Clinical trial NCT04021862
Conditions: Atopic Dermatitis Eczema
Sponsor: Janssen Research & Development, LLC
Start date: 2019-10-16; Completion date: 2020-11-19
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Study to Evaluate the Safety and Efficacy of Bermekimab in Patients With Moderate to Severe Atopic Dermatitis

Detailed description:
This is a phase II, randomized, double-blind, placebo-controlled study of bermekimab in patients with moderate to severe atopic dermatitis. The primary objective of the study is to analyze the safety and efficacy of different dose regimens of bermekimab compared to placebo treatment in adult patients with moderate-to-severe AD. The study is multicenter and will consist of three groups:

Treatment Arm 1: Bermekimab every week (qw)

Treatment Arm 2: Bermekimab every other week (q2w)

Arm 3 (Placebo): Placebo every week (qw)

Arms: arm 1: Loading Dose: 400 mg subcutaneous (SC) injection of bermekimab and a SC injection of matching placebo at week 0 (Baseline).

Treatment Dose: 400 mg subcutaneous injection of bermekimab administered weekly (qw) from week 1 through Week 31. arm 2: Loading Dose: 800 mg SC injection of bermekimab at week 0 (Baseline).

Treatment Dose: 400 mg SC injection of bermekimab administered every other week (q2w) alternating with matching placebo q2w through Week 31. arm 3: Loading Dose: Placebo matching to bermekimab (4 milliliters \[mL\]) SC injection at Week 0, (Baseline).

Treatment Dose: SC injection of matching placebo administered once weekly (qw) from week 1 to week 15 during placebo-controlled period. After completion of placebo-controlled period, participants will cross-over and receive bermekimab 400 mg SC injection qw at Week 16 through Week 31.
Interventions: intervention 1: Bermekimab Monoclonal Antibody intervention 2: Placebo
Intervention descriptions: intervention 1: Bermekimab 400 mg or 800 mg will be administered subcutaneously. intervention 2: Placebo will be administered subcutaneously.

Protocol documents:
Prot_000.pdf: 
Trial Protocol
A Phase II, Randomized, Double-Blind, Placebo-Controlled 
Study of Bermekimab in Patients with Moderate to Severe 
Atopic Dermatitis
SPONSOR
XBiotech USA Inc
22 January 2020
NCT04021862


Page 2 of 61
TABLE OF CONTENTS
Basic Information......................................................................................................................................4
Abbreviations...........................................................................................................................................15
1.
BACKGROUND ...........................................................................................................................16
1.1
OVERVIEW .............................................................................................................................................16
1.2
RATIONALE............................................................................................................................................17
2.
INVESTIGATIONAL PRODUCT...........................................................................................19
2.1
ACTIVE INGREDIENT, PHARMACOLOGIC CLASS, STRUCTURE.....................................19
2.2
DRUG PRODUCT (BERMEKIMAB 200 MG/ML) DESCRIPTION......................................20
2.3
STORAGE.................................................................................................................................................20
2.4
STABILITY ..............................................................................................................................................20
2.5
DESIGNATED INDIVIDUAL FOR DRUG ADMINISTRATION.............................................20
2.6
METHOD OF ADMINISTRATION..................................................................................................21
2.7
AGENT ORDERING..............................................................................................................................22
2.8
POTENTIAL DRUG INTERACTIONS............................................................................................22
2.9
CONCOMITANT THERAPY..............................................................................................................22
2.9.1
Antihistamine/NSAID Use....................................................................................... 22
2.9.2
Required Treatment.................................................................................................. 22
2.9.3
Permitted Medications and Procedures.................................................................... 23
2.10
PROHIBITED MEDICATIONS AND PROCEDURES................................................................23
2.11
RESCUE TREATMENT.......................................................................................................................24
3.
STUDY DESIGN AND OBJECTIVES....................................................................................24
4.
ELIGIBILITY CRITERIA.........................................................................................................29
4.1
INCLUSION CRITERIA.......................................................................................................................29
4.2
EXCLUSION CRITERIA ......................................................................................................................30
5.
TREATMENT PLAN ..................................................................................................................32
5.2
STUDY CALENDARS...........................................................................................................................39
5.2.1
Placebo-controlled Period ........................................................................................ 39
5.2.2
Blinded Active Dosing Period.................................................................................. 40
5.2.3
Follow-up Period...................................................................................................... 41
5.3
DISCONTINUATION OF THERAPY ..............................................................................................42
5.4
TRIAL STOPPING RULES .................................................................................................................42
5.5
EMERGENCY UNBLINDING............................................................................................................42
6.
CORRELATIVE STUDIES.......................................................................................................43
6.1
PHARMACOKINETICS (PK) SAMPLE COLLECTION.............................................................43
7.
ASSESSMENT OF SAFETY.....................................................................................................43
8.
STUDY VARIABLES..................................................................................................................44
8.1
DEMOGRAPHIC AND DISEASE CHARACTERISTICS............................................................44
8.2
STUDY ASSESSMENTS......................................................................................................................44
9.
ADVERSE EVENTS....................................................................................................................46
9.1
DEFINITION OF ADVERSE EVENT (AE)...................................................................................46
9.2
DEFINITION OF SERIOUS ADVERSE EVENT (SAE).............................................................46
9.3
RECORDING OF ADVERSE EVENTS............................................................................................47
9.4
EVALUATING ADVERSE EVENTS.................................................................................................47
9.5
ASSESSMENT OF CAUSALITY........................................................................................................48


Page 3 of 61
9.6
REPORTING REQUIREMENTS.......................................................................................................48
9.7
REFERENCE SAFETY INFORMATION: POTENTIAL ADVERSE REACTIONS............48
10.
STATISTICAL PLAN ............................................................................................................50
10.1
DETERMINATION OF SAMPLE SIZE...........................................................................................50
10.2
RANDOMIZATION...............................................................................................................................50
10.3
ANALYSIS SETS....................................................................................................................................50
10.4
PATIENT DISPOSITION....................................................................................................................51
10.5
STATISTICAL METHODS..................................................................................................................51
10.5.1
Demography and Baseline Characteristics .......................................................... 51
10.5.2
Safety Analysis .................................................................................................... 51
10.5.2.1
Analysis of Adverse Events............................................................................................................51
10.5.2.2
Other Safety..........................................................................................................................................52
10.5.3
Efficacy Analysis................................................................................................. 52
10.5.3.1
Primary Efficacy Analysis...............................................................................................................52
10.5.3.2
Secondary Efficacy Analyses.........................................................................................................53
10.5.4
Treatment Exposure............................................................................................. 53
10.5.5
Pharmacokinetic (PK) and Pharmacodynamics (PD) Analysis:.......................... 53
11.
STUDY MANAGEMENT AND ADMINISTRATION ..................................................54
11.1
ETHICAL CONDUCT OF STUDY (GCP).......................................................................................54
11.2
IRB AND ETHICS COMMITTEE APPROVAL.............................................................................54
11.3
PROTOCOL MODIFICATIONS.........................................................................................................54
11.4
SUBJECT INFORMATION AND CONSENT ................................................................................55
11.5
DATA PROTECTION AND CONFIDENTIALITY.......................................................................55
11.6
STUDY REPORT AND PUBLICATIONS.......................................................................................56
11.7
STUDY FILES AND RETENTION OF RECORDS ......................................................................56
11.8
CASE REPORT FORMS.......................................................................................................................56
11.9
DRUG ACCOUNTABILITY.................................................................................................................57
11.10
AUDITS AND INSPECTIONS ...........................................................................................................58
11.11
ACCESS TO INFORMATION FOR MONITORING....................................................................58
11.12
STUDY DISCONTINUATION............................................................................................................59
REFERENCES........................................................................................................................................60


Page 4 of 61
Basic Information
STUDY TITLE: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Bermekimab in 
Patients with Moderate to Severe Atopic Dermatitis
INVESTIGATIONAL PRODUCT:
Bermekimab 
IND Number:
112,459
PROTOCOL NUMBER:
2019-PT046
PROTOCOL VERSION / DATE:
2.0/ 22 January 2020
SPONSOR:
XBiotech USA, Inc. 
5217 Winnebago Ln.
Austin, Texas 78744 U.S.A.
Phone: +1 (512) 386-2900
SPONSOR’S MEDICAL OFFICER:
Phone: +
STUDY CHAIR
Phone: +
PPD
PPD
PPD
PPD


Page 5 of 61
Investigator/Sponsor Signatures
STUDY TITLE: A Phase II, Randomized, Double-Blind, Placebo-Controlled  Study of Bermekimab in 
Patients with Moderate to Severe Atopic Dermatitis
PROTOCOL VERSION / DATE: 2.0 / 22 January 2020
STUDY PRINCIPAL INVESTIGATOR SIGNATURE: I have read the protocol and appendices. 
I understand the contents and intend to comply fully with all requirements and the applicable current local 
and international regulations and guidelines. No changes will be made without formal authorization by 
XBiotech USA, Inc., in the form of a protocol amendment.
INVESTIGATOR SIGNATURE:
_____________________________________________ 
Printed name of Investigator 
_____________________________________________ 
Signature 
_____________________________________________ 
Date 
SPONSOR SIGNATURE: 
XBiotech USA, Inc.
____________________________________________ 
Printed Name
____________________________________________ 
Signature
____________________________________________ 
Date


Page 6 of 61
Clinical Protocol Synopsis
STUDY TITLE:  A Phase II, Randomized, Double-Blind, Placebo-Controlled  Study of Bermekimab in 
Patients with Moderate to Severe Atopic Dermatitis
Sponsor:  
XBiotech USA, Inc.
Study Chair:  
Seth Forman, M.D.
Sample Size:
Approximately 90 patients will be enrolled in the US
Approximate Duration:  
The duration of subject participation in the randomized, double-blind, placebo-controlled portion of the 
trial is approximately 40 weeks: including a screening period of up to 30 days, a 32-week treatment period,
and 4-week follow-up period. 
Study Endpoints:
Primary Endpoint(s):

Percentage of patients achieving Eczema Area and Severity Index-75 (EASI-75) (≥75% 
improvement from baseline) at week 16.
Secondary Endpoints:

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average peak 
daily Pruritus Numeric Rating Scale (NRS) score from baseline to weeks 4, 8, 12, 16, and 32 in 
patients with baseline score ≥4.*

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average overall 
Pruritus Numeric Rating (NRS) from baseline to weeks 4, 8, 12 16, and 32 in patients with baseline 
score ≥4.* 

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average peak 
daily Pain Numeric Rating Scale (NRS) score from baseline to weeks 4, 8, 12, 16, and 32 in patients 
with baseline score ≥4.*


Page 7 of 61

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average overall 
Pain Numeric Rating (NRS) from baseline to weeks 4, 8, 12, 16, and 32 in patients with baseline 
score ≥4.*

Percentage of patients achieving EASI-75 (≥75% improvement in Eczema Area and Severity Index 
Score [EASI] from baseline) at weeks 4, 8, 12, and 32.*

Percentage of patients achieving an Investigators Global Assessment (IGA) score of 0 or 1 (on a 5-
point scale) and a reduction in this measure from baseline of at least 2 points at week 16.

Percentage of patients achieving EASI-90 (≥90% improvement in Eczema Area and Severity Index 
Score [EASI] from baseline) at weeks 12, 16, and 32.*

Change in Dermatology Life Quality Index (DLQI) from baseline to weeks 8, 12, 16, and 32.*

Change in Hospital Anxiety Depression Scale (HADS) (Anxiety) from baseline to weeks 8, 12, 16, 
and 32.*

Change in Hospital Anxiety Depression Scale (HADS) (Depression) from baseline to weeks 8, 12, 
16, and 32.*

Change in Patient Oriented Eczema Measure (POEM) Scores from baseline to weeks 8, 12, 16, and 
32.*

Change in SCORing Atopic Dermatitis (SCORAD) score from baseline to weeks 8, 12, 16, and 
32.*

Change in Global Individual Signs Score (GISS) from baseline to weeks 8, 12, 16, and 32.*
Exploratory Endpoints:

Percentage of patients achieving an IGA score 0 or 1 (on a 5-point scale) and a reduction in this 
measure from baseline of at least 2 points at week 12.

Change in Eczema Area and Severity Index Score (EASI) from baseline to weeks 8, 12, 16, and 
32.

Change from baseline to week 4 in Dermatology Life Quality Index (DLQI).

Patients (%) achieving 50% reduction in SCORAD Score at Weeks 4, 8, 12, 16, and 32.*

Patients (%) achieving 75% reduction in SCORAD Score at Weeks 4, 8, 12, 16, and 32.*

Patients (%) achieving 90% reduction in SCORAD Score at Weeks 4, 8, 12, 16, and 32.*

Change from baseline to week 8, 12, 16, and 32 in percent Body Surface Area (BSA).*


Page 8 of 61
Safety Endpoints: 

Incidence of skin infection treatment-emergent adverse events (TEAEs) requiring systemic 
treatment from baseline through week 16 and 32.

Incidence of treatment-emergent serious adverse events (TESAEs) from baseline through week 16 
and 32.

Incidence of TEAEs leading to treatment discontinuation from baseline through week 16 and 32.
*Each listed time point (in weeks) will be measured separately and treated as an individual endpoint. 


Page 9 of 61
Trial Design:  
This is a phase II, randomized, double-blind, placebo-controlled study to further establish the efficacy and 
safety and explore dose effects for bermekimab monotherapy in adults with moderate to severe Atopic 
Dermatitis (AD). Patients will be assessed for study eligibility at the initial screening visit after providing 
informed consent. Thirty days are allowed in the screening window to complete all screening procedures 
and randomize the subject. During the screening period, certain treatments will be washed out, as 
applicable, according to eligibility requirements. Patients who fail initially may be re-screened once based
on the investigator discretion but only if inclusion criteria are met at time of re-screening.
The study is approximately 40 weeks (30 day screening period, 32-week treatment period and a 4-week 
follow-up period) for all subjects.
The primary efficacy endpoint is the percentage of patients achieving ≥75% improvement from baseline 
in EASI score at week 16. The EASI is a validated measure used in clinical practice and clinical trials to 
assess the severity and extent of AD. Secondary measures will include Pruritus NRS, Pain NRS, 
SCORAD, POEM, GISS, DLQI, HADS, BSA and IGA. 
Patients who meet the eligibility criteria at screening will be randomized in a 1:1:1 ratio to one of two
treatment arms or placebo:

Arm 1: 800 mg of bermekimab + placebo loading dose (2mL SC injection containing 400 mg of 
bermekimab and one 2mL SC injection of placebo) at week 0 followed by weekly (qw) 
subcutaneous (SC) injections of 400 mg bermekimab through week 31

Arm 2: 800 mg loading dose of bermekimab (2 x 400 mg SC injections) at week 0 followed by 
subcutaneous (SC) injections of 400 mg bermekimab every other week (q2w) alternating with 
matching placebo q2w through week 31.

Arm 3: 4mL loading dose of placebo (2 x 2mL SC injections) at week 0 followed by weekly 
placebo injections from week 1 through week 15. Patients in Arm 3 will begin to receive weekly 
(qw) blinded subcutaneous (SC) injections of 400 mg bermekimab beginning at week 16 through 
week 31.
In order to maintain blinding, all patients will receive two injections at week 0 and 16, followed by weekly 
injections from week 1 to 31. Additionally, at least one qualified individual will be designated at each 
study site to perform all preparation and injection of the investigational product. The designated 


Page 10 of 61
injector(s) should have no other contact with the participant during the study, should not discuss the 
participant’s treatment with the participant, participant’s caregiver, or other site personnel at any time, and 
will not be permitted to review the participant’s medical records, questionnaires, or the electronic CRF 
prior to each injection. The designated injector(s) should be documented in the source documents at each 
visit.
Study treatment will be administered weekly in the clinic for 31 weeks with weekly office visits for 32 
weeks. Patients will remain at the study site for a minimum of 30 minutes (+/- 10 minutes) after injections 
at weeks 0, 1, 2, 16, 17 and 18 injections for safety monitoring. 
During the 32-week treatment period, patients will attend weekly clinical study visits. Clinical 
assessments, collection of samples for bermekimab concentrations, and safety testing will be performed 
at specified clinic visits.  After completion of the 36-week study period, data will be locked and analyzed 
for safety and efficacy endpoints for all arms. In addition to the analyses that will be performed following 
the formal database lock at the end of the study at Week 36, an additional database lock may be performed 
at Week 16, and interim analyses utilizing unblinded efficacy data available as the study progresses, may 
also be conducted to help plan potential future development activities. An internal interim analysis 
committee (IAC) will be established to review the interim data and formulate recommended 
decisions/actions. The IAC will consist of at least a clinician and a statistician (neither of whom are 
involved in study conduct or compound development), one of whom will chair the committee, and may 
also include other members as required by the nature of the IAs. Details will be provided in a separate 
IAC charter, which will define the organization and roles and responsibilities of the committee, possible 
recommendations or requests, and the communication process following IA reviews. Results from the 
Week 16 database lock and/or interim analyses will not be disseminated to investigators or subjects 
participating in the study.  In addition, results of the interim analyses will not be disseminated to 
individuals associated with the conduct of the study.
Patients will be monitored at a follow up visit (visit 34/week 36) for safety and clinical assessments after 
completing the 32 week treatment period. 
Procedures and Assessments:
Multiple parameters will be collected during the study to evaluate the efficacy of bermekimab, including 
measures of AD severity, and patient-reported measures of AD symptoms and quality of life.


Page 11 of 61
The safety of bermekimab in this population will be assessed by evaluating treatment emergent adverse 
events (TEAEs), vital signs, thorough physical examination, detailed medical history, electrocardiograms 
(ECGs), and clinical laboratory testing. Concomitant medications and procedures will be collected from 
time of informed consent to the end of study.  Safety data will be reviewed on an ongoing basis by the 
sponsor.  
Blood samples will be collected for laboratory testing including chemistry, hematology, inflammation 
markers, bermekimab concentration (PK), PD marker(s), anti-drug antibody (ADA) and research analysis 
etc. at pre-determined time points.  
Figure 1. Study Flow Diagram
Inclusion Criteria: 
No waivers/exemptions will be granted for protocol inclusion/exclusion criteria.
Subjects are included in the study if they meet all of the following criteria:

Written informed consent provided by the patient.

Male or female, at least 18 years.

Willing and able to attend all clinic visits and comply with study-related procedures.

Is able to understand and complete study-related questionnaires.

Chronic atopic dermatitis present for at least 3 years.

EASI score ≥16 at screening and baseline visits.

IGA score ≥3 at screening and baseline visits.
Baseline
Endpoint 
Assessment
Visit (V)
V1
V33
Week (W)
W0
W32
Day (D)
D0
D224
W1 to W31
W36
D7 to D217
D252
Screening 
Treatment Period 
Follow-up 
Weekly Dosing
V2 to V32
V34
D -30 to -1 


Page 12 of 61

Baseline pruritis numerical rating scale average score for maximum intensity of at least 3, based 
on the average of daily pruritis numerical rating scale scores for maximum itch intensity reported 
during the 7 days prior to randomization.

Has applied a stable dose of topical moisturizer twice daily for at least 7 consecutive days 
immediately prior to the baseline visit and is willing to continue this regimen on a daily basis for 
the duration of the study.

≥10% body surface area (BSA) of AD involvement at screening and baseline visits.

Documented recent history (within 6 months prior to screening) of inadequate response to treatment 
with topical medications, or patients for whom topical treatments are medically inadvisable 
(because of important side effects or safety risks).
a)
Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state (comparable to an IGA score of 0-2), despite treatment with a daily 
regimen of topical corticosteroids of medium to higher potency (with or without topical 
calcineurin inhibitors as appropriate), applied for at least 28 days or for the maximum 
duration recommended by the product prescribing information, whichever is shorter.
b) Patients with documented systemic treatment for atopic dermatitis in the preceding 6 
months are also considered to be inadequate responders to topical treatments and are 
potentially eligible for treatment with bermekimab, after appropriate washout.
c)
Important side effects or risks are those that outweigh the potential treatment benefits, and 
include: intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and 
adverse systemic effects.
d) Acceptable documentation includes contemporaneous chart notes that record topical 
medication prescription and treatment outcome, or investigator documentation based on 
communication with the patient’s treating physician.
Exclusion Criteria:
Subjects with ANY of the following will be excluded from the study:

Age below 18 years as the current study is evaluating bermekimab in adult patients only.

Subject has been treated for AD with any investigational drug of chemical or biologic nature within 
a minimum of 30 days or 5 half-lives (whichever is longer) of the drug prior to baseline.

Treatment with bermekimab at any time in the past.

Treatment with immunosuppressive/immunomodulatory drugs or phototherapy for atopic


Page 13 of 61
dermatitis within 4 weeks of baseline, or any condition that, in the opinion of the investigator, is 
likely to require such treatment(s) during the first 4 weeks of study treatment.

Treatment with topical corticosteroids or topical calcineurin inhibitors for the treatment of AD 
within 14 days prior to baseline].

Treatment with biologics as follows:
a) Any cell-depleting agents including, but not limited to, rituximab, within 5 half-lives (if known) 
or 30 days prior to baseline visit, or until lymphocyte count returns to normal, whichever is longer.
b) Other biologics: within 5 half-lives (if known) or 30 days prior to baseline visit, whichever is 
longer

Initiation of treatment of atopic dermatitis with prescription moisturizers or moisturizers containing 
additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the 
screening period (patients may continue to use stable doses of such moisturizers if initiated before 
the screening visit).

Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the screening
visit.

Planned or anticipated use of any prohibited medications and procedures during study treatment.

Treatment with a live (attenuated) vaccine within 30 days prior to the screening visit.

Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals,
antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit, or superficial 
skin infections within 1 week prior to the baseline visit. NOTE: patients may be rescreened after 
infection resolves.

Known or suspected history of immunosuppression, including history of invasive opportunistic
infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis,
aspergillosis) despite infection resolution; or unusually frequent, recurrent, or prolonged infections, 
per investigator judgment.

History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening.

Positive for hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody at the
screening visit.

At baseline, presence of any conditions listed as criteria for study drug discontinuation.

Presence of skin comorbidities that may interfere with study assessments.

History of malignancy within 5 years before the screening visit, except completely treated in situ
carcinoma of the cervix, and completely treated and resolved non-metastatic squamous or basal
cell carcinoma of the skin.


Page 14 of 61

Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect the 
patient’s participation in the study. Examples include, but are not limited to, patients with short life 
expectancy, patients with uncontrolled diabetes (HbA1c ≥ 9%),  patients with cardiovascular 
conditions (eg, stage III or IV cardiac failure according to the New York Heart Association 
classification), severe renal conditions (eg, patients on dialysis), hepato-biliary conditions (eg, 
Child-Pugh class B or C), neurological conditions (eg, demyelinating diseases), active major 
autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other 
severe endocrinological, gastrointestinal, metabolic, pulmonary or lymphatic diseases. The specific 
justification for patients excluded under this criterion will be noted in study documents (chart notes, 
case report forms [CRFs], etc.).

Planned or anticipated major surgical procedure during the patient’s participation in this study.

Patient or immediate family member is part of the current clinical investigational team.

Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the
study.

Women unwilling to use adequate birth control, if of reproductive potential and sexually 
active. Adequate birth control is defined as consistent practice of an effective and accepted method 
of contraception throughout the duration of the study and for 120 days after the last dose of study 
drug. These methods include oral contraceptives (stable use for more than 3 months before 
Screening), intrauterine device (IUD), hormonal contraceptives such as Depo-Provera (stable use 
for more than 3 months before Screening), Implanon implants (stable use for more than 3 months 
before Screening), double barrier contraception such as condom or diaphragm used with 
contraceptive sponge, foam, or jelly. For men participating in the study, unwillingness of sexual 
partner to use any of the above contraception methods.

History of severe allergic or anaphylactic reactions to monoclonal antibodies.

Any other medical or psychological condition (including relevant laboratory abnormalities at
screening) that, in the opinion the investigator, may suggest a new and/or insufficiently understood 
disease, may present an unreasonable risk to the study patient as a result of his/her participation in 
the study, may make patient’s participation unreliable, or may interfere with study assessments. 
The specific justification for patients excluded under this criterion will be noted in study documents 
(chart notes, case report forms, etc.)


Page 15 of 61
Abbreviations
ADA
Anti-Drug Antibody
AD
Atopic Dermatitis
AE
Adverse event
ALT
Alanine aminotransferase (ALT, SGPT)
PT/aPTT
Prothrombin Time/Activated Partial Thromboplastin Time
ALP
Alkaline phosphate
BMI
Body mass index
BP
Blood pressure
BSA
Body Surface Area
CBC
Complete blood counts
CI
Confidence interval
CH
Heavy chain constant region
CL
Light chain constant region
eCRF
Electronic Case report form
CRA
Clinical Research Associate
CRP
C-Reactive Protein
CTCAE
Common terminology criteria for adverse events
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index Score
EC
Ethics Committee
ECG/EKG
Electrocardiogram
ELISA
Enzyme-linked immunosorbent assay
GISS
Global Individual Signs Score
GCP
Good clinical practice
HADS
Hospital Anxiety Depression Scale
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
IFN-Interferon Gamma
IGA
Investigator’s Global Assessment
IGRA
Interferon Gamma Release Assay
IgG
Immunoglobulin G
IL-6
Interleukin-6
IL-1 
Interleukin-1 
IL-1
Interleukin-1 
IL-1 RA
Interleukin-1 receptor antagonist
IRB
Institutional review board
NRS
Numerical Rating Scale
NSAID
Non-Steroidal Anti-Inflammatory Drug
PD
PharmacodynamicspI
Isoelectric Point
PK
Pharmacokinetics
POEM
Patient Oriented Eczema Measure
SAE
Serious Adverse Event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS 
Statistical analysis software
SCORAD
Severity Scoring of Atopic Dermatitis
TB
Tuberculosis
UV
Ultraviolet
VAS
Visual Analogue Scale
WOCBP
Women of childbearing potential


Page 16 of 61
1.
BACKGROUND
1.1 OVERVIEW
XBiotech USA, Inc. has developed a True Human recombinant IgG1 monoclonal antibody, bermekimab, 
that binds the cytokine interleukin-1alpha (IL-1) with high affinity and is an effective blocker of IL-1
biological activity. IL-1is a key mediator of sterile inflammatory responses and has been implicated in 
the pathology of advanced cancer, cardiovascular disease, and rheumatologic disease. Clinical evidence 
generated to date suggests that targeting IL-1may be an effective means of undermining the inflammatory 
process that drives a wide array of diseases, including dermatologic conditions.
The active ingredient in the drug product bermekimab is MABp1, a recombinant human IgG1 monoclonal 
antibody specific for human interleukin-1(IL-1). The entire MABp1 heavy and light chain sequences 
are identical to those found in naturally-occurring human IgG1, with the light and heavy chain variable 
regions being identical to those originally expressed by a peripheral blood B lymphocyte that was obtained 
from a healthy individual. No in vitro affinity maturation or modifications have been made to improve its 
natural binding affinity (211 +/- 31 pM). We believe that a true human antibody should be effectively non-
immunogenic in humans and thus exhibit optimal activity and pharmacokinetics.  
XBiotech has conducted 13 clinical studies to date using the bermekimab antibody.  These studies have 
been conducted in a wide range of therapeutic areas, from cancer to healthy volunteers, and have included 
several different dose levels and dosing schedules. Both intravenous and subcutaneous formulations have 
been explored for safety and evidence of efficacy. Five Phase II studies sponsored by XBiotech have been 
completed in dermatologic indications (psoriasis [NCT01384630], acne vulgaris [NCT01474798],
pyoderma gangrenosum [NCT01965613], atopic dermatitis [NCT03496974], and hidradenitis suppurativa
[NCT03512275]), as well as one investigator sponsored study in Hidradenitis Suppurativai,ii,iii.
Subjects with moderate to severe psoriasis experienced a rapid reduction in their psoriasis area and severity 
index (PASI), and subjects with acne vulgaris experienced reductions of inflammatory lesion counts, as 
well as reduced hospital anxiety and depression scores (HADS). Similarly, when MABp1 was used in 
patients with pyoderma gangrenosum, there was a marked improvement in lesions over a short period of 
time. In the two most recent studies for hidradenitis suppurativa and atopic dermatitis, statistically 
significant improvement was seen for nearly every efficacy endpoint by the end of the study.


Page 17 of 61
Results from atopic dermatitis study showed that bermekimab appeared to be safe, well tolerated, and active 
at reducing the severity of atopic dermatitis, including reducing itch and pain. This study was a phase II, 
open label, dose escalation study of bermekimab in subjects with moderate to severe atopic dermatitis. 
Thirty-eight patients across 9 clinical sites in two treatment groups received one of two subcutaneous (SC) 
doses: a low (200 mg, n=10) or high (400 mg, n=28) dose of bermekimab once weekly for either a 4 or 8-
week treatment regimen, respectively. Safety was assessed by pre- and post-treatment measurements of 
vital signs, clinical laboratory assessments (blood chemistry, urinalysis, hematology), allergic reaction 
monitoring, and adverse event monitoring. Efficacy was assessed by change in EASI, IGA, NRS, 
SCORAD, POEM, DLQI, and GISS from baseline to visit 9. The primary measure of efficacy was the 
EASI. In the study, 39% of high dose patients achieved 75% improvement in EASI score (EASI-75) after 
4 weeks of therapy and 75% of patients achieved EASI-75 at week 8. Of note, participants were not allowed 
to use concomitant topical corticosteroids during the study and thus these improvements were most likely 
due to the study drug alone.
While clinically and statistically significant improvement was seen for all clinical endpoints in the high 
dose group, also notable was the speed, magnitude, and trajectory of responses seen. In the high dose group, 
for example, after only four weeks of treatment, 61% of patients achieved a 4-point improvement in the 
Pruritus Numerical Rating Scale (NRS) for overall itch; and 75% of patients achieved a 4-point 
improvement by week 8. For the Pruritus Numerical Rating Scale (NRS) – worst moment itch after only 
four weeks of treatment, 63% of patients achieved a 4-point improvement and 78% of patients achieved a 
4-point improvement by week 8. Furthermore, 80% of patients achieved a 4-point improvement in the 
Numerical Rating Scale (NRS) for pain by week 8.
Overall, bermekimab appeared safe, well tolerated, and showed significant therapeutic activity in most 
subjects. In all of these trials, there were few adverse events, most of which were grade 1 (mild).
1.2 RATIONALE
Atopic dermatitis (AD), is an inflammatory skin disease affecting 1-20% of the adult population. Chronic 
eczema in AD and associated pruritus can be a significant cause of morbidity and can impact quality of life. 
Disease pathogenesis is complex but ultimately converges on a pathological inflammatory process that 
disrupts the protective barrier function of the skin. 


Page 18 of 61
IL-1⍺plays a key role in the pathophysiology of a wide range of inflammatory skin disordersv.  
Keratinocytes are a major reservoir of IL-1⍺and may be a key source of inflammatory stimulus in AD.  IL-
1⍺is present on leukocytes, where its role in leukocyte trafficking and infiltration may represent an essential 
step in the chronic inflammation of AD.  IL-1⍺is a key inducer of matrix metalloproteinases activity which 
could be directly involved in the epithelial barrier breakdown in ADvi. Further, in a study by Archer et al, 
IL-1⍺, rather than IL-1β, was not only a fundamental component for inducing chronic skin inflamation, but 
the primary driving forcevii. The study included mice with epidermal birth defects and showed that 
keratinocytes, which constitute approximately 90% of skin cells, secrete aberrant stores of intracellular IL-
1⍺in response to skin injury (e.g. scratching), leading to chronic skin inflammation. Atopic Dermatitis is 
strongly associated with epidermal barrier defects, most commonly caused by mutated copies of the 
filaggrin geneviii. Filaggrin deficiencies are associated with changes in the composition of bacteria living on 
the skin, whereby bacteria can colonize and infect the skin with greater success thereby exacerbating 
aberrant IL-1⍺secretionix. Neutralizing IL-1⍺activity resolved chronic skin inflammation in this study and 
strongly supported IL-1⍺as a key target for treating atopic dermatitis, along with other inflammatory skin 
diseases.
Endogenous anti-IL-1α antibodies are present in 5% to 28% of the general populationx,xi,xii,xiii.  No negative 
correlations with disease have been noted for these individuals. To the contrary, the presence of natural 
anti-IL-1α antibodies has been associated with favorable outcomes, both with respect to rheumatoid arthritis 
and ischemic heart disease. Animal studies also indicate that IL-1α loss or antagonism does not result in 
harm. Moreover, the well-tolerated use of other approved biological agents that employ alternative 
strategies to block IL-1 activity suggest that MABp1’s targeting of IL-1α represents a safe treatment 
approach. 
In previous dermatology studies bermekimab was well tolerated and showed impressive therapeutic 
activity. The safety data from XBiotech’s open label studies: PT044 atopic dermatitis and PT045 
hidradenitis suppurativa established good levels of safety and tolerability for 400mg bermekimab (2mL of 
200mg/mL) subcutaneous injections and in both studies no safety signals were identified and no study 
stopping rules were met. 


Page 19 of 61
2.
INVESTIGATIONAL PRODUCT
2.1
ACTIVE INGREDIENT, PHARMACOLOGIC CLASS, STRUCTURE
Figure 2: Bermekimab Antibody
The bermekimab primary glycoform has a molecular weight of 148.1 kilodaltons. Like all IgG1 molecules, 
the heavy chains are joined at their hinge regions through two disulfide linkages, and each heavy chain is 
joined to one light chain through one disulfide linkage between their CH1 and CL domains respectively.
The main isoform has a pI of about 9.2 and comprises about 70-80% of the total isoform population in all 
lots that have been manufactured to date, as determined by capillary isoelectric focusing. The heavy chain 
CH2 domains are glycosylated primarily with the oligosaccharide structure shown in Figure 2, as 
determined by mass spectroscopy of the cleaved glycans. The glycosylated residue (Asn-302 as numbered 
from the N-terminus of bermekimab) has been determined by peptide mapping to be in the same highly 
conserved N-linked glycosylation site as found in endogenous IgG1 (Asn-297 according to the generic 
numbering system). Similarly, the primary glycan, commonly referred to as G0F, is the same as that found 
on about 22% of endogenous human IgG moleculesxiv. 
The entire bermekimab heavy and light chain sequences are identical to those found in naturally-occurring 
human IgG1, with the light and heavy chain variable regions being identical to those originally expressed 
by a peripheral blood B lymphocyte that was obtained from a healthy individual.  
Endogenous anti-IL-1α antibody has been reported in 5% to 28% of healthy serum or plasma samplesx,xi
and cord bloodxv. The anti-IL-1α antibodies measured in human plasma are IgG, in particular IgG1, IgG2, 
and IgG4 sublasses. Relatively equal prevalence for these antibody are seen in male and female plasmaxvi.
Binding affinities reported for endogenous anti-IL-1α antibodies, ranging from 4 to 16 pM, are comparable 
to that for bermekimab, the specification for which is 22 to 260 pM.


Page 20 of 61
It is important to point out that affinity maturation had already taken place in the human host, and therefore 
no in vitro affinity maturation was required to increase the natural binding affinity of MABp1. Also 
important is the fact that, unlike most other therapeutic IgG products, for which the Fc regions are derived 
from a rare human allele, XBiotech’s product includes a heavy chain in which the constant (CH) region 
represents an allele found in approximately 70% of the human population. These two features should make 
for a drug product with reduced potential for immunogenicity.
2.2
DRUG PRODUCT (BERMEKIMAB 200 MG/ML) DESCRIPTION
XBiotech’s dosage form is a sterile liquid formulation of 200 mg/mL bermekimab in a stabilizing isotonic 
subcutaneous formulation buffer at pH 6.2-6.5 containing non-active ingredients of low concentrations of 
sodium phosphate, citric acid and trehalose. The drug product is packaged in pre-filled syringes. Drug 
product in syringes is stored at 2-8°C and is recommended to be protected from light.
2.3
STORAGE
The recommended storage condition is at 2-8°C.
2.4
STABILITY
The drug product is formulated in a buffer in which most of the tonicity comes from trehalose rather than 
salt. Trehalose is an effective stabilizer against oxidation, aggregation, and thermal or mechanical stress. 
Citrate was selected as the buffering agent due to its antioxidant properties.
Extensive stability data indicates that the drug product is very stable, even under thermally and 
mechanically stressed conditions. Short excursions to room temperature have been shown to have no 
negative effect on the product. However, the study treatment products are not to be frozen at any time.  The 
drug product is labeled with a 12-month retest date. Every lot is also subjected to ongoing stability analysis 
per ICH guidelines. 
2.5
DESIGNATED INDIVIDUAL FOR DRUG ADMINISTRATION
To ensure that no unintentional unblinding occurs during study drug administration, a qualified individual 
will be designated at each study site to perform all preparation and injection of the investigational 
product. The designated injector should have no other contact with the participant during the study, should 
not discuss the participant’s treatment with the participant, participant’s caregiver, or other site personnel 
at any time, and will not be permitted to review the participant’s medical records, questionnaires, or the 


Page 21 of 61
electronic CRF prior to each injection. The designated injector should be documented in the source 
documents at each visit.
2.6
METHOD OF ADMINISTRATION
Each injection should be administered at least one inch from previous injection sites.  
Instructions For Subcutaneous Injection
* At least 45 minutes prior to injection, remove the pre-filled syringe from refrigeration.
Lay the syringe on a flat surface and let it naturally warm to room temperature before injection. 
It may also be warmed by holding in hand. Do not heat the syringe.
Materials
Bermekimab pre-filled syringe for injection, warmed to room temperature
Sterile alcohol wipes
Band-aids, along with 2x2 gauze bandages and paper tape
Latex-free gloves
Injection Site
Abdomen, at least 2 inches away from the belly button (Figure 3)
(Note: avoid areas where the skin is burned, scarred, hardened, inflamed, swollen or damaged)
Figure 3
Injection

Put on gloves

Wipe injection site clean with alcohol pads


Page 22 of 61

Raise a fold of skin between the thumb and forefinger and insert needle as illustrated (Figure 4). 

Inject drug as rapidly as is comfortable for the patients.

Withdraw needle. Place band-aid over injection site if desired (Note: If bleeding occurs, hold 
pressure on the injection site for 90 seconds or until bleeding stops, and then apply gauze 
bandage secured by tape).
Figure 4
2.7
AGENT ORDERING
The Responsible Investigational Pharmacy will order study drug from XBiotech’s contract drug distributor 
as needed. 
2.8
POTENTIAL DRUG INTERACTIONS
There are no known drug interactions reported with bermekimab.
2.9
CONCOMITANT THERAPY
2.9.1
Antihistamine/NSAID Use
Concomitant medications such as antihistamines and/or NSAIDs (ibuprofen is recommended) are allowed 
based on the Investigator’s judgement, in order to prevent or treat injection site reaction or discomfort. This 
information must be captured in eCRF.
2.9.2
Required Treatment
All patients are required to apply moisturizers at least twice daily for at least 7 days before visit 1 (day 0) 
and to continue the treatment throughout the study (up to 36 weeks where applicable). All types of 
moisturizers are permitted, but patients may not initiate treatment with prescription moisturizers or 
moisturizers containing additives during the screening period or during the study. Patients may continue 


Page 23 of 61
using stable doses (for at least 7 days prior to screening visit) of such moisturizers if initiated before the 
screening visit. All moisturizer use must be captured in eCRF.
2.9.3
Permitted Medications and Procedures
Use of concomitant medications is permitted if not listed in section 2.9 Prohibited Medications and 
Procedures. Permitted concomitant medications includes basic skin care (cleansing and bathing, including 
bleach baths), moisturizers (required as background treatment), topical anesthetics, antihistamines, and 
topical and systemic anti-infective medications for any duration. In addition, medications used to treat 
chronic disease such as diabetes, hypertension, and asthma are permitted. 
Any questions regarding treatment with concomitant medication during the study, should be directed to the 
medical monitor. 
2.10
PROHIBITED MEDICATIONS AND PROCEDURES
Treatment with the following concomitant medications is prohibited during the entire duration of the study:

Topical tacrolimus and pimecrolimus

Treatment with a live (attenuated) vaccine

Treatment with other investigational drugs (besides Bermekimab) 

Treatment with topical corticosteroids or topical calcineurin inhibitors; such agents may be 
administered during the study only if required for atopic dermatitis rescue.  If topical corticosteroids 
and/or topical calcineurin inhibitors are used during the study, study treatment may continue as 
planned.

Treatment with systemic corticosteroids or nonsteroidal systemic immunosuppressive drugs (e.g., 
cyclosporine, methotrexate, mycophenolate-mofetil, azathioprine, etc.), except if required for 
atopic dermatitis rescue, or if critically medically needed to treat concurrent medical conditions 
(e.g., asthma).
o
The use of systemic corticosteroids for indications other than AD should be limited
to situations for which, in the opinion of the treating physician, there are no
adequate alternatives. They should be used on a short-term basis, preferably for
≤2 weeks. Longer-term use of corticosteroids should be discussed with the
medical monitor or designee and may require discontinuation of study drug.
Inhaled, otic, ocular, nasal or other routes of mucosal delivery of corticosteroids
are allowed throughout the study.

Leukotriene inhibitors


Page 24 of 61

Allergen immunotherapy

Systemic treatment for AD with an immunosuppressive/immunomodulating substance (including, 
but not limited to, cyclosporine, mycophenolate-mofetil, IFN-γ, azathioprine, methotrexate, or 
biologics)
Study drug will be discontinued if any of the following are used through week 16: 

Treatment with a live (attenuated) vaccine

Treatment with investigational drugs other than bermekimab.

Treatment with systemic corticosteroids or nonsteroidal systemic immunosuppressive drugs (e.g., 
cyclosporine, methotrexate, mycophenolate-mofetil, azathioprine, etc.)
The following concomitant procedures are prohibited during study participation:

Surgical procedures

Concomitant ultraviolet (UV) procedures (phototherapy [NBUVB, UVB, UVA1, or PUVA])

Tanning in a bed/booth

Patients are not allowed more than 2 bleach baths per week during study participation
2.11
RESCUE TREATMENT
Rescue treatment for AD may be provided to patients if medically necessary (ie, to control intolerable AD 
symptoms) at the discretion of the investigator. Topical calcineurin inhibitors may be used for rescue 
treatment, but should only be used for problem areas (e.g. face, neck, intertrinous and genital areas, etc). If 
possible, investigators should attempt to limit the first line of rescue treatment to topical medications. 
However, if the patient does not respond adequately to topical medications after at least 7 days, systemic 
medications may be used. 
3.
STUDY DESIGN AND OBJECTIVES
This is a phase II, randomized, double-blind, placebo-controlled study to further establish the efficacy and 
safety and explore dose effects for bermekimab monotherapy in adults with moderate to severe Atopic 
Dermatitis (AD). Patients will be assessed for study eligibility at the initial screening visit after providing 
informed consent. Thirty days are allowed in the screening window to complete all screening procedures 
and randomize the subject. During the screening period, certain treatments will be washed out, as 


Page 25 of 61
applicable, according to eligibility requirements. Patients who fail initially may be re-screened once based
on the investigator discretion but only if inclusion criteria are met at time of re-screening.
The study is approximately 40 weeks (30 day screening period, 32-week treatment period and a 4-week 
follow-up period) for all subjects. 
Patients who meet the eligibility criteria at screening will be randomized in a 1:1:1 ratio to one of two 
treatment arms or placebo:

Arm 1: 800 mg of bermekimab + placebo loading dose (2mL SC injection containing 400 mg of 
bermekimab and one 2mL SC injection of placebo) at week 0 followed by weekly (qw) 
subcutaneous (SC) injections of 400 mg bermekimab through week 31

Arm 2: 800 mg loading dose of bermekimab (2 x 400 mg SC injections) at week 0 followed by 
subcutaneous (SC) injections of 400 mg bermekimab every other week (q2w) alternating with 
matching placebo q2w through week 31

Arm 3: 4mL loading dose of placebo (2 x 2mL SC injections) at week 0 followed by weekly 
placebo injections from weeks 2 through week 15. Patients in Arm 3 will begin to receive weekly 
(qw) blinded subcutaneous (SC) injections of 400 mg bermekimab beginning at week 16 through 
week 31.
In order to maintain blinding, all patients will receive two injections at week 0 and 16, followed by weekly 
injections from week 1 to 31. Additionally, at least one qualified individual will be designated at each 
study site to perform all preparation and injection of the investigational product. The designated 
injector(s) should have no other contact with the participant during the study, should not discuss the 
participant’s treatment with the participant, participant’s caregiver, or other site personnel at any time, and 
will not be permitted to review the participant’s medical records, questionnaires, or the electronic CRF 
prior to each injection. The designated injector(s) should be documented in the source documents at each 
visit.
During the 32-week treatment period, patients will attend weekly clinical study visits. Clinical 
assessments, collection of samples for bermekimab concentrations, and safety testing will be performed 
at specified clinic visits.  After completion of the 36-week study period, data will be locked and analyzed 
for safety and efficacy endpoints for all arms. In addition to the analyses that will be performed following 
the formal database lock at the end of the study at Week 36, an additional database lock may be performed 


Page 26 of 61
at Week 16, and interim analyses utilizing unblinded efficacy data available as the study progresses, may 
also be conducted to help plan potential future development activities. An internal interim analysis 
committee (IAC) will be established to review the interim data and formulate recommended 
decisions/actions. The IAC will consist of at least a clinician and a statistician (neither of whom are 
involved in study conduct or compound development), one of whom will chair the committee, and may 
also include other members as required by the nature of the IAs. Details will be provided in a separate 
IAC charter, which will define the organization and roles and responsibilities of the committee, possible 
recommendations or requests, and the communication process following IA reviews. Results from the 
Week 16 database lock and/or interim analyses will not be disseminated to investigators or subjects 
participating in the study.  In addition, results of the interim analyses will not be disseminated to 
individuals associated with the conduct of the study.
Patients will be monitored at a follow up visit (visit 34/week 36) for safety and clinical assessments after 
completing the 32 week treatment period.. 
The protocol of the study will be approved by the Institutional Review Board (IRB) or the Ethics Committee 
(EC) of the participating study sites. Depending on the participating countries both local and central IRB/EC 
approvals will be granted. The study will be registered at www.clinicaltrials.gov before the enrollment of 
the first patient into the study.  The trial will be conducted in compliance with the protocol, GCP, and all 
applicable regulatory requirements.
3.1
Study Endpoints:
Primary Endpoint(s):

Percentage of Patients achieving Eczema Area and Severity Index-75 (EASI-75) (≥75% 
improvement from baseline) at week 16.
Secondary Endpoints:

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average peak 
daily Pruritus Numeric Rating Scale (NRS) score from baseline to weeks 4, 8, 12, 16, and 32 in 
patients with baseline score ≥4.*

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average overall 
Pruritus Numeric Rating (NRS) from baseline to weeks 4, 8, 12 16, and 32 in patients with baseline
score ≥4.* 


Page 27 of 61

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average peak 
daily Pain Numeric Rating Scale (NRS) score from baseline to weeks 4, 8, 12, 16, and 32 in patients 
with baseline score ≥4.*

Percentage of patients achieving ≥4-point improvement (reduction) in the weekly average overall 
Pain Numeric Rating (NRS) from baseline to weeks 4, 8, 12, 16, and 32 in patients with baseline 
score ≥4.*

Percentage of patients achieving EASI-75 (≥75% improvement in Eczema Area and Severity Index 
Score [EASI] from baseline) at weeks 4, 8, 12, and 32.*

Percentage of patients achieving an Investigators Global Assessment (IGA) score of 0 or 1 (on a 5-
point scale) and a reduction in this measure from baseline of at least 2 points at week 16.

Percentage of patients achieving EASI-90 (≥90% improvement in Eczema Area and Severity Index 
Score [EASI] from baseline) at weeks 12, 16, and 32.*

Change in Dermatology Life Quality Index (DLQI) from baseline to weeks 8, 12, 16, and 32.*

Change in Hospital Anxiety Depression Scale (HADS) (Anxiety) from baseline to weeks 8, 12, 16, 
and 32.*

Change in Hospital Anxiety Depression Scale (HADS) (Depression) from baseline to weeks 8, 12, 
16, and 32.*

Change in Patient Oriented Eczema Measure (POEM) Scores from baseline to weeks 8, 12, 16, and 
32.*

Change in SCORing Atopic Dermatitis (SCORAD) score from baseline to weeks 8, 12, 16, and 
32.*

Change in Global Individual Signs Score (GISS) from baseline to weeks 8, 12, 16, and 32.*
Exploratory Endpoints:

Percentage of patients achieving an IGA score 0 or 1 (on a 5-point scale) and a reduction in this 
measure from baseline of at least 2 points at week 12.

Change in Eczema Area and Severity Index Score (EASI) from baseline to weeks 8, 12, 16, and 
32.

Change from baseline to week 4 in Dermatology Life Quality Index (DLQI).

Patients (%) achieving 50% reduction in SCORAD Score at Weeks 4, 8, 12, 16, and 32.*

Patients (%) achieving 75% reduction in SCORAD Score at Weeks 4, 8, 12, 16, and 32.*

Patients (%) achieving 90% reduction in SCORAD Score at Weeks 4, 8, 12, 16, and 32.*

Change from baseline to week 8, 12, 16, and 32 in percent Body Surface Area (BSA).*


Page 28 of 61
Safety Endpoints: 

Incidence of skin infection treatment-emergent adverse events (TEAEs) requiring systemic 
treatment from baseline through week 16 and 32.

Incidence of treatment-emergent serious adverse events (TESAEs) from baseline through week 16 
and 32.

Incidence of TEAEs leading to treatment discontinuation from baseline through week 16 and 32.
*Each listed time point (in weeks) will be measured separately and treated as an individual endpoint. 


Page 29 of 61
4.
ELIGIBILITY CRITERIA
4.1
INCLUSION CRITERIA
No waivers/exemptions will be granted for protocol inclusion/exclusion criteria.
Subjects are included in the study if they meet all of the following criteria:

Written informed consent provided by the patient.

Male or female, at least 18 years.

Willing and able to attend all clinic visits and comply with study-related procedures

Is able to understand and complete study-related questionnaires

Chronic atopic dermatitis present for at least 3 years.

EASI score ≥16 at screening and baseline visits.

IGA score ≥3 at screening and baseline visits.

Baseline pruritis numerical rating scale average score for maximum intensity of at least 3, based 
on the average of daily pruritis numerical rating scale scores for maximum itch intensity reported 
during the 7 days prior to randomization.

Has applied a stable dose of topical moisturizer twice daily for at least 7 consecutive days 
immediately prior to the baseline visit and is willing to continue this regimen on a daily basis for 
the duration of the study.

≥10% body surface area (BSA) of AD involvement at screening and baseline visits.

Documented recent history (within 6 months prior to screening) of inadequate response to treatment 
with topical medications, or patients for whom topical treatments are medically inadvisable 
(because of important side effects or safety risks).
a)
Inadequate response is defined as failure to achieve and maintain remission or a low 
disease activity state (comparable to an IGA score of 0-2), despite treatment with a daily 
regimen of topical corticosteroids of medium to higher potency (with or without topical 
calcineurin inhibitors as appropriate), applied for at least 28 days or for the maximum 
duration recommended by the product prescribing information, whichever is shorter.
b) Patients with documented systemic treatment for atopic dermatitis in the preceding 6 
months are also considered to be inadequate responders to topical treatments and are 
potentially eligible for treatment with bermekimab, after appropriate washout.
c)
Important side effects or risks are those that outweigh the potential treatment benefits, and 
include: intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and 
adverse systemic effects.


Page 30 of 61
d) Acceptable documentation includes contemporaneous chart notes that record topical 
medication prescription and treatment outcome, or investigator documentation based on 
communication with the patient’s treating physician.
4.2
EXCLUSION CRITERIA
Subjects with ANY of the following will be excluded from the study:

Age below 18 years as the current study is evaluating bermekimab in adult patients only 

Subject has been treated for AD with any investigational drug of chemical or biologic nature within 
a minimum of 30 days or 5 half-lives (whichever is longer) of the drug prior to baseline

Treatment with bermekimab at any time in the past.

Treatment with immunosuppressive/immunomodulatory drugs or phototherapy for atopic
dermatitis within 4 weeks of baseline, or any condition that, in the opinion of the investigator, is 
likely to require such treatment(s) during the first 4 weeks of study treatment

Treatment with topical corticosteroids or topical calcineurin inhibitors for the treatment of AD 
within 14 days prior to baseline]

Treatment with biologics as follows:
a)
Any cell-depleting agents including, but not limited to, rituximab, within 5 half-lives (if 
known) or 30 days prior to baseline visit, or until lymphocyte count returns to normal, 
whichever is longer.
b) Other biologics: within 5 half-lives (if known) or 30 days prior to baseline visit, whichever 
is longer

Initiation of treatment of atopic dermatitis with prescription moisturizers or moisturizers
containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products 
during the screening period (patients may continue to use stable doses of such moisturizers if 
initiated before the screening visit)

Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the screening 
visit

Planned or anticipated use of any prohibited medications and procedures during study treatment

Treatment with a live (attenuated) vaccine within 30 days prior to the screening visit

Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit, or superficial 
skin infections within 1 week prior to the baseline visit. NOTE: patients may be rescreened after 
infection resolves


Page 31 of 61

Known or suspected history of immunosuppression, including history of invasive opportunistic 
infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, 
aspergillosis) despite infection resolution; or unusually frequent, recurrent, or prolonged infections, 
per investigator judgment.

History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening

Positive for hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody at the 
screening visit

At baseline, presence of any conditions listed as criteria for study drug discontinuation

Presence of skin comorbidities that may interfere with study assessments

History of malignancy within 5 years before the screening visit, except completely treated in situ 
carcinoma of the cervix, and completely treated and resolved non-metastatic squamous or basal 
cell carcinoma of the skin.

Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect the 
patient’s participation in the study. Examples include, but are not limited to, patients with short life 
expectancy, patients with uncontrolled diabetes (HbA1c ≥ 9%),  patients with cardiovascular 
conditions (eg, stage III or IV cardiac failure according to the New York Heart Association 
classification), severe renal conditions (eg, patients on dialysis), hepato-biliary conditions (eg, 
Child-Pugh class B or C), neurological conditions (eg, demyelinating diseases), active major 
autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other 
severe endocrinological, gastrointestinal, metabolic, pulmonary or lymphatic diseases. The specific 
justification for patients excluded under this criterion will be noted in study documents (chart notes, 
case report forms [CRFs], etc.)

Planned or anticipated major surgical procedure during the patient’s participation in this study

Patient or immediate family member is part of the current clinical investigational team

Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the 
study

Women unwilling to use adequate birth control, if of reproductive potential and sexually 
active. Adequate birth control is defined as consistent practice of an effective and accepted method 
of contraception throughout the duration of the study and for 120 days after the last dose of study 
drug. These methods include oral contraceptives (stable use for more than 3 months before 
Screening), intrauterine device (IUD), hormonal contraceptives such as Depo-Provera (stable use 
for more than 3 months before Screening), Implanon implants (stable use for more than 3 months 
before Screening), double barrier contraception such as condom or diaphragm used with 


Page 32 of 61
contraceptive sponge, foam, or jelly. For men participating in the study, unwillingness of sexual 
partner to use any of the above contraception methods.

History of severe allergic or anaphylactic reactions to monoclonal antibodies.

Any other medical or psychological condition (including relevant laboratory abnormalities at 
screening) that, in the opinion the investigator, may suggest a new and/or insufficiently understood 
disease, may present an unreasonable risk to the study patient as a result of his/her participation in 
the study, may make patient’s participation unreliable, or may interfere with study assessments. 
The specific justification for patients excluded under this criterion will be noted in study documents 
(chart notes, case report forms, etc.)
5.
TREATMENT PLAN
5.2
STUDY PROCEDURES 
PLACEBO-CONTROLLED PERIOD
Screening (maximum 30 days): The screening period begins once the informed consent is signed.  

Informed Consent 

Inclusion/ Exclusion

Demographics

Medical History 

Concomitant Medications/Treatments 

Physical Exam

Electrocariogram

Vital Signs (blood pressure, pulse, oxyen saturation, respiratory rate and body temperature) 

Height

Weight

Body Mass Index (BMI) [BMI= weight (kg)/height (m2)]

Patient Diary 

Patient Oriented Eczema Measure (POEM)

Hospital Anxiety and Depression Scale (HADS)

Dermatology Life Quality Index(DLQI)

Investigator’s Global Assessment (IGA)

Eczema Area and Severity Index (EASI)

Global Individual Signs Score (GISS)

SCORing Atopic Dermatitis (SCORAD)

Body Surface Area (BSA) involvement with atopic dermatitis (must be greater than 10%)

Urinalysis: pH, protein, glucose and blood cells (RBCs and WBCs)

Blood Draw:


Page 33 of 61

Chemistry panel: Albumin, Alkaline Phosphatase, ALT, AST, GGT, Bicarbonate (CO2), 
Calcium, Chloride, Creatinine, Glucose, Potassium, Sodium, Total Bilirubin, Total Protein, 
Urea Nitrogen

Hematology Panel:  Complete Blood Count (CBC) with differential and platelets

Infectious disease screening: HIV antibody, Hepatitis C antibody, Hepatitis B panel 
(HBsAg, anti-HBc, anti-HBs), and interferon gamma release assay (IGRA)

Serum pregnancy test for WOCBP

Inflammation Markers: CRP (C-Reactive Protein), ESR (Erythrocyte Sedimentation Rate)

Randomization to study arm (once confirmed patient has passed screening requirements).
***Patients will be monitored at the study site at visits 1, 2, 3, 17, 18 & 19 (weeks 0, 1, 2, 16, 17 & 18) 
for a minimum of 30-minutes after study drug administration. Vital signs and AE assessments will be 
done at 30 minutes (+/- 10 minutes) post-injection.***
Visit 1 (Baseline/Week 0/Day 0) (must occur within 30 days of signing informed consent)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat.

Pre-injection

Verify patient still meets all Inclusion/ Exclusion criteria

Height, Weight, BMI

Patient Diary

POEM, HADS, DLQI

EASI, GISS, SCORAD, BSA, IGA

Vital signs, Urine Pregnancy

Urinalysis 

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, PD (including 
IL-6), biomarker and research analysis

Bermekimab/placebo subcutaneous injection (To deliver a loading dose to subjects in the 
bermekimab groups while maintaining blinding, all subjects will receive two injections)

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 2 (Week 1/Day 7 ± 3 days); Visit 3 (Week2/Day 14 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat.

Pre-injection

Patient Diary

POEM, HADS, DLQI

IGA, EASI, GISS, SCORAD, BSA

Vital signs, Urine Pregnancy

Blood draw for PK/ADA, PD (including IL-6), biomarker and research analysis


Page 34 of 61

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 4 (Week 3/Day 21 ± 3 days); Visit 6 (Week 5/Day 35 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat.

Pre-injection

Patient Diary

Vital signs, Urine Pregnancy

Blood draw for PK/ADA, PD (including IL-6), biomarker and research analysis

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 5 (Week 4/Day 28 ± 3 days); Visit 13 (Week 12/Day 85 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat.

Pre-injection

Patient Diary

POEM, HADS, DLQI

EASI, GISS, SCORAD, BSA, IGA

Vital signs, Urine Pregnancy

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, PD (including 
IL-6), biomarker and research analysis

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 7 (Week 6/Day 42 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat.

Pre-injection
o
Patient Diary
o
POEM, HADS, DLQI
o
EASI, GISS, SCORAD, BSA, IGA
o
Vital signs, Urine Pregnancy 

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring


Page 35 of 61

Concomitant medications/treatments
Visit 8 (Week 7/Day 49 ± 3 days); Visit 10 (Week 9/Day 63 ± 3 days); Visit 11 (Week 10/Day 70 ± 3
days); Visit 12 (Week 11/Day 77 ± 3 days); Visit 14 (Week 13/Day 91 ± 3 days); Visit 15 (Week 
14/Day 98 ± 3 days); Visit 16 (Week 15/Day 105 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. The syringe may be held in the hand to warm. Do not heat. 

Pre-injection

Patient Diary

Vital signs, Urine Pregnancy

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 9 (Week 8/Day 56 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat.

Pre-injection

Patient Diary

POEM, HADS, DLQI

EASI, GISS, SCORAD, BSA, IGA

Vital signs, Urine Pregnancy 

Urinalysis 

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, PD (including 
IL-6), biomarker and research analysis

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
BLINDED ACTIVE DOSING PERIOD
Visit 17 (Week 16/Day 112 ± 3 days)

At least 45 minutes before injection: Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature. Syringe may be held in hand to warm. Do not heat

Pre-injection

Patient Diary

POEM, HADS, DLQI

EASI, GISS, SCORAD, BSA, IGA

Physical Examination, Vital signs, Urine Pregnancy

Urinalysis


Page 36 of 61

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, PD (including IL-6), 
biomarker and research analysis

Bermekimab/placebo subcutaneous injection 

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 18 (Week 17/Day 119 +/-3); Visit 19 (Week 18/Day 126 +/-3); Visit 20 (Week 19/Day 133 +/-3); 
Visit 22 (Week 21/Day 147 +/-3); Visit 23 (Week 22) (day 154 +/-3); Visit 24 (Week 23) (day 161 +/-
3); Visit 26 (Week 25/Day 175 +/-3); Visit 27 (Week 26/Day 182 +/-3); Visit 28 (Week 27/Day 189 +/-
3); Visit 30 (Week 29/Day 203 +/-3); Visit 31 (Week 30/Day 210 +/-3); Visit 32 (Week 31/Day 217 +/-
3):

At least 45 minutes before injection:  Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature.  Do not heat

Pre-injection

Patient Diary

Vital Signs, Urine Pregnancy 

Bermekimab/placebo subcutaneous injection 

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 21 (Week 20/Day 140 +/-3); Visit 29 (Week 28/Day 196 +/-3):

At least 45 minutes before injection:  Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature.  Do not heat

Pre-injection

Patient Diary

POEM, HADS, DLQI

EASI, GISS, SCORAD, BSA, IGA

Vital Signs, Urine Pregnancy 

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 25 (Week 24/Day 168 ± 3 days)

At least 45 minutes before injection:  Remove syringe from refrigeration and lay flat; allow to 
warm to room temperature.  Do not heat

Pre-injection

Patient Diary

POEM, HADS, DLQI

EASI, GISS, SCORAD, BSA, IGA


Page 37 of 61

Vital Signs, Urine Pregnancy 

Urinalysis

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, biomarkers and 
research analysis 

Bermekimab/placebo subcutaneous injection

Post-injection

Adverse event monitoring

Concomitant medications/treatments
Visit 33 (Week 32/Day 224 +/-3)

Patient Diary

POEM, HADS, DLQI

IGA, EASI, GISS, SCORAD, BSA

Physical Exam, Vital Signs, Urine Pregnancy 

Urinalysis 

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, biomarkers and 
research analysis 

Adverse event monitoring

Concomitant medications/treatments
FOLLOW-UP PERIOD

POEM, HADS, DLQI

IGA, EASI, GISS, SCORAD, BSA

Physical Exam, Vital Signs, Urine Pregnancy 

Urinalysis 

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, biomarkers and 
research analysis 

Adverse Events

Concomitant medications/treatments
UNSCHEDULED VISIT (if applicable)

Patient Diary

POEM, HADS, DLQI

IGA, EASI, GISS, SCORAD, BSA

Physical Exam, Vital Signs, Electrocardiogram, Urine/ Serum Pregnancy 

Urinalysis 

Blood draw for chemistry, hematology, inflammation markers, infectious disease panel, 
PK/ADA, biomarkers and research analysis 

Adverse Events

Concomitant medications/treatments


Page 38 of 61
EARLY TERMINATION VISIT (if applicable)

Patient Diary

POEM, HADS, DLQI

IGA, EASI, GISS, SCORAD, BSA

Physical Exam, Vital Signs 

Urinalysis 

Blood draw for chemistry, hematology, inflammation markers, infectious disease panel, 
PK/ADA, biomarkers and research analysis, Serum Pregnancy

Adverse Events

Concomitant medications/treatments








Page 42 of 61
5.3
DISCONTINUATION OF THERAPY
If a patient is discontinued from study, the reason for discontinuation/withdrawl must be clearly 
documented in the source documentation and the EDC. Every effort should be made by the investigative 
site to have subjects who discontinue early from study complete all assessments included in the Early 
Termination visit included in the study calendar provided in section 5. All subjects will be unblinded after 
clinical database lock.
Study therapy MUST immediately be discontinued for any the following reasons: 

Withdrawal of informed consent (subject’s decision to withdraw for any reason) 

Any clinical adverse event, laboratory abnormality, inter-current illness, or clinical progression of 
disease which, in the opinion of the Principal Investigator, indicates that continued participation 
in the study is not in the best interest of the subject 

Pregnancy 

Termination of the study by the sponsor

Imprisonment or the compulsory detention for medical treatment.
5.4
TRIAL STOPPING RULES
Sponsor may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause 
provided that written notice is submitted in advance of the intended termination. The investigator may also 
terminate the study at his/her site for reasonable cause, after providing written notice to Sponsor in advance 
of the intended termination. Advance notice is not required by either party if the study is stopped due to 
safety concerns. If Sponsor terminates the study for safety reasons, Sponsor will immediately notify the 
investigator by phone and subsequently provide written instructions for study termination.
5.5
EMERGENCY UNBLINDING
Subjects and investigators will be unblinded to their treatment allocation after database lock. In the event 
of an emergency that would require the investigator to be aware of the treatment allocation prior to the end 
of the trial, the investigator can obtain this information, on a per subject basis, after consultation with the 
Sponsor’s Medical Monitor, if possible. Every effort should be made to consult with the Medical Monitor 
prior to emergency unblinding. Events that qualify as emergencies are as follows:


Page 43 of 61

A grade 3 or greater AE which are “probably or definitely” related to study drug, and only if 
treatment assignment information is essential for the management of the event. This type of 
reaction would require that the patient receives no further doses, and is followed until the resolution 
of the toxicity.

Any suspected, unexpected, serious adverse reaction (SUSAR)

Pregnancy
6.
CORRELATIVE STUDIES
6.1
PHARMACOKINETICS (PK) SAMPLE COLLECTION
The process for the collection, storage, future use and disposal of biological samples will follow company 
policies and SOPs. Patient blood will be drawn into blood collection tubes at each collection time point per 
the study protocol for PK/ADA/PD/research analysis. These samples will be processed by the collection 
lab per the study laboratory manual and the obtained plasma/serum will be sent to a central laboratory 
before being shipped to XBiotech in monthly batches for analysis.
An enzyme-linked immunosorbent assay (ELISA) has been developed and validated to specifically 
measure bermekimab levels in human plasma. Blood samples will also be used to test for the presence of 
treatment-emergent antibodies against bermekimab. XBiotech has developed and validated an ELISA 
method to measure treatment-emergent ADA. Additionally, samples will be used for pharmacodynamic 
analysis and exploratory research.
7.
ASSESSMENT OF SAFETY
Safety will be assessed by monitoring adverse events, vital signs, physical examinations, ECG, and clinical 
laboratory measurements. Data from ECG will be included in safety analysis only when all of these 
measures are available for each subject (baseline and last visit). Adverse events will be monitored from 
visit 1 (post-injection) through visit 34 (week 36). Any serious adverse events whether related to study drug 
or not will be followed up until resolution.
Study drug, bermekimab, will be administered under close observation in a facility equipped to handle 
anaphylaxis or injection site reactions. Subjects must be closely monitored at the study site at visits 1, 2 and 
3 (for the first three injections) until at least 30 minutes following the administration of the antibody. Vital 
signs and AE assessments will be done at 30 minutes (+/- 10 minutes) post-injection.    


Page 44 of 61
Any grade 3 or greater injection site reaction must be reported to the sponsor within 24 hours of learning 
of the event.
8.
STUDY VARIABLES
8.1
DEMOGRAPHIC AND DISEASE CHARACTERISTICS
Demographic characteristics will include standard demography (age, sex, race, weight, and BMI) medical 
history, medication history, and prior biologic use for each patient. Characteristics of the patient’s atopic 
dermatitis, including duration of disease, baseline EASI score (including individual signs score), baseline 
Investigator’s Global Assessment, baseline body surface area involvement, baseline pruritus numerical 
rating score, baseline SCORAD score, baseline patient-oriented eczema measure, baseline DLQI, and 
baseline HADS score, will be collected. Baseline is defined as the week 0 (visit 1), pre-injection assessment.
8.2
STUDY ASSESSMENTS

Eczema Area and Severity Index
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent 
of AD. Four AD disease characteristics will be assessed for severity by the investigator or designee on a 
scale of “0” (absent) through “3” (severe). In addition, the area of AD involvement will be assessed as a 
percentage by body area of head, trunk, arms, and legs and converted to a score of 0 to 6.

Investigator’s Global Assessment
The IGA is an assessment scale used in clinical studies to determine severity of AD and clinical response 
to treatment based on a 5-point scale ranging from 0 (clear) to 4 (severe).  

Global Individual Signs Score
Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and
lichenification) will be rated globally (ie, each assessed for the whole body, not by anatomical region) on a 
4-point scale (from 0=none to 3=severe) using the EASI severity grading criteria.

SCORing Atopic Dermatitis
The SCORAD is a validated tool used in clinical research and clinical practice that was developed to 
standardize the evaluation of the extent and severity of AD.  There are 3 components to the assessment: A 
= extent or affected body surface area, B = severity, and C = subjective symptoms. The extent of AD is 
assessed as a percentage of each defined body area, and reported as the sum 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 


Page 45 of 61
using the following scale: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, 
assigned as “B” in the overall SCORAD calculation). Subjective assessment of itch and sleeplessness is 
recorded for each symptom by the patient or relative on a VAS, where 0 is no itch (or sleeplessness) and 
10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20. This parameter is 
assigned as “C” in the overall SCORAD calculation. The SCORAD is calculated as: A/5 + 7B/2 + C where
the maximum is 103.  
Body surface area affected by AD will be assessed for each section of the body (the possible highest score 
for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs 
[36%], and genitals [1%]) and will be reported as a percentage of all major body sections combined. Body 
Surface Area (BSA) will be extracted using SCORAD.

Numerical Rating Scale (NRS) for Pruritus & Pain
Patients will be given a diary to complete each night before bed. Patients will be asked to report “average 
pain”, and “worst moment pain” as well as “average itch” and “worst moment itch” on a 0-10 numeric 
rating scale. Patient diaries will be collected weekly. 

Patient Oriented Eczema Measure
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess disease 
symptoms in children and adults. The format is a response to 7 items (dryness, itching, flaking, cracking,
sleep loss, bleeding, and weeping) based on frequency during the past week (ie, 0 = no days, 1 = 1 to 2 
days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) with a scoring system of 0 to 28; the total score 
reflects disease-related morbidity.  The POEM is provided in the study reference manual.

Hospital Anxiety and Depression Scale
The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; repeated 
administration also provides information about changes to a patient’s emotional state. The HADS consists 
of 14 items, 7 each for anxiety and depression symptoms; possible scores range from 0 to 21 for each 
subscale. The following cut-off scores are recommended for both subscales: 7 to 8 for possible presence, 
10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.  The HADS is provided in 
the study reference manual.

Dermatology Life Quality Index
The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the 
impact of AD disease symptoms and treatment on QOL. The format is a simple response (0 to 3 where 0 is 
“not at all” and 3 is “very much”) to 10 questions, which assess QOL over the past week, with an overall 
scoring system of 0 to 30; a high score is indicative of a poor QOL.  The DLQI is provided in the study 
reference manual.


Page 46 of 61

Pharmacokinetics (PK) and Interleukin-6 (IL-6)
An enzyme-linked immunosorbent assay (ELISA) has been developed to specifically measure bermekimab 
levels in human plasma. Blood will be drawn into three 6 ml collection tubes at each research draw 
collection time point as outlined in section 5. These samples will be collected per the study lab manual and 
shipped to the Sponsor for PK and IL-6 analyses. The samples will also be used for various 
pharmacodynamic (PD), biomarker, and general research analyses. The PK samples will also be used to 
test for the presence of antibodies against bermekimab. The IL-6 samples will be used to test for change in 
serum IL-6 levels in patients, which has shown to correlate with disease severity in HS and potentially a 
more reliable predictor of treatment response in HS patients than CRPxvii, xviii. 
9.
ADVERSE EVENTS 
9.1
DEFINITION OF ADVERSE EVENT (AE)
An adverse event is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any of the following:

Any unfavorable and unintended sign (including laboratory findings), symptom, or disease temporally 
associated with the use of bermekimab, whether or not it is apparently related to bermekimab

A concurrent illness

An exacerbation, or an unexpected increase in frequency or intensity of a preexisting condition, 
including intermittent or episodic conditions.  However, anticipated day-to-day fluctuations or 
expected progression of the preexisting condition (based upon the Investigator’s clinical judgment) 
are not to be considered AEs

A significant or unexpected worsening of the condition/indication under investigation.  However, 
anticipated day-to-day fluctuations or expected progression of the disease under investigation (based 
upon the Investigator’s clinical judgment) are not to be considered AEs

A suspected interaction between the investigational drug and concomitant medications

Any clinically significant laboratory abnormality (including radiological interpretations, 
histopathological findings, etc.)
9.2
DEFINITION OF SERIOUS ADVERSE EVENT (SAE)
An adverse event is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: 

Death;


Page 47 of 61

A life-threatening adverse event;

Inpatient hospitalization or prolongation of existing hospitalization;

A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions;

Congenital anomaly/ birth defect;

An important medical event that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.
Note that seriousness and severity should not be confused. A subject could experience a severe headache 
that would not qualify as an SAE, while another might experience a mild stroke that, while not severe, 
would be considered serious.
9.3
RECORDING OF ADVERSE EVENTS
All untoward events occurring between visit 1 (week 0) (post-injection) and the end of study (or if subject 
terminates from study prior to visit 34 (week 36), five weeks after the last administration of bermekimab)
should be recorded on the eCRF, regardless of whether they are considered related to study drug.
All AEs should be recorded in standard medical terminology as concisely as possible.  The AE recorded 
should not be a procedure or a clinical/laboratory measurement but should reflect the event leading to the 
procedure or the cause of the clinical/laboratory abnormality, if known.  Whenever possible, AEs should 
be evaluated and recorded as a diagnosis, rather than individual signs and symptoms.  However, if a 
definitive diagnosis is not possible, the individual signs and symptoms should be recorded.  Any AE that 
worsens in intensity, or becomes serious, should be recorded as a new event.
9.4
EVALUATING ADVERSE EVENTS
All AEs will be graded according to the CTCAE version 5.


Page 48 of 61
9.5
ASSESSMENT OF CAUSALITY
Investigators are required to assess the relationship, if any, of each AE or SAE to the investigational drug 
using clinical judgment to determine the degree of certainty with which an AE can be attributed to the 
investigational drug.  Alternative causes, such as natural history of the underlying disease, other risk factors, 
and the temporal relationship of the event to the administration of the study medication must be considered.
Relationship to study drug is summarized as follows:

Not Related:  There is another obvious cause of the AE

Unlikely to be related:  There is another more likely cause of the AE

Possibly related:  The AE could have been due to the investigational drug

Probably related:  The AE is probably attributable to the investigational drug

Definitely related:  The AE is most likely attributable to the investigational drug
9.6
REPORTING REQUIREMENTS 
Any grade 3 or greater injection site reaction must be reported to the sponsor within 24 hours of learning 
of the event.
All serious adverse events (SAEs) should be reported to the Sponsor on the initial SAE report forms within 
24 hours of knowledge of the event.  These immediate reports should be followed promptly by detailed, 
written reports (follow-up SAE reports). The subject should be followed up with until stabilization of the 
reported SAE, either with full satisfactory resolution or resolution with sequelae, or until death of the 
subject. Before declaring the subject is lost to follow-up, three unsuccessful attempts at contact should be 
made and recorded on the SAE form. The immediate and follow-up reports should identify subjects by 
unique code numbers (generated by the safety database) assigned to the trial subjects rather than by the 
subjects' names, personal identification numbers, and/or addresses. The Investigator should also submit 
SAEs to the IRB/EC according to their IRB/EC guidelines [ICH-GCP E6].  Drug-related Serious Adverse 
Events will be reported to the FDA by XBiotech’s Medical Safety Officer according to 21 CFR 312.32.
9.7
REFERENCE SAFETY INFORMATION: POTENTIAL ADVERSE REACTIONS
911 patients have been treated using bermekimab (either by infusions or subcutaneous injections) in patients 
with advanced solid tumors, advanced hematologic malignancies, metastatic colorectal cancer, peripheral 
vascular disease, type II diabetes, acne vulgaris, plaque psoriasis, pyoderma gangrenosum, atopic dermatitis 
and hidradenitis suppurativa.  Over 5000 doses of bermekimab were administered intravenously at 7.5 


Page 49 of 61
mg/kg and over 900 doses of bermekimab were administered subcutaneously with 50 mg/mL, 100 mg/mL 
and 200 mg/ mL formulations.
Bermekimab is a recombinant human IgG1 monoclonal antibody specific for human interleukin-1(IL-
1).  As such, it is an immunomodulator that has anti-inflammatory and anti-neoplastic properties.  Other 
agents that could be considered in the same pharmacologic class include biologic agents that target IL-1 
receptor antagonist and IL-1 beta. Potential risks for agents in this class include infusion or injection site 
reactions and risk of infection.
Bermekimab is considered to be a True Human monoclonal antibody. Unlike previous generations of 
humanized or fully human antibodies, the entire bermekimab heavy and light chain sequences are identical 
to those found in naturally-occurring human IgG1, with the light and heavy chain variable regions being 
identical to those originally expressed by a peripheral blood B lymphocyte that was obtained from a healthy 
individual.  No in vitro affinity maturation or modifications have been made to improve its natural binding 
affinity (211 +/- 31 pM).  We believe that a true human antibody should be effectively non-immunogenic 
in humans and thus exhibit optimal activity and pharmacokinetics.  To date, no treatment emergent anti-
drug antibodies specific to bermekimab have been identified.
The mechanism behind infusion or injection site reactions is not well understood. In some cases, it may 
involve a reaction against the antibody products themselves, particularly where the primary sequence of the 
antibody has been modified in vitro or is derived from non-human system or, against some minor residual 
component from the manufacturing process (i.e. host cell proteins). Bermekimab is derived from and has 
undergone immunological selection in humans, thus anti-bermekimab responses are highly unlikely. To 
date, there has been a very low incidence of injection site or infusion reactions observed (27 patients out of 
911 total; 3.0%).  In order to mitigate this class-specific risk, close monitoring is required during the 
bermekimab infusion/ injection and for at least 30 minutes after the end of the infusion/ injection for the 
first 3 doses.  Availability of resuscitation equipment must be ensured although this has never been used 
for any patient in any of our studies.  Pre-medication with antihistamines, NSAIDs or corticosteroids is not 
required but allowed at PI’s discretion.
An expanded discussion of potential risks and monitoring with bermekimab therapy is located in Section 
4.6 of the Investigator’s Brochure.


Page 50 of 61
For the purposes of expedited safety reporting in clinical trials, the following should be considered 
expected events:

Infusion Related Reactions

Injection Site Reactions
10.
STATISTICAL PLAN
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 statistical analysis plan (SAP).
10.1
DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint is percentage of patients with Eczema Area and Seveirty Index-75 (EASI-
75) (≥75% improvement from baseline) at week 16 . The sample size is calculated for the bermekimab 
weekly injection group (arm 1) versus placebo group (arm 3) comparison (the primary comparison).
Assuming EASI-75 is achieved in 60% of intent-to treat (ITT) patients treated in the bermekimab weekly 
injection group (arm 1) versus 20% in placebo treated patients (arm 3), then, for a randomization ratio of 
1:1:1, a sample size of 69 patients (23 in each treatment group) is required for approximately 80% power 
at a 0.05 significance level using a 2-sided Pearson chi-square test.  In order to account for possible dropouts 
and to provide adequate safety data, approximately 90 patients will be randomized and treated.
10.2
RANDOMIZATION
A centralized block randomization schedule with a 1:1:1 allocation ratio will be utilized using an electronic 
randomization system. Patients will be randomly assigned to either the bermekimab weekly injection group 
(arm 1), the bermekimab every other week injection group (arm 2), or the placebo group (arm 3).  The 
randomization schedule will be stratified by baseline EASI severity (less severe (EASI ≥16 and <28) or 
more severe (EASI ≥28)).
10.3
ANALYSIS SETS

The safety analysis set (SAF) population will consist of all patients who receive at least one dose 
of study medication and will be analyzed as treated.

The modified intent-to-treat (mITT) population will consist of all randomized and treated patients.


Page 51 of 61
10.4
PATIENT DISPOSITION
A listing of all patients prematurely discontinued from the study, along with reasons for
discontinuation will be provided. In addition, the total number of patients for each of the
following categories will be summarized.

The total number of screened patients: met the inclusion criteria regarding the target indication and 
signed the informed consent

The total number of patients in each analysis set (SAF, and mITT)

The total number of patients who complete the study

The total number of patients who discontinued the study, and the reasons for discontinuation
10.5
STATISTICAL METHODS
Continuous data will be summarized for each treatment group using the number of observations available 
(N), means, standard deviation (SD), minimums, medians, and maximums.  Categorical data will be 
summarized for each treatment group using counts and percentages.  All statistical tests will be two-sided 
unless otherwise noted. 
10.5.1 Demography and Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
Continuous variables will be summarized with mean, median, SD, minimum, and maximum.  Categorical 
variables will be summarized with frequency and percentage.
10.5.2 Safety Analysis
The primary objective of the study is to analyze the safety and efficacy of different dose regimens of 
bermekimab compared to placebo treatment in adult patients with moderate-to-severe AD
Safety endpoints will be evaluated by monitoring adverse events from clinical and laboratory reporting. 
The safety analysis will be based on the SAF population. A summary of safety results will be presented for 
each treatment group.
10.5.2.1
Analysis of Adverse Events
Adverse events reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary (version 22.0 or newer). Coding will be to lowest level terms. The verbatim 
text, the PT, and the primary SOC will be listed in patient listings. 


Page 52 of 61
Pre-treatment AEs are defined as those that develop or worsen in severity from the time the patient provides 
informed consent, prior to the first dose of study drug.  Treatment emergent AEs (TEAEs) are defined as 
AEs that develop or worsen in severity following the first dose of study drug through the last study visit.
TEAEs will be grouped by MedDRA System Organ Class (SOC) and Preferred Term (PT) within SOC and 
will be presented for each treatment group. The number and percentage of patients experiencing AEs and 
TEAEs will be summarized by seriousness (SAEs), severity (grades 1-5), and relationship.
10.5.2.2
Other Safety
Vital Signs
Summaries of vital sign parameters by treatment dose cohort will include:

Each vital sign parameter and change from baseline
Laboratory Tests
Clinical laboratory values will be converted to standard international units. Clinical laboratory (as described 
in the treatment plan) data will be listed for each subject. Laboratory data will be summarized by treatment 
group. Summaries of laboratory variables by treatment group will include:

Each laboratory result and change from baseline

Listing will be provided for patients with grade 2 or greater laboratory AEs
Electrocardiogram
12-lead ECG status (ie, normal, abnormal, clinically significant) will be summarized descriptively by 
treatment group.
10.5.3
Efficacy Analysis
In general, efficacy  analyses will include all randomized participants (mITT population) and will be 
analyzed based on the randomized treatment groups, regardless of the treatment they actually received.
10.5.3.1
Primary Efficacy Analysis
For the primary efficacy endpoint, the two bermekimab treatment groups will be compared with placebo.  
To account for these two comparisons, testing will be done in a sequential manner, each at the 0.05 alpha 
level.  The bermekimab weekly injection group (Group 1) will be compared to the placebo group (Group 
3) first.  If this test is significant at the 0.05 level, then the bermekimab every other week injection group 
(Group 2) will be compared to the placebo group (Group 3).  Otherwise, the P-value for Group 2 vs Group 


Page 53 of 61
3 will be considered nominal. This method to control the type-1 error will only be implemented for the 
primary efficacy analysis variable.
The number and percentage of patients with Eczema Area and Seveirty Index-75 (EASI-75) (≥75% 
improvement from baseline) at week 16 will be presented by treatment group.  Patients who terminate from 
the study early prior to week 16 will count as non-responders (non-achievers) in the primary efficacy 
analysis (Non-Responder Imputation).  If a patient received rescue medication, the patient will be counted 
as a non-responder from the start of rescue medication.  Additional treatment failure rules and sensitivity 
analyses will be discussed in the statistical analysis plan.  
A Cochran-Mantel-Haenszel (CMH) general association test stratified by baseline EASI severity will be 
used to compare each bermekimab dose separately with placebo.  The primary efficacy analysis population 
will be the mITT population.  
10.5.3.2
Secondary Efficacy Analyses
Secondary and exploratory efficacy endpoints will be summarized using descriptive statistics for 
continuous variables (n, mean, standard deviation, median, minimum and maximum value) and number 
and percentage for categorical variables.. The 95% CI of the mean change from baseline will be provided. 
The change from baseline in these endpoints at each week will be analyzed using a restricted maximum 
likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for treatment, 
week, stratification factor (baseline EASI severity), baseline score, baseline score by week interaction, 
and the treatment-by-week interaction, if applicable.  The impact of the stratification factor will also be 
assessed.  Categorical variables will be analyzed using CMH tests as used for the primary efficacy 
analysis.  Full details will be provided in the SAP.
10.5.4 Treatment Exposure
The number and percentage of patients exposed to study drug along with duration of exposure will be 
summarized descriptively by treatment group.
10.5.5 Pharmacokinetic (PK) and Pharmacodynamics (PD) Analysis:
Descriptive statistics of PK and PD concentrations and parameters will be presented.


Page 54 of 61
11.
STUDY MANAGEMENT AND ADMINISTRATION
11.1
ETHICAL CONDUCT OF STUDY (GCP)
The guidelines of the World Medical Association Declaration of Helsinki in its revised edition (48th General 
Assembly, Somerset West, Republic of South Africa, October 1996), the guidelines of ICH GCP 
(CPMP/ICH/135/95), as well as the demands of national drug and data protection laws and other applicable 
regulatory requirements, will be strictly followed.  Approval will be obtained from the appropriate 
regulatory authorities before sites are initiated. 
11.2
IRB AND ETHICS COMMITTEE APPROVAL 
Prior to initiation of the study, the protocol, the informed consent form, the subject information sheet(s), 
details of the subject recruitment procedures and any other relevant study documentation will be submitted 
to the responsible IRB or Ethics Committee (EC). The Investigator will report promptly to the IRB/EC any 
new information that may adversely affect the safety of subjects or the conduct of the study. Similarly, the 
Investigator will submit written summaries of the study status to the IRB/EC annually, or more frequently 
if requested by the IRB/EC.  Upon completion of the study, the Investigator will provide the IRB/EC with 
a brief report of the outcome of the study, if required.
11.3
PROTOCOL MODIFICATIONS 
Modifications of the signed protocol are only possible by approved protocol amendments and with the 
agreement of all responsible persons.  The procedure for approval of a protocol amendment is identical to 
that for approval of the protocol.  The IRB/EC must be informed of all protocol amendments and should be 
asked for its opinion as to whether a full re-evaluation of the ethical aspects of the study is necessary by the 
committee.  This should be fully documented.  The Investigator must not implement any deviation from or 
change to the protocol, without discussion with and agreement by the study Sponsor. There also must first 
be prior review and documented approval/favorable opinion of the amendment from the relevant IRB/EC, 
except where it is necessary to eliminate an immediate hazard to study subjects, or where the change(s) 
involves only logistical or administrative aspects of the study (e.g., change in CRA(s), change of telephone 
number(s)). Protocol amendments will be submitted to the appropriate authority(s) as required by the 
applicable regulatory requirement(s).


Page 55 of 61
11.4
SUBJECT INFORMATION AND CONSENT 
The Investigator is responsible for ensuring that no subject will receive any study-related examination or 
activity before that subject has given an IRB/EC approved informed consent.  The subject must give written 
consent after the receipt of detailed information.  The verbal explanation will cover all the elements 
specified in the written information provided for the subject.  The Investigator will inform the subject of 
the aims, methods, anticipated benefits and potential hazards of the study, including any discomfort it may 
entail.  The subject must be given every opportunity to clarify any points he/she does not understand and,
if necessary, to ask for more information.  At the end of the interview, the subject may be given time to 
reflect if this is required, or if the subject requests more time.  Subject and/or legal guardian forms will be 
kept and archived by the Investigator in the Investigator's study file.  It should be emphasized that the 
subject is at liberty to withdraw their consent to participate at any time, without penalty or loss of benefits 
to which the subject is otherwise entitled.  Subjects who refuse to give, or withdraw, written informed 
consent may not be included or continued in this study, but this will not impact their subsequent care.  The 
Investigator will notify in writing each subject’s primary care physician (or equivalent) of the subject’s 
intent to participate in the study.
11.5
DATA PROTECTION AND CONFIDENTIALITY 
By signing the final protocol, every participating Investigator agrees to keep all information and results 
concerning the study and the investigational product confidential.  The confidentiality obligation applies to 
all personnel involved at the investigational site.  The Investigator must ensure that each participant’s 
anonymity will be maintained in accordance with applicable laws. On eCRFs or other documents submitted 
to the Sponsor, subjects should not be identified by their name, but by subject ID number.  The Investigator 
should keep a separate log of ID numbers, names and addresses.  Documents that contain the names 
associated with these ID numbers (e.g., written consent/assent forms), are not for submission to the Sponsor 
and should be maintained by the Investigator in strict confidence except to the extent necessary to allow 
auditing by regulatory authorities, and auditing or monitoring by the Institutional Review Board/EC,the 
Sponsor personnel or their affiliates and designees (such as CRAs). 
Copies of radiological scans and autopsy reports (and other documents) that may be requested by the 
Sponsor should be de-identified.  The Investigator shall obtain all such permissions and authorizations as 
may be necessary or desirable to allow the collection and use of information protected under federal privacy 
laws and state privacy laws, including permission/authorization for monitoring and analysis (including re-


Page 56 of 61
analysis in combination with results of other studies), for regulatory submission purposes and for applicable 
reporting (if any) required to be made by Sponsor, its affiliates and their designee. 
Access to the study data will be strictly controlled. These data will be processed and archived in accordance 
with the applicable policies and SOPs. The Sponsor’s Electronic Database has security features which 
include but are not limited to the following: all application ports are secured behind a firewall; all data and 
network traffic is encrypted; the database is role-based and roles are customized to allow restricted access 
to specific features; a password policy is enforced including a secure password length and complexity; all 
database changes and user logins are logged to an audit trail; fields containing Protected Health Information 
are obfuscated from study users (sponsor, data managers, etc.); and EU data are contained on a dedicated 
data server in the EU, so the data is not stored offshore.
11.6
STUDY REPORT AND PUBLICATIONS 
A final integrated clinical/statistical report will be prepared that is compliant with the ICH Harmonized 
Tripartite Guideline: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95).  The results of 
this study will be published and/or presented at scientific meetings in a timely manner.  The publication 
policy is described in the contract between the Sponsor and Investigator. 
11.7
STUDY FILES AND RETENTION OF RECORDS 
Copies of all study documents should be retained by the Investigator until at least two 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 at least two years have elapsed since the formal discontinuation 
of clinical development of the investigational product, in accordance with 21 CFR 312.62.  These 
documents should be retained for a longer period however, if required by regulatory requirements or by 
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. The final database will be archived according to 
the regulatory requirements. 
11.8
CASE REPORT FORMS
Data for this protocol will be collected on to the source documents and later will be captured electronically 
in an Electronic Data Capture (EDC) system by the site coordinators.  Source documents are original 


Page 57 of 61
records of clinical findings, observations, or other activities in a clinical trial necessary for the evaluation 
of the trial. Examples of source documents (electronic or hardcopy documents) include but are not limited 
to subject diaries, physician and/or patient completed questionnaires or scales, laboratory results, ECGs and 
reports. Designated study personnel will be provided unique usernames and passwords with specific access 
within the electronic data collection system based on their role. The EDC system contains an audit trail 
associated with each individual's unique password that will document date and time of data entry and 
revisions.  All protocol-specified data is to be entered into the EDC system in a timely manner for review 
and audit by XBiotech. All data is to be entered such that it will allow accurate interpretation and tabulation.  
It is the Investigator's responsibility to ensure that all discontinued orders or changes in study or other 
medications entered into the database correspond to entries in the subject's medical records (i.e. source 
documents) and to acknowledge accurate completion of the eCRF.
11.9
DRUG ACCOUNTABILITY 
A Drug Dispensing Log must be kept current and should contain the following information: 

Initial inventory upon receipt of supplies at the study site 

Identification number of each subject to whom test drug was administered 

Date(s), quantities, lot numbers and calculations for all test drugs administered 

Final inventory (upon completion of the study)
This inventory must be available for inspection by the Clinical Research Associate.  The Investigator (or 
pharmacist, as appropriate) must maintain records of the delivery of the study medication to the study site, 
the inventory at the site, the usage for each subject, and destruction. The inventory must be available for 
monitoring, auditing or inspection.  A drug dispensing log must be kept current and should contain the 
following information: 

The subject identification number to whom the drug is dispensed 

The lot number of the drug dispensed 

The date(s) and the quantity of the drug dispensed to the subject
The sites will follow their internal SOPs for discarding the used (empty) syringes after the injection. The 
designated personnel at the sites will review drug accountability logs to account for administered syringes. 
Unused inventory by investigative sites at study completion should be returned to drug distributor for 
destruction per guidance provided in the study’s pharmacy manual.


Page 58 of 61
11.10 AUDITS AND INSPECTIONS 
Investigator sites, the study database and study documentation may be subject to quality assurance audits
during the course of the study either by the Sponsor or their appointed representatives.  In addition, 
regulatory bodies at their discretion may conduct inspections.  The Investigator shall permit the authorized 
Sponsor, agents of the Sponsor, and regulatory agency employees to enter and inspect any site where the 
drug or records pertaining to the drug are held, and to inspect all records relating to an investigation, 
including subject records.  The Sponsor will not, however, copy any source data from the patient’s dossier.  
Completed eCRFs must be made available by the Investigator for review by the Sponsor, agents of the 
Sponsor, the CRA and the regulatory agencies.  To ensure the accuracy of data submitted, it is mandatory 
that representatives of the Sponsor and of the regulatory agencies have direct access to source documents 
(e.g., subject medical records, charts, laboratory reports, etc.).  Subject confidentiality will be protected at 
all times. 
11.11 ACCESS TO INFORMATION FOR MONITORING 
The study will be conducted in compliance with Good Clinical Practice (GCP). Sponsor will arrange the 
clinical research associates (CRAs) to monitor the conduct of the clinical trial at the investigative sites. 
XBiotech ensures that appropriate monitoring procedures are performed before, during and after the study. 
All aspects of the study are reviewed with the investigator and the staff at a study initiation visit (SIV). 
Prior to enrolling subjects into the study, a XBiotech representative will review the protocol, eCRFs, 
procedures for obtaining informed consent, record keeping, and reporting of AEs/SAEs with the 
investigator and his/her staff. Monitoring will include on-site visits at regular intervals with the investigator 
and his/her staff as well as any appropriate communications by mail, email, facsimile, or telephone. During 
monitoring visits, the facilities, IP storage area and conditions, eCRFs, subject’s source documents, and all 
other study documentation will be inspected/reviewed by the XBiotech representative. Accuracy and 
protocol compliance will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation. Any resulting discrepancies 
or deviations from the protocol will be reviewed with the investigator and/or his/her staff. Any necessary 
corrections will be made directly to the eCRFs or via queries by the investigator and/or his/her staff. 
Monitoring procedures require that informed consents, adherence to study protocol and documentation of 
AEs and SAEs and their proper recording be verified. The CRA will make written reports to the Sponsor 
on each occasion when contact with the Investigator is made, regardless of whether it is by phone or in 
person. 


Page 59 of 61
11.12 STUDY DISCONTINUATION 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and the reason(s) 
for the termination or suspension.  The IRB/EC will also be promptly informed and provided with the 
reason(s) for the termination or suspension by the Sponsor or by the Investigator/institution, as specified 
by the applicable regulatory requirement(s).


Page 60 of 61
REFERENCES
i Coleman KM, Gudjonsson JE, Stecher M.  Open-Label Trial of MABp1, a True Human Monoclonal 
Antibody Targeting Interleukin 1α, for the Treatment of Psoriasis.  JAMA Dermatol. 2015 
May;151(5):555-6. doi: 10.1001/jamadermatol.2014.5391.
ii Carrasco D, Stecher M, Lefebvre GC, Logan AC, Moy R.  An Open Label, Phase 2 Study of MABp1 
Monotherapy for the Treatment of Acne Vulgaris and Psychiatric Comorbidity.  J Drugs Dermatol. 2015 
Jun;14(6):560-4.
iii Kanni T et al. MABp1 Targeting Interleukin-1Alpha for Moderate to Severe Hidradenitis Suppurativa 
not Eligible for Adalimumab: A Randomized Study. J Invest Dermatol. 2017 Nov 9. 
iv Bieber T. Mechanisms of disease: atopic dermatitis. N Engl J Med 2008; 358:1483-94.
v Bou-Dargham MJ et al. The Role of Interleukin-1 in Inflammatory and Malignant Human Skin Diseases 
and the Rationale for Targeting Interleukin-1 Alpha. Med Res Rev. 2017 Jan;37(1):180-216.
vi Han et al.  Interleukin-1alpha-induced proteolytic activation of metalloproteinase-9 by human skin. 
Surgery. 2005 Nov;138(5):932-9.
vii Archer et al. Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte 
IL-1α release. J Allergy Clin Immunol. 2019 Apr;143(4):1426-1443.
viii McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin 
Immunol.2013;131:280-91.
ix Irvine, A. D., McLean, W. I., & Leung, D. Y. (2011). Filaggrin mutations associated with skin and 
allergic diseases. New England Journal of Medicine, 365(14), 1315-1327.
x Miossec. Anti-interleukin 1α autoantibodies. Ann Rheum Dis 2002; 61: 577-579.
xi Gallay et al. Characterization and detection of naturally occurring antibodies against IL-1α and IL-1β in 
normal human plasma. Eur Cytokine Network 1991; 2: 329-338.
xii Suzuki et al. Anti- IL-1α autoantibodies in patients with rheumatic diseases and in healthy subjects. 
Clin Exp Immunol 1991; 85: 407-412.
xiii Saurat et al. Anti-IL-1α autoantibodies in humans: characterization, isotype distribution, and receptor-
binding inhibition—higher frequency in Schnitzler’s syndrome (urticaria and macroglobulinemia). J 
Allergy Clin Immunol 1991; 88: 244-256.
xiv Jang et al.  Mass spectrometric quantification of neutral and sialylated N-glycans from a recombinant 
therapeutic glycoprotein produced in Chinese hamster ovary cell lines. Anal. Biochem. 386 (2009) 228-
236.
xv Müller et al. Autoantibodies to IL-1α  in sera from umbilical cords, children, and adults, and from 
patients with juvenile chronic arthritis. Scand J Rheumatol. 1996; 25 (3): 164-7.
                                                       


Page 61 of 61
                                                                                                                                                                                  
xvi Svenson et al. Distribution and characterization of autoantibodies to interleukin 1 alpha in normal 
human sera. Scand J Immunol. 1990: 32 (6): 695-701.
xvii Xu H et al. Increased serum interleukin-6 levels in patients with hidradenitis suppurativa. Postepy 
Dermatol Alergol. 2017 Feb;34(1):82-84. doi: 10.5114/ada.2017.65626. Epub 2017 Feb 7.
xviii Montaudié H et al. Interleukin 6 and high-sensitivity C-reactive protein are potential predictive 
markers of response to infliximab in hidradenitis suppurativa. J Am Acad Dermatol. 2017 Jan;76(1):156-
158. doi: 10.1016/j.jaad.2016.08.036.


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 27 April 2020
Janssen Research & Development*
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Bermekimab in 
Patients with Moderate to Severe Atopic Dermatitis
Protocol JNJ-77474462ADM2002; Phase 2
JNJ-77474462 (bermekimab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved
Date:
27 April 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-37782 version 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
JNJ-77474462
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.
NCT04021862


COVID-19 Appendix
JNJ-77474462 (bermekimab)
Clinical Protocol JNJ-77474462ADM2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 27 April 2020
COVID-19 APPENDIX
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 patients 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 patient management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government guidelines or requirements or the clinical 
judgement of the investigator to protect the health and well-being of patients and site staff. If, at 
any time, a patient’s safety is considered to be at unacceptable risk, drug product 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, patients will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Patients 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 patients on drug 
product, including follow up. Modifications to protocol-required assessments may be permitted 
via COVID-19 Appendix after consultation between the patient and investigator, and with the 
agreement of the sponsor (see below).
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 patient has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for drug product 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.


COVID-19 Appendix
JNJ-77474462 (bermekimab)
Clinical Protocol JNJ-77474462ADM2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 27 April 2020
ADDITIONAL ELEMENTS, WHERE APPLICABLE:

Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of patient care and study integrity. Certain 
measures, such as those listed below, may be necessary and should be instituted in accordance 
with applicable (including local) laws, regulations, guidelines, and procedures:
o
remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and patients for study procedures e.g. those related to 
safety monitoring / efficacy evaluation / drug product storage and administration 
(including training where pertinent)
o
procurement of drug product by patients (or designee) or shipment of drug product 
from the study site directly to patients for at home administration (including the 
potential for self-administration of drug product)
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 case report form (CRF) for protocol
deviations. Discontinuations of drug products and withdrawal from the study should be 
documented with the prefix “COVID-19-related” in the CRF.
o
other relevant study data elements impacted by the pandemic should also be 
documented / labeled as “COVID-19-related” in CRFs and / or other study systems, 
as directed by detailed sponsor guidance. These may include missed / delayed / 
modified study visits / assessments / dosing, and instances where temporary 
measures such as those above are implemented.

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study 
data and additional data analyses will be outlined in study SAP(s).

Precaution: for those who may carry a higher risk for severe COVID-19 illness (eg, those 
aged over 65 years), follow guidance from local health authorities when weighing the 
potential benefits and risks during participation in the study.



SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 24 June 2020
Janssen Research & Development
Statistical Analysis Plan
A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Bermekimab in 
Patients with Moderate to Severe Atopic Dermatitis
Protocol JNJ77474462ADM2002; Phase 2  
JNJ77474462  (Bermekimab)
Status:
Approved
Date:
24 June 2020
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-206310784
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.
NCT04021862


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 24 June 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 8
1.5.1.
Procedures for Randomization and Stratification ......................................................................... 8
1.5.2.
Maintenance of Blind .................................................................................................................... 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Imputation Rules for Partial or Missing AE Dates............................................................................ 9
2.2.
Visit Windows................................................................................................................................. 10
2.3.
Pooling Algorithm for Analysis Centers.......................................................................................... 10
2.4.
Analysis Sets.................................................................................................................................. 11
2.4.1.
Efficacy Analysis Set(s) .............................................................................................................. 11
2.4.1.1.
Full Analysis Set ...................................................................................................................... 11
2.4.1.2.
Per Protocol Analysis Set........................................................................................................ 11
2.4.2.
Safety Analysis Set..................................................................................................................... 12
2.4.3.
Pharmacokinetics Analysis Set .................................................................................................. 12
2.4.4.
Pharmacodynamics Analysis Set ............................................................................................... 12
2.4.5.
Immunogenicity Analysis Set...................................................................................................... 12
2.5.
Definition of Subgroups.................................................................................................................. 12
2.6.
Study Day and Relative Day .......................................................................................................... 13
2.7.
Baseline and Endpoint ................................................................................................................... 13
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 13
4.
SUBJECT INFORMATION................................................................................................................ 13
4.1.
Demographics and Baseline Characteristics ................................................................................. 14
4.1.1.
Demographic .............................................................................................................................. 14
4.1.2.
Baseline Disease Characteristics ............................................................................................... 14
4.1.3.
Medical History ........................................................................................................................... 14
4.2.
Disposition Information................................................................................................................... 15
4.3.
Treatment Compliance................................................................................................................... 15
4.4.
Extent of Exposure......................................................................................................................... 15
4.5.
Protocol Deviations ........................................................................................................................ 16
4.6.
Concomitant Medications............................................................................................................... 16
5.
EFFICACY ......................................................................................................................................... 16
5.1.
General Method of Analysis........................................................................................................... 16
5.2.
Analysis Specifications................................................................................................................... 17
5.2.1.
Level of Significance................................................................................................................... 17
5.2.2.
Data Handling Rules................................................................................................................... 17
5.2.3.
Treatment Groups....................................................................................................................... 18
5.3.
Primary Efficacy Endpoint(s).......................................................................................................... 19
5.3.1.
Definition..................................................................................................................................... 19
5.3.2.
Estimands ................................................................................................................................... 19
5.3.3.
Data Handling ............................................................................................................................. 20
5.3.4.
Analysis Methods........................................................................................................................ 20
5.3.5.
Analysis for Supplementary Estimands...................................................................................... 21
5.3.6.
Subgroup Analysis...................................................................................................................... 21
5.3.7.
Per-protocol Analysis.................................................................................................................. 22
5.4.
Secondary Efficacy Endpoints ....................................................................................................... 22


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 24 June 2020
5.4.1.
Data Handling ............................................................................................................................. 22
5.4.2.
EASI............................................................................................................................................ 22
5.4.2.1.
Definition.................................................................................................................................. 22
5.4.2.2.
Analyses Related to EASI ....................................................................................................... 23
5.4.3.
Numerical Rating Scale (NRS) for Itch & Pain ........................................................................... 24
5.4.3.1.
Definition.................................................................................................................................. 24
5.4.3.2.
Analyses Related to NRS........................................................................................................ 24
5.4.4.
Investigators Global Assessment (IGA)...................................................................................... 25
5.4.4.1.
Definition.................................................................................................................................. 25
5.4.4.2.
Analyses Related to IGA ......................................................................................................... 25
5.4.5.
DLQI............................................................................................................................................ 25
5.4.5.1.
Definition.................................................................................................................................. 25
5.4.5.2.
Analyses Related to DLQI ....................................................................................................... 26
5.4.6.
Hospital Anxiety Depression Scale (HADS) ............................................................................... 26
5.4.6.1.
Definition.................................................................................................................................. 26
5.4.6.2.
Analyses Related to HADS...................................................................................................... 27
5.4.7.
Patient Oriented Eczema Measure (POEM)............................................................................... 27
5.4.7.1.
Definition.................................................................................................................................. 27
5.4.7.2.
Analysis Methods .................................................................................................................... 27
5.4.8.
SCORing Atopic Dermatitis (SCORAD) ..................................................................................... 27
5.4.8.1.
Definition.................................................................................................................................. 27
5.4.8.2.
Analysis Methods .................................................................................................................... 28
5.4.9.
Global Individual Signs Score (GISS)......................................................................................... 28
5.4.9.1.
Definition.................................................................................................................................. 28
5.4.9.2.
Analysis Methods .................................................................................................................... 28
6.
SAFETY............................................................................................................................................. 29
6.1.
Adverse Events .............................................................................................................................. 30
6.2.
Clinical Laboratory Tests................................................................................................................ 31
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 32
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 32
7.1.
Pharmacokinetics........................................................................................................................... 32
7.1.1.
Bermekimab Concentrations ...................................................................................................... 32
7.1.1.1.
Data Handling Rules................................................................................................................ 33
7.1.2.
PK vs Efficacy............................................................................................................................. 34
7.1.3.
Population PK Analysis............................................................................................................... 34
7.2.
Immunogenicity.............................................................................................................................. 34
7.2.1.
Antibodies to Bermekimab.......................................................................................................... 34
7.2.2.
Antibody vs PK/Efficacy/Safety .................................................................................................. 35
7.3.
Biomarkers ..................................................................................................................................... 35
REFERENCES............................................................................................................................................ 36


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 24 June 2020
ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
ALT/SGPT
ALP
alanine aminotransferase
alkaline phosphate
ANCOVA
analysis of covariance
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
AUC
area under the curve
BMI
body mass index
BSA
body surface area
CI
confidence interval
CL
total systemic clearance
Cmax
maximum concentration
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
DLQI
coefficient of variation
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DPS
EASI
Data Presentation Specifications
Eczema Area and Severity Index Score
ECG
ELISA
Electrocardiogram
Enzyme-linked immunosorbent assay
eCRF
electronic case report form
F (%)
absolute SC bioavailability
FAS
full analysis set
FDA
GISS
HADS
Food and Drug Administration
Global Individual Signs Score
Hospital Anxiety Depression Scale
ICH
IGA
International Conference on Harmonization
Investigator’s Global Assessment
IQ
interquartile
IL-6
Interleukin-6
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimum required dilution
Nab
NRS
neutralizing antibodies
Numerical Rating Scale
PD
pharmacodynamic
PI
principal investigator
PK
POEM
pharmacokinetic(s)
Patient Oriented Eczema Measure
PP
SCORAD
per protocol
Severity Scoring of Atopic Dermatitis
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
TB
standardised MedDRA queries
Tuberculosis
TEAE
treatment-emergent adverse event
US NCI
United States National Cancer Institute
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 24 June 2020
Summary of Amendment 1
This amendment is to add additional statistical method of Fisher’s Exact test for the binary efficacy 
endpoints in case of rare events. Originally, the planned analysis for treatment comparison in 
binary response endpoints is to use a Cochran-Mantel-Haenszel test. 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 24 June 2020
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the analysis of efficacy, safety, pharmacokinetics (PK), pharmacodynamics 
(PD), Immunogenicity and health-related quality of life in the JNJ77474462ADM2002(PT-046)
study.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate the initial efficacy, safety of different dose 
regimens of bermekimab in adult participants with moderate to severe Atopic Dermatitis (AD).
Secondary Objectives
The secondary objectives of this study are:

To evaluate the effect of bermekimab on the dermatologic health-related quality of life in adult 
participants with moderate to severe AD.

To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of 
bermekimab therapy in adult participants with moderate to severe AD.
1.2.
Trial Design
This is a phase II, randomized, double-blind, placebo-controlled study to further establish the 
efficacy, safety, PK, and explore dose effects for bermekimab monotherapy in adults with 
moderate to severe Atopic Dermatitis (AD). The participant population will comprise men and 
women who have had chronic atopic dermatitis present for at least 3 years. The study is 
approximately 40 weeks (30 day screening period, 32-week treatment period and a 4-week follow-
up period) for all subjects. 
A diagram of the study design (Figure 1) is provided below, approximately 90 patients who meet 
the eligibility criteria at screening will be randomized in a 1:1:1 ratio to one of two active 
treatment arms or placebo:

Arm 1: 400 mg loading dose of bermekimab (2mL SC injection containing 400 mg 
of bermekimab and one 2mL SC injection of placebo) at Week 0 followed by weekly 
(qw) subcutaneous (SC) injections of 400 mg bermekimab through Week 31

Arm 2: 800 mg loading dose of bermekimab (2 x 400 mg SC injections) at Week 0
followed by subcutaneous (SC) injections of 400 mg bermekimab every other week 
(q2w) alternating with matching placebo q2w through Week 31.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved, Date: 24 June 2020

Arm 3: 4mL loading dose of placebo (2 x 2mL SC injections) at Week 0 followed by 
weekly placebo injections from Week 1 through Week 15. Patients in Arm 3 will 
begin to receive weekly (qw) blinded subcutaneous (SC) injections of 400 mg 
bermekimab beginning at Week 16 through Week 31.
Patients will be monitored at a follow up visit (week 36) for safety and clinical assessments after 
completing the 32 week treatment period.
Efficacy assessments include Eczema Area and Severity Index Score (EASI) score, Itch Numerical 
Rating Scale (NRS), Pain NRS, Severity Scoring of Atopic Dermatitis (SCORAD), Patient 
Oriented Eczema Measure (POEM), Global Individual Signs Score (GISS), Dermatology Life 
Quality Index (DLQI), Hospital Anxiety Depression Scale (HADS), Body Surface Area (BSA)
and Investigator’s Global Assessment (IGA) will be performed according to the Study Calendars 
(Section 5.2 of the protocol). 
Blood samples will be collected for laboratory testing including chemistry, hematology, 
inflammation markers, bermekimab concentration (PK), PD marker(s), and anti-drug antibody 
(ADA).  
Figure 1:
Study Flow Diagram of JNJ77474462ADM2002
After completion of the 36-week study period, data will be locked and analysed for safety and 
efficacy. In addition to the analyses that will be performed following the formal Week 36 database 
lock at the end of the study, an additional database lock will be performed at Week 16 and the 
unblinded efficacy data analyses will be conducted to help plan potential future development 
activities.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis is that bermekimab treatment is superior to placebo as assessed by the 
proportion of participants achieving Eczema Area and Severity Index-75 (EASI-75) (≥75% 
improvement from baseline in EASI score) at Week 16.
Baseline
Endpoint 
Assessment
Visit (V)
V1
V33
Week (W)
W0
W32
Day (D)
D0
D224
W1 to W31
W36
D7 to D217
D252
Screening 
Treatment Period 
Follow-up 
Weekly Dosing
V2 to V32
V34
D -30 to -1 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status: Approved, Date: 24 June 2020
1.4.
Sample Size Justification
The primary efficacy endpoint is percentage of patients with Eczema Area and Severity Index-75 
(EASI-75) (≥75% improvement from baseline) at Week 16. The sample size is calculated for the 
bermekimab weekly injection group (Arm 1) versus placebo group (Arm 3) comparison.
Assuming EASI-75 is achieved in 60% of intent-to treat (ITT) patients treated in the bermekimab 
weekly injection group (Arm 1) versus 20% in placebo treated patients (Arm 3), then, for a 
randomization ratio of 1:1:1, a sample size of 69 patients (23 in each treatment group) is required 
for approximately 80% power at a 2-sided 0.05 significance level using Pearson chi-square test.  
In order to account for possible dropouts and to provide adequate safety data, approximately 90 
patients will be randomized and treated.
1.5.
Randomization and Blinding
1.5.1.
Procedures for Randomization and Stratification
A centralized block randomization schedule with a 1:1:1 allocation ratio will be utilized using an 
electronic randomization system. Patients will be randomly assigned to either the bermekimab 
weekly injection group (Arm 1), the bermekimab every other week injection group (Arm 2), or the 
placebo group (Arm 3).  The randomization schedule will be stratified by baseline EASI severity 
(less severe [EASI <28] or more severe [EASI ≥28]).
1.5.2.
Maintenance of Blind
The study blind will be maintained for the duration of the study, until after the Final (Week 36) 
DBL.
In order to maintain blinding, all patients will receive two injections at Week 0, followed by weekly 
injections from Week 1 to 31. Additionally, to ensure that no unintentional unblinding occurs 
during study drug administration, a qualified individual will be designated at each study site to 
perform all preparation and injection of the investigational product. The designated injector 
should have no other contact with the participant during the study, should not discuss the 
participant’s treatment with the participant, participant’s caregiver, or other site personnel at any 
time, and will not be permitted to review the participant’s medical records, questionnaires, or the 
electronic CRF prior to each injection. The designated injector should be documented in the source 
documents at each visit.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the Electronic Data Capture (EDC) system, 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-bermekimab antibodies, and intervention allocation) will be handled with 
special care to ensure that the integrity of the blind is maintained and the potential for bias is 
minimized. This can include making special provisions, such as segregating the data in question 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9
Status: Approved, Date: 24 June 2020
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. However, a number of prospectively identified Sponsor 
individuals will be unblinded at the Week 16 DBL. Identification of sponsor personnel who will 
have access to the unblinded data at subject-level and who will have access to the unblinded data 
at group-level will be documented prior to unblinding at the Week 16 DBL. All site personnel and 
participants will remain blinded to the treatment assignments until the last participant completes 
Week 36 evaluations and the database has been locked. 
In the event of an emergency that would require the investigator to be aware of the treatment 
allocation prior to the end of the trial, the investigator can obtain this information, on a per subject 
basis, after consultation with the Sponsor’s Medical Monitor, if possible. Every effort should be 
made to consult with the Medical Monitor prior to emergency unblinding. Events that qualify as 
emergencies are as follows:

A grade 3 or greater AE which are “probably or definitely” related to study drug, and only 
if treatment assignment information is essential for the management of the event. This type 
of reaction would require that the patient receives no further doses and is followed until 
the resolution of the toxicity.

Any suspected, unexpected, serious adverse reaction (SUSAR)

Pregnancy
The investigator may, in an emergency, determine the identity of the intervention through the EDC
system. 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 unblinding must be documented in the appropriate section of the eCRF, and in the source 
document. 
Participants who have had their intervention assignment unblinded by the investigator will not be 
eligible to receive further study intervention but should continue to complete evaluations specified 
in the Study Calendars (Section 5.2 of the protocol).
2.
GENERAL ANALYSIS DEFINITIONS
This analysis plan provides the general analysis definitions and describes the planned subject
information, efficacy, safety, pharmacokinetics, and antibody analyses for the two planned DBLs.
2.1.
Imputation Rules for Partial or Missing AE Dates
Partial AE onset dates will be imputed as follows:


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 24 June 2020

If the onset date of an adverse event is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of the study agent start 

The day of study agent start, if the month/year of the onset of AE is the same as 
month/year of the study agent start date and month/year of the AE resolution date is 
different

The day of study agent start or day of AE resolution date, whichever is the earliest, if 
month/year of the onset of AE and month/year of the study agent start date and 
month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:

January 1 of the year of onset, as long as this date is on or after the study agent start date 

Month and day of the study agent start date, if this date is in the same year that the AE 
occurred

Last day of the year if the year of the AE onset is prior to the year of the study agent start 
date, 

The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the earliest of 
the last day of the month of occurrence of resolution or the date of death, if the death occurred 
in that month.

If the resolution date of an adverse event is missing both day and month, it will be set to the 
earliest of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.

Completely missing resolution dates will not be imputed.
2.2.
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 36 should occur within ± 3 days of the scheduled visit. The sponsor must be 
contacted for any significant deviation in the scheduling of a visit outside the appropriate window 
and determine how the subject should resume his/her normal dosing schedule relative to the 
baseline visit (Week 0). 
2.3.
Pooling Algorithm for Analysis Centers
Unless otherwise specified, data from all investigational centers/sites will be pooled for analyses. 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 24 June 2020
2.4.
Analysis Sets
There will be two database locks at Weeks 16 and 36 respectively.
Week 16 database lock
Week 16 database lock will include selected efficacy, safety, and PK data through Week 16 for all 
randomized and treated participants. The data will be primarily used in planning for future 
bermekimab clinical development in AD. The selected efficacy and safety data include but are not 
limited to the following:
1.
Eczema Area and Severity Index (EASI) 
2. Investigators Global Assessment (IGA) score 
3. Itch Numeric Rating Scale (NRS) score 
4. Pain Numeric Rating Scale (NRS) score 
5. Baseline Disease Characteristics for 1-4 above
6. Demography
7. AE
8. PK
Week 36 database lock
Week 36 DBL would include all data through Week 36 for all randomized and treated participants.
2.4.1.
Efficacy Analysis Set(s)
2.4.1.1.
Full Analysis Set
The full analysis set (FAS) population includes all randomized participants who received at least 
1 dose of study agent.  This analysis set will be used for the efficacy analyses of the endpoints 
through Week 36, unless otherwise specified.
In the efficacy analyses, participants will be analyzed according to the randomized treatment 
groups they were assigned to, regardless of the treatments they actually received.  
2.4.1.2.
Per Protocol Analysis Set
The primary endpoint will also be analyzed using the per-protocol population, which includes 
participants who are generally compliant with the protocol.
Specifically, the per protocol population includes participants in FAS except those

who did not meet the inclusion criteria in the protocol as listed below:

EASI score ≥16 at screening and baseline visits.

IGA score ≥3 at screening and baseline visits.

≥10% body surface area (BSA) of AD involvement at screening and baseline visits.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Status: Approved, Date: 24 June 2020

NRS Weekly Average of worst daily Skin Itch Scores at least 3 at screening

who did not receive all scheduled study agent administrations prior to Week 16.
However, for those who discontinued the study agent prior to Week 16 will be included in the per 
protocol analysis and the data handling rule specified in section 5.2.2 will apply.
2.4.2.
Safety Analysis Set
The safety analysis set includes all randomized participants who received at least 1 dose of study 
agent, i.e., the treated population.
2.4.3.
Pharmacokinetics Analysis Set
The pharmacokinetic (PK) analysis set includes all participants who received at least 1 dose of 
bermekimab and had at least 1 valid blood sample drawn for PK analysis after their first dose of 
bermekimab.
2.4.4.
Pharmacodynamics Analysis Set
The Pharmacodynamics (PD) analysis set includes all participants who received at least 1 dose of 
bermekimab and had at least 1 valid blood sample drawn for PD analysis after their first dose of 
bermekimab.
2.4.5.
Immunogenicity Analysis Set
The immunogenicity analysis set includes all participants who received at least 1 dose of 
bermekimab and who have at least 1 sample obtained after their first dose of bermekimab for the 
detection of antibodies to bermekimab.
2.5.
Definition of Subgroups
To evaluate the consistency in the primary efficacy endpoint (proportion of participants who 
achieve EASI-75 at Week 16) over demographics, baseline disease characteristics, and prior and 
baseline medication use, subgroup analyses will be performed when sample sizes are permitted.  
The subgroups include, but are not limited to, the following:
Baseline demographics:

Sex (male, female)

Race 

Baseline Age (<40 years, 40 to <65 years, 65 years)

Baseline weight (80 kg, >80 kg) 

BMI (Normal [<25], Overweight [25 -<30], Obese [≥ 30])


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved, Date: 24 June 2020
Baseline disease characteristics and AD medication:

Age at diagnosis (years) (< median, ≥ median)

AD disease duration (years) (< median, ≥ median)

Baseline EASI severity (less severe [EASI <28] or more severe [EASI ≥28])

Baseline IGA (3, 4)

Baseline C-reactive protein (CRP) (< median, ≥ median)

Baseline Erythrocyte Sedimentation Rate (ESR) (< median, ≥ median)

Prior biologic therapy (Yes/No)
2.6.
Study Day and Relative Day
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.
2.7.
Baseline and Endpoint
In general, the baseline measurement is defined as the closest measurement taken prior to or at the 
time of the first study agent administration date unless otherwise specified.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis or data monitoring committee review is planned for this study.
4.
SUBJECT INFORMATION
Unless specified otherwise, FAS will be used for the subject information analyses and participants
will be analyzed according to the treatment group to which they were randomized, regardless of 
the treatment they actually received. The number of participants in each analysis set will be 
summarized by treatment group and overall. 
Simple descriptive statistics, such as mean, median, standard deviation, interquartile range, 
maximum, and minimum for continuous variables, and counts and percentages for discrete 
variables will be used to summarize most data and no formal hypothesis testing for treatment 
comparisons will be performed. In addition, subject listings will also be used to present the data.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status: Approved, Date: 24 June 2020
4.1.
Demographics and Baseline Characteristics
The FAS will be used for all tabulations. Participants’ demographic data and baseline disease 
characteristics will be summarized by treatment group.  If imbalances are found at baseline, then 
additional analyses may be performed adjusting for baseline differences.
4.1.1.
Demographic
Table 1 presents a list of the demographic variables that will be summarized by treatment group, 
and overall for the FAS.
Table 1:
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight (kg) 
Height (cm)
Categorical Variables:
Age (<40 years, 40 to <65 years, and 65 years)  
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female)
Weight (kg) (<= 80 kg, > 80 kg)
Race (American Indian or Alaska Native, Asian, Black or African 
American, White, Other)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
BMI (Normal [<25], Overweight [25 -<30], Obese [30])
4.1.2.
Baseline Disease Characteristics
Baseline disease characteristics (e.g., duration of AD disease, EASI score, GISS, POEM, 
SCORAD score, BSA, baseline IGA, NRS pain, NRS Itch, HADS, DLQI) will be summarized by 
treatment group. 
4.1.3.
Medical History
Summaries of participants’ alcohol intake, and smoking status will be provided by treatment group. 
In addition, the distribution of participants by prior biologic use (yes/no) and type of biologic 
therapy will also be provided.
Medical history will be listed including body systems and condition/non-drug allergy as captured 
on the eCRF.  


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
15
Status: Approved, Date: 24 June 2020
4.2.
Disposition Information
The number of participants in the following disposition categories will be summarized by 
treatment group and overall:

Participants screened: met the inclusion criteria regarding the target indication and signed 
the informed consent

Participants randomized 

Participants randomized and received at least 1 study agent

Participants who completed the study through Week 16 and Week 36

Participants who discontinued study and the reasons for discontinuation through Week 
16 and Week 36
Listings of participants will be provided for the following categories:

Participants who discontinued study 

Participants who were unblinded during the study period 
4.3.
Treatment Compliance
Study agent compliance will be summarized descriptively through Week 16 and through the end 
of the study (Week 36) for the FAS. Number of the participants receiving each scheduled treatment 
will be summarized. In addition, treatment compliance will also be assessed by protocol deviations 
related to study agent administration (i.e., incorrect study agent or dose received). 
4.4.
Extent of Exposure
The exposure data will be summarized through Week 16 and Week 36. The number and percentage 
of participants who receive study agent will be summarized by treatment group for the safety 
analysis set. Descriptive statistics will be presented for the following parameters:

Number of administrations

Cumulative total dose 
In addition, the average exposure (number of administrations) and average duration of follow-up 
(weeks) will also be summarized by treatment group in the safety tables through different study 
time periods.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved, Date: 24 June 2020
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical trial. 
Participants with major protocol deviations will be identified prior to database lock and will be 
summarized by category by treatment group through Week 16 and Week 36 for the FAS.

Entered study and did not satisfy entry criteria

Received wrong treatment or incorrect dose

Received excluded concomitant or non-drug therapy

Out of window visit

Out of window procedure

Other
A listing of participants with major protocol deviations and a listing of patients who missed 
scheduled study agent administration will also be provided by randomized treatment group. In 
addition, analyses of COVID-19 related protocol deviations will be provided.
4.6.
Concomitant Medications
Concomitant medications for atopic dermatitis will be summarized by treatment group for the 
FAS. Prior medications are defined as any therapy used before the day of first dose (partial or 
complete) of study agent. Concomitant medications are defined as any therapy used on or after the 
same day as the first dose of study agent, including those that started before and continued after 
the first dose of study agent.
A list of participants who received a concomitant treatment that could improve AD will be 
provided.
5.
EFFICACY
5.1.
General Method of Analysis
Unless specified otherwise, efficacy data summaries will be provided by treatment group for the 
FAS. Statistical comparisons will be made between each of the bermekimab treatment groups (qw, 
q2w) and the placebo treatment group.
In general, for response efficacy endpoints, treatment comparisons will be performed using a 
Cochran-Mantel-Haenszel (CMH) test stratified by the baseline EASI severity (less severe
EASI<28, more severe EASI ≥28) or the Fisher’s Exact test in case of rare events. For continuous 
efficacy endpoints, treatment comparisons will be performed using a Mixed-Effect Model 
Repeated Measure (MMRM) with treatment group, visit, baseline EASI severity (less severe, more 
severe) and baseline value for the efficacy endpoint as explanatory factors. The MMRM model 
will also include treatment group by visit interaction, baseline EASI severity by visit and baseline 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved, Date: 24 June 2020
value by visit interaction as additional explanatory factors. In addition, treatment differences and 
their associated 95% confidence intervals will be presented.
Descriptive statistics, such as mean, median, standard deviation, minimum and maximum,
interquartile range for continuous variables, and counts and percentages for categorical variables 
will be used to summarize the data. Graphical data displays and subject listings may also be used 
to summarize the data.
5.2.
Analysis Specifications
5.2.1.
Level of Significance
Unless otherwise specified, all statistical testing procedures will be performed at a 2-sided 
significance level of 0.05. Multiplicity adjustment was planned for the primary endpoint as 
specified in protocol Section 10.5.3 to maintain an overall Type I error of 0.05 or less for the 
primary endpoint analysis. 
However, since this is a Phase 2 trial and stricter multiplicity adjustment for the primary endpoint 
at an overall alpha level of 0.05 is not required; a less stringent type I error control will be 
implemented instead. The study would be considered as positive if any of the comparisons for 
primary endpoint analysis (weekly injection group vs placebo, and every other week injection 
group vs placebo) is less than or equal to 0.05. Therefore, an overall Type I error rate will be 
maintained at 0.1 or less for the primary endpoint analysis. Nominal p-values will be reported for 
secondary analyses.
5.2.2.
Data Handling Rules
No imputation will be performed for missing baseline values.
For the main analysis of primary endpoint of EASI-75 response at Week 16, a subject who 
discontinued treatment will be considered as a non-responder from that point onward. The 
remaining missing data will be imputed as non-responder. Supplementary analyses will be 
performed and include (1) using observed data regardless of whether the subject discontinued 
treatment or have missing data, and (2) data after treatment discontinuation will be considered as 
missing, missing response will be imputed by multiple imputation methods under the assumption 
of missing at random. Similar data handling rules (i.e., main analysis with non-responder 
imputation and 2 supplementary analyses) will also be applied for EASI-75 response over time 
through Week 16. The following data handling rules will be applied for other endpoints:
Binary secondary endpoints:

Analyses will be similar to the main analysis of the primary endpoint.  A subject who 
discontinued treatment will be considered as a non-responder from that point onward. 
The remaining missing data will be imputed as non-responder. Supplementary analyses 
will be performed for selected endpoint (i.e IGA responses) in the same manner as the 
primary endpoint.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Status: Approved, Date: 24 June 2020
Continuous secondary endpoints:

If a subject discontinued treatment, zero will be assigned to improvement or percent 
improvement. Remaining missing data will not be imputed. A MMRM model will adjust 
for missing post baseline data and all available data from the 3 treatment groups through 
Week 16 or from Week 16 through Week 36 will be included. Under the assumption of 
missing at random (MAR), the missing data will be accounted for through correlation of 
repeated measures in the model. Supplementary analyses will be performed for selected 
endpoints (i.e. EASI total score, NRS itch score) and include (1) using observed data 
regardless of whether the subject discontinued treatment or have missing data, and (2) 
data after treatment discontinuation will be considered as missing, missing data will be 
addressed by MMRM model.
5.2.3.
Treatment Groups
In the efficacy analyses, FAS will be used and the participants will be analyzed according to the 
randomized treatment groups they were assigned to, regardless of the treatments they actually 
received. Unless otherwise specified, efficacy analyses during each of study periods below are in 
general displayed as follows:

Analysis through Week 16 

Efficacy analyses for placebo comparison at Week 16 or through Week 16 will be 
summarized by randomized treatment group:
o
Placebo:  Participants randomized to placebo group.
o
Bermekimab 400 mg q2w:  Participants randomized to bermekimab 400 mg every 
other week injection group.
o
Bermekimab 400 mg qw: Participants randomized to bermekimab 400 mg weekly 
injection group.
o
Combined Column: Combined column which combines the data from the 
randomized and treated participants who are assigned to bermekimab 400 mg q2w 
or qw treatment groups.

Analysis from Week 16 through Week 36

Efficacy data from Week 16 through Week 36 will be summarized by the following 
treatment groups:  
o
Placebo Bermekimab 400 mg qw: efficacy in participants randomized to placebo 
group.  

Only placebo participants crossover to bermekimab 400 mg qw and received 
bermekimab at Week 16 will be included in the summary for the visits after 
Week 16.
o
Bermekimab 400 mg q2w: Participants randomized to bermekimab 400 mg every 
other week injection group.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status: Approved, Date: 24 June 2020
o
Bermekimab 400 mg qw: Participants randomized to bermekimab 400 mg weekly 
injection group.
o
Combined Column: Combined column which combines the data from the 
randomized and treated participants who are assigned to bermekimab q2w or qw 
treatment groups at baseline.
These presentations allow assessment of efficacy over time between treatment groups.
5.3.
Primary Efficacy Endpoint(s)
5.3.1.
Definition
The primary efficacy endpoint is the proportion of patients achieving an EASI-75 response at 
Week 16. The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD. Four AD disease characteristics will be assessed for severity by the 
investigator or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of 
AD involvement will be assessed as a percentage by body area of head, trunk, arms, and legs and 
converted to a score of 0 to 6. 
For each region, severity score is the sum of intensity for each of four signs.

Severity score = Erythema + Edema/Papulation + Excoriation + lichenification intensity
For each 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-75 responder is defined as at least a 75% improvement from baseline in EASI total score.
5.3.2.
Estimands
Primary Estimand:
The Composite Estimand will be targeted for the primary endpoint.  The Composite Estimand 
for the primary endpoint is defined by the following 5 attributes:

Treatment:
Bermekimab 400mg q2w
Bermekimab 400mg qw


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Status: Approved, Date: 24 June 2020
Placebo
Note: treatment regimen includes protocol specified rescue therapy as needed.

Population:  Adult participants with chronic moderate to severe atopic dermatitis present 
for at least 3 years.

Variable (Endpoint):  EASI-75 binary responder variable at Week 16, where a subject 
who discontinues treatment is considered as non-responder after discontinuation.

Intercurrent event:  The intercurrent event of treatment discontinuation is addressed by 
the composite strategy, as reflected in the variable definition.

Population-level summary:  Difference in the proportions of subjects achieving EASI-75
response at Week 16 between the bermekimab and placebo treatment groups.
Supplementary Estimands for primary endpoint:
Supplementary Estimand 1
Same components as the primary estimand, except for the strategy used for treatment 
discontinuation.
Hypothetical strategy: assess the treatment effect as if the participants would not have 
discontinued treatment.
Note: Under this hypothetical strategy, EASI data collected after treatment discontinuation will 
not be used and will be set to missing in analysis. 
Supplementary Estimand 2
Same components as the primary estimand, except for the strategy used for treatment 
discontinuation.
Treatment policy strategy:  assess the treatment effect regardless of treatment discontinuation. 
Note: Under the treatment policy strategy, EASI data collected after treatment discontinuation will 
also be used in analysis.
5.3.3.
Data Handling
Participants who discontinued treatment prior to Week 16 will be considered EASI-75 non-
responder at Week 16. In addition, participants with missing EASI evaluation at Week 16 will be 
considered as non-responders at Week 16. 
5.3.4.
Analysis Methods
The primary endpoint will be compared between the each bermekimab group and the placebo 
group. The primary endpoint will be analyzed at Week 16 based on the composite estimand 
(Section 5.3.2) and the data from all participants in FAS (Section 2.4.1.1) will be analyzed 
according to randomized treatment group regardless of the treatment actually received.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Status: Approved, Date: 24 June 2020
In this primary analysis, the number and proportion of participants who achieve an EASI-75 at 
Week 16 will be summarized for each treatment group. To address the primary objective, a CMH 
chi-square statistic stratified by baseline EASI severity (less severe [EASI <28] or more severe 
[EASI ≥28]) at an alpha level of 0.05 will be used to compare each bermekimab group separately 
with placebo. The proportion difference between each bermekimab group and placebo group and 
its 2-sided 95% CI will be provided based on normal approximation with Mantel-Haenszel weights 
adjusting for baseline EASI severity.
5.3.5.
Analysis for Supplementary Estimands
Supplementary Analysis 1 (Hypothetical Estimand)
Under this estimand, for subjects who do not return for evaluation or discontinued study treatment 
for any reason, EASI score will be considered missing after discontinuation and missing data will 
be imputed using multiple imputations (MI)1 by fully conditional specification (FCS).
More specifically, the missing EASI-75 response will be imputed with FCS logistic regression 
including treatment group, baseline EASI, and EASI-75 response status through Week 16 in the 
model with seed = 789 and 500 imputations. The proportion difference of EASI-75 response at 
Week 16 adjusted for baseline EASI severity using Mantel-Haenszel weight between the 
bermekimab groups and the placebo group and its 95% CI combining multiple datasets will also 
be provided. In addition, the p-value for testing the treatment difference will be obtained from SAS 
PROC MIANALYZE based on these combined Mantel-Haenszel estimates from the multiple 
imputation datasets.
Supplementary Analysis 2 (Treatment Policy Estimand)
The primary endpoint will be analyzed utilizing the treatment policy estimand. For participants 
who do not return for evaluation or skipped visit at Week 16, the analysis will be performed using 
observed data regardless of treatment discontinuation. The EASI-75 values collected after 
treatment discontinuation will be used in analysis and missing data will not be imputed.
5.3.6.
Subgroup Analysis
For each of the subgroups defined in Section 2.5, the difference between each of the bermekimab
treatment group and placebo group in the proportion of participants achieving EASI-75 at Week 16 
and its 95% confidence interval (when the number of participants permits) will be calculated.  
Subgroup analyses will not be stratified by baseline EASI severity.
In addition, the proportion of participants achieving EASI-75 at Week 16 by investigator site will 
be summarized. The same data handling rules specified in Section 5.2.2 will apply for subgroup 
analysis.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
22
Status: Approved, Date: 24 June 2020
5.3.7.
Per-protocol Analysis
The primary estimand will also be performed on per-protocol analysis set (Section 2.4.1.2). The 
same data handling rules specified in Section 5.3.3 will apply.
5.4.
Secondary Efficacy Endpoints
This section outlines the definition and analyses of these secondary endpoints related to NRS, 
EASI, IGA, DLQI, HADS, POEM, SCORAD, and GISS.  Data from all participants in FAS will 
be included and analyzed according to the randomized treatment groups. For participants 
randomized to placebo, only participants who crossed over to receive bermekimab at Week 16 will 
be included in the efficacy summaries for the visits after Week 16. All statistical testing will be 
performed at the 2-sided 0.05 significance level. Nominal p-values will be presented.
Secondary efficacy endpoints will be summarized using descriptive statistics for continuous 
variables (n, mean, standard deviation, median, minimum and maximum value) and number and 
percentage for categorical variables. Continuous endpoints will be analyzed using a MMRM model 
to test the difference between treatment groups and adjust for missing data.  The MMRM will 
includes treatment, visit, baseline EASI severity, baseline score, baseline score by visit interaction, 
baseline EASI severity by visit interaction and the treatment-by-visit interaction, if applicable. The 
Least Square mean (LSmean) estimates and their corresponding 95% confidence interval (CI) will 
be provided at each time points.  In addition, the estimates of LSmean difference and 95% CIs 
between treatment groups will be provided over time through Week 16 and p-values will be 
calculated at Week 16.
For the MMRM model, an unstructured covariance matrix for repeated measure within a 
participant will be used. In case that convergence cannot be achieved, autoregressive (1)
covariance structure will be used.
For binary response endpoints, treatment comparisons will be performed using a Cochran-Mantel-
Haenszel (CMH) test stratified by baseline EASI severity with missing data imputed with Non-
Responder Imputation (NRI) defined in Section 5.2.2. In case of rare events, the Fisher’s Exact 
test will be used for treatment comparisons in binary response endpoints.
Graphical data displays may also be used to summarize the over time data if applicable.
5.4.1.
Data Handling
Unless otherwise specified, data handling rules specified in Sections 5.2.2 will be applied to the 
secondary analyses. 
5.4.2.
EASI
5.4.2.1.
Definition
Refer to Section 5.3.1 for the definition of EASI score.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
23
Status: Approved, Date: 24 June 2020
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.
5.4.2.2.
Analyses Related to EASI

The proportion of participants who achieve EASI-50, EASI-90, EASI-100 at Week 16 will 
be compared between each of the bermekimab group and the placebo group. 

The improvement from baseline in EASI total score at Week 16 will be compared between 
each bermekimab group and placebo group using a MMRM model including treatment 
group, visit, treatment group by visit interaction as factors, baseline EASI score, and 
baseline EASI score by visit interaction as covariates.

The proportion of participants who achieve EASI-50, EASI-75, EASI-90, and EASI-100 
will be summarized by treatment group over time. In addition, for participants who 
discontinued study treatment or have missing data, the proportion of participants who 
achieve EASI-75 through Week 16 will be analyzed utilizing the hypothetical estimand
(i.e. MI method) and treatment policy estimand (i.e. observed data).

The proportion of participants who achieve EASI-75 by baseline EASI severity will be 
summarized by treatment group over time through Week 16. In addition, a line plot 
displaying the proportions and 95% CIs for EASI-75 response through Week 16 by 
treatment group will be provided.

The improvement from baseline and percent improvement from baseline in EASI total 
score will be summarized by treatment group over time.

The proportion of subjects who achieve 100% improvement, 90%, 75%, or 50% 
improvement from baseline in EASI component (Edema/Papulation, erythema, and 
Excoriation) and region component (heck/neck, trunk, upper extremities, and lower 
extremities) will be summarized over time by treatment group. 
In addition, two supplementary analyses (a) improvement from baseline in EASI total score at 
Week 16, and (b) improvement from baseline and percent improvement from baseline in EASI 
total score over time will be performed with the following data handling rules:

Data is considered as missing after the discontinuation of study intervention, missing data 
is handled through the MMRM model.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
24
Status: Approved, Date: 24 June 2020

Data will be analyzed based on observed data regardless of whether the subject 
discontinued treatment or have missing data.
5.4.3.
Numerical Rating Scale (NRS) for Itch & Pain
5.4.3.1.
Definition
Patients will be given a diary to complete each night before bed. Patients will be asked to report 
“average pain”, and “worst moment pain” as well as “average itch” and “worst moment itch” on a 
0-10 numeric rating scale. Patient diaries will be collected weekly. A higher score indicates more 
severe disease (0 indicate no itch or no pain). 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.
5.4.3.2.
Analyses Related to NRS

The improvement (reduction) from baseline in NRS score (weekly average overall pain, 
weekly average worst daily pain, weekly average overall Itch, weekly average worst daily 
Itch) at Week 16 will be compared between each bermekimab group and placebo group 
using a MMRM model.  

The proportion of participants who achieve ≥4-point improvement (reduction) in NRS 
score (weekly average overall pain, weekly average worst daily pain, weekly average 
overall Itch, weekly average worst daily Itch) from baseline at Week 16 will be compared 
between each bermekimab group and placebo group using a CMH test stratified by baseline 
EASI severity in patients with baseline score ≥4.

The improvement (reduction) from baseline in NRS score (weekly average overall pain, 
weekly average worst daily pain, weekly average overall Itch, weekly average worst daily 
Itch) will be summarized by treatment group over time.

The proportion of participants who achieve ≥4-point improvement (reduction) in NRS 
score (weekly average overall pain, weekly average worst daily pain, weekly average 
overall Itch, weekly average worst daily Itch) from baseline will be summarized by 
treatment group over time in patients with baseline score ≥4.
In addition, two supplementary analyses (a) improvement from baseline in NRS itch score at 
Week 16, and (b) improvement from baseline in NRS itch score over time will be performed with 
the following data handling rules:

Data is considered as missing after the discontinuation of study intervention, missing data 
is handled through the MMRM model.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
25
Status: Approved, Date: 24 June 2020

Data will be analyzed based on observed data regardless of whether the subject 
discontinued treatment or have missing data.
5.4.4.
Investigators Global Assessment (IGA)
5.4.4.1.
Definition
The Investigator’s Global Assessment (IGA) documents the investigator’s assessment of severity 
of AD and clinical response to treatment based on a 5-point scale clear (0), almost clear (1), mild 
(2), moderate (3), or severe (4). A higher score indicates more severe disease
5.4.4.2.
Analyses Related to IGA

The proportion of subjects achieve an IGA score of clear (0), IGA score of clear (0) or 
almost clear (1), and IGA score of mild or better (2) and at least 2 grade improvement 
from baseline at Week 16 will be compared between each of the bermekimab groups and 
the placebo group.

The proportions of subjects who achieve an IGA score of clear (0) response, IGA score of 
clear (0) or almost clear (1) response, and IGA score of mild or better (2) and at least 2 
grade improvement from baseline response over time will be summarized by treatment 
group. In addition, supplementary analyses for the proportion of participants who achieve 
IGA responses through Week 16 will be performed utilizing the hypothetical estimand (i.e. 
MI method where appropriate using the similar method as for EASI-75) and treatment 
policy estimand (i.e. observed data).

Line plots will be provided displaying the proportions and 95% CIs of subjects achieve an 
IGA score of clear (0); and an IGA score of clear (0) or almost clear (1) through Week 16
by treatment group.
5.4.5.
DLQI
5.4.5.1.
Definition
The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of AD
disease on a subject’s quality of life.  It is a simple response (0 to 3 where 0 is “not at all” and 3 is 
“very much”) to 10-item questionnaire that, in addition to evaluating overall quality of life, can be 
used to assess 6 different aspects that may affect quality of life:  symptoms and feelings, daily 
activities, leisure, work or school performance, personal relationships, and treatment. The DLQI 
is calculated by summing the score of each question resulting in a maximum of 30 and a minimum 
of 0. A higher score indicates more severe disease. A score of ≤1 indicates no effect at all of disease 
on subject’s health related quality of life, and a reduction of 5 points or more in total DLQI score 
is considered clinically meaningful improvement.
For a partially answered questionnaire (eg, not all 10 answers in the DLQI questionnaire were 
available):


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
26
Status: Approved, Date: 24 June 2020

If one question’s answer is not available, this question will be scored 0.  The total score will 
then be calculated.

If two or more questions’ answers are unavailable, the questionnaire is not scored.  Hence, the 
total score and each of the 6 component scores will be set to missing.
If one question from one of the 6 component scores is missing, the affected component score will 
be set to be missing.
5.4.5.2.
Analyses Related to DLQI

The change from baseline in DLQI at Week 16 will be compared between each 
bermekimab group and placebo group using a MMRM model to test the difference between 
treatment groups.

The proportions of participants with DLQI score of 0 and 1 at Week 16 for the participants 
with baseline DLQI score >1 and the proportion of participants with a reduction of 5 or 
more points in DLQI score for the participants with baseline DLQI score ≥ 5 at Week 16 
will be compared between each of the bermekimab groups and the placebo group.

The change from baseline in DLQI total score will be summarized over time by treatment 
group.

The proportions of participants with DLQI score of 0 and 1 for the participants with 
baseline DLQI score >1 and the proportion of participants with a reduction of 5 or more
points in DLQI score for the participants with baseline DLQI score ≥ 5 will be summarized 
by treatment group over time.

The change from baseline in each DLQI component score will be summarized by treatment 
at Week 16.
5.4.6.
Hospital Anxiety Depression Scale (HADS)
5.4.6.1.
Definition
The HADS is an instrument for screening anxiety and depression in non-psychiatric populations; 
repeated administration also provides information about changes to a patient’s emotional state. 
The HADS consists of 14 items, 7 each for anxiety and depression symptoms; Each item on the 
questionnaire is scored from 0-3 resulting in a score between 0 and 21 for either anxiety or 
depression. The following cut-off scores are recommended for both subscales: 7 to 8 for possible 
presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.  The HADS 
is provided in the study reference manual.
If one or more of the items within each domain are left unanswered, that HADS component score 
will be considered missing.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
27
Status: Approved, Date: 24 June 2020
5.4.6.2.
Analyses Related to HADS

The improvement from baseline in Hospital Anxiety and Depression scale at Week 16 will 
be compared between each of the bermekimab groups and placebo group using a MMRM 
model.

The proportion of participants with hospital anxiety scale <8 and depression scale <8 at 
Week 16 will be compared between each of the bermekimab groups and placebo groups 
among participants with a baseline hospital anxiety scale and depression scale >=8.

Hospital anxiety scale and depression scale shift from baseline to Week 16 with respect to 
the hospital anxiety and depression scale category (<8, >=8) will be summarized.

The improvement from baseline in Hospital Anxiety and Depression Scale will be 
summarized by treatment group over time.
5.4.7.
Patient Oriented Eczema Measure (POEM)
5.4.7.1.
Definition
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults. The format is a response to 7 items (dryness, itching, 
flaking, cracking, sleep loss, bleeding, and weeping) based on frequency during the past week (ie, 
0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) with a scoring 
system of 0 to 28; the total score reflects disease-related morbidity.  The POEM is provided in the 
study reference manual.
5.4.7.2.
Analysis Methods

The change from baseline in POEM total score at Week 16 will be compared between each 
of the bermekimab groups and placebo group using a MMRM model.

The change from baseline in POEM total score will be summarized by treatment group 
over time.

The change from baseline in each POEM component score will be summarized by 
treatment group at Week 16.
5.4.8.
SCORing Atopic Dermatitis (SCORAD)
5.4.8.1.
Definition
The SCORAD is a validated tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD.  There are 3 components to the 
assessment: A = extent or affected body surface area, B = severity, and C = subjective symptoms. 
The extent of AD is assessed as a percentage of each defined body area, and reported as the sum 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
28
Status: Approved, Date: 24 June 2020
of all areas, with a maximum score of 100% (assigned as “A” in the overall SCORAD calculation). 
The severity of 6 specific symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin 
thickening/ lichenification, dryness) is assessed using the following scale: none (0), mild (1), 
moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall 
SCORAD calculation). Subjective assessment of itch and sleeplessness is recorded for each 
symptom by the patient or relative on a VAS, where 0 is no itch (or sleeplessness) and 10 is the 
worst imaginable itch (or sleeplessness), with a maximum possible score of 20. This parameter is 
assigned as “C” in the overall SCORAD calculation. The SCORAD is calculated as: A/5 + 7B/2 
+ C where the maximum is 103.  A higher score indicates more severe disease.
Body surface area (BSA) affected by AD will be assessed for each section of the body (the possible 
highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper 
limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a percentage of all 
major body sections combined. Body Surface Area will be extracted using SCORAD.
5.4.8.2.
Analysis Methods

The improvement from baseline in SCORAD total score at Week 16 will be compared 
between each of the bermekimab groups and the placebo group using a MMRM.

The improvement from baseline in BSA total score at Week 16 will be compared between 
each of the bermekimab groups and the placebo group using a MMRM.

The improvement from baseline in SCORAD total scores will be summarized by treatment 
group over time.

The improvement from baseline in SCORAD component scores (extent, severity, and 
subjective symptoms) will be summarized by treatment group at Week 16.

The improvement from baseline in BSA will be summarized by treatment group over time.
5.4.9.
Global Individual Signs Score (GISS)
5.4.9.1.
Definition
Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and 
lichenification) are rated globally (ie, each assessed for the whole body, not by anatomical region) 
on a 4-point scale (from 0=none to 3=severe) using the EASI severity grading criteria. The 
cumulative score, which ranges from 0 to 12, is the sum of the four components. A higher score 
indicates more severe disease.
5.4.9.2.
Analysis Methods

The improvement from baseline in GISS total score at Week 16 will be compared between 
each of the bermekimab groups and the placebo group using a MMRM.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
29
Status: Approved, Date: 24 June 2020

The improvement from baseline in GISS total score will be summarized by treatment group 
over time.

The 
improvement
from 
baseline 
in 
GISS
component 
score
(erythema, 
infiltration/papulation, excoriations, and lichenification) will be summarized by treatment 
group at Week 16.
6.
SAFETY
Safety will be assessed by summarizing the incidence and type of AEs and examining changes in 
laboratory parameters (hematology and chemistry), and vital signs data.
In all the safety analysis, randomized participants who received at least 1 (partial or complete) 
dose of study agent administration will be included. For safety analyses, participants will be 
analyzed according to the randomized treatment groups they were assigned to, regardless of the 
treatments they actually received. No formal statistical comparison is planned.
Depending on the safety data categories, the cumulative safety data will be analyzed through 
different study periods through Week 16 and Week 36. Unless otherwise specified, tabular 
summaries of safety events for key study periods are in general presented as following:
Summaries through Week 16 (placebo controlled): 
Safety data through Week 16 will be summarized by treatment groups
1. Placebo   
2. Bermekimab q2w
3. Bermekimab qw
4. Combined Bermekimab
This allows between-group comparisons of safety between the bermekimab regimens and the 
placebo group based on similar follow-up period in each group.
Summaries through Week 36
Safety data through Week 36 will be summarized by treatment groups including 
1. Placebo → bermekimab qw
2. Bermekimab q2w
3. Bermekimab qw
4. Combined Bermekimab
This allows safety comparisons between each bermekimab regimen through Week 36 based on the 
similar follow-up time in each group. 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
30
Status: Approved, Date: 24 June 2020
The list of actual treatment groups for safety analyses and inclusions of participants and safety 
events/measurements in each group are defined as follows:
1.
Placebo: all participants who were randomized to placebo and received treatment with 
placebo only or received treatment with placebo prior to receiving treatment with 
bermekimab. For participants who started treatment with placebo but later received 
bermekimab, the safety events/measurements on and after the first dose of bermekimab will 
be excluded from this group.  Only the safety events/measurements that occurred while the 
participants had been receiving placebo only will be included in this group.  
2.
Placebo → bermekimab 400 mg qw: all participants who were randomized to placebo 
started treatment with placebo only and later received treatment with bermekimab qw.  Only 
the safety events/measurements from these participants that occurred on and after their first 
administration of bermekimab will be included in this group.
3.
Bermekimab 400 mg qw: all participants who were randomized to bermekimab qw and 
received bermekimab qw. All the safety events/measurements from these participants that 
occurred on and after their first administration of bermekimab will be included in this group.
4.
Bermekimab 400 mg q2w: all participants who were randomized to bermekimab q2w and 
received bermekimab q2w. All the safety events/measurements from these participants that 
occurred on and after their first administration of bermekimab will be included in this group.
6.1.
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 starting at or after the initial 
administration of study agent through the end of the trial is considered as treatment emergent. If 
the event occurs on the day of the initial administration of study agent, 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 as
treatment emergent unless it is known to be prior to the first administration of study agent based 
on partial onset date or resolution date. All reported treatment-emergent adverse events will be 
included in the analysis. 
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.

AEs of severe intensity

AEs leading to discontinuation of study

The incidence and type of reasonably related AEs.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
31
Status: Approved, Date: 24 June 2020
These summary tables will provide the count and percentage of participants with 1 or more of the 
specified AEs by treatment group. In addition to the summary tables, listings will be provided for 
participants who:

Had SAEs

Had AEs leading to discontinuation of study 

Had AEs of severe or life threating, or fatal based on CTCAE (grade>=3) intensity

Had anaphylactic or serum sickness-like reactions.
Since safety should be assessed relative to exposure and follow-up, most AE summary tables will 
include average weeks of follow-up and average number of study agent administrations, and 
injections for each treatment group.
In addition, a participant who had injection site reaction(s) in 30 minutes (+/- 10) post injection at 
Weeks 0, 1, and 2 were recorded in eCRF. The incidence of injection-site reaction during this time 
frame will be summarized. 
6.2.
Clinical Laboratory Tests
All clinical laboratory reports will be displayed for the participants included in the safety analysis 
set. The clinical laboratory parameters to be evaluated by the central laboratory include but are not 
limited to:

Hematology: Basophils, Eosinophils, Hemoglobin, Lymphocytes, Monocytes, Neutrophils, 
Platelets and WBC.

Chemistry: Albumin, Alkaline Phosphatase, Bicarbonate (CO2), Calcium, Chloride, 
Creatinine, GGT, Glucose, Potassium, SGOT, SGPT, Sodium, Total Bilirubin, Total Protein, 
Urea Nitrogen.
Box plots of laboratory measurements and change from baseline will be provided for the selected 
laboratory measurement. 
Applicable laboratory results will be graded according to National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0). The worst NCI-CTCAE will 
be summarized by treatment group. 
A listing of participants with 1 or more NCI-CTCAE toxicity grade 2 in hematology and clinical 
chemistry laboratory measurements will be provided.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
32
Status: Approved, Date: 24 June 2020
6.3.
Vital Signs and Physical Examination Findings
Vital signs including pulse, blood pressure (systolic and diastolic), body temperature, peripheral 
blood oxygen saturation (SpO2) and respiratory rate will be measured at visits (pre-injection and 
post-injection) as per the schedule of activities in the protocol. Descriptive statistics of the 
observed value and change from baseline of the vital signs will be summarized by treatment group
over time.
Physical exam findings will not be analyzed. When physical exam findings are captured as AEs, 
those will be included in the analyses of AEs.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Blood was drawn into three 6 ml collection tubes at each specified time point. These samples will 
be used for PK, immunogenicity, PD, biomarker, and general research analyses. 
7.1.
Pharmacokinetics
All PK analyses will be based on the PK analysis set (Section 2.4.3). Participants will be analyzed 
according to the randomized treatment groups they were assigned to, regardless of the treatments 
they actually received. Unless otherwise specified, tabular summaries of PK for key study periods 
are in general presented as following:
Summaries through Week 16:
PK data through Week 16 will be summarized by treatment groups

Bermekimab 400 mg q2w

Bermekimab 400 mg qw 
Summaries through Week 36:
PK data through Week 36 will be summarized by treatment groups including 

Placebo → Bermekimab 400 mg qw

Bermekimab 400 mg q2w 

Bermekimab 400 mg qw
7.1.1.
Bermekimab Concentrations
Bermekimab concentrations will be summarized using descriptive statistics, including n, 
arithmetic mean, SD, coefficient of variation (%CV), median, interquartile range, range (minimum 
and maximum), by treatment group at each PK sampling time where appropriate.  PK data may be 
displayed graphically.  The following analyses will be performed as appropriate:

Summary of bermekimab concentrations at each visit by treatment group


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved, Date: 24 June 2020

Proportion of participants without detectable bermekimab concentration (below the lower 
limit of quantification) at each visit by treatment group

Summary of bermekimab concentrations at each visit by treatment group and baseline body 
weight (quartiles). Other covariates may also be applied.

Summary of bermekimab concentrations at each visit by treatment group and baseline EASI 
severity. 

Plot of mean (SD) bermekimab concentrations over time by treatment group

Plot of median (IQ) bermekimab concentrations over time by treatment group
7.1.1.1.
Data Handling Rules
Unless otherwise specified, the following data handling rules will apply to PK analyses:

Participants will be analyzed according to the treatment groups that they actually received. 

All concentration summaries for a particular timepoint will include data obtained from treated 
participants at the timepoint of interest without imputing any missing data. 

A concentration not quantifiable (below the lower limit of quantification) will be treated as 0 
in the summary statistics and shown as the lower limit of quantification (< LLOQ) in the data 
listings. 

The data from a subject who meets 1 of the following dosing deviation criteria (if applicable) 
will be excluded from the by-visit data analyses from that point onwards:

Discontinue bermekimab administrations.

Skipped a bermekimab administration.

Received an incomplete/ incorrect dose (if applicable).

Received an incorrect study agent (if applicable).

Received an additional bermekimab dose.
In addition, if a subject has an administration outside of dosing windows (Table 2), the 
concentration data collected at and after that visit will be excluded from the by-visit data analyses. 
Additional exclusions for incongruous PK data to be implemented based on Janssen SOP-07948.
All participants and samples excluded from the analysis will be clearly documented in the Clinical 
Study Report.
Table 2:
Dosing Window
Visit
Window
Week 0 through Week 32
± 3 days from scheduled visit day
Final Safety and Efficacy Follow-up visits
Week 36
± 7 days from scheduled visit day


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved, Date: 24 June 2020
7.1.2.
PK vs Efficacy 
The relationship between bermekimab concentrations and efficacy endpoints may be explored, 
e.g.: 

The relationship between bermekimab concentrations (quartiles) and proportion of 
participants achieving EASI-75 
7.1.3.
Population PK Analysis
When appropriate, population PK analysis may be performed using bermekimab concentration-
time data with the nonlinear mixed-effects modeling (NONMEM) approach.  Details will be 
provided in a separate technical report.
7.2.
Immunogenicity
Immunogenicity analyses will be based on the Immunogenicity Analysis Set (Section 2.4.5).
Participants will be analyzed according to the randomized treatment groups they were assigned to, 
regardless of the treatments they actually received. No imputation for missing concentration data 
will be performed.
Immunogenicity data through Week 36 will be summarized by treatment groups including 

Placebo → Bermekimab 400 mg qw

Bermekimab 400 mg q2w 

Bermekimab 400 mg qw 

Combined Bermekimab
7.2.1.
Antibodies to Bermekimab
Blood samples will be collected to examine the formation of anti-drug antibody (ADA) to 
bermekimab at the specified visits as shown in the schedule of activities in the protocol. Samples 
will also be collected at the final visit from participants who terminate study participation early. 
The antibodies to bermekimab status (positive/negative) and titers will be summarized by 
treatment group for participants who receive at least one dose of bermekimab and have appropriate 
samples for detection of antibodies to bermekimab. The maximum titers of antibodies to 
bermekimab will be provided for participants who are positive for antibodies to bermekimab.
A listing of participants who are positive for antibodies to bermekimab will be provided. This 
listing will provide information regarding dose administered, bermekimab concentration, and 
antibody status for all visits. 


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
35
Status: Approved, Date: 24 June 2020
7.2.2.
Antibody vs PK/Efficacy/Safety
To explore the relationship between antibodies to bermekimab status and bermekimab
concentrations, efficacy and safety, the following analysis may be performed if sufficient numbers 
of participants are positive for antibodies:  

Summary of bermekimab concentrations by antibodies to bermekimab status

Plots of mean (SD) trough bermekimab concentrations over time by antibodies to bermekimab
status 

Summary of clinical response status (e.g., proportion of participants achieving EASI-75) by 
antibodies to bermekimab status 

Summary of injection-site reactions by antibodies to bermekimab status (if applicable)

List of antibodies to bermekimab status in participants who discontinued study early 
7.3.
Biomarkers
Biomarker assessments will include the evaluation of relevant markers in serum for all 
participants. The samples will be used to better understand the biology of AD in some or all of the 
following ways: to provide mechanistic assessment of the pharmacodynamic response of 
participants to treatment with bermekimab, to analyze differences between responders and 
nonresponders, and to determine if the markers might be used to classify participants as potential 
responders prior to treatment.
Serum samples will be analyzed for circulating factors such as cytokines and other inflammatory 
markers, and other categories of biomarkers potentially associated with the development and 
progression of AD or related to the bermekimab mechanism of action. These analyses are 
considered exploratory and will be summarized in a separate biomarker technical report.


JNJ77474462  (Bermekimab)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved, Date: 24 June 2020
REFERENCES
1.
Rubin DB, Multiple Imputations for Nonresponse in Surveys. New York: John Wiley & Sons. 1987.