies:
Any topical therapies (such as corticosteroid, calcineurin inhibitors) used for atopic 
dermatitis (except for topical moisturizers).
Phototherapy or Systemic Therapies:
Any systemic corticosteroid used for an indication of “Atopic Dermatitis”.
Any other systemic or biologic therapy for atopic dermatitis.
Phototherapy of UVB/ PUVA or tanning beds, excimer laser, bleach baths.
5.3.2.2.
Treatment Policy Estimand (Estimand 2):
This supplementary estimand has the same components as the primary estimand, except for the 
strategies used for ICEs 1-3.
Treatment policy strategy:  assess the treatment effect regardless of whether or not intercurrent 
events had occurred. Under the treatment policy strategy, observed EASI data collected after ICEs 
will be used in analysis.
5.3.3.
Analysis Methods for Primary Estimand
The primary endpoint will be analyzed at Week 16 based on the primary estimand (Section 5.3.2.1) 
and the data from all participants in mFAS (Section 4) will be analyzed according to randomized 
intervention group regardless of the treatment actually received. Participants whose projected 
Week 16 visits occur after study termination will be excluded in the primary analysis. Participants 
with ICEs 1-3 before Week 16 will be considered as EASI-75 non-responders at Week 16.
Participants with ICE 4-5, observed data after these ICEs will be utilized in the analysis. A listing 
of participants with intercurrent events will be provided. 
After accounting for the ICEs for the primary estimand, a participant with missing data will be 
considered as a non-responder.
In this primary analysis, the proportion of participants who achieve an EASI-75 at Week 16 will 
be summarized for each intervention group. To address the primary objective, a CMH chi-square 
test stratified by baseline EASI severity (less severe [EASI score<28] or more severe [EASI 
score≥28]) at an alpha level of 0.05 will be used to compare each bermekimab group separately 
with placebo. The proportion difference between each bermekimab group and placebo group and 
its 2-sided 95% CI will be provided based on normal approximation with Mantel-Haenszel weights 
adjusting for baseline EASI severity. In case of rare events, the Fisher’s Exact test will be used for 
treatment comparisons in primary endpoint.
The study would be considered as positive if any of the comparisons for primary endpoint analysis 
(bermekimab 700 mg vs placebo, and bermekimab 350 mg vs placebo) is less than or equal to 
p-value of 0.05. Therefore, an overall Type I error rate will be maintained at 0.1 or less for the 
primary endpoint analysis. 


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In addition, the proportion of participants achieving EASI-75 at Week 16 by investigator site will 
be summarized. 
5.3.4.
Analysis for Supplementary Estimand
The primary endpoint will be analyzed utilizing the treatment policy estimand in mFAS. The 
analysis will be performed using observed data regardless of intercurrent event. The EASI-75 
values collected after intercurrent event will be used in analysis and missing data will not be 
imputed. A CMH test stratified by baseline EASI severity will be used to analyze the data.
5.4.
Secondary Endpoints Analysis
5.4.1.
Multiplicity Adjustment for Testing Procedures
No multiplicity adjustments will be made for the secondary endpoints. All statistical testing will 
be performed at the 2-sided 0.05 significance level. Nominal p-values will be presented.
5.4.2.
Key Secondary Endpoint(s)
Objective: to characterize additional assessments of efficacy for bermekimab relative to placebo
in participants with moderate to severe AD.
The key secondary endpoints to address the objective are the following:

Proportion of participants with both vIGA-AD 0 or 1 and a reduction from baseline of ≥2 
points at Week 16

The proportion of participants with improvement of eczema-related itch NRS ≥4 from 
baseline to Week 16 among participants with a baseline itch value ≥4

Proportion of participants with EASI-90 at Week 16
Objective: to evaluate the efficacy for bermekimab relative to dupilumab in participants with 
moderate to severe AD.
The key secondary endpoints to address the objective are the following:

Proportion of participants with EASI-75 at Week 16

Proportion of participants with EASI-90 at Week 16

Proportion of participants with both vIGA-AD 0 or 1 and a reduction from baseline of ≥2 
points at Week 16

The proportion of participants with improvement of eczema-related itch NRS ≥4 from 
baseline to Week 16 among participants with a baseline itch value ≥4


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5.4.2.1.
Definition of Endpoints
5.4.2.1.1.
Eczema Area and Severity Index
Details refer to section 5.3.1.
5.4.2.1.2.
Validated Investigator Global Assessment for Atopic Dermatitis 
The vIGA-AD™ developed by Eli Lilly and Company is an assessment instrument used in clinical 
studies to rate the severity of AD, based on a 5-point scale ranging from 0 (clear) to 4 (severe). 
The IGA score is selected using the morphological descriptors that best describe the overall 
appearance of the AD lesions at a given time point.
The key secondary endpoint is the proportion of participants with vIGA-AD 0 or 1 (on a 5-point 
scale) and a reduction from baseline of ≥2 points at Week 16.
5.4.2.1.3.
Eczema Skin Pain and Itch Numeric Rating Scale 
The Eczema Skin Pain and Itch NRS is a two-item patient-reported outcome developed by the 
sponsor that participants will use to rate the severity of their eczema-related skin pain and 
eczema-related itch daily. Participants will be asked the following questions:

Please rate the severity of your eczema-related skin pain at its worst in the past 24 hours.

Please rate the severity of your eczema-related itch at its worst in the past 24 hours.
Each item is on a 0 to 10 NRS ranging from 0 “none” to 10 “worst possible” and will be scored 
separately. Participants will complete the rating scale daily from the screening visit through the 
last study visit as detailed in the protocol SoA. 
The baseline is defined as the average score of last 7 days prior to Week 0 study agent 
administration. If there are more than 3 days missing data, then baseline is set as missing. Missing 
baseline will not be imputed.
Seven daily NRS scores are averaged into a weekly score (ie 7 days [from day -7 to -1] prior to a 
visit). Four days out of 7 days (either consecutive or nonconsecutive) are necessary to derive a 
weekly score; otherwise data are considered missing for that week.
5.4.2.2.
Estimands for Key Secondary Endpoints
5.4.2.2.1.
Estimands 3-5
The following describes the attributes of the estimands for the key secondary endpoints (Estimands 
3-5)
Study intervention:

Bermekimab 350 mg, 700 mg SC qw through Week 15


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
Dupilumab 300 mg SC q2w through Week 14 with dupilumab 600 mg at Week 0

Placebo SC qw through Week 15
Population: adult participants with moderate to severe AD
Variable: variables (for estimands 4-6) are listed below
Summary measure (population-level summary): Difference in proportions of responses 
between each bermekimab group and placebo.
Intercurrent events and their corresponding strategies: The intercurrent events for all key
secondary endpoints at Week 16 are the same as those used in the primary estimand specified in 
section 5.3.2.1.
5.4.2.2.2.
Estimands 6-9
The following describes the attributes of the estimands for the key secondary endpoints (Estimands 
6-9)
Study intervention:

Bermekimab 350 mg, 700 mg SC qw through Week 15

Dupilumab 300 mg SC q2w through Week 14 with dupilumab 600 mg at Week 0

Placebo SC qw through Week 15
Population: adult participants with moderate to severe AD
Variable: variables (for estimands 6-9) are listed below
Estimand
Variable (Endpoint)
3
Binary response variable, where a responder is defined as a participant achieving 
vIGA-AD 0 or 1 and a reduction from baseline of ≥2 points at Week 16 who does 
not have ICEs 1-3 (definition of ICEs in 5.3.2.1)
4
Binary response variable, where a responder is defined as a participant with 
improvement of eczema-related itch NRS ≥4 from baseline to Week 16 among 
participants with a baseline itch value ≥4 who does not have ICEs 1-3
5
Binary response variable, where a responder is defined as a participant with EASI-90 
response at Week 16 who does not have ICEs 1-3
Estimand
Variable (Endpoint)


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Summary measure (population-level summary): Difference in proportions of responders 
between each bermekimab group and dupilumab group.
Intercurrent events and their corresponding strategies: The intercurrent events for all key 
secondary endpoints at Week 16 are the same as those used in the primary estimand specified in 
section 5.3.2.1.
5.4.2.3.
Analysis Methods
The key secondary efficacy analyses of data will be based on the mFAS. The key secondary 
analyses are:
Comparison between bermekimab and placebo

The proportion of participants with both vIGA-AD 0 or 1 (on a 5-point scale) and a reduction 
from baseline of ≥2 points at Week 16 will be compared between each of the bermekimab 
group and the placebo group.

The proportion of participants with improvement (reduction) of eczema-related itch NRS ≥4 
from baseline to Week 16 among participants with a baseline itch value ≥4 will be compared 
between each of the bermekimab group and the placebo group.

The proportion of participants who achieve EASI-90 at Week 16 will be compared between 
each of the bermekimab group and the placebo group. 
Estimation of treatment effect between bermekimab and dupilumab

The difference in the EASI-75 response rate between each of the bermekimab groups and the 
dupilumab group and the corresponding 80% CIs will be provided at Week 16.

The difference in the EASI-90 response rate between each of the bermekimab groups and the 
dupilumab group and the corresponding 80% CIs will be provided at Week 16.
6
Binary response variable, where a responder is defined as participants with EASI-75 
response at Week 16 who does not have ICEs 1-3
7
Binary response variable, where a responder is defined as participants with EASI-90 
response at Week 16 who does not have ICEs 1-3
8
Binary response variable, where a responder is defined as participant achieving 
vIGA-AD 0 or 1 and a reduction from baseline of ≥2 points at Week 16 who does 
not have ICEs 1-3
9
Binary response variable, where a responder is defined as participants with 
improvement of eczema-related itch NRS ≥4 from baseline to Week 16 among 
participants with a baseline itch value ≥4 who does not have ICEs 1-3


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
The difference and 2-sided 80% CIs in the proportion of participants with both vIGA-AD 
0 or 1 (on a 5-point scale) and a reduction from baseline of ≥2 points at Week 16 between 
each of the bermekimab groups and the dupilumab group will be provided.

The difference and 2-sided 80% CIs in the proportion of participants with improvement 
(reduction) of eczema-related itch NRS ≥4 from baseline to Week 16 among participants with 
a baseline itch value ≥4 between each of the bermekimab groups and the dupilumab group 
will be provided.
The proportions of participants for the above key secondary efficacy endpoints will be summarized 
for each intervention group. A CMH chi-square test stratified by baseline EASI severity (less 
severe [EASI score<28] or more severe [EASI score≥28]) at an alpha level of 0.05 will be used 
for comparison. In case of rare events, the Fisher’s Exact test will be used for treatment 
comparisons in binary response endpoints. The proportion differences between active intervention 
groups and placebo and their 2-sided CIs will be provided based on normal approximation with 
Mantel-Haenszel weights adjusting for baseline EASI severity.
The key secondary endpoints will be analyzed using the estimands described in sections 5.4.2.2. 
The analysis strategy for ICEs and missing data will be handled in the same manner as the primary 
estimand for the primary endpoint. 
5.5.
Exploratory Efficacy Analyses
5.5.1.
Definition of Endpoints
5.5.1.1.
Eczema Area and Severity Index
The definition of EASI score is described in section 5.3.1.
5.5.1.2.
Eczema Skin Pain and Itch Numeric Rating Scale 
The definition of NRS score is described in section 5.4.2.1.3
5.5.1.3.
Validated Investigator Global Assessment for Atopic Dermatitis 
The definition of vIGA-AD is described in section 5.4.2.1.2.
5.5.2.
Analysis Methods
Unless otherwise specified, the exploratory efficacy analyses for mFAS outlined in the following 
sections in general will be carried out for 2 periods:
Analyses through Week 16 
The efficacy analyses at Week 16 and through Week 16 will be summarized by randomized 
intervention group at Week 0.

Placebo


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
bermekimab 350 mg

bermekimab 700 mg

dupilumab
Analyses from Week 16 through Week 36
The efficacy analyses from Week 16 through Week 36 will be summarized by following 
intervention group based on mFAS.
Placebo → bermekimab 700 mg: include participants randomized to placebo at Week 0 and 
crossed over to receive bermekimab 700 mg at or after Week 16.
Bermekimab 350 mg: include participants randomized to bermekimab 350 mg at Week 0 and 
continued to receive bermekimab 350 mg at or after Week 16.
Bermekimab 700 mg (non-responders): include participants who were randomized to 
bermekimab 700 mg at Week 0, were EASI-75 non-responder at week 16 and continued to receive 
bermekimab 700 mg at or after Week 16.
Bermekimab 700 mg (responders): include participants who were randomized to bermekimab 
700 mg at Week 0, were EASI-75 responders at week 16 and were re-randomized to:

Bermekimab 700 mg: participants received bermekimab 700 mg at or after Week 16

Bermekimab 350 mg: participants received bermekimab 350 mg at or after Week 16
Dupilumab: include participants who were randomized to dupilumab at Week 0, were EASI-75 
responders at week 16 and continued to receive dupilumab at or after Week 16.
Dupilumab → bermekimab 700 mg include participants who were randomized to dupilumab at 
Week 0, were EASI-75 non-responders at week 16, and crossed over to receive bermekimab 700 
mg at or after Week 16.
5.5.2.1.
Analyses for Binary and Continuous Endpoints
This section outlines the definition and analyses of exploratory endpoints.  All statistical testing 
will be performed at the 2-sided 0.05 significance level. Nominal p-values will be presented.
Exploratory efficacy endpoints will be summarized using descriptive statistics, such as mean, 
median, standard deviation, minimum and maximum, interquartile range for continuous variables, 
and counts and percentages for categorical variables will be used to summarize the data. Graphical 
data displays and participant listings may also be used to summarize the data.
Binary Endpoints


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For binary response endpoints, treatment comparisons will be performed using Cochran-Mantel-
Haenszel (CMH) test stratified by the baseline EASI severity (less severe EASI<28, more severe 
EASI ≥28) or the Fisher’s Exact test in case of rare events. The proportion difference between 
each active group and placebo group and its 2-sided 95% CI will be provided based on normal 
approximation with Mantel-Haenszel weights adjusting for baseline EASI severity. Additionally, 
the proportion difference between each bermekimab group and dupilumab group and 
corresponding 2-sided 80% CI will be provided.
Unless otherwise specified, the analyses for binary endpoints through Week 16, and from Week 
16 through Week 36 will be based on the following strategies to handle ICEs. 
ICEs in categories 1-3 (definitions in Section 5.3.2) will be handled with the composite 
strategy. Participants experiencing ICEs 1-3 will be considered not to have achieved the 
binary endpoints.
ICE 4-5 (definitions in Section 5.3.2) will be handled with the treatment policy strategy, 
which targets the treatment effect regardless of the occurrence of this ICE. For participants 
experiencing ICEs 4-5, their observed clinical response status will be used.
Participants with any missing data for an endpoint after application of ICE categories 1-5 will be 
imputed as not achieving the associated binary endpoints. 
Continuous Endpoints
For continuous endpoints, treatment comparisons will be performed using a Mixed-Effect Model 
Repeated Measure (MMRM) model under the assumption of missing at random (MAR) with
intervention group, visit, baseline EASI severity (less severe, more severe), baseline value for the 
efficacy endpoint, treatment by visit, baseline EASI severity by visit and baseline value by visit 
interaction as explanatory factors, if appropriate. An unrestricted (UN) variance-covariance matrix 
for repeated measures within a participant will be used unless there are issues related to 
convergence, where an autoregressive matrix structure will be used instead. In addition, LSmean 
estimate of treatment differences and their associated 95% confidence intervals will be presented
for the analyses through Week 16.
Unless otherwise specified, the analyses for continuous endpoints through Week 16, and from 
Week 16 through Week 36 will be based on the following strategies to handle ICEs. 
ICEs in categories 1 - 3 (definitions in Section 5.3.2) will be handled with the composite 
strategy. Participants experiencing ICEs 1-3 will have a zero change (or zero improvement) 
from baseline assigned from that point onward.
ICE 4-5 (definitions in Section 5.3.2) will be handled with the treatment policy strategy, 
which targets the treatment effect regardless of the occurrence of this ICE. For participants 
experiencing ICEs 4-5, their observed clinical response status will be used.


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To account for the missing data for continuous endpoints of change (or percent change) from 
baseline measured at more than one post-baseline visit, a MMRM will be used. In MMRM, 
missing data will not be imputed, but rather missing data will be accounted for through correlation 
of repeated measures in the model. For the analyses from W16 through W36, MMRM model will 
be used only for the treatment comparison between 700 mg and 350 mg among participants who 
were randomized in 700 mg group at Week 0, were EASI-75 responder at Week 16, and were re-
randomized at Week 16. The analyses from Week 16 through Week 36 for other study intervention 
groups will be based on observed data.
5.5.2.1.1.
Analyses Related to EASI

The improvement from baseline in EASI total score at Week 16 will be compared between
each of the active groups and placebo group.

The percent improvement from baseline in EASI total score at Week 16 will be compared 
between each of the active groups and placebo group.

The proportion of participants who achieve EASI-50, EASI-75, EASI-90, and EASI-100 
will be summarized over time by intervention group.

The improvement from baseline in EASI total score will be summarized over time by
intervention group.

The percent improvement from baseline in EASI total score will be summarized over time 
by intervention group.

The proportion of participants who achieve EASI-75 will be summarized by baseline EASI 
severity and intervention group over time through Week 16.

The proportion of participants who achieve 100% improvement, 90%, 75%, or 50% 
improvement from baseline in EASI component (Edema/Papulation, erythema, and 
Excoriation) and region component (heck/neck, trunk, upper extremities, and lower 
extremities) will be summarized through Week 16 by intervention group.
5.5.2.1.2.
Analyses Related to NRS

The proportion of participants with improvement (reduction) of eczema-related itch NRS 
≥4 from baseline among participants with a baseline itch NRS value ≥4 will be summarized 
over time by intervention group.

The proportion of participants with improvement (reduction) of eczema-related pain NRS 
≥4 from baseline over time among participants with a baseline pain NRS value ≥4 will be 
summarized over time by intervention group.

The improvement from baseline in eczema-related itch NRS will be summarized over time 
by intervention group.


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
The improvement from baseline in eczema-related pain NRS will be summarized over time 
by intervention group.
5.5.2.1.3.
Analyses Related to vIGA-AD

The proportion of participants who achieve a vIGA-AD score of 0, vIGA-AD score of 0 or 
1 and a reduction from baseline of ≥2 points at Week 16, vIGA-AD score of mild or better 
(≤2) and a reduction from baseline of ≥2 points will be summarized through Week 16 by 
intervention group.

The proportion of participants who achieve a vIGA-AD score of 0, vIGA-AD score of 0 or 
1 and a reduction from baseline of ≥2 points at Week 16, vIGA-AD score of mild or better 
(≤2) and a reduction from baseline of ≥2 points will be summarized from Week 16 through 
Week 36 by intervention group.
5.6.
Safety Analyses
All safety analyses will be performed using safety analysis set based on actual intervention
received. No formal statistical comparison is planned.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages.
Depending on the safety data, the cumulative safety data will be analyzed through different study 
periods which include but are not limited to from Week 0 through Week 16, and from Week 0 
through Week 36 as appropriate. Unless otherwise specified, tabular summaries of safety events 
are in general presented as following:
Summaries through Week 16 (placebo controlled)
Safety data through Week 16 will be summarized by following intervention group:

Placebo

bermekimab 350 mg

bermekimab 700 mg

dupilumab
Summaries through Week 36 
Safety data through Week 36 will be summarized by following intervention groups. 

Placebo 

Placebo → Bermekimab 700 mg


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
Bermekimab 350 mg

Bermekimab 700 mg

Bermekimab 700 mg → Bermekimab 350 mg

Dupilumab

Dupilumab → Bermekimab 700 mg
5.6.1.
Extent of Exposure
The number and percentage of participants who receive study intervention (placebo, bermekimab
350 mg, bermekimab 700 mg, and dupilumab) will be summarized. The number and percentage 
of participants will also be summarized by visit.
Descriptive statistics will be presented by intervention group for the following parameters:

Number of administrations

Cumulative total dose

Duration of study intervention (weeks)
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention +1)/7.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention is considered to be treatment emergent. If the event 
occurs on the day of the initial administration of study intervention, and either event time or time 
of administration are missing, then the event will be assumed to be treatment emergent. If the event 
date is recorded as partial or completely missing, then the event will be considered to be treatment 
emergent unless it is known to be prior to the first administration of study intervention based on 
partial onset date or resolution date. All reported treatment-emergent adverse events will be 
included in the analysis.  For each adverse event, the number and percentage of participants who 
experience at least 1 occurrence of the given event will be summarized by intervention group.
Summary tables will be provided for treatment-emergent adverse events:

AEs

Serious AEs (SAEs)

AEs of infections


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
AEs leading to discontinuation of study intervention

AEs of severe intensity

AEs reasonably related to study intervention

AEs of injection site reaction
In addition to the summary table, listings will be provided for participants who:

Had SAEs

Had AEs leading to discontinuation of study intervention

Had AEs of severe intensity 

Had anaphylactic or serum sickness-like reactions
Since safety should be assessed relative to exposure and follow-up, most AE summary tables will 
include average weeks of follow-up and average number of study agent administrations for each 
intervention group.
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments 
5.6.3.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set.
Descriptive statistics of change from baseline through Week 16 and through Week 36 will be 
presented for selected chemistry and hematology laboratory tests at scheduled time points.

Hematology will include but are not limited to the following: Basophils, Eosinophils, 
Hemoglobin, Lymphocytes, Monocytes, Neutrophils, Platelets, WBC, CRP and ESR.

Chemistry will include but are not limited to the following: ALT, AST, Albumin, Alkaline 
Phosphatase, Calcium, Chloride, Creatinine, Glucose, Potassium, Sodium, Total Bilirubin, 
Total Protein, Urea Nitrogen.
Applicable laboratory results will be graded according to National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE). The proportion of participants with post-
baseline values by maximum toxicity grade for clinical laboratory tests will be summarized by 
study intervention group. Participants with toxicity grades ≥2 will be listed.


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5.6.3.2.
Vital Signs 
Continuous vital sign parameters including temperature, pulse, blood pressure (systolic and 
diastolic) and respiratory rate will be summarized. Change from baseline will be summarized 
through Week 16 and Week 36. Descriptive statistics (mean, standard deviation, median, minimum 
and maximum) will be presented.
Incidence of treatment-emergent abnormal vital signs during intervention, as defined in Table 4, 
will be summarized for participants who had a baseline assessment and at least 1 postbaseline 
assessment for that vital sign.
Table 4: Clinically Important/Markedly Abnormal Vital Signs
Vital Sign
Criteria
Pulse
>[120] bpm and with >[30] bpm increase from baseline
<[50] bpm and with >[20] bpm decrease from baseline
Systolic blood pressure
>[180] mm Hg and with >[40] mm Hg increase from baseline
<[90] mm Hg and with >[30] mm Hg decrease from baseline
Diastolic blood pressure
>[105] mm Hg and with >[30] mm Hg increase from baseline
<[50] mm Hg and with >[20] mm Hg decrease from baseline
Respiratory rate
>[20] breaths per minute
5.6.3.3.
Electrocardiogram
The overall interpretation (i.e., normal, abnormal, not evaluable) of the ECGs as determined by 
investigator will be summarized by the number and percentage of participants at Week 0 and Week 
16.
A listing of participants with abnormal ECG interpretation will be provided.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
Blood samples will be collected for the measurement of serum bermekimab concentrations and
antibodies to bermekimab at the timepoints presented in the Schedules of Activities. Blood 
samples should also be collected at the final visit or at the Early Termination Visit from participants 
who are discontinued from intervention or withdrawn from the study. A random venous blood 
sample for population PK analysis will be collected from all participants on any day between 
Weeks 2 to 12, except on the days of the scheduled study visits. Additionally, this blood sample 


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must be collected at least 24 hours prior to or after the actual time of study intervention 
administration.
PK analyses will be performed on the PK analysis set, defined as participants who have received 
at least 1 complete dose of bermekimab and have at least 1 valid blood sample drawn for PK 
analysis. Subjects will be analyzed according to the treatment groups that they actually receive. 
No imputation for missing concentration data will be performed.
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to 
summarize serum bermekimab concentrations at each sampling time point. PK data may be 
displayed graphically. The following analyses will be performed by treatment group as 
appropriate:

Summary of serum bermekimab concentrations at each visit by treatment group

Proportion of subjects without detectable serum bermekimab concentration at each visit by 
treatment group

Summary of serum bermekimab concentrations at each visit by treatment group and 
baseline body weight (>=median or < median)

Summary of serum bermekimab concentrations at each visit by treatment group and 
baseline EASI score categories (EASI <28 or EASI ≥28)

Plot of median (IQ) serum bermekimab concentrations over time by treatment group

Plot of median (IQ) serum bermekimab concentrations over time by baseline body weight 
and treatment group
For summary statistics of serum bermekimab concentrations, concentration values below the lower 
limit of quantification will be treated as zero. Once a subject meets one of the following dosing 
deviation criteria, the subject’s data will be excluded from the by-visit data analyses from that 
point onwards.
Dosing deviation criteria:

Discontinue SC bermekimab administrations.

Skipped an SC bermekimab administration.

Received an incomplete/ incorrect SC dose.

Received an incorrect SC study agent.

Received an additional SC bermekimab dose.


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In addition, if a subject has an administration outside of visit windows (Section 5.1.1), the 
concentration data collected at and after that visit will be excluded from the by-visit data analyses.
Additional exclusions for incongruous PK data to be implemented based on Janssen SOP-07948. 
All participants and samples excluded from the analysis will be clearly documented.
If sufficient data are available, then population PK analysis using serum bermekimab
concentration-time data will be performed using nonlinear mixed-effects modeling. Details will 
be given in a population PK analysis plan and the results of the analysis will be presented in a 
separate report.
PK analyses will be summarized through the end of study (Week 36). For the analyses, a subject 
is included in one and only one treatment group on the basis of the treatment regimen followed. 
The description of treatment groups are as follows:
o
Placebo → Bermekimab 700 mg qw
o
Bermekimab 350 mg qw
o
Bermekimab 700 mg qw → Bermekimab 350 mg qw (EASI-75 responders)
o
Bermekimab 700 mg qw → Bermekimab 700 mg qw (EASI-75 responders)
o
Bermekimab 700 mg qw → Bermekimab 700 mg qw (EASI-75 non-responders)
o
Combined bermekimab 700 mg qw
5.7.2.
Immunogenicity (Antibodies to Bermekimab)
Blood samples will be collected to examine the formation of antibodies to bermekimab at the 
specified visits as shown in the schedule of activities in the protocol. Samples will also be collected 
at the final visit from participants who terminate study participation early.  
Participants evaluable for immunogenicity are defined as having at least 1 dose (complete or 
partial) of bermekimab and have at least 1 valid blood sample drawn for antibody detection. The
antibodies to bermekimab summary and analysis will be based on the observed data; therefore no 
imputation of missing data will be performed. 
The following analysis of antibodies to bermekimab will be performed by treatment group:

Summary of incidence of antibody to bermekimab status

List of subjects positive for antibodies to bermekimab
In addition, to explore the relationship between antibodies to bermekimab status and serum
bermekimab concentrations, and safety, the following analysis may be performed as appropriate:

Summary of injection-site reactions by antibody to bermekimab status


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
Summary of serum bermekimab concentrations by antibody to bermekimab status

Plots of median (IQ) serum bermekimab concentrations over time by antibody to 
bermekimab status
Immunogenicity analyses will be summarized through the following time periods:

Through Week 16

Through End of Study (Week 36)
For the analyses, a subject is included in one treatment group (or combined group) on the basis of 
the treatment regimen followed. The description of treatment groups are as follows:

Through Week 16
1. Bermekimab 350 mg qw
2. Bermekimab 700 mg qw
3. Combined (Groups 1/2)

Through End of Study (Week 36)
1. Placebo → Bermekimab 700 mg qw
2. Bermekimab 350 mg qw
3. Bermekimab 700 mg qw → Bermekimab 350 mg qw (EASI-75 responders)
4. Bermekimab 700 mg qw → Bermekimab 700 mg qw (EASI-75 responders)
5. Bermekimab 700 mg qw → Bermekimab 700 mg qw (EASI-75 non-responders)
6. Bermekimab 700 mg qw combined (Groups 3/4/5)
7. All Bermekimab combined (Groups 1/2/3/4/5) 
5.7.3.
Biomarkers
Biomarker analyses will be provided in a separate document.
5.7.4.
Definition of Subgroups
To evaluate the consistency of the primary efficacy endpoint EASI-75 at Week 16, subgroup 
analyses may be performed when the number of participants in the subset permits. The subgroups 
for subgroup analysis may include, but are not limited to the following:


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Table 5 Demographic subgroups
Subgroup
Variant
Definition
Region
1
Define based on UN guidance as per the M49 standard
Asian Pacific
North America
Latin America
Europe
Sex 
1
male
female
Race
1
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or other Pacific Islander
White
Other
Age Group
1
<40
40-64
>=65
BMI
1
<25 kg/m2
25-<30 kg/m2
>=30 kg/m2
Body Weight Group
1
<80 kg
>=80 kg
Table 6 Baseline disease characteristics and AD medication
Subgroup
Variant
Definition
Age at diagnosis (years)
1
<18 yrs
≥18 yrs
AD disease duration (years) 
1
< median
≥ median 
Baseline EASI severity
1
less severe [EASI <28]
more severe [EASI ≥28]
Baseline IGA 
1
3
4
Systemic Corticosteroids
Never used
Ever used
The primary estimand will be used for these subgroup analyses and missing data rule (Section 
5.3.3) used for primary estimand will be applied.
5.8.
Interim Analyses
An interim analysis will be conducted prior to the Week 16 DBL when approximately 50% of 
participants have completed their Week 16 visit. The interim analysis will be used to inform the 
future development planning of bermekimab for AD based on the data accrued up to the interim 
analysis. No changes to the current study are planned. Details of the plan for the interim analysis 
will be specified in a separate interim analysis plan.


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5.9.
Data Monitoring Committee (DMC) or Other Review Board
An independent, external DMC, whose members are not directly involved in the conduct of study 
77474462ADM2001, will review unblinded safety data to ensure the safety of the participants 
enrolled in this study. The committee will meet regularly to review unblinded safety data. After 
the review, the DMC will make recommendations to the study team regarding the conduct of the 
study. The DMC will consist of at least one clinical physician and one statistician, not involved in 
the conduct of the study. DMC responsibilities, authorities, and procedures will be documented in 
the DMC charter.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AD
ADIS
Atopic dermatitis
Atopic Dermatitis Itch Scale
AE
adverse event
ALT/SGPT
alanine aminotransferase
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
AUC
area under the curve
BMI
body mass index
BSA
body surface area
CI
confidence interval
Cmax
maximum concentration
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
eCRF
electronic case report form
FAS
full analysis set
FDA
Food and Drug Administration
ICH
IGA
International Conference on Harmonisation
Investigator Global Assessment
IQ
interquartile
IWRS
interactive web response system
LLOQ
lower limit of quantification
MedDRA
MMRM
Medical Dictionary for Regulatory Activities
Mixed-Effect Model Repeated Measure 
MRD
minimum required dilution
NAb
neutralizing antibodies
PD
pharmacodynamic(s)
PI
principal investigator
PK
POEM
pharmacokinetic(s)
Patient-oriented eczema measure
PP
PROMIS
per protocol
Patient-reported outcomes measurement information system
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
TEAE
treatment-emergent adverse event
Tmax
time to maximum concentration
vIGA-AD
Validated Investigator Global Assessment for Atopic Dermatitis
WHO
World Health Organization


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
N/A


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention 
group, combined active intervention group, and overall. In addition, the distribution of participants 
by region, country, and site ID will be presented unless otherwise noted.
Table 7 presents a list of the demographic variables that will be summarized by intervention group, 
combined active intervention group, and overall for the FAS analysis set.  
Table 7: Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
Body Surface Area (BSA) (m2)
Categorical Variables
Age (<40 years, 40-64 years, and >=65 years)
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female)
Weight (<80 kg, >=80 kg)
Race (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI ([normal <25 kg/m2, overweight 25-<30 kg/m2, obese >=30 kg/m2])
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
Baseline disease characteristics (e.g., duration of AD disease, EASI score, vIGA-AD, hand 
dermatitis IGA, GISS, POEM, ADIS, SCORAD score, BSA, NRS pain, NRS Itch, DLQI, 
PROMIS-29, PGIS) will be summarized by intervention group.


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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category through Week 16 and 
through the end of study.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior medications are defined as any therapy used before the day of first dose (partial or complete) 
of study intervention. Previous atopic dermatitis medications/therapy will be summarized by 
intervention group.
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). Concomitant medications are defined as any therapy used on or after the same day as 
the first dose of study intervention, including those that started before and continue on after the 
first dose of study intervention.
Summaries of concomitant medications will be presented by anatomic and therapeutic class (ATC)
term, and intervention group. The proportion of participants who receive each concomitant 
medication will be summarized as well as the proportion of participants who receive at least 1
concomitant medication. 


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6.6.
Appendix 6 Medical History
Summaries of participants’ alcohol intake, and smoking status will be provided by intervention 
group. In addition, the distribution of participants by prior biologic use (yes/no) and type of 
biologic therapy will also be provided.
Medical history will be summarized by intervention groups.  


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6.7.
Appendix 7 Intervention Compliance
Compliance to randomized intervention versus actual intervention will be presented in a summary 
table.
In addition, a listing of participants with missed study intervention administration will be provided.


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6.8.
Appendix 8 Adverse Events of Special Interest
Not applicable.


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6.9.
Appendix 9 Medications of Special Interest
Not applicable.


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Status: Final, Date: 02 March 2022
6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE 5.0)’.
If a laboratory value falls within the grading as specified below but also within the local laboratory 
normal limits, the value is considered to be normal and will be reset to grade 0.
Pre-baseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken pre-baseline and on baseline.
Text in gray italic in the table is present in the grading scale, but is not applied by Janssen when 
grading lab data.














JNJ-77474462  (bermekimab)
Statistical Analysis Plan 77474462ADM2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
49
Status: Final, Date: 02 March 2022
7.
REFERENCES
Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab versus placebo in atopic 
dermatitis. N Engl J Med. 2016;375(24):2335-2348.