Conditions: Dermatitis, Atopic
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of Bermekimab, compared with placebo, in participants with moderate-to-severe atopic dermatitis (AD).

Detailed description:

Arms:
arm 1: Participants will receive bermekimab Dose 1 or placebo as an intravenous (IV) infusion weekly from Week 0 to Week 15. arm 2: Participants will receive bermekimab Dose 2 or placebo as an IV infusion weekly from Week 0 to Week 15. arm 3: Participants will receive bermekimab or placebo at a higher or lower dose (not less than \[\<\] Dose 1) than Part B, but with a maximum dose of Dose 3 IV weekly based on pharmacokinetic (PK), pharmacodynamic (PD), efficacy, and safety analysis.

Interventions: intervention 1: Bermekimab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive bermekimab IV. intervention 2: Participants will receive placebo IV.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status:Approved, Date: 23 November 2021
Janssen Research & Development*
Clinical Protocol
A Phase 2a, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Interventional Study
to Assess the Efficacy, Safety, Pharmacokinetics, and Immunogenicity of Multiple IV doses of
Bermekimab for the Treatment of Adult Participants with Moderate-to-Severe Atopic Dermatitis
Protocol 77474462ADM2003; Phase 2
Amendment 1
Bermekimab(JNJ-77474462)
*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
Registry  
ID
IND
112459
EudrCT  
2020-005900-21
Status: 
Approved
Document Date: 
23 November 2021
Prepared by: 
Janssen Research & Development, LLC
EDMS Number: 
EDMS-RIM-280762, 4.0
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.
NCT04990440


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status:Approved, Date: 23 November 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 1 
23-Nov-2021
Original Protocol 
17-Jun-2021
Amendment 1 (23November 2021)
Overall Rationale for the Amendment: To add additional sample collections for lipid panels in order to
provide a more robust safety check for participants. In addition, grammar and inconsistencies have been
amended throughout the protocol.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of Activities 
(SoA) 
 Added “fasting” to lipid panel and 
added additional collections at 
Weeks 1 and 8 for participants in
Parts B and C.
 Footnote ‘aa’ added for clarity.
To provide a more robust safety
profile.
Realigned the parameters under “Whole blood 
(Pharmacogenomics)” under the
‘Pharmacogenomics’ heading from previously
under ‘Biomarker’ heading.
Grammatical error.
 
Collection of Total body 
photography at Week 20 was deleted. 
 
Footnote ‘c’ added to ICF for skin 
barrier function substudy. 
 
The footnote was updated to remove
biomarkers and added ‘optional skin
barrier function assessments, and
optional total body photography’.
To align with amended
footnote. The final collection
timepoint is Week 16 (end of
treatment).
Removed informed consent form for optional 
biomarker sample collection since this is 
being removed from the study.
Skin swabs will no longer be
collected as part of the study.
Vital signs collection removed for Week 16. 
The corresponding footnote ‘w’was updated
to state Week 15 since the last dose is on
Week 15 not Week 16.
Fixed numerical error.
Added visit window ±3 days for all visits to 
match footnote ‘y’
Added to provide clarity
Removed height collection at Week 0 
Redundant since collected at
screening and unnecessary at
Week 0.
Added electrocardiogram at Week 16 
timepoint. 
To provide more comprehensive
safety review.
1.3. SoA  
8.6.1. Skin Biomarkers 
Removed the row corresponding to ‘skin 
swab-optional’ since there were no longer 
plans to collect and analyze biomarkers
samples; corresponding footnote ‘o’ was
deleted.
Removed paragraph pertaining to skin swab
collection and analysis.
Skin swabs will no longer be
collected as part of the study.
2.2. Background 
Updated wording (deleted textand revised 
text) in clinical studies to match the achieved
Eczema Area and Severity Index (EASI)-75
To provide clarity.


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status:Approved, Date: 23 November 2021
Section Number 
and Name
Description of Change 
Brief Rationale
results after 4 weeks of therapy at Week 7
updated to match study results ie, “7571%
achieved EASI-75 at Week 87” reported in
the clinical study report.
Nonclinical Pharmacology: 
The KD for human IL-1αwas updated from 
0.14 nM to 0.029 nM and for cynomolgus 
monkey from 3 nM to 1.3 nM.
To align with the latest
information in the investigator’s
brochure.
2.3. Benefit-Risk 
Assessment 
Updated to remove injection site reactions 
pertaining to risks in this study. 
This study is IV infusion so
there is no risk for injection site
reactions.
2.3.1. Benefit Risk 
Assessment for Study 
Participation  
Updated with the addition of "approximately" 
for infusion and monitoring in the Infusion  
related reactions subsection of Table 1.
To provide flexibility around
timing of monitoring
1.1. Synopsis (Objectives 
and Endpoints) 
3. Objectives and Endpoints
Abbreviations updated to include 
pharmacodynamics.
For consistency with the table.
4.1. Overall Design  
Added ‘approximately’ to all timepoints and 
number of participants. 
To provide flexibility around
timing and number of
participants
4.2. Scientific Rationale for 
Study Design
Removed placeholder of “insert text here”. 
Fixed error.
4.4. End of Study Definition 
Updated the wording for the definition of 
EOS.
To provide more clarity.
Updated the wording for the definition of
Study completion ie, included completion of
all study interventions at Week 15.
5.1. Inclusion Criteria; 
5.3. Lifestyle Considerations 
Criteria 17:Updated the laboratory values 
with appropriate superscripts (×103).
Fixed formatting errors.
Criteria 19:was updated to include 
‘strongly’for recommendation and “including
COVID-19 vaccines prior to screening”.
In addition, the updated criteria was moved to
Section 5.3: Lifestyle Considerations.
To provide clarity.
Criteria 20:fixed incorrect reference to
inclusion criterion 21b which was changed to
20a.
5.2. Exclusion Criteria 
Criteria 24: updated timeline pertaining to the 
use of any prescription topical treatment for 
atopic dermatitis from within 1 week to 4 
weeks of the baseline visit.
Clarification and to align with
inclusion criteria 18 for
consistency.
Criteria 25:was amended to reflect 4 weeks 
prior to the first administration of study 
intervention.
To provide consistency with the
rest of the criterion.
Criteria 27:was deleted as it has been 
captured in exclusion criterion 25.
Redundant exclusion criteria.
Criteria 35:was deleted as it has been 
captured in exclusion criterion 16.
Redundant exclusion criteria.
Criteria 38:was deleted as it has been 
captured in exclusion Criteria 9.
Redundant exclusion criteria.
Criteria 10:was updated to reflect hepatitis B 
surface antigen (HBsAg) or hepatitis C
antibody (anti-hepatitis C virus) which was
originally part of a separate Criteria 37 which
Redundant exclusion criteria.


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status:Approved, Date: 23 November 2021
Section Number 
and Name
Description of Change 
Brief Rationale
has now been deleted. Conditions for
participants with antibodies to HCV have been
included.
Criteria 39:updated wording since drug and 
alcohol use are not being test at screening.
To provide clarity.
5.3. Lifestyle Considerations 
Updated points 1 and 3 to reflect correct 
inclusion criterion numbering. 
Align with amended inclusion
criteria and numbering.
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding 
Under ‘Blinding’- Language was amended to 
clarify blinded versus unblinded participants. 
In addition, wording around emergency
unblinding was added.
Clarification of blinding
criteria.
Under ‘Procedures for Randomization’ –the 
sentence was revised as, “…randomly
assigned to either the bermekimab or placebo
1 of 2intervention groups”
To be more specific.
6.8.3. Prohibited 
Therapies/Medications 
Text added for oral corticosteroid use to 
indicate ‘for conditions other than AD’. 
To provide clarity around use of
oral corticosteroids during the
study
6.8.4. Rescue Medication 
Wording was added for clarity regarding use 
of hydrocortisone.
To provide clarity.
6.8. Concomitant Therapy; 
6.8.6. Vaccinations 
(including COVID-19) 
Paragraphs pertaining to concomitant use of 
COVID-19 or influenza vaccine was moved 
from Concomitant Therapy to a dedicated 
subsection pertaining to vaccinations.
To provide more clarity around
vaccinations in a dedicated
subsection.
7.1. Discontinuation of 
Study Intervention 
Removed ‘>’ symbol for oral corticosteroids 
since it was redundant when used along with
the wording “more than”.
Redundant text.
Discontinuation criteria pertaining to serious 
adverse reactions was updated to include 
infusions. 
To correctly align with the route
of administration of study
treatment in this study.
1.1. Synopsis (Efficacy 
Evaluations); 
8.1. Efficacy Assessments
vIGA was added to list of endpoints. 
Consistency with objectives and
efficacy endpoints.
8.2.3. Electrocardiograms 
Week 16 timepoint was added. 
To align with the SoA.
8.2.4. Clinical Safety 
Laboratory Assessments 
8.2.5. Pregnancy Testing 
 Serum pregnancy testing was added 
alongside urine pregnancy test; 
timeline for testing was amended 
from Week 22 to Week 20.
 The aforementioned, amended
paragraph was also moved from
clinical laboratory assessment section
to pregnancy testing section as it was
better placed under the latter heading
ie, Section 8.2.5.
Clarification of language and
relocation to a more appropriate
section.
8.5. Pharmacogenomics 
Statement regarding option to participate in 
either or both studies was deleted as it was a 
carry-over from a different study protocol.
Language correction to apply to
this study.
8.6.4. Gene Expression 
Analysis in Whole Blood
Total ribonucleic acid. 
Completion of the term.


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
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Status:Approved, Date: 23 November 2021
Section Number
and Name
Description of Change 
Brief Rationale
9.4.2. Primary Endpoint
Analyses
 Section and Table 4 updated for 
primary endpoint wherein 
intercurrent events (ICEs) were
updated to include ‘prior to Week 16’
timeline and definition/criteria for
EASI-75 non-responders was
clarified.
 It was also indicated that, “No
adjustment for multiple
comparisons will be made for
primary.”
 Variable/endpoint was reformatted as it
is 1 of 5 attributes.
 ICEs were updated to include 1
through 4.
To provide more clarity.
To align with Table 4.
‘Missing data’ was updated to ‘data handling’.
10.2. Appendix 2: Clinical
Laboratory Tests
Changed alanine aminotransferase 
(ALT)/serum glutamic “oxaloacetic” to
alanine aminotransferase (ALT)/Serum
glutamic-“pyruvic”.
To provide clarity.
Lactic acid dehydrogenase (LDH) was added 
to the Chemistry panel 
Was missed in the original draft
and is required for disease
monitoring.
10.3.6. Committees
Structure
Fixed repetitive phrase placeholder. 
To provide clarity.
10.3.7. Publication
Policy/Dissemination of
Clinical Study Data
Deleted duplicate phrases. 
Typographical errors corrected
10.5. Appendix 5: 
Contraceptive and Barrier 
Guidance 
Updated wording around tubal ligation based
on European Medicines Agency guidance ie,
tubal closure eg, bilateral tubal ligation has
been added.
Updated EMEA guidance
10.7. Appendix 7: Liver 
Safety: Suggested Actions 
and Follow Up Assessments 
Fixed incorrect symbol from £ to ≤for
international normalized ratio criteria.
Typographical errors corrected
Under Phase 2 Liver Chemistry Stopping
Criteria and Follow Up Assessments, table
title was revised from Suggested to Required
Actions
To clarify that these actions are
mandatory and not suggested as
an option.
10.8. Appendix 8: Hepatitis 
B Virus (HBV) Screening 
with HBV DNA Testing 
In the “Require testing for presence HBV
DNA*” changed it from positive (+)to
negative (-).
To provide clarity.
10.19. Appendix 19: Remote 
Endpoint Assessment Using 
Total Body Photography 
Language was updated to specify 4 visits,
including Week 20 and that total body
photography will only be performed at the
sites and not at home by participants.
In addition, Week 0 was added in parenthesis
to baseline and the Week 16 visit was updated
to Week 20.
To provide clarity.
Throughout the protocol 
 Added “approximately” to numerical
values for infusion times, observation
times, and number of participants.
 Removed the term “injection” from
document and replaced with
“infusion” where appropriate.
 Minor errors were noted
 Grammatical errors were
corrected.
 Edits were made to
accommodate revisions


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
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Status:Approved, Date: 23 November 2021
Section Number
and Name
Description of Change 
Brief Rationale
 The full form of ‘ET’ was corrected 
from “end of treatment” to “early 
termination” including Appendix 1:
Abbreviations
 Corrected bermekimab capitalization
and lower case, as applicable.
 Inclusion and exclusion criteria were
renumbered to accommodate
additions and deletions under
respective categories. Subsequently,
cross-referenced criteria were also
appropriately renumbered.
 Minor grammatical, formatting, or
spelling changes were made.
for consistency and
accuracy


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status:Approved, Date:23 November 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 7
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 10
1. 
PROTOCOL SUMMARY................................................................................................................... 11
1.1. 
Synopsis......................................................................................................................................... 11
1.2. 
Schema.......................................................................................................................................... 15
1.3. 
Schedule of Activities (SoA)........................................................................................................... 16
2. 
INTRODUCTION................................................................................................................................ 20
2.1. 
Study Rationale.............................................................................................................................. 20
2.2. 
Background .................................................................................................................................... 21
2.3. 
Benefit-Risk Assessment............................................................................................................... 23
2.3.1. 
Benefit-Risk Assessment for Study Participation ....................................................................... 24
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 27
4. 
STUDY DESIGN ................................................................................................................................ 30
4.1. 
Overall Design................................................................................................................................ 30
4.2. 
Scientific Rationale for Study Design............................................................................................. 31
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 32
4.3. 
Justification for Dose...................................................................................................................... 33
4.4. 
End of Study Definition................................................................................................................... 34
5. 
STUDY POPULATION ...................................................................................................................... 35
5.1. 
Inclusion Criteria............................................................................................................................ 35
5.2. 
Exclusion Criteria........................................................................................................................... 38
5.3. 
Lifestyle Considerations................................................................................................................. 42
5.4. 
Screen Failures.............................................................................................................................. 43
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention......................................... 43
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 44
6.1. 
Study Intervention Administered.................................................................................................... 44
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 46
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 46
6.4. 
Study Intervention Compliance...................................................................................................... 48
6.5. 
Dose Modification........................................................................................................................... 48
6.6. 
Continued Access to Study Invervention After the End of the Study............................................. 48
6.7. 
Treatment of Overdose .................................................................................................................. 48
6.8. 
Concomitant Therapy..................................................................................................................... 49
6.8.1. 
Atopic Dermatitis Management .................................................................................................. 49
6.8.2. 
Required Treatment.................................................................................................................... 49
6.8.3. 
Prohibited Therapies/Medications .............................................................................................. 49
6.8.4. 
Rescue Medication ..................................................................................................................... 50
6.8.5. 
Drugs Metabolized by Cytochrome P450................................................................................... 51
6.8.6. 
Vaccinations (including COVID-19)............................................................................................ 51
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 52
7.1. 
Discontinuation of Study Intervention ............................................................................................ 52
7.1.1. 
Liver Chemistry Stopping Criteria............................................................................................... 53
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 54
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 54
7.3. 
Lost to Follow-up............................................................................................................................ 55


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status:Approved, Date:23 November 2021
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 56
8.1. 
Efficacy Assessments .................................................................................................................... 57
8.1.1. 
Eczema Area and Severity Index (EASI).................................................................................... 58
8.1.2. 
Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD™).......................... 58
8.1.3. 
Severity Scoring of Atopic Dermatitis (SCORAD) ...................................................................... 58
8.1.4. 
Hand Dermatitis Investigator Global Assessment (IGA) ............................................................ 59
8.1.5. 
Eczema Skin Pain and Itch Numeric Rating Scale (NRS).......................................................... 59
8.1.6. 
Patient-Reported Dermatology Life Quality Index (DLQI).......................................................... 59
8.1.7. 
Patient-Oriented Eczema Measure (POEM) .............................................................................. 59
8.1.8. 
Patient Global Impression of Severity (PGIS) ............................................................................ 59
8.1.9. 
Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29).................... 60
8.1.10. 
Atopic Dermatitis Itch Scale (ADIS)............................................................................................ 60
8.1.11. 
Remote Endpoint Assessment Using Total Body Photography................................................. 60
8.1.12. 
Skin Barrier Function Assessments............................................................................................ 61
8.2. 
Safety Assessments....................................................................................................................... 61
8.2.1. 
Physical Examinations................................................................................................................ 61
8.2.2. 
Vital Signs................................................................................................................................... 62
8.2.3. 
Electrocardiograms..................................................................................................................... 62
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 62
8.2.5. 
Pregnancy Testing...................................................................................................................... 62
8.2.6. 
Concomitant Medication ............................................................................................................. 63
8.2.7. 
Allergic Reactions....................................................................................................................... 63
8.2.8. 
Infusion-Related Reactions ........................................................................................................ 63
8.2.9. 
Tuberculosis Evaluations............................................................................................................ 64
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 66
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 66
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 67
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 67
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 67
8.3.5. 
Pregnancy................................................................................................................................... 68
8.3.6. 
Adverse Events of Special Interest............................................................................................. 68
8.4. 
Pharmacokinetics and Immunogenicity ......................................................................................... 68
8.5. 
Pharmacogenomics ....................................................................................................................... 69
8.6. 
Biomarkers..................................................................................................................................... 70
8.6.1. 
Skin Biomarkers.......................................................................................................................... 70
8.6.2. 
Serum Biomarkers...................................................................................................................... 70
8.6.3. 
Flow Cytometry Analysis ............................................................................................................ 70
8.6.4. 
Gene Expression Analysis in Whole Blood ................................................................................ 71
8.7. 
Medical Resource Utilization and Health Economics .................................................................... 71
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 72
9.1. 
Statistical Hypotheses.................................................................................................................... 72
9.2. 
Sample Size Determination ........................................................................................................... 72
9.3. 
Populations for Analysis Sets ........................................................................................................ 73
9.4. 
Statistical Analyses ........................................................................................................................ 73
9.4.1. 
General Considerations.............................................................................................................. 73
9.4.2. 
Primary Endpoint ........................................................................................................................ 73
9.4.3. 
Exploratory Endpoints................................................................................................................. 75
9.4.4. 
Safety Analyses.......................................................................................................................... 75
9.4.5. 
Other Analyses ........................................................................................................................... 76
9.5. 
Interim Analysis.............................................................................................................................. 78
9.6. 
Data Review Committee ................................................................................................................ 78
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 79
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 79
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 81


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
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Status:Approved, Date:23 November 2021
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 82
10.3.1. 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................................ 82
10.3.2. 
FINANCIAL DISCLOSURE......................................................................................................... 85
10.3.3. 
INFORMED CONSENT PROCESS ........................................................................................... 85
10.3.4. 
DATA PROTECTION.................................................................................................................. 86
10.3.5. 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH............ 87
10.3.6. 
COMMITTEES STRUCTURE .................................................................................................... 87
10.3.7. 
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................. 87
10.3.8. 
DATA QUALITY ASSURANCE .................................................................................................. 89
10.3.9. 
CASE REPORT FORM COMPLETION ..................................................................................... 89
10.3.10. SOURCE DOCUMENTS ............................................................................................................ 89
10.3.11. MONITORING ............................................................................................................................ 90
10.3.12. ON-SITE AUDITS....................................................................................................................... 91
10.3.13. RECORD RETENTION .............................................................................................................. 91
10.3.14. STUDY AND SITE START AND CLOSURE.............................................................................. 92
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting................................................................................................................................. 93
10.4.1. 
Adverse Event Definitions And Classifications........................................................................... 93
10.4.2. 
Attribution Definitions.................................................................................................................. 94
10.4.3. 
Severity Criteria.......................................................................................................................... 94
10.4.4. 
Special Reporting Situations ...................................................................................................... 94
10.4.5. 
Procedures ................................................................................................................................. 95
10.4.6. 
Product Quality Complaint Handling........................................................................................... 96
10.4.7. 
Contacting Sponsor Regarding Product Quality......................................................................... 96
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 97
10.6. 
Appendix 6: Tuberculin Skin Testing ........................................................................................... 100
10.7. 
Appendix 7: Liver Safety: Suggested Actions and Follow-Up Assessments............................... 102
10.8. 
Appendix 8: Hepatitis B Virus (HBV) Screening with HBV DNA Testing..................................... 105
10.9. 
Appendix 9: Study Conduct During a Natural Disaster................................................................ 106
10.10. Appendix 10: Eczema Area and Severity Index (EASI)............................................................... 108
10.11. Appendix 11: Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD)......... 109
10.12. Appendix 12: Severity Scoring of Atopic Dermatitis (SCORAD).................................................. 110
10.13. Appendix 13: Hand Dermatitis Investigator Global Assessment (IGA)........................................ 111
10.14. Appendix 14: Patient-Reported Dermatology Life Quality Index (DLQI) ..................................... 112
10.15. Appendix 15: Patient Global Impression of Severity (PGIS)........................................................ 113
10.16. Appendix 16: Patient-Reported Outcomes Measurement Information System
(PROMIS)-29............................................................................................................................... 114
10.17. Appendix 17: Eczema Skin Pain and Itch Numeric Rating Scale (NRS)..................................... 117
10.18. Appendix 18: Atopic Dermatitis Itch Scale (ADIS)....................................................................... 118
10.19. Appendix 19: Remote Endpoint Assessment Using Total Body Photography ............................ 120
10.20. Appendix 20: Protocol Amendment History................................................................................. 121
11. REFERENCES................................................................................................................................. 122
INVESTIGATOR AGREEMENT............................................................................................................... 124


Bermekimab (JNJ-77474462) 
Clinical Protocol 77474462ADM2003 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status:Approved, Date:23 November 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Benefit-Risk for Study Participants (Bermekimab) ................................................................... 24
Table 2: 
Description of Interventions ...................................................................................................... 45
Table 3: 
Power to detect a treatment difference in EASI-75 at Week 16*.............................................. 72
Table 4: 
Analysis Strategy for Addressing Intercurrent Events (ICEs)................................................... 74
FIGURES
Figure 1 
Schematic Overview of the Study.............................................................................................15


Bermekimab (JNJ-77474462) 
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Status:Approved, Date:23 November 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2a, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Interventional Study
to Assess the Efficacy, Safety, Pharmacokinetics, and Immunogenicity of Multiple IV doses of
Bermekimab for the Treatment of Adult Participants with Moderate-to-Severe Atopic Dermatitis
DESCRIPTION OF COMPOUND
Bermekimab (also known as JNJ-77474462 and monoclonal antibody protein-1 [MABp1]) is a recombinant
human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) specific for human interleukin-1
alpha (IL-1α). Interleukin-1 alpha is a key mediator of cutaneous inflammation and is constitutively and
inducibly expressed by several cell types, including keratinocytes where high levels of IL-1α are present in
healthy individuals, these data suggest that IL-1α has the potential to mediate inflammation in the skin.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of 16 weeks of multiple IV 
doses of bermekimab, compared with placebo, in 
participants with moderate-to-severe AD
Proportion of participants with EASI-75 (≥75%
improvement from baseline) at Week 16.
Secondary
To evaluate the PK and immunogenicity of
16 weeks of multiple IV doses of bermekimab,
compared with placebo, in adult participants with
moderate-to-severe AD
Analyses of the following at all applicable visits
from Week 0 through Week 16:
 
Serum concentrations of bermekimab over
time, including steady-state trough serum
concentrations.
 
The incidence and titers of antibodies to
bermekimab
To assess the safety and tolerability of 16 weeks of
multiple IV doses of bermekimab, compared with
placebo, in participants with moderate-to-severe
AD
 
Proportion of participants with TEAEs
 
Proportion 
of 
participants 
with
treatment-emergent SAEs
 
Proportion of participants with AEs leading to
discontinuation of study intervention.
 
Proportion 
of 
participants 
with 
AEs
reasonably related to study intervention.
 
Proportion of participants with AEs of
infusion-related reactions.
 
Proportion of participants with AEs of
infections, including serious infections and
infections requiring oral or parenteral
antimicrobial treatment.


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Objectives 
Endpoints
 
Proportion of participants with Clinically
significant abnormalities in vital signs and
laboratory tests.
To characterize additional assessments of efficacy
of 16 weeks of multiple IV doses of bermekimab,
compared with placebo, in participants with
moderate-to-severe AD
Analyses of the following at applicable visits
through Week 16 by visit, respectively:
 
Proportion 
of 
participants 
with 
both
vIGA-AD of 0 or 1 and a reduction from
baseline of ≥2 points
 
Proportion of participants with improvement
(reduction) of eczema-related itch NRS ≥4
from baseline among participants with a
baseline itch value ≥4
 
Proportion of participants with EASI-90
Exploratory
To further characterize efficacy of 16 weeks of
multiple IV doses of bermekimab, compared with
placebo, 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 ADIS
 
Proportions of participants with a PGIS score
of 1 (none) or 2 (mild) at Week 16
 
Change from baseline to Week 16 in
PROMIS-29 total score and sub-scores
 
Improvement in Hand Dermatitis IGA from
baseline to Week 16.
To assess the impact of treatment with 16 weeks of
multiple IV doses of bermekimab, compared with
placebo, on selected biomarkers.
Analyses of the following at all applicable visits
from Week 0 through Week 16:
 
Changes in cellular and molecular PD
biomarkers levels in skin and blood from
baseline compared with placebo.
 
Changes in skin barrier function from baseline
compared with placebo.


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Abbreviations: AD=atopic dermatitis; ADIS=Atopic Dermatitis Itch Scale; AE=adverse event;
DLQI=Dermatological Life Quality Index; EASI=Eczema Area and Severity Index; IGA=Investigator Global
Assessment; -IV=intravenous; NRS=numeric rating scale; PD=pharmacodynamics; PGIS=Patient Global
Impression of Severity; PK=pharmacokinetics; PROMIS=Patient-Reported Outcomes Measurement Information
System; POEM=Patient-Oriented Eczema Measure; SAE=serious adverse event; SCORAD=Severity Scoring of
Atopic Dermatitis; TEAE=treatment-emergent adverse event; vIGA-AD=validated Investigator Global
Assessment for Atopic Dermatitis.
HYPOTHESIS
The hypothesis for this study is that intravenous (IV) bermekimab treatment is superior to placebo as
assessed by the proportion of participants achieving an Eczema Area and Severity Index (EASI)-75 (≥75%
improvement from baseline) at Week 16.
OVERALL DESIGN
This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter, interventional study designed
to assess the efficacy, safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarkers, and
immunogenicity of multiple doses of bermekimab administered via IV infusion for the treatment of
moderate-to-severe AD in adult participants.
The study has 3 phases that will include: a screening phase of up to 4 weeks, a double-blinded,
placebo-controlled phase of 16 weeks, and a safety follow-up phase of 4 weeks. The study will have 3
treatment parts which will run in parallel and/or staggered during the active treatment or placebo-controlled
phase, namely Parts A, B, and C.
All participants will receive a weekly IV infusion of either bermekimab or placebo, in a 4:1 randomization
ratio. Part A will consist of approximately 10 participants receiving bermekimab 800 mg IV weekly or
placebo. Part B will consist of approximately 30 participants receiving bermekimab 1200 mg IV weekly or
placebo. An analysis of the data from all 10 participants of Part A and the first 10 participants of Part B will
support optimization and selection of the bermekimab dose for Part C. Selection of the Part C bermekimab
dose will be based on PK, PD, efficacy, and safety analysis. Part C will consist of approximately  20
participants receiving bermekimab or placebo at a higher or lower dose (not <800 mg) than Part B, but with
a maximum dose of 2400 mg IV weekly.
The study also includes 4 mandatory skin biopsies (2 at baseline and 2 post-dosing). All participants of Part
A and the first 10 participants of Part B will have skin biopsies done at Week 0 (1 lesional and 1
non-lesional), and at Week 6 (2 lesional). The rest of the participants will be biopsied at Week 0 (1 lesional
and 1 non-lesional), and at Week 16 (2 lesional).
All participants will have an extended in-clinic observation period of approximately 4 hours during the first
2 infusions. In this period, vital signs will be taken at the following time points: 0 hour (start of infusion),
30 minutes (mins), 1 hour, 1 hour and 30 mins, 2 hours (end of infusion), 2 hours and 30 mins, 3 hours, 3
hours and 30 mins, and 4 hours (post-infusion). Beyond the first 2 infusions, all participants will have
approximately a 1 hour infusion period and at least a 1 hour observation post infusion, as well as vital signs
taken approximately every 30 minutes.
An internal and Independent Data Review Committee (DRC) will be commissioned for this study.
NUMBER OF PARTICIPANTS
A target of approximately 60 participants will be randomly assigned in this study.
INTERVENTION GROUPS AND DURATION
Approximately, 10 participants are planned to receive weekly 800 mg of IV bermekimab or placebo in Part
A. Approximately, 30 participants are planned to receive weekly dose of 1200 mg of IV bermekimab or


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placebo in Part B. After the initial 10 participants (8A [active]:2P [placebo]) have completed 6 weeks of
dosing in Part B, safety, PK, PD and efficacy will be analyzed to determine an appropriate dose to be used
in Part C. Approximately, 20 participants are planned to receive the determined dose of bermekimab or
placebo in Part C. The maximum dose to be considered for Part C will be 2400 mg IV weekly.
EFFICACY EVALUATIONS
Efficacy assessments (EASI, validated Investigator Global Assessment for Atopic Dermatitis [vIGA
AD™], percent body surface area [BSA] involvement, Severity Scoring of Atopic Dermatitis (SCORAD),
and Hand Dermatitis Investigator Global Assessmen [IGA]) and electronic patient reported outcome
(ePRO) measures (Dermatological Life Quality Index [DLQI], Patient Oriented Eczema Measure [POEM],
Patient Global Impression of Severity [PGIS], Patient Reported Outcomes Measurement Information
System [PROMIS]-29, Eczema Skin Pain and Itch numeric rating scale [NRS], and Atopic Dermatitis Itch
Scale [ADIS]) will be performed at visits according to the Schedules of Activities. Evaluation of EASI,
SCORAD, and validated investigator global assessment (vIGA) 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 (SoA).
Serum samples will also be collected at the final visit from participants who terminate study participation
early.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
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.
Biomarker assessment will include the evaluation of relevant markers in serum, blood, skin biopsies, and
tape strips for all participants. Blood samples will be separated into serum and peripheral blood
mononuclear cell (PBMC) for biomarker analysis. Samples for serum biomarkers, flow cytometry, and
gene expression from blood will be collected at time points according to the SoA.
PHARMACOGENOMIC (DNA) EVALUATIONS
A whole blood sample will be collected to allow for pharmacogenomic research, from which the genes for
filaggrin and IL-1⍺alpha will be evaluated in participating volunteers. Participation in additional whole
genome research analyses is optional.
SAFETY EVALUATIONS
Safety data, including but not limited to, adverse events (AEs), serious adverse events (SAEs), infections,
mortality, changes in laboratory assessments, 12-lead electrocardiogram, allergic reactions, infusion-related
reactions, and changes in vital signs will be summarized. The treatment-emergent adverse events (TEAEs)
will be summarized by treatment groups and Medical Dictionary for Regulatory Activities (MedDRA)
system organ class and preferred terms.
STATISTICAL METHODS
Safety Analyses
All safety analyses will be made on the Safety Population, which include all participants who received at
least 1 dose of study intervention. Safety data, including but not limited to, AEs, SAEs, infections, changes


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in laboratory assessments, and changes in vital signs will be summarized. Treatment‑emergent AEs will be
summarized by treatment group and MedDRA system organ class and preferred terms.
1.2. 
Schema
Figure 1 
Schematic Overview of the Study
DBL database lock; DRC Data Review Committee; FPD first participant dosed; LPO last participant out; n number of
participants; PD pharmacodynamics; PK pharmacokinetics; Rand randomization.
The DRC in Part A is planned to review unblinded safety data after the 7th participant has completed Week 4 dose
administration, and it will include the first 7 participants in Part A.
The DRC in Part B is planned to review unblinded safety data after the 8th participant has completed Week 4 dose
administration, and it will include the first 8 participants in Part B.
The DRC in Part C is planned to review unblinded safety data after the 8th participant has competed week 4 of dose
administration, and it will include the first 8 participants in Part C.
Ad hoc DRC may also convene as requested by the clinical team.








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r. 
Skin barrier function assessment should be evaluated together with tape stripping. Skin barrier function evaluation before tape stripping and after every 5 tapes.
s. 
Vital signs (Heart rate, respiratory rate, temperature, blood pressure) to be collected every 30 mins between 0 to 4 hrs. This applies to the first 2 infusions only.
t. 
For the first 2 doses, the study drug will be infused over approximately 2 hours to reduce the risk for IRR, followed by at least approximately a 2 hour observation. For the
subsequent infusions, the infusion time may be decreased to approximately one hour with a minimum of approximately 1 hour observation period.
u. 
Triplicate ECG to be done pre dose and post end of first infusion (after approximately 2 hours), at Week 0 only.
v. 
Vital signs (heart rate, respiratory rate, temperature, blood pressure) to be collected approximately every 30 mins between 0 to 2 hours for infusions 3 through 15. This does not
apply to the first 2 infusions.
w. 
Additional serial TEWL, SCH, and EIS measurements will be acquired after every 5 tape strips at Weeks 0, 4, and 16.
x. 
Study visits in Weeks 1 through 19 must be calculated from the first study intervention administration visit in Week 0. Visit and study intervention administrations should occur
within ±3 days of the scheduled visit.
y. 
These Safety Follow Up visits can be performed via phone calls and must be documented in the source document. Should the participant present any issue deemed clinically
significant, they must be bought in to the clinic for follow up consultation.
z. 
Fasting lipid panel at Screening and Weeks 1, 8, and 16 are for participants in Parts B and C only. Participants in Part A do not need to fast for lipid panel collection and only need
samples collected at Screening and Week 16.
Abbreviations: ADIS Atopic Dermatitis Itch Scale; DLQI Dermatological Life Quality Index;EASI Eczema Area and Severity Index; ECG  electrocardiogram; EIS Electrical
Impedance Spectroscopy; FSH follicle stimulating hormone; HIV human immunodeficiency virus; EOS end of study; ET early termination; ICF informed consent form;
IGA Investigator Global Assessment; IRR infusion related reaction; NRS numeric rating scale; PBMC  peripheral blood mononuclear cells; PGIS Patient Global Impression of
Severity; POEM Patient Oriented Eczema Measure; PK pharmacokinetic; PROMIS 29 Patient Reported Outcomes Measurement Information System 29; RNA ribonucleic acid;
SCH Stratum Corneum Hydration; SCORAD Severity Scoring of Atopic Dermatitis; TB tuberculosis; TEWL Transepidermal Water Loss; vIGA AD validated Investigator Global
Assessment for Atopic Dermatitis.


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2. 
INTRODUCTION
Bermekimab (also known as JNJ-77474462 and MABp1) is a recombinant human
immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) specific for human interleukin-1
alpha (IL-1α). Interleukin-1 alpha is a key mediator of cutaneous inflammation and is
constitutively and inducibly expressed by several cell types, including keratinocytes where high
levels of IL-1α are present in healthy individuals, these data suggest that IL-1α has the potential to
mediate inflammation in the skin.
Bermekimab has been investigated in dermatologic clinical studies and other indications. Two
Phase 2 studies are currently ongoing: one in atopic dermatitis (AD; Study 2018-PT044
[NCT03496974]) and one in hidradenitis suppurativa (HS; Study 2018-PT045). Bermekimab has
been administered intravenously (IV) at doses ranging from 0.25 mg/kg to 7.5 mg/kg and
subcutaneously (SC) at doses ranging 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) and Addenda for Bermekimab.
The term “study intervention” throughout the protocol, refers to study drug as defined in
Section 6.1. Study Intevention Administered. For the purpose of this study protocol, the study
intervention will be referred to as ‘bermekimab’.
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
Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by intense
pruritus (ie, itchiness), xerosis (skin dryness), and eczematous lesions whose features include
erythema, infiltration/papulation, oozing with crusting, excoriations, and lichenification. It is often
associated with other atopic disorders, such as allergic rhinitis and asthma. Severe disease can be
extremely disabling due to several factors: major psychological problems, significant sleep loss,
and impaired quality of life (QoL) that lead to a high socioeconomic cost. An estimated 2% to 10%
of adults are affected by AD (Bieber 2008).
Inhibition of IL-1⍺has been shown clinically to resolve chronic skin inflammation. However, it is
not fully known what levels of IL-1⍺are present in active skin lesions from patients with AD and
what dose level of bermekimab would maximally neutralize IL-1⍺in active lesions. Evaluating
this question in the context of clinical response would improve our understanding of the role of
IL-1⍺in AD disease pathophysiology.
Efficacy results from 2 open label studies (2018 PT-044 and PT-045), and preliminary results from
an ongoing randomized phase 2 trial (77474462ADM2002, NCT04021862) of bermekimab SC
400 mg weekly show a dose-response relationship. However, the data suggests additional room
for improvement in efficacy outcomes.
Given the favorable safety profile observed to date in multiple trials including at the highest dose
(1200 mg IV) in a single dose evaluation, this study has been designed to evaluate the efficacy of


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higher doses of bermekimab, which need to be administered as weekly in IV infusions, coupled
with detailed tissue evaluations. The purpose is to provide a comprehensive analysis of safety,
pharmacokinetics (PK), pharmacodynamics (PD), including target engagement, and efficacy, in
patients with moderate-to-severe AD, to understand the full potential of IL-1⍺inhibition in AD.
In summary, this is a Phase 2a, randomized, adaptive, placebo-controlled, double-blind,
multicenter, interventional study to assess the safety, efficacy, PK, and immunogenicity of
multiple IV doses of bermekimab in adult participants with moderate-to-severe AD using a placebo
control by means of:
 Assessment of the efficacy of multiple IV infusions of bermekimab through Week 16
 Evaluating safety and tolerability data for bermekimab in these participants with AD.
The scientific rationale in support of the study as well as relevant background information
pertaining to nonclinical and clinical studies of bermekimab are summarized in Section 2.2.
Background.
An overview of the protocol design, supportive rationale, and justification for dose are described
in Sections 4.1 (Overall Design), 4.2 (Scientific Rationale for Study Design), and 4.3 (Justification
for Dose), respectively.
2.2. 
Background
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. Interlukin-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 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.
Clinical evidence generated to date suggests that targeting IL-1α maybe an effective treatment in
undermining the inflammatory process that drives a wide array ofdiseases, including dermatologic
conditions.
In previous dermatology studies, bermekimab demonstrated therapeutic activity and a
well--tolerated safety profile.
Nonclinical Studies
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.
A comprehensive overview of the nonclinical development program for bermekimab is available
in Section 3 of the latest version of the bermekimab IB.


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Nonclinical Pharmacology
Bermekimab binds with high affinity and specificity to human IL-1α with a dissociation rate
constant (KD) of 0.029 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 1.3 nM and did not bind with mouse, rat, or pig IL-1α at
the highest concentrations tested.
Toxicology
A 1-month single- and repeat-intraperitoneal (IP) dose mouse study tested JNJ-77474462 up to
3 doses of 312 mg/kg/week. There were no treatment-related deaths following the single- or
short-term repeat-dose administration. There were no treatment effects on clinical observation,
body weight, food consumption, body temperature, clinical pathology, and histopathology
evaluations. Mice that received a single high dose or 2 intermediate doses had minimal, but
statistically significant decreases in blood urea nitrogen (BUN) which were attributed to intergroup
variation since no similar decrease was observed in the mice that received 3 high doses. Slight
increases in total protein and globulin seen in the high dose animals were likely due to the
administration of the protein test article.
The potential toxicity of bermekimab was evaluated in a 6-week repeat IV and SC exploratory and
tolerability study with toxicokinetics in female cynomolgus monkey, at dose levels of 0, 50 (IV),
300 (IV), and 300 (SC) mg/kg/week for 6 weeks. The toxicology evaluations included mortality,
clinical observation, body weight, food consumption, veterinary physical examination,
ophthalmology, clinical pathology (hematology, chemistry, coagulation, and urinalysis), organ
weight, gross necropsy, and histopathology. In addition, safety pharmacology and physiology
endpoints (electrocardiogram, blood pressure, heart rate, respiratory rate, and body temperature)
were evaluated. There was a transient decrease in blood pressure only at the high dose for both IV
and SC administrations on Day 6 and the values returned to baseline at the end of dosing period
(Day 37). There were no other treatment-related findings at any dose levels. The no observed
adverse effect level (NOAEL) was 300 mg/kg for both IV and SC administrations. At the NOAEL
dose, the exposures maximum serum concentration (Cmax)and area under the curve (AUC)for IV
administration were 9048.26 µg/mL and 26032.83 µg·day/mL respectively and Cmax and AUC for
SC administration were 4482.98 µg/mL and 22623.84 µg·day/mL respectively following dosing
on Day 36.
Clinical Studies
Results from a Phase 2, open label, dose escalation study of bermekimab in participants with
moderate-to-severe atopic dermatitis showed that bermekimab appeared to be safe, well tolerated,
and active at reducing the severity of atopic dermatitis, 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,


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urinalysis, and hematology), allergic reaction monitoring, and adverse event monitoring. Efficacy
was assessed by change in Eczema Area and Severity Index (EASI), Investigator Global
Assessment (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 71% achieved EASI-75 at Week 7. 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
is the percentage of patients achieving EASI-75 at Week 16. Preliminary results from this study
are discussed in Section 4.3. Justification for Dose.
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.
2.3. 
Benefit-Risk Assessment
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 (PG), 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).
As of 26 February 2020, unblinded data is available from 911 patients treated with JNJ-77474462
in patients with advanced solid tumors, advanced hematologic malignancies, metastatic colorectal
cancer, peripheral vascular disease, type II diabetes, acne vulgaris, plaque psoriasis, PG, AD, and
HS. To date there has been little evidence of drug-related toxicity, with most adverse events (AEs)
appearing to be secondary to worsening of patients’ underlying disease states.
An Independent Data Review Committee (DRC) with at least 3 members external to the study
team and consisting of a statistician and 2 physicians from clinical science and medical safety will
be established to review unblinded safety data at pre-specified timepoints during the study. The
DRC may also convene on Ad Hoc basis at the request of the Study Team. The DRC unblinded


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safety data review and recommendation will be required for the study to proceed to the higher
doses of IV bermekimab in patients with AD. Details will be further described in the DRC Charter.
The potential risks for bermekimab in this study are infections, hypersensitivity reactions, and
infusion-related reactions.
More detailed information about the known and expected benefits and risks of bermekimab may
be found in the IB.
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 to the safety laboratory and physical examinations, the Sponsor will implement the
additional measures to ensure the safety of the study participants. These additional measures
include: 1) a 2-hour, extended infusion time for the first 2 doses to reduce the risk of
infusion-related reaction (IRR; 2) a 2-hour post dose observation time for the first 2 doses to ensure
tolerability; 3) weekly visits to the investigative site for close monitoring; 4) the establishment of
a DRC to review the unblinded safety data at prespecified timepoints in Parts A, B, and C as well
as on an ad hoc basis.
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 moderate-to-severe AD.
2.3.1. 
Benefit-Risk Assessment for Study Participation
Table 1: 
Benefit-Risk for Study Participants (Bermekimab)
Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk
Mitigation Strategy
Risks Due to Study Intervention
Increased risk of infection. 
JNJ-77474462 is a recombinant 
human IgG1k mAb specific for 
human IL-1α. As such, it is 
considered to be an 
immunomodulator. Other agents 
that could be considered in the 
same pharmacologic class include 
biologic agents that target IL-1Ra 
and IL-1β. 
Bacterial infections have been 
reported in clinical trials using 
JNJ-77474462; however, the 
infections vary based upon the 
disease being treated and do not 
appear to be related to blockade of 
IL-1α. No opportunistic infections 
have been reported. 
In this study participants with a
history of, or ongoing, chronic or
recurrent infectious disease,
evidence of active or untreated
latent opportunistic infections
including TB, will be excluded
from the study.
As a precaution, participants should
be evaluated for TB before
administration ofstudy
intervention. In addition,
participants will be screened for TB
prior to study entry and receive
regular ongoing evaluation.
Participants will be instructed to
seek medical attention if they
develop signs or symptoms
suggestive of an infection, and
investigators are instructed in the
protocol to monitor for signs or


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Table 1: 
Benefit-Risk for Study Participants (Bermekimab)
Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk
Mitigation Strategy
symptoms of infections, including
TB (Section 8.2.9, Tuberculosis
Evaluations).
A participant’s study intervention
must be discontinued if an
opportunistic infection including
TB develops, and study
intervention must be interrupted if
the participant develops a serious
infection, and continuation or
discontinuation of study
intervention should be discussed
and decided with the Medical
Monitor or designee
Infusion-related reactions 
IRR have been reported with the 
first or second IV infusions of 
bermekimab. In the largest 
oncology study, PT023 Version 3, 
there were reports of infusion 
reaction in 2.6% (11 of 430) 
participants compared to 0% in 
placebo. The majority (n=10) were 
mild to moderate (Grade 1 to 2) and 
did not result in discontinuation. 
There was one Grade 3 infusion 
reaction, an SAE that resulted in 
patient discontinuation. 
In order to mitigate the risk of
IRRs, the study drug will be infused
over approximately 2 hours for the
first 2 doses in the study followed
by close monitoring for
approximately 2 hours at the
investigative site.
Availability of resuscitation
equipment must be ensured.
Any participant who has
experienced a Grade 2 IRR, will
continue with the 2-hour infusion
regimen (and a 2-hour post infusion
observation) for the duration of the
study.
Participants who experience a
Grade ≥3 IRR should be
discontinued from the study.
Pre-medication with antihistamines
or corticosteroids is not
recommended at this time as a
lower risk of occurrence for IRR is
expected with the approximately
2-hour infusion time. However,
based on emerging clinical
experience, the sponsor may
implement a premedication regimen
for all future participants if >1
incidents of IRR Grade 2 is
observed in Part A, or ≥1 incidents
of IRR Grade 2 is observed in Parts
B or C. Such a premedication
regimen would be administered
approximately 30 minutes before
the infusion of the study drug and
will consist of an oral non-sedating
H1 histamine blocker (eg,
loratadine 10 mg orally or


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Table 1: 
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Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk
Mitigation Strategy
equivalent) and oral paracetamol
(eg, acetaminophen 650 mg orally
or equivalent).
Serious hypersensitivity reactions
(including anaphylaxis and serum
sickness).
Serious hypersensitivity reactions
(including anaphylaxis and serum
sickness) may occur at any time and
not only during administration of
bermekimab.
Study intervention must not be
administered to individuals with
known or suspected intolerance or
hypersensitivity to any biologic
medication or known allergies or
clinically significant reactions to
any components of the formulation
used in this study.
IgG immunoglobulin G; IL interleukin; IRR
infusion related reactions; TB
tuberculosis.
More detailed information about the known and expected benefits and risks of bermekimab may
be found in the IB.


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3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of 16 weeks of multiple IV 
doses of bermekimab, compared with placebo, in 
participants with moderate-to-severe AD  
 
Proportion of participants with EASI-75
(≥75% improvement from baseline) at
Week 16
Secondary
To evaluate the PK and immunogenicity of 16 weeks of 
multiple IV doses of bermekimab, compared with 
placebo, in adult participants with moderate-to-severe
AD
Analyses of the following at all applicable
visits from Week 0 through Week 16:
 Serum concentrations of bermekimab
over time, including steady-state trough
serum concentrations.
 The incidence and titers of antibodies
to bermekimab
To assess the safety and tolerability of 16 weeks of 
multiple IV doses of bermekimab, compared with 
placebo, in participants with moderate-to-severe AD
 Proportion of participants with
TEAEs
 Proportion of participants with
treatment-emergent SAEs
 Proportion of participants with AEs
leading to discontinuation of study
intervention.
 Proportion of participants with AEs
reasonably 
related 
to 
study
intervention.
 Proportion of participants with AEs
of infusion-related reactions.
 Proportion of participants with AEs
of infections, including serious
infections and infections requiring
oral or parenteral antimicrobial
treatment.
 Proportion of participants with
Clinically significant abnormalities
in vital signs and laboratory tests.
To characterize additional assessments of efficacy of 
16 weeks of multiple IV doses of bermekimab, 
compared 
with 
placebo, 
in 
participants 
with 
moderate-to-severe AD  
Analyses of the following at applicable visits
through Week 16 by visit, respectively:
 
Proportion of participants with both
vIGA-AD of 0 or 1 and a reduction from
baseline of ≥2 points
 
Proportion 
of 
participants 
with
improvement 
(reduction) 
of
eczema-related itch NRS ≥4 from


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Objectives 
Endpoints
baseline among participants with a
baseline itch value ≥4
 
Proportion of participants with EASI-90
Exploratory
To further characterize efficacy of 16 weeks of multiple 
IV doses of bermekimab, compared with placebo, 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 ADIS
 
Proportions of participants with a PGIS
score of 1 (none) or 2 (mild) at Week 16
 
Change from baseline to Week 16 in
PROMIS-29 total score and sub-scores
 
Improvement in Hand Dermatitis IGA
from baseline to Week 16.
To assess the impact of treatment with 16 weeks of 
multiple IV doses of bermekimab, compared with 
placebo, on selected biomarkers.
Analyses of the following at all applicable
visits from Week 0 through Week 16:
 
Changes in cellular and molecular PD
biomarkers levels in skin and blood from
baseline compared with placebo.
 
Changes in skin barrier function from
baseline compared with placebo.
Abbreviations: AD=atopic dermatitis; ADIS=Atopic Dermatitis Itch Scale; AE=adverse event;
DLQI=Dermatological Life Quality Index; EASI=Eczema Area and Severity Index; IGA=Investigator Global
Assessment; IRR=infusion-related reaction; IV=intravenous; NRS=numeric rating scale;
PD=pharmacodynamics; PGIS=Patient Global Impression of Severity; PROMIS=Patient-Reported Outcomes
Measurement Information System; POEM=Patient-Oriented Eczema Measure; SAE=serious adverse event;
SCORAD=Severity Scoring of Atopic Dermatitis; TEAE=treatment-emergent adverse event;
vIGA-AD=validated Investigator Global Assessment for Atopic Dermatitis.
Refer to Section 8., Study Assessments and Procedures for evaluations related to endpoints.


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HYPOTHESIS
The hypothesis for this study is that IV bermekimab treatment is superior to placebo as assessed
by the proportion of participants achieving an EASI-75 (≥75% improvement from baseline) at
Week 16.


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4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter, interventional study
designed to assess the efficacy, safety, PK, biomarkers, and immunogenicity of multiple doses of
bermekimab administered via IV infusion 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 moderate-to-severe AD, that has been present for at least 1 year before the first administration
of study intervention, as determined by the investigator through participant 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 target ofapproximately 60 participants will be randomly assigned in this study. The study has 3
periods namely: a screening period of up to 4 weeks, a double-blinded placebo-controlled period
of 16 weeks, and a Safety Follow-Up period of 4 weeks, which includes an End of Study (EOS)
visit. The study will have 3 parts within the double-blinded placebo-controlled period that will run
in parallel and/or staggered: A, B, and C.
All participants will receive a weekly IV infusion of either bermekimab or placebo, in a 4:1
randomization ratio. Part A will consist of approximately 10 participants receiving bermekimab
800 mg IV weekly or placebo. Part B will consist of approximately 30 participants receiving
bermekimab 1200 mg IV weekly or placebo. An analysis of the data from all 10 participants of
Part A and the first 10 participants of Part B will support optimization and selection of the
bermekimab dose for Part C. Selection of the Part C bermekimab dose will be based on PK, PD,
efficacy, and safety analysis. Part C will consist of approximately  20 participants receiving
bermekimab or placebo at a higher or lower dose (not <800 mg) than Part B, but with a maximum
dose of 2400 mg IV weekly.
The study also includes 4 mandatory skin biopsies (2 at baseline and 2 after dosing). All
participants of Part A and the first 10 participants of Part B will have skin biopsies done at Week 0
(1 lesional and 1 non-lesional), and at Week 6 (2 lesional). The rest of the participants will be
biopsied at Week 0 (1 lesional and 1 non-lesional), and at Week 16 (2 lesional). Instructions for
the collection and shipment of these samples can be found in the biopsy collection manual.
All participants will have an extended in-clinic observation period of approximately4 hours during
the first 2 infusions. In this period, vital signs will be taken at the following time points: 0 hour
(start of infusion), 30 minutes, 1 hour, 1 hour and 30 mins, 2 hours (end of infusion), 2 hours and
30 mins, 3 hours, 3 hours and 30 mins, and 4 hours (post-infusion). Beyond the first 2 infusions,
all participants will have approximately a 1 hour infusion period and at least a 1 hour observation
post infusion, as well as vital signs taken approximately every 30 minutes.


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An internal and independent DRC  will be commissioned for this study. Refer to Committees
Structure in Section 10.3, Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
for details.
One planned database lock (DBL) will occur at the end of the study. Additional DBLs could be
considered.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
This Phase 2a study is an Experimental Medicine trial designed to evaluate a study intervention
(JNJ-77474462/bermekimab) that has a scientific rationale to benefit AD participants through
inhibition of IL-1⍺. This study is designed to better understand what levels of IL-1⍺are present in
active skin lesions from patients with AD and what dose level of bermekimab would maximally
neutralize IL-1⍺in active lesions. By evaluating this question in the context of clinical response it
would help us better understand the role of IL-1⍺in AD disease pathophysiology.
JNJ-77474462 efficacy and safety data from 2 open label studies (2018 PT-044 and PT-045), along
with preliminary results from an ongoing randomized phase 2 trial (77474462ADM2002,
NCT04021862) of bermekimab SC 400 mg weekly, have shown a dose-response relationship and
a favorable safety profile. However, the data suggests additional room for improvement in efficacy
outcomes and the possibility of having more target engagement. As such, this study is designed to
evaluate the efficacy of higher doses of bermekimab administered by weekly IV infusions, along
with detailed skin tissue evaluations.
Blinding, Control, Study Phase/Periods, Intervention Parts
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. Randomization will be used to
minimize bias in the assignment of participants to intervention parts, 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.
Selection of Dose for PartC
An interim analysis will be conducted when the 10th  participant of Part B completes dose
administration at Week 6. The interim analysis will be used to inform the dose decision for Part C
based on the safety, preliminary efficacy, PK and PD data accrued up to the interim analysis from
both Parts A and B. Safety review will be conducted by an internal and independent DRC.
Preliminary analyses will be performed to evaluate dose-response and exposure-response
relationship for the efficacy and PD (including target engagement). The dose for Part C will be
determined based on the totality of the available data and the preliminary analyses conducted
thereof, but it will not be higher than 2400 mg.


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Deoxyribonucelic Acid 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, and 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 inter-individual 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.
Deoxyribonucleic acid 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 primary ethical concern is that the IV dose levels of the interventional therapy and frequency
evaluated in this study will be higher than what has previously been studied in patients and/or
healthy volunteers. In Part A, a starting dose level of 800 mg IV dose was selected, as this dose
constitutes a 1.9-fold exposure increase to the 7.5 mg/kg dose administered in the oncology studies
with bermekimab. Furthermore, the advancement to higher doses will be based on safety reviews
by the DRC.
As with all clinical and PK studies, there are risks associated with venipuncture and multiple blood
sample collection. To avoid multiple venipunctures, which cause additional discomfort and other
potentially toxic effects, the use of IV indwelling catheters is permitted in this study. The blood
sample collection scheme was designed to collect the blood samples that accurately and completely
describe the PK and the study intervention. This minimizes the number of venipunctures and the
total volume of blood collected from each participant during the study.
The total blood volume to be collected from each participant in each part is far less than the
American Red Cross standard limit for whole blood donation (approximately 475 mL once 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,
Study Assessments and Procedures.


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4.3. 
Justification for Dose
In this study, bermekimab dose regimens of 800 and 1200 mg IV qw will be evaluated in Parts A
and B, respectively. Following the interim analysis, and for the purpose of analyzing target
coverage at a higher dose of bermekimab in this population, a bermekimab dose regimen of up to
2400 mg IV qw (Part C) may be evaluated. These dose regimens were chosen to build upon the
bermekimab PK, efficacy and safety data from a Phase 2 placebo-controlled study in participants
with AD (77474462ADM2002, NCT04021862), a Phase 1 open-label study in healthy volunteers
(77474462ADM1001, NCT04544813), and a Phase 2 placebo-controlled study in participants with
HS (Kanni 2018, NCT02643654). Additionally, safety margins derived from predicted human
exposure and the exposure observed during preclinical toxicity studies in cynomolgus monkeys
were also considered in selection of the dose regimens.
The Week 16 data from study 77474462ADM2002 (NCT04021862) in patients with AD showed
significant effect of bermekimab 400 mg SC qw group relative to placebo (EASI-75: 34.5% vs
13.8%, respectively), while the 400 mg SC once every 2 weeks (q2w) group showed numerically
higher EASI-75 response relative to placebo (EASI-75: 24.1% vs 13.8%, respectively). The
dose-response observed between 400 mg SC qw and 400 mg SC q2w (EASI-75: 34.5% vs 24.1%)
warranted additional dose-ranging studies in order to expand the dose range to explore target
engagement in skin tissue and maximize efficacy in AD. A Phase 2 placebo-controlled study
(77474462ADM2001) is being conducted with SC administration of bermekimab at doses of 350
and 700 mg qw.
In this current Phase 2 study, IV infusion will be utilized in order to further expand the dose range
potentially up to 2400 mg qw. The dose regimens of 800, 1200 and 2400 mg IV qw are predicted
to provide 1.9-, 2.9- and 5.7-fold higher exposure (AUC) at steady-state compared to 700 mg SC
qw (assuming 60% bioavailability), respectively. Overall, the IV doses proposed in this current
study is expected to maximize the target coverage in the skin tissue and potentially contribute to
improved 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 necessitating weekly dosing to maintain adequate drug
exposure over the entire dosing interval.
Bermekimab was well tolerated with no safety concerns following single administration of 800
and 1200 mg IV in study 77474462ADM1001 (NCT04544813)in healthy volunteers. The highest
multiple IV dose of bermekimab studied was 7.5 mg/kg IV q2w in HS patients (equivalent to
675 mg IV dose for 90 kg body weight which is the average body weight of HS patients) where
no AE was related to bermekimab (Kanni 2018, NCT02643654). The 7.5 mg/kg IV dose is
equivalent to 675 mg IV dose for a 90 kg individual (average body weight of HS patients). The
800 and 1200 mg IV qw dose regimens proposed in this study (Parts A and B) are predicted to
result in 2.4- and 3.6-fold higher AUC compared to 7.5 mg/kg IV q2w, while the 2400 mg IV qw,
which is proposed as the maximum dose for Part C, is predicted to result in a 7.1-fold higher AUC.
Bermekimab was also well tolerated with no safety concerns in 2 studies in AD patients
(77474462ADM2002 [NCT04021862] and 2018-PT044 [NCT03496974]). In these studies, a
loading dose of up to 800 mg SC was studied and the highest maintenance dose regimen studied
was 400 mg SC qw. In this study, dose escalation from 800 mg IV to 1200 mg IV, and from


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1200 mg IV to up to 2400 mg IV will be performed after safety review by the DRC. This internal
and independent DRC will be commissioned to actively monitor unblinded safety data after a
limited number of participants reach Week 4 in Parts A, B, and C.
Further details about the pre-specified timepoints and ad-hoc reviews by the DRC are provided in
Section 9.6, Data Review Committee.
In addition, to predict the safety margins up to 2400 mg IV qw, a population PK model for
bermekimab was used to simulate human serum concentration-time profiles of bermekimab. The
safety margins for predicted human exposure at 800, 1200, and up to 2400 mg IV qw was 34.3-,
22.8-, and 11.4-fold for Cmax,ss and 21.3-, 14.2-, and 7.1-fold for AUC1week,ss, respectively, relative
to the cynomolgus monkey NOAEL (300 mg/kg IV qw, Section 2.2, Background). Therefore, it
was modeled that dose regimens of up to 2400 mg IV qw proposed in this Phase 2 study would
have adequate safety margins.
Overall, the high doses delivered via IV infusion in this study would provide the opportunity to
explore the potential maximum efficacy, dose-response and PK/PD relationships of bermekimab
while maintaining safety of participants. The findings from this study will contribute to optimal
dose selection for subsequent clinical trials in participants with moderate-to-severe AD.
For more details, refer Section 2.1, Study Rationale.
4.4. 
End of Study Definition
End of Study Definition
The EOS is considered as the last scheduled study assessment shown in the SoA 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 assessment 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 15 and has completed all assessments at both
Week 16 and Week 20 of the safety follow-up period.


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5. 
STUDY POPULATION
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 is 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 9.1,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
≥18 to ≤65 years (or the legal age of consent in the jurisdiction in which the study is taking
place).
Type of Participant and Disease Characteristics
2. 
be otherwise healthy on the basis ofphysical examination, medical history, vital signs, and
12-lead electrocardiogram (ECG) 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. 
have an EASI score ≥16 at screening and at baseline.
6. 
have an IGA score ≥3 at screening and at baseline.
7. 
have an involved BSA ≥10% at screening and at baseline.
Sex and Contraceptive/Barrier Requirements
8. 
male or female (according to their reproductive organs and functions assigned by
chromosomal complement)
9. 
all woman of childbearing potential must have a negative highly sensitive serum (-human
chorionic gonadotropin [-hCG]) at pregnancy test at screening and a negative urine
pregnancy test at Week 0 prior to administration of study intervention.


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10. A woman must be (as defined in Section 10.5, Appendix 5: Contraceptive and Barrier
Guidance)
a. 
Not of childbearing potential, OR
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 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 Section 10.5, Appendix 5: Contraceptive and
Barrier Guidance. However, the method selected must meet local/regional
regulations/guidelines for highly effective contraception.
11. a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 12 weeks after the last dose of study
intervention.
12. a male 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
13. a male participant must agree not to donate sperm for the purpose of reproduction during the
study and for a minimum 12 weeks after receiving the last dose of study intervention
Informed Consent
14. must sign an informed consent form (ICF)indicating that he or she understands the purpose
of, and procedures required for, the study and is willing to participate in the study.
15. must sign a separate ICF if he or she agrees to provide an optional DNA sample for research
(where local regulations permit)or any other samples for optional substudies. Refusal to give
consent for the optional DNA research sample and/or other optional substudies does not
exclude a participant from participation in the study.
16. willing and able to adhere to the lifestyle restrictions specified in this protocol.
Laboratory Parameters:
17. 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 (Système Internationale [SI]: ≥100 g/L)
b. White blood cells ≥3.5 × 103/μL (SI: ≥3.5 GI/L)
c. Neutrophils ≥1.5 × 103/μL (SI: ≥1.5 GI/L)
d. Platelets ≥100 × 103/μL (SI: ≥100 GI/L)
e. Serum creatinine ≤1.5 mg/dL (SI: ≤137 μmol/L)


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f. Aspartate aminotransferase ≤2 × upper limit of normal (ULN)
g. Alanine aminotransferase ≤2 × ULN
h. Alkaline phosphatase ≤2 × ULN.
Other Therapies and Vaccines
18. agree 
to 
discontinue 
any 
topical 
medications/treatments/therapies 
(excluding
non-prescription moisturizers, which are required for daily use per protocol, see Section 6.8.2,
Required Treatment) and/or ultraviolet (UV) therapy for AD within 4 weeks before the first
administration of study intervention.
Tuberculosis
19. 
are considered eligible according to the following tuberculosis (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 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.
o 
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.
o 
Within 2 months before the first administration of study intervention, have a negative
QuantiFERON-TB test result, or have a newly identified positive QuantiFERON-TB
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.


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NOTE A negative tuberculin skin test result (see Section 10.6, Appendix 6: Tuberculin
Testing) 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 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 20a.
a. 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 computed tomography (CT)scan is also
acceptable if already available or obtained outside of the study protocol.
Miscellaneous
20. must be willing and able to complete electronic patient reported outcome (ePRO)
questionnaires and diaries (Section 8.1, Efficacy Assessments) per the Schedule of Activities
(SoA; Section 1.3).
21. willing and able to adhere to the lifestyle restrictions specified in this protocol.
22. must be willing to undergo 4 skin biopsies.
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; has a QT corrected according to Fridericia's formula (QTcF) interval
>450 msec for males, and >470 msec for females, has a complete left or right bundle branch
block, or has a history or current evidence of additional risk factors for torsades de pointes
(eg, heart failure, hypokalemia, family history of Long QT Syndrome) at screening or at
Day 1/Week 0 (baseline).
3. 
Criterion modified per Amendment 1
has 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


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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. Criterion modified per Amendment 1
tests positive for hepatitis B virus (HBV) infection (see Section 10.8, Appendix  8: HBV
Screening with HBV DNA Testing) or has clinically active liver disease, or is seropositive
for antibodies to hepatitis C virus (HCV) at screening unless they satisfy one of the following
conditions:
 have a history of successful treatment (defined as being negative for HCV ribonucleic
acid [RNA] at least 6 months after completing antiviral treatment) and have a
negative HCV RNA test result at screening,
OR
 while seropositive, have a negative HCV RNA test results at least 6 months prior to
screening and a negative HCV RNA test result at screening regardless of vaccination
status.
11. During the 6 weeks prior to baseline, have had any of (a) confirmed severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2; Coronavirus Disease 2019 [COVID-19]) infection
(test positive), OR (b) suspected serious adverse reactions (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:
a. 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
b. 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:


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a. 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.
b. 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. Criterion modified per Amendment 1
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 20
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.
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.
17. has a transplanted organ (with exception of a corneal transplant >3 months before the first
administration of study intervention).
18. known allergies, hypersensitivity, or intolerance to bermekimab or its excipients (refer to the
IB).
Prior/Concomitant Therapy
19. has taken any of the medications or therapies outlined in the inclusion/exclusion criteria
within the specified period, or has plans to receive any disallowed therapies as noted in
Section 6.8, Concomitant Therapy throughout the study.
20. has ever received any IL-1 antagonist (eg, including but not limited to anakinra, rilonacept)
21. has previously received dupilumab.
22. 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).
23. 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.
24. Criterion modified per Amendment 1


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use of any prescription topical treatment for AD within 4 weeks of the baseline visit,
including prescription moisturizer, unless the prescribed moisturizer can be obtained over
the counter (OTC) and it doesn’t require a prescription.
25. Criterion modified per Amendment 1
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 other than AD that, in the opinion of the investigator, is likely to require such
treatment(s) within 4 weeks before the baseline visit.
26. 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.
27. has received, or is expected to receive, any live virus or bacterial vaccination within 12 weeks
before the first administration of study intervention. Non-live vaccines approved or
authorized for emergency use (eg, COVID-19) by local health authorities are allowed.
28. has had a Bacille Calmette-Guerin (BCG)vaccination within 12 months prior to screening.
Prior/Concurrent Clinical Study Experience
29. has received any non-biologic investigational intervention (including investigational
vaccines) 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
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.
33. 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.
Diagnostic Assessments –Not applicable
Other Exclusions
34. 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
35. Criterion modified per Amendment 1


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history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental
Disorders (5th edition) criteria within 12 months before screening.
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 Section 10.3,
Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
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 10) 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.
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 12)
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.
5. Participants must comply with restrictions on concomitant medications and therapies specified
in the protocol (refer to Section 6.8, Concomitant Therapy, for details).
6. 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; see Section 6.8, Concomitant Therapy, for details).
7. Participants must not receive a live virus or bacterial vaccination during the study and for 3
months after the last administration of any study intervention. See lifestyle consideration for
information regarding BCG vaccination.
8. Participants must not receive a BCG vaccination during the study and for 12 months after the
last administration of any study intervention.
9. Agree to follow all requirements that must be met during the study as noted in the inclusion
and exclusion criteria (eg, contraceptive requirements).
10. Criterion modified per Amendment 1
It is strongly recommended that participants are up-to-date on age-appropriate vaccinations
including COVID-19 vaccines 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,


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guidelines, and standards of care for patients receiving immune-targeted therapy when
determining an appropriate interval between vaccination and study enrolment (see also
Section 6.8 Concomitant Therapy).
5.4. 
Screen Failures
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.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened. Rescreened participants will be assigned a new participant number, undergo the
informed consent process, and then start a new screening period.
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention
Guidelines for study intervention administration affected by the COVID-19 pandemic are found
in Section 10.9, Appendix 9: Study Conduct During A Natural Disaster.


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6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention Administered
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF).
Bermekimab will be manufactured and provided under the responsibility of the sponsor. Refer to
the IB for a list of excipients.
For details on rescue medications, refer to Section 6.8.4, Rescue Medication. For a definition of
study intervention overdose, refer to Section 6.7, Treatment of Overdose.
Approximately 10 participants are planned to receive weekly 800 mg of IV bermekimab or placebo
in Part A. Approximately 30 participants are planned to receive weekly 1200 mg of IV
bermekimab or placebo in Part B. After the initial 10 participants (8A:2P) have completed 6 weeks
of dosing in Part B, safety, PK, PD, and efficacy will be analyzed to determine an appropriate dose
to be used in Part C. Approximately 20 participants are planned to receive the determined dose of
bermekimab and placebo. The maximum dose to be considered for Part C will be 2400 mg IV
weekly (Table 2).


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Table 2: 
Description of Interventions
Part Name 
Part A 
Part B  
Part C  
N/A
Intervention Name 
bermekimab 
bermekimab 
bermekimab 
Placebo
Dose Formulation 
sterile liquid formulation of 
350 mg (175 mg/mL) of 
bermekimab in a prefilled 
syringe (PFS) with an 
injectable volume of 2.0 mL.
sterile liquid formulation of 
350 mg (175 mg/mL) of 
bermekimab in a PFS with an 
injectable volume of 2.0 mL. 
sterile liquid formulation of 
350 mg (175 mg/mL) of
bermekimab in PFS with an
injectable volume of 2.0 mL.
Saline vials
Unit Dose Strength(s) 
175 mg/mL 
175 mg/mL 
175 mg/mL 
N/A
Dosage Level(s) 
800 mg intravenous (IV) 
infusion weekly from Week 0 
through Week 15
1200 mg IV infusion weekly 
from Week 0 through Week15 
TBD mg IV infusion weekly 
from Week 0 through Week 15 
IV infusion weekly from Week
0 through Week 15
Route of Administration 
IV infusion  
IV Infusion 
IV Infusion  
IV Infusion
Use 
Experimental 
Experimental 
Experimental 
Placebo comparator
Investigational Medicinal 
Product
Yes 
Yes 
Yes 
No
Non-Investigational 
Medicinal Product
/Auxiliary Medicinal
Product
No 
No 
No 
No
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Provided centrally by the
Sponsor
Packaging and Labeling 
The investigational supplies 
will be uniquely packaged to 
assure that they are 
appropriately managed 
throughout the supply chain 
process. Study intervention 
labels will contain information 
to meet the applicable 
regulatory requirements 
The investigational supplies 
will be uniquely packaged to 
assure that they are 
appropriately managed 
throughout the supply chain 
process. Study intervention 
labels will contain information 
to meet the applicable 
regulatory requirements 
The investigational supplies 
will be uniquely packaged to 
assure that they are 
appropriately managed 
throughout the supply chain 
process. Study intervention 
labels will contain information 
to meet the applicable 
regulatory requirements 
The investigational supplies
will be uniquely packaged to
assure that they are
appropriately managed
throughout the supply chain
process. Study intervention
labels will contain information
to meet the applicable
regulatory requirements
Delivery instructions 
See Investigational Product 
Preparation Instructions (IPPI)
See IPPI 
See IPPI 
See IPPI
Current/Former Name or 
Alias
JNJ-77474462 
JNJ-77474462 
JNJ-77474462 
N/A


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6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored at controlled temperatures ranging from 36°F to 46°F (2°C
to 8°C) and must be protected from light. Placebo must be stored at controlled temperatures, as
indicated on the product-specific labeling.
Refer to the IPPI for additional guidance on study intervention preparation, handling, and storage.
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.
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  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 intervention accountability purposes.
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 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
Central randomization will be implemented in this study. Participants in Part A, Part B, and Part
C will be randomly assigned to either the bermekimab or placebo intervention groups (4:1 ratio)
based on a computer-generated randomization schedule prepared before the study by or under the
supervision of the sponsor. The randomization will be balanced by using randomly permuted
blocks. The interactive web response system (IWRS)will assign a unique intervention code, which


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will dictate the intervention assignment and matching study intervention kit for the participant.
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 while the remainder of site personnel will remain
blinded. The volume of the placebo will match the volume of the active intervention in each cohort.
Prepared doses may be covered to mask potential visual differences between the active 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. Administration of study intervention to the participants
will be performed by a blinded, qualified healthcare provider. Independent drug monitors will be
used to monitor drug accountability and all unblinded study data.
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, anti-JNJ-77474462 antibodies, study intervention preparation/accountability data,
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 DBL and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed
the study and the database is finalized. Otherwise, the blind should be broken only if specific
emergency intervention/course of action would be dictated by knowing the intervention status of
the participant. In such cases, 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.
For the purpose of the interim analysis of safety data and preliminary PK, efficacy, and PD analysis,
designated sponsor personnel will be unblinded to the relevant data as is required (Section 8.4,
Pharmacokinetics and Immunogenicity). The randomization code will be disclosed to those
authorized and only for those participants included in the interim analysis. All site personnel and
participants will remain blinded to the treatment assignments until the last participant completes
the Week 20 evaluations and the final database is locked.


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Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations and are not eligible to receive further study intervention.
Additionally, a given participant’s treatment assignment may be unblinded to the sponsor, the
Independent Ethics Committee/Institutional Review Board (IEC/IRB), and site personnel to fulfill
regulatory reporting requirements for suspected unexpected serious adverse reactions (SUSARs).
A separate code break procedure will be available for use by the sponsor’s Global Medical Safety
group to allow for unblinding of individual participants to comply with specific requests from
regulatory or health authorities.
6.4. 
Study Intervention Compliance
Study intervention will be administered by IV infusion by blinded qualified study-site personnel
and the details of each administration will be recorded in the eCRF (including date and time of
study intervention administration).
The investigator or designated study-site personnel will maintain a log of all study interventions
dispensed and returned. Intervention  supplies for each participant will be inventoried and
accounted 
for 
throughout 
the 
study. 
At 
all 
times, 
study 
intervention  under
preparation/administration must be supervised to ensure proper handling and to avoid potential
dosing errors or tampering.
Any accidental administration of study intervention to a non-study participant must be reported
immediately to the sponsor’s medical monitor.
Additional details are provided in the instructions provided by the sponsor (IPPI).
6.5. 
Dose Modification
No treatment or dose adjustment will be permitted throughout the study.
6.6. 
Continued Access to Study Invervention After the End of the 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 determine standard of care.
6.7. 
Treatment of Overdose
For this study, any dose of bermekimab greater than the highest dose at a single dosing visit within
a 24-hour time period 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.
 Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
intervention should be interrupted or whether the dose should be reduced.
 Closely monitor the participant for AE/SAE and laboratory abnormalities


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 Document the quantity of the excess dose as well as the duration of the overdosing in the eCRF.
6.8. 
Concomitant Therapy
Pre-study therapies administered up to 30 days before the screening visit should be continued.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a participant into the study.
Every effort should be made to keep participants on stable concomitant medications. 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.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the eCRF. 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. Any questions regarding treatment with concomitant
medication during the study, should be directed to the medical monitor.
6.8.1. 
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.
6.8.2. 
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.
6.8.3. 
Prohibited Therapies/Medications
The following therapies will not be allowed during the course of the study.
 Topical corticosteroids, except for rescue therapy (see Section 6.8.4, Rescue Medication)
 Topical calcineurin inhibitors (eg, tacrolimus and pimecrolimus)


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 Topical phosphodiesterase inhibitors 4 (eg, crisaborole)
 Leukotriene inhibitors
 Allergen immunotherapy
 Phototherapy (including psoralen and UV-A, UV-B, tanning beds, and excimer laser)
 Bleach baths
 Systemic corticosteroids (oral)
o A single course of oral systemic corticosteroids per standard of care for conditions other
than AD, for a maximum of 10 days, will be allowed. The use of intramuscular (IM) and
IV corticosteroid formulations is prohibited, and will lead to participant discontinuation of
study intervention.
o 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, dupilumab)
 Topical and systemic janus kinase inhibitors
 Systemic immunosuppressant, cytotoxic, and immunomodulatory agents, including, but not
limited to, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil. and
immunomodulatory biologic therapies (eg, guselkumab, risankizumab, secukinumab,
rituximab, alemtuzumab, abatacept, or visilizumab)
 Any prescription topical treatment for AD, including prescription moisturizer, unless the
prescribed moisturizer can be obtained OTC and it doesn’t require a prescription.
 Interlukin-1αinhibiting agents (eg, anakinra, rilonacept, canakinumab)
 Live vaccines, including BCG vaccine.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.8.4. 
Rescue Medication
In the event that a participant experiences any unacceptable or worsening symptoms of AD,
investigators should first attempt to control symptoms in participants 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. The rationale for rescue must be
documented in source.
Hydrocortisone 2.5% ointment may be given to the participant for rescue treatment of any problem
areas on the body  unless otherwise contraindicated in that participant. In the event that
hydrocortisone 2.5% ointment is not available for use in the locale of a study site, an alternate,
equivalent potency topical corticosteroid may be supplied.
Participants should use rescue therapy only for as long as necessary to control problem areas, or
for a maximum of 2 consecutive weeks. Participants using rescue by topical therapy will continue


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to take investigational product and use of rescue therapy will be documented in the eCRF. 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.
If topical rescue therapy as stipulated above fails to control AD symptoms sufficiently, the
investigator should consider discontinuing the participant from the study.
For guidelines on management of IRR, refer to Section 2.3.1, Benefit-Risk Assessment for Study
Participation.
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 (Food and Drug Administration [FDA] Guidance 2020). Therefore,
upon initiation or discontinuation of bermekimab in participants 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)
Concomitant therapies (including any authorized for emergency use or fully approved, eg,
COVID-19 or influenza vaccination) must be recorded throughout the study beginning with start
of the first dose of study intervention to 4 weeks after the last dose of study intervention
Concomitant therapies 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.
When considering use of locally-approved (including emergency use-authorized) COVID-19
vaccines in study patients, follow applicable local vaccine labelling, guidelines, and standards of
care for patients receiving immune-targeted therapy. For study participants receiving a
locally-approved (including emergency use-authorized) COVID-19 vaccine, 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.


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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 investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the best
interest of the participant to discontinue study intervention
 Participants who experience a Grade ≥3 IRR should be discontinued from the study
 The participant has a serious adverse reaction that is related to an infusion of the study drug
administration including a hypersensitivity reaction resulting 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 or systolic
blood pressure <90 mm Hg (Sampson 2006). In general, discontinuation of study intervention
administration must be considered for participants who develop a nonserious but severe
infusion-related 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) occurring 1 to 14 days after an infusion of study intervention.
These may be 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
Section 10.5, Appendix 5:Contraceptive and Barrier 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:
o A diagnosis of active TB is made.
o 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.
o 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 8.2.9, 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).


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o 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.
 Abnormal liver tests as outlined in Section 10.7, Appendix 7:Liver Safety: Suggested Actions
and Follow-Up Assessments.
 Use of prohibited corticosteroids:
o IM and IV formulations
o Oral corticosteroids for more than 10 days.
 The participant has his/her treatment assignment unblinded by the investigator.
 Sponsor decision.
If a participant discontinues study intervention for any reason before the end of the double-blind
phase,then the end-of-intervention assessments should be obtained and scheduled assessments off
study intervention should be continued. Study intervention assigned to the participant who
discontinued study intervention may not be assigned to another participant. Additional participants
will not be entered.
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.
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
Discontinuation of study intervention for abnormal liver tests is required by the investigator when
a participant meets one of the conditions outlined in Section 10.7, Appendix 7: Liver Safety:
Suggested Actions and Follow-Up Assessments 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.


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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.
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent then no additional assessments are allowed.
Withdrawal of Consent
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 sample:
 The collected sample 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 sample, in which case the sample
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 sample
has 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 sample will be destroyed. The sample destruction process will
proceed as described above.


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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 Section 10.3, Appendix 3, 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.
 Site personnel will attempt to collect the vital status of the participant within legal and ethical
boundaries for all participants randomized, including those who did not get study intervention.
Public sources may be searched for vital status information. If vital status is determined as
deceased, this will be documented and the participant will not be considered lost to follow-up.
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 SoA summarizes the frequency and timing of efficacy, PK, immunogenicity, biomarker,
pharmacogenomics and safety measurements applicable to this study. It is strongly recommended
that the same investigator performs the efficacy assessment 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.
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
Section 10.9, Appendix 9: Study Conduct During a Natural Disaster.
Blood Sample Collection
The total blood volume to be collected from each participant will not exceed 500 mL over a 56-day
period. This is considered to be an acceptable amount of blood to be collected over this time period
from the population in this study based upon the standard of the American Red Cross. Repeat or
unscheduled samples may be taken for safety reasons or for technical issues with the samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF  or laboratory
requisition form. Refer to the SoA  (Section 1.3) for the timing and frequency of all sample
collections.


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Instructions for the collection, handling, storage, and shipment of samples are found in the
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the Laboratory Manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 Investigator's Brochure for bermekimab
 
Protocol
 
Site Investigational Product Binder
 
Laboratory Manual
 
Laboratory Kits
 
IWRS Manual
 
Sample eCRF
 
eCRF Completion Guidelines
 ePRO equipment (tablet device questionnaires, completion instructions)
 Participant Diary
 Digital photographic equipment and instructions manual (at participating sites)
 Participant Study Participation Card
 Investigative Site File
 iPhone XR
 SWIFT Vision infrared camera iPhone add-on
 Scibase Nevisense Go device
 GPskin barrier device
 Recruitment materials, as needed.
8.1. 
Efficacy Assessments
Efficacy assessments (EASI, validated Investigator Global Assessment for Atopic Dermatitis
[vIGA AD™], percent BSA involvement, SCORAD, and Hand Dermatitis IGA) and ePRO
measures (DLQI, POEM, Patient Global Impression of Severity [PGIS], Patient Reported
Outcomes Measurement Information System [PROMIS]-29, Eczema Skin Pain and Itch numeric
rating scale [NRS], and Atopic Dermatitis Itch Scale [ADIS]) will be performed at visits according
to the Schedules of Activities. Evaluation of EASI, SCORAD, and vIGA endpoints from digital
photographs will be completed from a subgroup of participants who consent to these optional
substudies at selected sites.
Investigator assessments and PROs of efficacy are included in this section.


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 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/Ethics Review Committee
submissions.
 The PRO and AE data will not be reconciled with one another.
8.1.1. 
Eczema Area and Severity Index (EASI)
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity
and extent of AD (Hanifin 2001). The EASI 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  (Section 1.3). See Section 10.10,
Appendix 10:EASI for a representative example of the index.
8.1.2. 
Validated Investigator Global Assessment for Atopic Dermatitis
(vIGA-AD™)
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 (Section 1.3). See Section 10.11, Appendix 11: vIGA-AD for a
representative example of the assessment.
8.1.3. 
Severity Scoring of Atopic Dermatitis (SCORAD)
The SCORAD is a validated tool used in clinical research and clinical practice that was developed
to standardize the evaluation of the extent and severity of AD. There are 3 components to the
assessment: A  extent or affected BSA, 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 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 participant 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


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limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a percentage of all
major body sections combined. Body surface area will be extracted using SCORAD.
See Section 10.12, Appendix 12: SCORAD for a representative example of the assessment.
8.1.4. 
Hand Dermatitis Investigator Global Assessment (IGA)
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
Section 10.13, Appendix 13: Hand Dermatitis IGA for a representative example of the assessment.
8.1.5. 
Eczema Skin Pain and Itch Numeric Rating Scale (NRS)
The Eczema Skin Pain and Itch NRS is a 2-item PRO 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 Section 10.17, Appendix 17:Eczema Skin Pain and Itch
NRS for a representative example of the scale.
8.1.6. 
Patient-Reported Dermatology Life Quality Index (DLQI)
The DLQI is a dermatology-specific QoL instrument designed to assess the impact of the disease
on a participant's health-related quality of life (HRQoL; Finlay 1994). It is a 10-item questionnaire
that assesses HRQoL over the past week and in addition to evaluating overall HRQoL, can be used
to assess 6 different aspects that may affect QoL: 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 HRQoL. See Section 10.14, Appendix 14:
DLQI for a representative example of the index.
8.1.7. 
Patient-Oriented Eczema Measure (POEM)
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.
8.1.8. 
Patient Global Impression of Severity (PGIS)
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


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severe”. The PGIS questionnaire will be used as an anchor to establish a clinical response criterion
of other participant or physician reported outcomes for future reference. The questionnaire will be
administered at time points according to the SoA. See Section 10.15, Appendix 15: PGIS for a
representative example of the questionnaire.
8.1.9. 
Patient-Reported Outcomes Measurement Information System-29
(PROMIS-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
Section 10.16, Appendix 16: PROMIS-29for a representative example of the questionnaire.
8.1.10. 
Atopic Dermatitis Itch Scale (ADIS)
The ADIS will be used to assess pruritus (itching) among participants with AD, a condition
commonly referred to as eczema. It will be evaluated by participants in 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 participant 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 Section 10.18, Appendix 18: ADIS for a representative example of the
scale.
8.1.11. 
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 77474462ADM2003, 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 Section 10.19, Appendix 19: Remote Endpoint Assessment Using Total Body
Photography 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.


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8.1.12. 
Skin Barrier Function Assessments
To explore the utility of digital health devices to measure skin barrier function before and after
treatment, devices measuring transepidermal water loss (TEWL), Stratum Corneum Hydration
(SCH) and electrical impedance of skin will be used. TEWL, SCH and Electrical Impedance
Spectroscopy (EIS) will be measured at each visit (Weeks 0 through 16) from both lesional and
non-lesional skin of participants. In addition, serial TEWL, SCH and EIS measurements will be
acquired after every 5 tape strips at weeks 0, 4 and 16 on lesional skin. TEWL and SCH will be
measured using the gpskin barrier device and EIS will be measured using the Scibase Nevisense
GO device. The results of these analyses will be presented in a separate report.
8.2. 
Safety Assessments
Safety data, including but not limited to, AEs, SAEs, infections, mortality, changes in laboratory
assessments, and changes in vital signs will be summarized. Treatment-emergent AEs will be
summarized by treatment groups and Medical Dictionary for Regulatory Activities (MedDRA)
system organ class and preferred terms. Details will be specified in the statistical analysis plan
(SAP).
Details regarding the internal and independent DRC  are provided in Committees Structure in
Section 10.3, Appendix 3, 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 Report and Section 10.4, Appendix 4:
Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the SoA (Section 1.3).
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.


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8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, blood pressure will be obtained prior to study
intervention administration at visits specified in the schedule of activities.
In addition, all participants will have an extended in-clinic observation period of approximately 4
hours during the first 2 infusions. In this period, vital signs will be taken at the following time
points: 0 hour (start of infusion), 30 minutes, 1 hour, 1 hour and 30 mins, 2 hours (end of infusion),
2 hours and 30 mins, 3 hours, 3 hours and 30 mins, and 4 hours (post-infusion). Beyond the first 2
infusions, all participants will have approximately a 1 hour infusion period and at least a 1 hour
observation post infusion, as well as vital signs taken every 30 minutes.
Blood pressure and pulse/heart rate measurements should be preceded by approximately5 minutes
of rest in a quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Electrocardiograms
Participants should rest in a supine position for approximately 5 minutes before ECG collection
and should refrain from talking or moving arms or legs. If blood sampling or vital sign
measurement is scheduled for the same time point as ECG recording, the procedures should be
performed in the following order: ECG(s), vital signs, blood draw.
A triplicate 12-lead ECG will be performed during screening to serve as a baseline reference for
comparison, should a subsequent cardiovascular related safety event occur. A triplicate 12-lead
ECG will also be performed at Week 0 (pre-dose, and post end of infusion [2 hours]), and at
Week16. At each time point at which triplicate ECGs are required, 3 individual ECG tracings
should be obtained as closely as possible in succession, but no more than 2 minutes apart. The full
set of triplicates should be completed in approximately 5 minutes.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Section 10.2,
Appendix 2: 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
AE section of the eCRF. 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 Section 10.2, Appendix 2:Clinical Laboratory Tests.
8.2.5. 
Pregnancy Testing
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.
Female participants of childbearing potential will undergo a serum pregnancy test at screening,
and a urine pregnancy test before each study intervention administration, and at the Week 20 or
early termination visit.


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8.2.6. 
Concomitant Medication
Concomitant medications will be reviewed at each visit and recorded in the source documents and
eCRF.
8.2.7. 
Allergic Reactions
Before any IV infusion, 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 infusions are being administered.
Participants who experience serious adverse reactions related to an infusion should be discontinued
from further study intervention administrations.
Participants who experience reactions following an infusion 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
infusion 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.
8.2.8. 
Infusion-Related Reactions
In order to mitigate the risk of IRRs, the study drug will be infused over approximately 2 hours for
the first 2 doses in the study followed by close monitoring for approximately 2 hours at the
investigative site.
Availability of resuscitation equipment must be ensured.
Any participant who has experienced a Grade 2 IRR, will continue with the approximate 2-hour
infusion regimen (and approximately a 2-hour post infusion observation) for the duration of the
study.
Participants who experience a Grade ≥3 IRR should be discontinued from the study.
Pre-medication with antihistamines or corticosteroids is not recommended at this time as a lower
risk of occurrence for IRR is expected with the approximately 2-hour infusion time. However,
based on emerging clinical experience, the sponsor may implement a premedication regimen for
all future participants if>1 incidents of IRR Grade 2 is observed in Part A, or ≥1 incidents of IRR


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Grade 2 is observed in Parts B or C. Such a premedication regimen would be administered
approximately 30 minutes before the infusion of the study drug and will consist of an oral
non-sedating H1 histamine blocker (eg, loratadine 10 mg orally  or equivalent) and oral
paracetamol (eg, acetaminophen 650 mg orally or equivalent).
8.2.9. 
Tuberculosis Evaluations
8.2.9.1. 
Initial Tuberculosis Evaluation
Participants must undergo testing for TB (refer to Section 10.2, Appendix 2: Clinical Laboratory
Tests 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 judgement, 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
participants. If no local country guidelines for immunocompromised participants 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-SPOTtest 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.


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8.2.9.2. 
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 SoA  [Section 1.3]). The following series of questions is suggested for use during the
evaluation:
 
“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 participants. If no local country guidelines for immunocompromised
participants 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
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intervention and be encouraged to return for all subsequent scheduled study visits according to the
SoA (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 AEs,
serious AEs, 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 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, or
surrogate) for the duration of the study.
Further details on AEs, SAEs, and PQC can be found in Section 10.4, Appendix 4: 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 AEs 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 SAEs, 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.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the eCRF, 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 AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local at the infusion 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 AEs are all AEs 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 AE, SAE, 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
Section 10.4, Appendix 4: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 AEs 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 AE that commonly occurs in the study population independent of
exposure to the drug under investigation. For the purposes of this study the following SAEs will
be considered anticipated events: No anticipated events have been identified for this study.
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the intervention group than in the
control group and the sponsor concludes there is a reasonable possibility that the drug under
investigation caused the anticipated event.


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The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries in which the studies are conducted.
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 SAEs and must be reported using the Serious Adverse Event 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 Section 10.4, Appendix 4: Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-Up, and Reporting. 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
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 SoA (Section 1.3).
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, 1 for antibodies to
bermekimab, and 1 back-up.
Serum samples will also be collected at the final visit from participants who terminate study
participation/intervention early. Blood samples collected for serum bermekimab concentrations
and/or antibodies to bermekimab may also be used for exploratory biomarker analyses.
A random venous blood sample for population PK analysis will be collected from the first 20
participants of the study on any day between Weeks 2 to 12, except on the days of the scheduled
study visits. If possible, we would like to encourage obtaining this sample between Week 2 and
Week 6, although if it is done after Week 6, it would not constitute a protocol deviation.
Additionally, this blood sample must be collected at least 24 hours prior to or after the actual time


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of study intervention administration. All the remaining participants (last 20 participants of Part B,
and all 20 participants of Part C) may choose to also participate in the collection of this population
PK sample as optional. 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.
Pharmacokinetic Analytical Procedures
Serum samples will be analyzed to determine serum bermekimab concentrations using a validated,
specific, and sensitive immunoassay method by or 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 pharmacogenomic whole blood sample will be collected to allow for pharmacogenomic
research, as necessary (where local regulations permit). Participation in the pharmacogenomic
research is optional.
Genotyping or sequencing techniques will be used to assess variation in the filaggrin 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.


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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 bermekimab and aid in evaluating the
intervention-clinical response relationship.
Biomarker assessment will include the evaluation of relevant markers in serum, blood, skin
biopsies, and tape strips for all participants. 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
samples will be separated into serum and peripheral blood mononuclear cells (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, and 16, 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 biopsy samples will be collected from all participants of the study at time points specified in
the SoA. At the baseline sampling time point (Week 0), biopsy samples will be collected from
both lesional and adjacent non-lesional areas; at Week 6 or 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 vs nonresponders. At Week 6 or 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.
8.6.2. 
Serum Biomarkers
Serum samples will be collected from all participants at time points specified in the SoA
(Section 1.3). 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
(Section 1.3), and PBMC will be isolated. Flow cytometry analysis of blood cell samples will be


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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.
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
(Section 1.3). Total ribonucleic acid will be isolated and used for differential gene expression
analyses to better understand the pathologic mechanisms involvedin 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. 
Medical Resource Utilization and Health Economics
Health Economics parameters are not evaluated in this study.


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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 is outlined
below. Specific details will be provided in the SAP.
9.1. 
Statistical Hypotheses
The hypothesis for this study is that at least 1 of the test doses/dosages IV bermekimab treatment
is superior to placebo as assessed by the proportion of participants with an  EASI-75 (≥75%
improvement from baseline) at Week 16.
9.2. 
Sample Size Determination
This study is designed to enroll approximately 60 participants in order to have sufficient power to
detect a difference between the participants receiving bermekimab and the participants receiving
placebo for the primary endpoint of the proportion of participants achieving EASI-75 at Week 16.
The EASI-75 response rate in the bermekimab 400 mg qw group was approximately 70% at
Week 7 from the open label study (2018-PT044 [NCT03496974]). The EASI-75 response rates in
placebo group at Week 16 were 15% and 12%, in the 2 Phase 3 trials of dupilumab vs placebo in
the treatment of adult participants with moderate-to-severe AD (Simpson 2016).
The EASI-75 response at Week 16 is assumed to be 15% for placebo, and 65% to 70% for the
bermekimab treatment population  (Table 3). Based on these assumptions, approximately 60
participants (10 in Part A, 30 in Part B, and 20 in Part C) are planned to be randomized. In each
Part, participants will be randomized in a 4:1 ratio to bermekimab or placebo. Thus, there will be
8 participants in the bermekimab 800 mg group, 24 participants in the bermekimab 1200 mg group,
16 participants in the bermekimab C dose, and 12 participants total across the placebo groups.
These sample sizes provide the study with at least 80% power to detect a treatment difference
between the each bermekimab treatment group and the pooled placebo treatment group in EASI-75
at Week 16 based on a Fisher’s Exact test at a Type I error rate of 0.1 (2-sided).
Table 3: 
Power to detect a treatment difference in EASI-75 at Week 16*
Placebo 
Bermekimab 
Difference 
Power
Bermekimab 1200 mg (n=24) vs placebo (n=12)
15%  
65% 
50% 
85%
15%  
70% 
55%  
92%
12%  
60%  
48% 
83%
12%  
65% 
53%  
90%
12%  
70% 
58%  
96%
Bermekimab dose C (n=16) vs placebo (n=12)
15%  
70% 
55%  
86%
15%  
75% 
60%  
92%
12%  
65% 
53%  
83%
12%  
70% 
58%  
91%
EASI Eczema Area and Severity Index.
*Power is not calculated for Part A due to small sample size.


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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 efficacy analyses.
Safety analyses will include all participants who received at least 1 dose 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 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
Efficacy and participant information analyses will include all randomized participants who
received at least 1 dose of study intervention and will be analyzed based on the randomized
treatment groups, regardless of the treatment they actually received.
Simple descriptive summary statistics, such as n, mean, standard deviation, median, inter quantile
range, minimum, and maximum for continuous variables, and counts and percentages for discrete
variables will be used to summarize most data.
In addition, treatment comparisons for binary endpoints will be performed using a Chi-Square test
or Fisher’s exact test in the case of rare events. For continuous efficacy endpoints, treatment
comparisons will be performed using a mixed-effect model repeated measure (MMRM) model.
The MMRM model includes treatment group, baseline value for the corresponding efficacy
endpoint, visit, baseline value by visit, and treatment by visit interaction, if applicable. In addition,
treatment differences and their associated 2-sided 90% confidence intervals (CIs)will be presented.
9.4.2. 
Primary Endpoint
The primary efficacy endpoint is the proportion of participants with EASI-75 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: 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 (ICE)in
categories 1 to 3 defined below will be considered a non-responder.
 Study intervention:
 Bermekimab 800 mg, 1200 mg, dose C mg IV qw
 Placebo IV qw


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 Intercurrent Events:
Table 4: 
Analysis Strategy for Addressing Intercurrent Events (ICEs)
Intercurrent Events (ICEs) 
Analysis Strategy for Addressing Intercurrent Events (ICEs)
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 after these events.
The occurrence of these intercurrent event being captured in
the variable definition.
4. Discontinuation of study intervention 
for reasons other than above defined 
reasons prior to Week 16
Treatment policy: Use observed data regardless of whether or
not this intercurrent event had occurred
 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 group.
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 Fisher's exact test at an alpha level
of 0.1 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 90% CI will be
provided.
The study would be considered as positive if any of the comparisons for primary endpoint analysis
(bermekimab 1200 mg vs placebo, and bermekimab C dose vs placebo) is less than or equal to
p-value of 0.1. No formal statistical testing will be performed for the 800 mg vs placebo. For the
analyses described above, participants with ICEs 1 through 3 before Week 16 will be considered
as EASI-75 nonresponders at Week 16. For participants with ICE 4, observed data after this ICE
will be utilized in the analysis. 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 data handling approaches; these analyses will be
described in the SAP. To evaluate the consistency of the efficacy, subgroup analysis of the primary
endpoint will be performed.
No adjustment for multiple comparisons will be made for primary endpoints.


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Secondary Endpoints
The secondary analyses pertaining to efficacy 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.
No adjustments for multiple comparisons will be made for the secondary endpoints.
9.4.3. 
Exploratory Endpoints
The exploratory endpoints are:
 
The improvement from baseline in SCORAD at Week 16 will be compared between each
bermekimab and the pooled placebo group.
 
The change from baseline in DLQI at Week 16 will be compared between each bermekimab
and the pooled placebo group.
 
The improvement from baseline in POEM at Week 16 will be compared between each
bermekimab and the pooled placebo group.
 
The improvement from baseline in eczema-related itch NRS at Week 8 will be compared
between each bermekimab and the pooled placebo group.
 
The improvement from baseline in eczema-related pain NRS at Week 8 will be compared
between each bermekimab and the pooled placebo group.
 
The improvement from baseline in eczema-related pain NRS at Week 16 will be compared
between each bermekimab and the pooled placebo group.
 
The improvement from baseline in ADIS itch at Week 16 will be compared between each
bermekimab and the pooled placebo group.
 
The proportions of participants with a PGIS score of 1 (none) or 2 (mild) at Week 16 will be
compared between each bermekimab and the pooled placebo group.
 
The change from baseline in PROMIS-29 total score and sub-scores at Week 16 will be
compared between each bermekimab and the pooled placebo group.
 
Hand Dermatitis IGA at Week 16 will be compared between each bermekimab and the pooled
placebo group.
9.4.4. 
Safety Analyses
All safety analyses will be made on the Safety Population, which include all participants who
received at least 1 dose of study intervention. Safety data, including but not limited to, AEs, SAEs,
infections, changes in laboratory assessments, and changes in vital signs will be summarized.


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Treatment‑emergent AEs will be summarized by treatment group and MedDRA system organ
class and preferred terms. Details will be specified in the SAP.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
MedDRA. Any AE occurring at or after the initial administration of study intervention is
considered to be treatment emergent. All reported 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.
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.
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 infusion-related reactions.
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. Listings of participants with SAEs, severe AEs, anaphylactic reaction/serum sickness
reactions, and AEs leading to discontinuation of study intervention will be provided.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for selected laboratory analyte and changes from baseline at each scheduled time point.
A listing of participants with common toxicity criteria Grade 2 or higher laboratory results will
also be provided.
Vital Signs
Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic
and diastolic) will be summarized over time, using descriptive statics.
9.4.5. 
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.


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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.
Biomarkers 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 and skin 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.
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.
If applicable, 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.
Pharmacokinetic/Pharmacodynamic Analyses
If data permit, the relationships between serum bermekimab concentration and efficacy (and/or
biomarker levels) 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.


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Pharmacogenomic Analyses
DNA samples will be used for research related to bermekimab or moderate-to-severe AD. They
may also be used to develop tests/assays related to bermekimab and moderate-to-severe 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 moderate-to-severe AD clinical endpoints.
Results will be presented in a separate report.
9.5. 
Interim Analysis
An interim analysis will be conducted when the 10th  participant of Part B reaches Week 6. The
interim analysis will be used to inform the dose decision for Part C based on the safety, preliminary
efficacy, PK and PD data accrued up to the interim analysis. Apart from the dose decision for Part
C, no changes to the current study design 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. Sponsor representatives including but not limited to the individuals involved in the
PK and PD analyses may be unblinded. An unblinding plan will be documented prior to the interim
analysis. An additional Interim Analysis may also be considered.
9.6. 
Data Review Committee
An internal and independent DRC, whose members are not directly involved in the conduct of
study 77474462ADM2003, 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 DRC will make recommendations to the study team regarding the
conduct of the study. The DRC will consist of at least 1 clinical physician and one statistician, not
involved in the conduct of the study. DRC responsibilities, authorities, and procedures will be
documented in the DRC charter.
The DRC in Part A is planned to review unblinded safety data after the 7th  participant has
completed Week 4 dosing, and it will include the first 7 participants in Part A.
The DRC in Part B is planned to review unblinded safety data after the 8th  participant has
completed Week 4 dosing, and it will include the first 8 participants in Part B.
The DRC in Part C is planned to review unblinded safety data after the 8th participant has competed
week 4 of dosing, and it will include the first 8 participants in Part C.
The DRC is also planned to review unblinded data from the IA.
Ad hoc DRC may also convene as requested by the clinical team.


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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 transaminase
AUC  
Area under the curve
BCG  
Bacille Calmette-Guerin
BSA 
Body surface area
BUN  
Blood urea nitrogen
CI 
Confidence interval
COVID-19 
Coronavirus Disease-19
CT  
Computed tomography
CYP  
Cytochrome
DBL 
Database lock
DILI 
Drug induced liver injury
DLQI 
Dermatology Life Quality Index
DRC  
Data Review Committee
EASI 
Eczema Area and Severity Index
ECG  
Electrocardiogram
eCRF  
Electronic case report form
eDC  
Electronic data capture
EIS  
Electrical Impedance Spectroscopy
EOS  
End of Study
ET  
Early termination
FAS  
Full analysis set
FDA  
Food and Drug Administration
FSH  
Follicle stimulating hormone
GCP  
Good Clinical Practice
HBsAg 
Hepatitis B surface antigen
HBV  
Hepatitis B Virus
HCV  
Hepatitis C virus
HIV  
Human immunodeficiency virus
HRQoL 
Health-Related Quality of life
HRT  
Hormonal replacement therapy
HS  
Hidradenitis suppurativa
IB  
Investigator’s Brochure
ICF  
Informed consent form
ICH  
International Council for Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent ethics committee
IGA  
Investigator Global Assessment
IgG1κ  
Recombinant human immunoglobulin g1 kappa
IL-1α 
Human interleukin-1 alpha
IM  
intramuscular
IND  
Investigational New Drug
INR  
International normalized ratio
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional review board
IRR  
Infusion-related reaction
IWRS  
Interactive web response system
KD 
Dissociation rate constant (KD)
mAb 
Monoclonal antibody


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MedDRA  
Medical Dictionary for Regulatory Activities
MMRM  
Mixed-Effect Model Repeated Measure
NAbs 
Neutralizing antibodies
NOAEL 
No observed adverse effect level
NRS  
Numeric Rating Scale
OTC  
Over the counter
PBMC  
Peripheral blood mononuclear cell
PD 
Pharmacodynamic(s)
PFS  
Preffilled syringe
PG 
Pyoderma gangrenosum
PGIS  
Patient Global Impression of Severity
PK 
Pharmacokinetic(s)
POEM  
Patient-oriented eczema measure
PPD 
Purified protein derivative
PQC  
Product quality complaint
PRO  
Patient-reported outcome(s) (paper or electronic as appropriate for this study)
PROMIS  
Patient-reported outcomes measurement information system
QoL 
Quality of life
QTcF  
QT corrected according to Fridericia's formula
SAE 
Serious adverse event
SAP  
Statistical analysis plan
SARS-CoV-2 
Severe acute respiratory syndrome Coronavirus-2
SC 
subcutaneous(ly)
SCH  
Stratum corneum hydration
SCORAD  
Scoring of Atopic Dermatitis
SoA  
Schedule of Activities
SUSAR  
Suspected unexpected serious adverse reactions
TB  
Tuberculosis
TBP  
Total body photography
TEAEs 
Treatment-emergent adverse events
TEWL 
Transepidermal water loss
TU 
Tuberculin units
US  
United States
UV  
Ultraviolet
vIGA-AD  
Validated Investigator Global Assessment for Atopic Dermatitis
Definitions of Terms
Electronic source 
system  
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a eCRF as determined by the protocol. Data in this system may be
considered source documentation.
PRO  
Reports directly from the patient without interpretation by clinician or anybody else.




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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation (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 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) involves 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
situation and agree on an appropriate course of action. The data recorded in the eCRF 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


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 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
 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


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 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
 Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 Reports of AEs 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


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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.
10.3.2. 
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.
10.3.3. 
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.
Informed consent may be obtained remotely. Refer to Monitoring Guideline.
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


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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 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
on rescreening.
10.3.4. 
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.


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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.
10.3.5. 
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
moderate-to-severe AD, to understand differential intervention responders, and to develop
tests/assays related to bermekimab and moderate-to-severe AD. 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 in Future
Research).
10.3.6. 
COMMITTEES STRUCTURE
Data Review Committee
An  internal and independent DRC  will be established to ensure the continuing safety of
participants enrolled in this study. This committee will consist of at least one medical expert in the
relevant therapeutic area and at least one statistician; committee membership responsibilities,
authorities, and procedures will be documented in its charter. The committee will meet periodically
to review interim data. After the review, the internal and independent DRC  will make
recommendations regarding the continuation of the study.
10.3.7. 
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 ofbermekimab, 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.


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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
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 EOS in order to ensure
the statistical analyses are relevant.


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10.3.8. 
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 eCRF completion will be provided and reviewed with study site personnel before
the start of the study.
10.3.9. 
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 eCRF. All eCRF 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 eCRF 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.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
the eCRF in English. The eCRF 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 electronic data capture (eDC) tool. If corrections to
an eCRF are needed after the initial entry into the eCRF, 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
studysite personnel.
10.3.10. 
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 AEs and follow-up of AEs; 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.


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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 eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source 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 eCRF in the protocol include the
eSource system, but information collected through eSource may not be limited to that found in the
eCRF.
10.3.11. 
MONITORING
The sponsor will use a combination of monitoring techniques: central, remote, or on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. 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 regulations. 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); a sample may be reviewed. 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.


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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.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.12. 
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 studysite 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.
10.3.13. 
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
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.


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10.3.14. 
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 intervention.
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
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development


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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
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 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 Event and Serious
Adverse Event 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 judgement 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 AE 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.
10.4.2. 
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.
10.4.3. 
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 judgement in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention 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
 Medication error, intercepted medication error or potential medication error involving a
Johnson & Johnson medicinal product (with or without participant 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 breastfeeding


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Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the SAE page of the eCRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. 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 eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE 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 SAEs 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
 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)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as a SAE, except hospitalizations for the following:


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 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
eCRF). 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 SAEs. Any adverse event that results in a prolongation of the originally
planned hospitalization is to be reported as a new SAE.
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 SAE.
Information regarding serious adverse events will be transmitted to the sponsor using a serious
adverse event reporting form and safety report form of the eCRF, 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.
10.4.6. 
Product Quality Complaint Handling
Definition
A product quality complaint (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.
This definition includes any PQC related to a device constituent in a combination product,
including those used in the administration of the study intervention or the comparator. A device
deficiency is an inadequacy of a device with respect to its identity, quality, durability, reliability,
safety, or performance. Device deficiencies include malfunctions, use errors, and inadequate
labeling.
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.
10.4.7. 
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safetyissues, PQC, or questions regarding the studyare listed in the Contact Information
page(s), which will be provided as a separate document.


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10.5. Appendix 5: Contraceptive and Barrier 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
Section 10.4, Appendix 4: 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, and
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 STUDYINCLUDE:
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)
(Azoospermia 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 ofcontraception should be used.
Spermatogenesis cycle is approximately 74days.)
USER DEPENDENT
Highly Effective Methods That Are User DependentFailure 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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10.6. Appendix 6: 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 TB. 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 participants, 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
participants should be consulted for the interpretation of tuberculin skin test results. If no local country
guidelines for immunocompromised participants exist, US guidelines must be followed.
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised participants should be consulted for acceptable
antituberculous treatment regimens for latent TB. If no local country guidelines for immunocompromised
participants 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.


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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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10.7. Appendix 7: Liver Safety: Suggested Actions and Follow-Up Assessments
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are met.
Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase, INR=international normalized ratio;
SAE=serious adverse event; ULN=upper limit of normal, Tbili=Total bilirubin.
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate
liver event etiology.
Phase 2 Liver Chemistry Stopping Criteria and Follow-Up Assessments
Liver Chemistry Stopping Criteria
ALT or AST-absolute 
ALT or AST ³5×ULN
ALT or AST Increase 
ALT or AST ³3×ULN persists for ³4 weeks
Bilirubin1,2
ALT or AST ³3×ULN and total bilirubin ³2×ULN
INR2 
ALT or AST ³3×ULN and international normalized ratio (INR) >1.5
Cannot Monitor 
ALT or AST ³3×ULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT or AST ³3×ULN associated with symptoms (new or worsening)
believed to be related to liver injury or hypersensitivity
Required Actions, Monitoring, and Follow-up Assessments
Actions 
Follow-Up Assessments
Immediately discontinue study intervention  
 Report the event to the sponsor within 24 hours 
 Complete the liver event/expedited reporting form, 
and complete an SAE eCRF if the event also met 
the criteria for an SAE2 
 Viral hepatitis serology4
 Obtain blood sample for pharmacokinetic
(PK) analysis after the most recent dose5
 Obtain serum creatine phosphokinase,
lactate dehydrogenase,


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 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
MONITORING:
If ALT or AST ³3×ULN AND total bilirubin
³2×ULN or INR >1.5:
 Repeat liver chemistry tests (include ALT, aspartate
transaminase [AST], alkaline phosphatase, total
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 hepatology consultation is recommended
 If ALT or AST ³3×ULN AND total bilirubin
<2×ULN and INR ≤1.5:
 Repeat liver chemistry tests (include ALT, AST,
alkaline phosphatase, total bilirubin and INR) and
perform liver chemistry follow-up assessments
within 24 to 72 hours
 Monitor participants weekly until liver chemistry
abnormalities resolve, stabilize, or return to baseline
 Do not restart/rechallenge participant with study
intervention unless allowed per protocol and
sponsor approval is granted
gamma-glutamyltransferase, glutamate
dehydrogenase, and serum albumin
 Fractionate bilirubin, if total bilirubin
³2×ULN
 Obtain complete blood count with
differential to assess eosinophilia
 Record the appearance or worsening of
clinical symptoms of liver injury, or
hypersensitivity, on the liver
event/expedited reporting form
 Record use of concomitant medications
(including acetaminophen, herbal
remedies, and other over-the-counter
medications) on the concomitant
medications eCRF
 Record alcohol use on the liver event
alcohol intake form.
 If ALT or AST ³3×ULN AND total
bilirubin ³2×ULN or INR >1.5 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)
to evaluate liver disease, complete liver
imaging form
 Liver biopsy may be considered and
discussed with local specialist if available,
for instance:
 In participants when serology raises the
possibility of autoimmune hepatitis
 In participants when suspected drug
induced liver injury (DILI) progresses or
fails to resolve on withdrawal of study
intervention
 In participants with acute or chronic
atypical presentation
 If liver biopsy is conducted complete a
liver biopsy form.
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.


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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 3xULN and total bilirubin 2xULN (>35% direct bilirubin) or ALT or AST 3xULN
and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to sponsor in an
expedited manner and as an SAE if SAE criteria met (excluding studies of hepatic impairment or cirrhosis).
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. PK sample may not be required for participants known to be receiving placebo or noncomparator 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 eCRF. 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 OR a PK sample cannot be collected in
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in
the Study Reference Manual.




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10.9. Appendix 9: Study Conduct During a Natural Disaster
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 eCRF.
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 participant 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:
o remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions
between site staff (or designees) and participants for study procedures eg, those related
to safety monitoring / efficacy evaluation / study drug storage and administration
(including training where pertinent)


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o laboratory assessments using a suitably accredited local laboratory; for selected
measures (eg, urine pregnancy), home testing may be employed
o 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 eCRF.
o other relevant study data elements impacted by the pandemic should also be
documented / labeled as “COVID-19-related” in  eCRFs 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).
NOTES on COVID-related exclusion:
The field of COVID-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 (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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10.10. Appendix 10: Eczema Area and Severity Index (EASI)
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
to 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). Below is a sample
Score.


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10.11. Appendix 11: Validated Investigator Global Assessment for Atopic
Dermatitis (vIGA-AD)
Below is a sample scale.


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10.12. Appendix 12: Severity Scoring of Atopic Dermatitis (SCORAD)
Below is a sample form.


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10.13. Appendix 13: Hand Dermatitis Investigator Global Assessment (IGA)
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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10.14. Appendix 14: Patient-Reported Dermatology Life Quality Index (DLQI)
Below is a sample questionnaire.


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10.15. Appendix 15: Patient Global Impression of Severity (PGIS)
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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10.16. Appendix 16: Patient-Reported Outcomes Measurement Information
System (PROMIS)-29
Below is a sample questionnaire.


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10.17. Appendix 17: Eczema Skin Pain and Itch Numeric Rating Scale (NRS)
Below is a sample 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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10.18. Appendix 18: Atopic Dermatitis Itch Scale (ADIS)
Eczema Itching Severity Diary
[Morning Administration]
1. How would you rate your eczema-related itching rightnow?
□ 
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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10.19. Appendix 19: Remote Endpoint Assessment Using Total Body
Photography
A previous study (Hughes 2019) has described the capture of digital images of participants 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 AD, the well-established and validated scoring systems of the EASI
(Section 10.10, Appendix 10: Eczema Area and Severity Index) and SCORAD (Section 10.12,
Appendix 12: Severity Scoring of Atopic Dermatitis) 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 AD 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 0),
Week 8, and Week 16 visits.
Participants will agree to have multiple series of total body photographs taken at specified visits.
Instructions and photographic guides will be provided to the sites. Captured images will be
transferred and stored in a secure manner. The site investigator (at some point after the Week 20
visit), will access the images for the participants at their site and will assess the participants’
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 site), and central reader assessment by images.


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10.20. Appendix 20: Protocol Amendment History
This is an original protocol.


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11. 
REFERENCES
American Red Cross. http://www.redcrossblood.org/donating-blood. Accessed 21 January 2021.
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.
Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-1494.
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.
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.
Han YP, 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.
Investigator's Brochure: JNJ-77474462 Edition 3. Janssen Research & Development, LLC (April 2021).
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.
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.
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.
NCT04544813. ClinicalTrials.gov Identifier. Bermekimab. A Study of JNJ-77474462 in Healthy Participants.
Available at: https://clinicaltrials.gov/ct2/show/NCT04544813.
NCT02643654. ClinicalTrials.gov Identifier. Adalimumab. MABp1 In Hidradenitis Suppurativa Refractory To
Adalimumab. Available at: https://clinicaltrials.gov/ct2/show/NCT02643654.
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.


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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.
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.
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


Signature
User 
Date 
Reason
 
23-Nov-2021 
15:42:54
(GMT)
Document Approval
PPD

SAP_001.pdf: 
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Status: Approved, Date: 24 February 2022
Janssen Research & Development
Statistical Analysis Plan
A Phase 2a, Multicenter, Randomized, Placebo-Controlled, Double-blind, Interventional 
Study to Assess the Efficacy, Safety, Pharmacokinetics, and Immunogenicity of Multiple 
IV doses of Bermekimab for the Treatment of Adult Participants with Moderate to Severe 
Atopic Dermatitis
Protocol 77474462ADM2003; Phase 2a  
JNJ-77474462  (bermekimab)
Status:
Approved
Date:
24 February 2022
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-RIM-468063, 2.0
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.
NCT04990440


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Objectives and Endpoints ................................................................................................................ 4
1.2.
Study Design.................................................................................................................................... 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 7
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 7
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 8
5.
STATISTICAL ANALYSES................................................................................................................. 9
5.1.
General Considerations ................................................................................................................... 9
5.1.1.
Visit Windows ............................................................................................................................... 9
5.1.2.
Polling Algorithm for Analysis Centers ......................................................................................... 9
5.1.3.
Reference Date, Study Day and Relative Day ............................................................................. 9
5.2.
Participant Dispositions.................................................................................................................... 9
5.3.
Primary Endpoint Analysis ............................................................................................................. 10
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 10
5.3.2.
Analysis Methods for Primary Endpoint...................................................................................... 10
5.4.
Secondary Endpoints Analysis ...................................................................................................... 11
5.4.1.
Definition of Secondary Endpoints ............................................................................................. 11
5.4.1.1.
Eczema Area and Severity Index ............................................................................................ 11
5.4.1.2.
Validated Investigator Global Assessment for Atopic Dermatitis ............................................ 11
5.4.1.3.
Eczema Skin Pain and Itch Numeric Rating Scale.................................................................. 11
5.4.2.
Analysis Methods........................................................................................................................ 11
5.5.
Exploratory Endpoints Analyses .................................................................................................... 12
5.5.1.
Definition of Endpoints................................................................................................................ 12
5.5.1.1.
Eczema Area and Severity Index ............................................................................................ 12
5.5.1.2.
Eczema Skin Pain and Itch Numeric Rating Scale.................................................................. 12
5.5.1.3.
Validated Investigator Global Assessment for Atopic Dermatitis ............................................ 12
5.5.2.
Analysis Methods........................................................................................................................ 12
5.6.
Safety Analyses ............................................................................................................................. 12
5.6.1.
Extent of Exposure ..................................................................................................................... 12
5.6.2.
Adverse Events........................................................................................................................... 12
5.6.3.
Clinical Laboratory Tests ............................................................................................................ 13
5.6.4.
Vital Signs................................................................................................................................... 13
5.7.
Other Analyses............................................................................................................................... 13
5.7.1.
Pharmacokinetics and Immunogenicity (Antibodies to Bermekimab) ........................................ 13
6.
SUPPORTING DOCUMENTATION .................................................................................................. 14
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 14
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 15
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 16
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 17
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 18
6.6.
Appendix 6 Medical History ........................................................................................................... 19
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 20
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 21
6.9.
Appendix 9 Medications of Special Interest................................................................................... 22
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 23


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VERSION HISTORY
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
Final
Not Applicable
Initial release


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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 20 final 
database lock (DBL) for the study 77474462ADM2003. Due to early termination of the study by 
the sponsor with only a small number of participants enrolled, listings will be provided for efficacy 
and safety data. No formal analyses will be performed.
1.1.
Objectives and Endpoints 
Objectives
Endpoints
Primary
To evaluate the efficacy of 16 weeks of multiple IV 
doses of bermekimab, compared with placebo, in 
participants with moderate-to-severe AD
Proportion of participants with Eczema Area and 
Severity Index (EASI)-75 (≥75% improvement 
from baseline) at Week 16.
Secondary
To evaluate the PK and immunogenicity of 
16 weeks of multiple IV doses of bermekimab, 
compared with placebo, in adult participants with 
moderate-to-severe AD
Analyses of the following at all applicable visits 
from Week 0 through Week 16:

Serum concentrations of bermekimab over 
time, including steady-state trough serum 
concentrations.

The incidence and titers of antibodies to 
bermekimab
To assess the safety and tolerability of 16 weeks of 
multiple IV doses of bermekimab, compared with 
placebo, in participants with moderate-to-severe
AD

Proportion of participants with TEAEs

Proportion 
of 
participants 
with 
treatment-emergent SAEs

Proportion of participants with AEs leading to 
discontinuation of study intervention.

Proportion 
of 
participants 
with 
AEs 
reasonably related to study intervention.

Proportion of participants with AEs of 
infusion-related reactions.

Proportion of participants with AEs of 
infections, including serious infections and 
infections 
requiring 
oral 
or 
parenteral 
antimicrobial treatment.

Proportion of participants with Clinically 
significant abnormalities in vital signs and 
laboratory tests.
To characterize additional assessments of efficacy 
of 16 weeks of multiple IV doses of bermekimab, 
compared with placebo, in participants with 
moderate-to-severe AD
Analyses of the following at applicable visits 
through Week 16 by visit, respectively:


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Objectives
Endpoints

Proportion 
of 
participants 
with 
both 
vIGA-AD of 0 or 1 and a reduction from 
baseline of ≥2 points

Proportion of participants with improvement 
(reduction) of eczema-related itch NRS ≥4 
from baseline among participants with a 
baseline itch value ≥4

Proportion of participants with EASI-90
Exploratory
To further characterize efficacy of 16 weeks of 
multiple IV doses of bermekimab, compared with 
placebo, 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 ADIS

Proportions of participants with a PGIS score 
of 1 (none) or 2 (mild) at Week 16

Change from baseline to Week 16 in 
PROMIS-29 total score and sub-scores

Improvement in Hand Dermatitis IGA from 
baseline to Week 16.
To assess the impact of treatment with 16 weeks of 
multiple IV doses of bermekimab, compared with 
placebo, on selected biomarkers.
Analyses of the following at all applicable visits 
from Week 0 through Week 16:

Changes in cellular and molecular PD 
biomarkers levels in skin and blood from 
baseline compared with placebo.

Changes in skin barrier function from baseline 
compared with placebo.
Abbreviations: AD=atopic dermatitis; ADIS=Atopic Dermatitis Itch Scale; AE=adverse event; 
DLQI=Dermatological Life Quality Index; EASI=Eczema Area and Severity Index; IGA=Investigator Global 
Assessment; -IV=intravenous; NRS=numeric rating scale; PGIS=Patient Global Impression of Severity; 
PK=pharmacokinetics; PROMIS=Patient-Reported Outcomes Measurement Information System; 
POEM=Patient-Oriented Eczema Measure; SAE=serious adverse event; SCORAD=Severity Scoring of Atopic 
Dermatitis; TEAE=treatment-emergent adverse event; vIGA-AD=validated Investigator Global Assessment for 
Atopic Dermatitis.


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1.2.
Study Design
This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter, interventional study
designed to assess the efficacy, safety, pharmacokinetics (PK), pharmacodynamics (PD), 
biomarkers, and immunogenicity of multiple doses of bermekimab administered via IV infusion 
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 moderate-to-severe AD, that has been
present for at least 1 year before the first administration of study intervention, as determined by 
the investigator through participant 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 target of 60 participants will be randomly assigned in this study. The study has 3 periods namely: 
a screening period of up to 4 weeks, a double-blinded placebo-controlled period of 16 weeks, and 
a Safety Follow-Up period of 4 weeks, which includes an End of Study (EOS) visit. The study will 
have 3 parts within the double-blinded placebo-controlled period that will run in parallel and/or 
staggered: A, B, and C. 
All participants will receive a weekly IV infusion of either bermekimab or placebo, in a 4:1 
randomization ratio. Part A will consist of 10 participants receiving bermekimab 800 mg IV 
weekly or placebo. Part B will consist of 30 participants receiving bermekimab 1200 mg IV 
weekly or placebo. An analysis of the data from all 10 participants of Part A and the first 10 
participants of Part B will support optimization and selection of the bermekimab dose for Part C. 
Selection of the Part C bermekimab dose will be based on PK, PD, efficacy, and safety analysis. 
Part C will consist of 20 participants receiving bermekimab or placebo at a higher or lower dose 
(not <800 mg) than Part B, but with a maximum dose of 2400 mg IV weekly.
The study also includes 4 mandatory skin biopsies (2 at baseline and 2 after dosing). All 
participants of Part A and the first 10 participants of Part B will have skin biopsies done at Week 0 
(1 lesional and 1 non-lesional), and at Week 6 (2 lesional). The rest of the participants will be 
biopsied at Week 0 (1 lesional and 1 non-lesional), and at Week 16 (2 lesional). Instructions for 
the collection and shipment of these samples can be found in the biopsy collection manual.
All participants will have an extended in-clinic observation period of 4 hours during the first 2 
infusions. In this period, vital signs will be taken at the following time points: 0 hour (start of 
infusion), 30 minutes, 1 hour, 1 hour and 30 mins, 2 hours (end of infusion), 2 hours and 30 mins, 
3 hours, 3 hours and 30 mins, and 4 hours (post-infusion). Beyond the first 2 infusions, all 
participants will have a 1 hour infusion period and at least a 1 hour observation post infusion, as 
well as vital signs taken every 30 minutes.
An internal and independent DRC will be commissioned for this study to ensure the safety of the 
participants enrolled in this study. In addition, an interim analysis will be conducted when the 10th 


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participant of Part B reaches Week 6. The interim analysis will be used to inform the dose decision 
for Part C based on the safety, preliminary efficacy, PK and PD data accrued up to the interim 
analysis.
One planned database lock (DBL) will occur at the end of the study. Additional DBLs could be 
considered. 
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
2.
STATISTICAL HYPOTHESES
The hypothesis for this study is that intravenous (IV) bermekimab treatment is superior to 
treatment with 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 (800 mg, 1200 mg, or Dose C) and placebo 
treatment based on the primary efficacy endpoint.
3.
SAMPLE SIZE DETERMINATION
This study is designed to enroll approximately 60 participants in order to have sufficient power 
to detect a difference between the participants receiving bermekimab and the participants 
receiving placebo for the primary endpoint of the proportion of participants achieving EASI-75 
at Week 16.
The EASI-75 response rate in the bermekimab 400 mg qw group was approximately 70% at 
Week 7 from the open label study (2018-PT044 [NCT03496974]). The EASI-75 response rates 


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in placebo group at Week 16 were 15% and 12%, in the 2 Phase 3 trials of dupilumab vs placebo 
in the treatment of adult participants with moderate-to-severe AD (Simpson 2016).
The EASI-75 response at Week 16 is assumed to be 15% for placebo, and 65% to 70% for the 
bermekimab treatment population (Table 1). Based on these assumptions, approximately 60 
participants (10 in Part A, 30 in Part B, and 20 in Part C) are planned to be randomized. In each 
Part, participants will be randomized in a 4:1 ratio to bermekimab or placebo. Thus, there will be 
8 participants in the bermekimab 800 mg group, 24 participants in the bermekimab 1200 mg 
group, 16 participants in the bermekimab C dose, and 12 participants total across the placebo 
groups.
These sample sizes provide the study with at least 80% power to detect a treatment difference 
between the each bermekimab intervention group and the pooled placebo intervention group in 
EASI-75 at Week 16 based on a Fisher’s Exact test at a Type I error rate of 0.1 (2-sided).
Table 1:
Power to detect a treatment difference in EASI-75 at Week 16*
Placebo
Bermekimab
Difference
Power
Bermekimab1200 mg (n=24) vs placebo (n=12)
15%
65%
50%
85%
15%
70%
55%
92%
12%
60%
48%
83%
12%
65%
53%
90%
12%
70%
58%
96%
Bermekimabdose C (n=16) vs placebo (n=12)
15%
70%
55%
86%
15%
75%
60%
92%
12%
65%
53%
83%
12%
70%
58%
91%
EASI=Eczema Area and Severity Index.
*Poweris notcalculatedforPartA dueto smallsamplesize.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The populations for analysis are defined in Table 2 below.
Table 2:
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.
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.
Safety
The safety analysis set includes all participants who received at least 1 dose of study 
intervention.


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5.
STATISTICAL ANALYSES
5.1.
General Considerations
The statistical analyses will include all analyses from Week 0 through Week 20 (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 
through Week 20 should occur within ± 3 days of the scheduled visit. 
5.1.2.
Polling Algorithm for Analysis Centers
Unless otherwise specified, data from all investigational centers/sites will be pooled for analyses.
5.1.3.
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 
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
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 yet did not receive study intervention.


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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 (erythema, thickness [induration, 
papulation, edema], [excoriation], and lichenification) 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. 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%). 
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 region, multiple the severity score by the region score and by a multiplier. The multiplier 
is different for each body site.

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.
Analysis Methods for Primary Endpoint
Due to the early termination of the study, the primary endpoint of EASI-75 response at Week 16 
will be listed. No formal analyses will be performed.


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5.4.
Secondary Endpoints Analysis
5.4.1.
Definition of Secondary Endpoints
5.4.1.1.
Eczema Area and Severity Index
Details refer to section 5.3.1.
5.4.1.2.
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.
5.4.1.3.
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.
Analysis Methods
The following secondary efficacy endpoints will be listed. 

The 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 (reduction) of eczema-related itch NRS ≥4 
from baseline to Week 16.

The proportion of participants with EASI-90 response at Week 16.


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5.5.
Exploratory Endpoints 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 5.4.1.3
5.5.1.3.
Validated Investigator Global Assessment for Atopic Dermatitis 
The definition of vIGA-AD is defined in section 5.4.1.2.
5.5.2.
Analysis Methods
The following efficacy data from all participants in FAS will be included and listed by study
intervention groups from Week 0 through Week 20.

EASI

vIGA-AD

eczema-related NRS
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.
5.6.1.
Extent of Exposure
A list of study intervention administration through Week 15 will be provided.
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.  
Listings will be provided for treatment-emergent adverse events.


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5.6.3.
Clinical Laboratory Tests
The clinical laboratory parameters to be evaluated by the central laboratory include but are not 
limited to:

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, Bicarbonate (CO2), Calcium, Chloride, Creatinine, GGT, Glucose, Potassium, 
SGOT, SGPT, Sodium, Total Bilirubin, Total Protein, Urea Nitrogen.
Participants in the safety analysis set with toxicity grades ≥2 will be listed.
5.6.4.
Vital Signs 
Participants with markedly abnormal vital signs will be listed.
Table 3: 
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
Temperature
>[38]oC and with >=[1]oC increase from baseline
Respiratory rate
>[20] breaths per minute
5.7.
Other Analyses
5.7.1.
Pharmacokinetics and Immunogenicity (Antibodies to Bermekimab)
Due to early termination of the study by the sponsor with a small number of participants 
enrolled, pharmacokinetics and immunogenicity analyses will not be performed.


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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
alanine aminotransferase
AST
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
DRC
Data Review Committee
DPS
EASI
Data Presentation Specifications
Eczema Area and Severity Index
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
interbermekimab web response system
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NRS
Numeric Rating Scale
PD
PGIS
pharmacodynamic(s)
Patient Global Impression of Severity
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
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
Due to early termination of the study with a small number of participants enrolled, only data 
listings will be provided. No formal analyses will be performed.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The demographic (age, weigh, height, BMI, race, sex, and ethnicity) and baseline disease 
characteristics (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 
listed.


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6.4.
Appendix 4 Protocol Deviations
Major protocol deviations will be listed by following category.

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 listed 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.
A listing of concomitant medications will be provided. 


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6.6.
Appendix 6 Medical History
Medical history will be listed by intervention groups.  


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6.7.
Appendix 7 Intervention Compliance
A listing of 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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6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE)’.
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.
Participants with toxicity grades ≥2 will be listed.