Clinical trial NCT04019041
Conditions: Hidradenitis Suppurativa Acne Inversa Suppurative Hidradenitis
Sponsor: Janssen Research & Development, LLC
Start date: 2019-09-16; Completion date: 2020-11-17
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study further evaluates the efficacy of bermekimab in treating moderate to severe hidradenitis suppurativa in adults. 1/3 of patients will receive weekly injections of bermekimab, 1/3 will receive alternating every other week injections of bermekimab or placebo, and 1/3 will receive weekly injections of placebo.

Detailed description:

Arms: arm 1: 2 800 mg bermekimab loading dose subcutaneous injections, followed by weekly 400 mg bermekimab injections arm 2: 2 800 mg loading dose subcutaneous injections, followed by alternating weekly 400 mg bermekimab injections with matching placebo injections arm 3: 2 800 mg placebo loading dose subcutaneous injections, followed by weekly placebo subcutaneous injections
Interventions: intervention 1: bermekimab intervention 2: placebo
Intervention descriptions: intervention 1: bermekimab 2 mL (200 mg/mL) pre-filled syringe intervention 2: placebo 2 mL pre-filled syringe

Protocol documents:
Prot_000.pdf: 
NCT04019041


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TABLE OF CONTENTS
BASIC INFORMATION........................................................................................................................ 4
INVESTIGATOR/SPONSOR SIGNATURES ...................................................................................... 5
CLINICAL PROTOCOL SYNOPSIS ................................................................................................... 6
ABBREVIATIONS .............................................................................................................................. 13
1. BACKGROUND............................................................................................................................... 14
1.1 OVERVIEW.......................................................................................................................................... 14
1.2 RATIONALE......................................................................................................................................... 16
2. INVESTIGATIONAL PRODUCT................................................................................................... 18
2.1 ACTIVE INGREDIENT, PHARMACOLOGIC CLASS, STRUCTURE............................................................ 18
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 .................................................................. 21
2.6 METHOD OF ADMINISTRATION ......................................................................................................... 21
2.7 AGENT ORDERING.............................................................................................................................. 23
2.8 POTENTIAL DRUG INTERACTIONS...................................................................................................... 23
2.9 PROHIBITED THERAPY........................................................................................................................ 23
2.10 CONCOMITANT THERAPY................................................................................................................. 24
2.10.1  Concomitant Corticosteroid use for Conditions Other than HS.............................................. 24
2.10.2 Wound Care ............................................................................................................................. 24
2.11 RESTRICTED THERAPY....................................................................................................................... 24
2.11.1 Analgesic Therapy.................................................................................................................... 24
2.11.2 Antibiotic Rescue Therapy ....................................................................................................... 25
2.11.3 Lesion Intervention................................................................................................................... 25
3. STUDY DESIGN AND OBJECTIVES ............................................................................................ 26
3.1 STUDY ENDPOINTS ............................................................................................................................. 28
4. ELIGIBILITY CRITERIA .............................................................................................................. 30
4.1 INCLUSION CRITERIA.......................................................................................................................... 30
4.2 EXCLUSION CRITERIA ......................................................................................................................... 31
5. TREATMENT PLAN....................................................................................................................... 32
5.1 STUDY PROCEDURES.......................................................................................................................... 32
5.2 STUDY CALENDARS............................................................................................................................. 40
5.2.1 Placebo-controlled Period......................................................................................................... 40
Blinded Active Dosing Period............................................................................................................. 41
5.2.2 Follow-Up Period ...................................................................................................................... 42
5.3 DISCONTINUATION OF THERAPY ....................................................................................................... 43
5.4 TRIAL STOPPING RULES ...................................................................................................................... 43
5.5
EMERGENCY UNBLINDING ............................................................................................................. 43
6. CORRELATIVE STUDIES ............................................................................................................. 44
6.1 PHARMACOKINETICS (PK)/ ANTI-DRUG ANTIBODY (ADA)/ PHARMACODYNAMICS (PD)/ BIOMARKER,
RESEARCH SAMPLE COLLECTION ............................................................................................................. 44
7. ASSESSMENT OF SAFETY ........................................................................................................... 44


3
8. STUDY VARIABLES....................................................................................................................... 45
8.1 DEMOGRAPHIC AND DISEASE CHARACTERISTICS............................................................................... 45
8.2
STUDY ENDPOINTS ......................................................................................................................... 45
9. ADVERSE EVENTS ........................................................................................................................ 48
9.1 DEFINITION OF ADVERSE EVENT (AE) ................................................................................................ 48
9.2 DEFINITION OF SERIOUS ADVERSE EVENT (SAE)................................................................................ 49
9.3 RECORDING OF ADVERSE EVENTS ..................................................................................................... 49
9.4 EVALUATING ADVERSE EVENTS ......................................................................................................... 50
9.5 ASSESSMENT OF CAUSALITY.............................................................................................................. 50
9.6 REPORTING REQUIREMENTS ............................................................................................................. 50
9.7 REFERENCE SAFETY INFORMATION:  POTENTIAL ADVERSE REACTIONS ........................................... 51
9.8 TOXICITY MANAGEMENT ................................................................................................................... 52
10. STATISTICAL PLAN.................................................................................................................... 53
10.1 DETERMINATION OF SAMPLE SIZE ................................................................................................... 53
10.2 RANDOMIZATION............................................................................................................................. 53
10.3 ANALYSIS SETS.................................................................................................................................. 53
10.4 PATIENT DISPOSITION ...................................................................................................................... 54
10.5 STATISTICAL METHODS .................................................................................................................... 54
10.5.1 Demography and Baseline Characteristics.............................................................................. 54
10.5.2 Safety Analysis ......................................................................................................................... 54
10.5.2.1 Analysis of Adverse Events................................................................................................................ 54
10.5.2.2 Other Safety...................................................................................................................................... 55
10.5.3 Efficacy Analysis...................................................................................................................... 55
10.5.3.1 Primary Efficacy Analysis................................................................................................................... 56
10.5.3.2 Secondary Efficacy Analyses.............................................................................................................. 56
10.5.4 Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis ............................................. 57
10.5.5 Treatment Exposure ................................................................................................................. 57
11. STUDY MANAGEMENT AND ADMINISTRATION.................................................................. 57
11.1 ETHICAL CONDUCT OF STUDY (GCP)................................................................................................ 57
11.2 IRB AND ETHICS COMMITTEE APPROVAL ........................................................................................ 57
11.3 PROTOCOL MODIFICATIONS............................................................................................................ 58
11.4 SUBJECT INFORMATION AND CONSENT.......................................................................................... 58
11.5 DATA PROTECTION AND CONFIDENTIALITY .................................................................................... 59
11.6 STUDY REPORT AND PUBLICATIONS................................................................................................ 59
11.7 STUDY FILES AND RETENTION OF RECORDS .................................................................................... 59
11.8 CASE REPORT FORMS....................................................................................................................... 60
11.9 DRUG ACCOUNTABILITY................................................................................................................... 60
11.10 INSPECTIONS.................................................................................................................................. 61
11.11 ACCESS TO INFORMATION FOR MONITORING.............................................................................. 61
11.12 STUDY DISCONTINUATION............................................................................................................. 61
REFERENCES..................................................................................................................................... 62


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Basic Information
STUDY TITLE: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of 
Bermekimab in Patients with Moderate to Severe Hidradenitis Suppurativa
INVESTIGATIONAL PRODUCT:
Bermekimab
IND NUMBER:
112,459
PROTOCOL NUMBER:
2019-PT047
PROTOCOL VERSION / DATE:
2.0/ 22 January 2020
SPONSOR:
XBiotech USA, Inc.
5217 Winnebago Lane
Austin, Texas 78744 U.S.A.
Phone: 512-386-2900
SPONSOR’S MEDICAL OFFICER:
STUDY CHAIR:
PPD
PPD


5
Investigator/Sponsor Signatures
STUDY TITLE: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of 
Bermekimab in Patients with Moderate to Severe Hidradenitis Suppurativa
PROTOCOL VERSION / DATE: 2.0 / 22 January 2020
STUDY 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


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Clinical Protocol Synopsis
Study Title: A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Bermekimab in 
Patients with Moderate to Severe Hidradenitis Suppurativa
Sponsor:  
XBiotech USA, Inc.
Study Chair:  
Sample Size:
Approximately 150 patients will be enrolled in the USA.
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 Objectives:
Primary Endpoint:

Proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at 
week 12
Secondary Endpoints:

Change from baseline to week 32 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score

Change from baseline to week 16 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score

Change from baseline to week 12 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score

Change from baseline to week 8 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score
PPD


7

Proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at 
week 32

Proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at
week 16

Change in Modified Hidradenitis Suppurativa Score (mHSS), Hidradenitis Suppurativa 
Physician’s Global Assessment (HS-PGA) and Hurley Stage from baseline to week 32

Change in Modified Hidradenitis Suppurativa Score (mHSS), Hidradenitis Suppurativa 
Physician’s Global Assessment (HS-PGA) and Hurley Stage from baseline to week 16

Change in Modified Hidradenitis Suppurativa Score (mHSS), Hidradenitis Suppurativa 
Physician’s Global Assessment (HS-PGA) and Hurley Stage from baseline to week 12

Change in patient reported outcomes from baseline to week 32, including: Hospital 
Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), Health 
Status Questionnaire (EQ-5D-3L), Patient Global Impression of Change (PGI-c), Patient 
Global Impression of Severity (PGI-s) and Hidradenitis Suppurativa Symptom Diary 
(HSSD) HS related Pain Symptom Score in the past 24 hours and total symptom score 

Change in patient reported outcomes from baseline to week 16, including: Hospital 
Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), Health 
Status Questionnaire (EQ-5D-3L), Patient Global Impression of Change (PGI-c), Patient 
Global Impression of Severity (PGI-s) and Hidradenitis Suppurativa Symptom Diary 
(HSSD) HS related Pain Symptom Score in the past 24 hours and total symptom score 

Change in patient reported outcomes from baseline to week 12, including: Hospital 
Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), Health 
Status Questionnaire (EQ-5D-3L), Patient Global Impression of Change (PGI-c), Patient 
Global Impression of Severity (PGI-s) and Hidradenitis Suppurativa Symptom Diary 
(HSSD) HS related Pain Symptom Score in the past 24 hours and total symptom score

Assessment of Pharmacokinetics (PK)

Reduction in serum IL-6 from baseline to week 32

Reduction in serum IL-6 from baseline to week 16

Reduction in serum IL-6 from baseline to week 12

Reduction in serum IL-6 from baseline to week 8
Exploratory Endpoints:

Change from baseline to week 32 in International Hidradenitis Suppurativa Severity 
Score System (IHS4)


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
Change from baseline to week 16 in International Hidradenitis Suppurativa Severity 
Score System (IHS4)

Change from baseline to week 32 in Hidradenitis Suppurativa Quality of Life Measure 
(HiSQOL)

Change from baseline to week 16 in Hidradenitis Suppurativa Quality of Life Measure 
(HiSQOL)

Change from baseline to week 32 in Physician’s Global Assessment of Inflammatory Skin 
Disease (PGA-ISD)

Change from baseline to week 16 in Physician’s Global Assessment of Inflammatory Skin 
Disease (PGA-ISD)
Trial Design*
This is a 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 
HS. Approximately 50% of patients enrolled will have failed prior targeted biologic therapy(ies) 
and approximately 50% will be naïve to these forms of biologic therapy in each arm. 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.
Patients who meet eligibility criteria at screening will be randomized in a 1:1:1 fashion to one of 
three treatment arms:

Arm 1: 800 mg loading dose of bermekimab (2 x 400 mg SC injections) at weeks 0 and 
1 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 weeks 0 and 


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1 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 weeks 0 and 1 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 1, followed 
by weekly injections from weeks 2 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.
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. The primary endpoint data will be collected at week 12.
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 


10
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.
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, age ≥18 years. 

Naïve to OR failure of prior targeted biologic therapy for HS (including anti-TNF, anti-IL-17, 
or JAK inhibitor therapy).

Must agree to daily use (throughout the entirety of the study) of one of the following over-the-
counter treatments to the body areas affected with HS lesions: either soap and water, or a topical 
antiseptic wash containing chlorhexidine gluconate, triclosan, or benzoyl peroxide, or a dilute 
bleach bath.

Diagnosis of HS for at least 1 year prior to screening. 

HS affecting at least two distinct anatomic areas, one of which is Hurley II or III stage. 

A total body count of abscesses and inflammatory nodules (A+N) of at least 3. 
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 


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
Full understanding of the procedures of the study protocol and willingness to comply with 
them. 
o
In case of female patients of childbearing potential, willingness to use one method of 
contraception of high efficacy during the entire study period. This method can be 
hormonal contraceptives or one of the following: condoms, diaphragm, or an
intrauterine device. Women of non-childbearing potential include those considered to 
have a medical history that indicates that pregnancy is not a reasonable risk, including 
post-menopausal women and those with a history of hysterectomy or surgically 
sterilized. 

If you are a male participating in this clinical research study, you should not get a sexual partner 
pregnant during your participation in this research study as the effect of the study drug on sperm 
is not known. 
Exclusion Criteria:
Subjects with ANY of the following will be excluded from the study: 

Age below 18 years.

History of treatment with bermekimab for any reason. 

Receipt of oral antibiotic treatment for HS within 28 days prior to baseline.

Receipt of prescription topical therapies for the treatment of HS within 14 days prior to baseline 

Receipt of systemic non-biologic therapies for HS (immunosuppressants, corticosteroids, 
retinoids, or hormonal therapies) within 28 days prior to screening.

Subject has been treated with any 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.

History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine 
monoclonal antibodies.

Has received a live (attenuated) vaccine over the 28 days prior to screening.

If entering the study on a dose of opioid analgesics that has not been stable for at least 14 days 
prior to baseline visit (PRN is not considered a stable dose).

Subject received non-opioid analgesics within 24 hours of baseline visit. 

Subject has a draining fistula count of greater than 20 at baseline.

Major surgery (requiring general anesthesia or respiratory assistance) within 28 days prior to 
Day 0 of start of study drug.


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
Hepatic dysfunction defined as any value of transaminases, of γ-glutamyl transpeptidase (γGT) 
or of total bilirubin > 3x upper normal limit.

Known or suspected history of immunosuppression, including history of invasive opportunistic 
infections 
(e.g.
tuberculosis 
[TB], 
histoplasmosis, 
listeriosis, 
coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution.

Stage C Child-Pugh liver cirrhosis.

History of human immunodeficiency virus (HIV) or active infection with hepatitis B virus 
(HBV) or hepatitis C virus (HCV).

Neutropenia defined as <1,000 neutrophils/mm3.

Pregnancy or lactation.


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Abbreviations
ADA
Anti-Drug Antibody
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 count
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
EC
Ethics Committee
ELISA
Enzyme-linked immunosorbent assay
GCP
Good clinical practice
GLP
Good laboratory practice
GMP
Good manufacturing practice
HADS
Hospital Anxiety Depression Scale
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HiSCR
Hidradenitis Suppurativa Clinical Response Score
HiSQOL
Hidradenitis Suppurativa Quality of Life Measure
HIV
Human immunodeficiency virus
HS
Hidradenitis Suppurativa
HS-PGA
Hidradenitis Suppurativa Physicians Global Assessment
IDEOM
International Dermatology Outcome Measures
IFN-Interferon Gamma
IHS4
International Hidradenitis Suppurativa Severity Score System
IgG
Immunoglobulin G
IL-6
Interleukin-6
IL-1
Interleukin-1 
IL-1
Interleukin-1 
IL-1RA
Interleukin-1 receptor antagonist
IRB
Institutional review board
mHSS
Modified Hidradenitis Suppurativa Score
NRS
Numerical Rating Scale
NSAID
Non-Steroidal Anti-inflammatory Drug
PD
Pharmacodynamics
PK
Pharmacokinetics
PGA-ISD
Physician’s Global Assessment of Inflammatory Skin Disease
PGI-c
Patient’s Global Impression of Change
PGI-s
Patient’s Global Impression of Severity
pI
Isoelectric Point
SAE
Serious Adverse Event
TNF
Tumor Necrosis Factor
ULN
Upper limit of normal
UV
Ultraviolet
VAS
Visual Analog Scale
WOCBP
Women of childbearing potential


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1. BACKGROUND
1.1 OVERVIEW
XBiotech USA, Inc. has developed a True Human monoclonal antibody, Bermekimab, that binds 
the cytokine 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 treatment in 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 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. XBiotech has conducted 10 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 a several different dose levels and dosing 
schedules. Both intravenous and subcutaneous formulations have been explored for safety and 
evidence of efficacy.
Five phase 2 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]), along with one investigator sponsored study in Hidradenitis Suppurativa1,2,3.  
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). Similar 
preliminary treatment efficacy was demonstrated for atopic dermatitis, with patients experiencing 
rapid reduction in pain and itch, as well as improved quality of life. In all of these trials, there were 


15
few adverse events, most of which were grade 1 (mild) and the only events that appeared to be 
related to therapy were mild injection site reactions in two patients.
The investigator-initiated phase II RCT trial among patients not eligible for adalimumab (EudraCT 
number 2015-002321-20; ClinicalTrials.gov NCT02643654) was recently completed and showed 
promising results for activity of bermekimab in HS. Twenty patients with severe HS and with either 
primary or secondary failure of previous anti-TNF agents, or who were unwilling to receive 
subcutaneous adalimumab treatment, were randomly allocated (1:1) to receive, in a blinded fashion, 
every other week treatment with placebo or bermekimab at a dose of 7.5 mg/kg IV. Treatment was 
administered intravenously for 12 weeks.  The primary efficacy endpoint was the positive HiSCR 
score, that was achieved among 10% of patients allocated to placebo and 60% of patients allocated 
to bermekimab. The odds ratio for positive HiSCR after 12 weeks of treatment was 13.50 (95% 
confidence intervals 1.19-152.51, p: 0.035). Analysis of the secondary endpoints showed some 
remarkable advantages of bermekimab treatment versus placebo treatment: a) blind follow-up for 
12 weeks after stopping treatment showed that clinical efficacy was sustained, in that a positive 
HiSCR score was found in 40% of the treatment group and 0% of patients receiving placebo (p: 
0.043); b) positive patient reported outcomes were found at week 12 in 70% and 30% respectively 
(p: 0.010); c) the median time to new HS flare-up was prolonged to 11 weeks and 7 weeks 
respectively; d) with the use of dermal ultrasound at week 12, a 20% or more decrease in total depth 
of involved skin lesions was found in 77.8% and 22.2%, respectively (p: 0.029); and e) serum IL-
8 was decreased at week 12 in 90% and 40% respectively (p: 0.029)4.
Data from XBiotech’s recent 2018-PT045 open-label Phase 2 study of bermekimab treating HS
corroborated the positive results generated from the investigator led study. 18 patients with no prior 
treatment with anti-TNF treatment (Group B) and 24 whom had failed previous anti-TNF treatment 
(Group A) were enrolled into the study. A positive HiSCR was again used as the primary efficacy 
endpoint.  A positive HiSCR after 12 weeks was found in 63% of patients in Group A, and 61% of 
in group B. In addition to patients achieving a meaningful clinical response, patients also 
experienced a marked reduction in pain, with Group A patients reporting a 54% reduction in pain 
(p <.0001) and Group B Patients reports a 64% reduction in pain (p<.0001).


16
1.2 RATIONALE
Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin 
disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed 
lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and 
anogenital regions (Dessau definition, 1st International Conference on Hidradenitis 
suppurativa/Acne inversa, March 30–April 1, 2006, Dessau, Germany)5. The clinical course is 
characterized by exacerbations and remissions of flare-ups. During these flare-ups, hair follicles in 
the affected regions become occluded, leading to tissue inflammation and the formation of lesions6. 
The duration of a flare-up is typically 3-5 days and is characterized by pain and difficulty in 
movement. Emotional stress is commonly associated with flare-ups, and flare-ups are commonly 
present in women before menses7. As the disease progresses, fistulas are formed under the dermis. 
These fistulas often suppurate continuously8. This chronic inflammation and the accompanying 
pain account for the fact that HS is ranked first among skin disorders in terms of adversely affecting 
quality of life9. In addition to the well understood comorbidity of pain, the often-overlooked
comorbidity of pruritus further diminishes patient quality of life. A possible explanation for HS 
associated pruritus is the degranulation of tryptase-positive mast cells, found in high densities in 
HS affected anatomical regions. This degranulation is thought to release histamine and other 
mediators of pruritus. 211 patients in a recent cross sectional- study of reported an average Pruritus 
NRS score of 6.1 +/- 2.0, with 121 patients reporting a baseline pruritus NRS score of >3. Of these 
121 patients, 70% reported pruritus at least occasionally affected their sleep, while 53% reported it 
occasionally affected activities of daily living10. Although HS is commonly understood to be an 
extremely painful disease, the quality of life impairments brought about by HS associated pruritus 
highlight the importance of assessing improvements in patient reported pruritus levels. 
HS reportedly has an overall disease prevalence in the United States of 0.10%, reaching nearly 3 
times that amount in African Americans11. The average disease prevalence in Europe is an order of 
magnitude higher, estimated at 1.0%6. A recent review of electronic records in the United States 
revealed an incidence of 11.4 per 100,000 in the general population12. The incidence was 2.5 times 
higher among African Americans than among white Americans13. The reported disease incidence 
in Europe is roughly half of that seen in the USA, with mean incidence found to be 6 cases in 
100,000 person-years11. 


17
Based on findings showing high expression of tumor necrosis factor-alpha (TNFα) in the lesions 
of patients14, the fully humanized monoclonal anti-TNF antibody adalimumab was studied for
treatment of HS. Two large-scale randomized clinical studies (RCT) were conducted, designated 
PIONEER I and PIONEER II, which shared a common study design. Following an initial loading 
dose of 160 mg and a second 80 mg dose after two weeks, adalimumab was administered 
subcutaneously at a dose of 40 mg every week, and efficacy was compared to that in placebo-
treated patients. The primary efficacy endpoint for both PIONEER studies was set at 12 weeks of 
treatment. This efficacy endpoint was the achievement of a positive hidradenitis suppurativa 
clinical response (HiSCR) score. After the initial 12-week treatment course, patients allocated to 
placebo were maintained to placebo whereas patients allocated to adalimumab were either switched 
to an open label extension (OLE) arm, or were further randomized to placebo, adalimumab 40 mg 
every other week or adalimumab 40 mg every week. Results showed that a positive HiSCR was 
found in 28.6% of placebo-treated patients and in 41% of adalimumab-treated patients of the 
PIONEER I study and in 27.6% of placebo-treated patients and in 58.9% of adalimumab-treated 
patients in the PIONEER II study15. As stated above, after the first 12 weeks of treatment patients 
initially treated with adalimumab could be further randomized and received another 12 weeks of 
treatment with placebo, 40mg adalimumab weekly or every other week. Analysis showed that 
approximately half of patients showed a positive initial response to treatment, and half of these 
maintained this response long-term. As also stated above, after the first 12 weeks of treatment, 88 
patients were switched to an OLE receiving 40 mg of adalimumab every week; positive HiSCR 
was achieved at weeks 120 and 168 in 56.8% and 52.3% respectively16. Adalimumab has been 
registered in both USA and Europe for moderate to severe HS based on the results of the two 
PIONEER studies.
Adalimumab is an important advance for the treatment of HS. However, there remains considerable 
unmet need for patients with HS, including 41% to 58% of patients who have primary response 
failures after 12 weeks of adalimumab treatment and the 30-50% patients that have a positive initial 
response to treatment but relapse after 12 weeks of therapy. These primary and secondary failures 
to adalimumab treatment may reflect the biological heterogeneity of the HS. About half of patients,
for example, over-express TNFα in their lesions, whereas others have lesions better characterized 
by the production of cytokines like interleukin (IL)-1β and IL-1α17. In a small randomized study 
ten patients were allocated to treatment with placebo and nine patients to treatment with anakinra 
(IL-1 receptor antagonist targeting both IL-1β and IL-1α). A positive HiSCR score was achieved 
in 30% and 78% of patients, respectively (p: 0.039)18. These results suggested that inhibition of IL-


18
1 may be a promising treatment strategy, including that for patients evidencing primary or 
secondary failure of adalimumab. Interluekin-6 (IL-6) levels have shown to be correlated with 
disease severity in HS and potentially have a greater reliability for predicting response to HS 
treatment than CRP levels19,20. In previous clinical studies, decreased IL-6 levels have been 
demonstrated in patients receiving bermekimab therapy21,22. Therefore, IL-6 may be considered as 
a candidate pharmacodynamic measure of response to bermekimab in HS.
Endogenous anti-IL-1α antibodies are present in 5% to 28% of the general population23,24,25,26.  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 other strategies to block IL-1 activity suggest that 
bermekimab’s targeting of IL-1α represents a safe treatment approach. 
In previous dermatology studies bermekimab was well tolerated and showed impressive therapeutic 
activity. 
2. INVESTIGATIONAL PRODUCT
2.1 ACTIVE INGREDIENT, PHARMACOLOGIC CLASS, STRUCTURE
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 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.


19
Figure 1.0: 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 1.0, 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 
molecules27. 
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 
samples28,29. It has been measured in cord blood, children and adults30. The anti-IL-1α antibodies 
measured in human plasma have been strictly of the IgG class, particularly IgG1, IgG2, and IgG4. 
Relatively equal distribution is seen in male and female plasma31. Binding affinities reported for 
endogenous anti-IL-1α antibodies, ranging from 4 to 16 pM.


20
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 
bermekimab. 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, thermal, and 
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 shown no negative 
effect on the product. However, the study treatment products are not to be frozen at any time.  The 
200 mg/ml drug product is labeled with a 12-month retest date. Every lot of 200mg/ml dosage 
form is also subjected to ongoing stability analysis per ICH guidelines. 


21
2.5 DESIGNATED INDIVIDUAL FOR DRUG ADMINISTRATION
To ensure that no unintentional unblinding occurs during study drug administration, at lease 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.
2.6 METHOD OF ADMINISTRATION
Following two initial 800 mg loading doses of either bermekimab or placebo, patients in all arms
will receive 400 mg of either bermekimab or placebo via subcutaneous injection administered 
weekly. Each injection should be administered at least one inch from previous injection sites.  
* 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
(Note: avoid areas where the skin is burned, scarred, hardened, inflamed, swollen, or damaged).


22
Injection

Put on gloves

Wipe injection site clean with alcohol pads

Raise a fold of skin between the thumb and forefinger and insert needle as illustrated

Insert needle as illustrated in adjacent diagram

Inject drug slowly 

Withdraw needle. Place band-aid over injection site if necessary (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).
***Investigator may, at their judgement, administer antihistamines/NSAIDs to prevent or treat 
injection site reaction. This must be captured in eCRF.


23
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 PROHIBITED THERAPY

Phototherapy (PUVA and/or UVB)

All biologic therapy with a potential therapeutic impact on the HS presented 
by the patient, including but not limited to the following:
o
Abatacept (Orencia ®)
o
Anakinra (Kineret ®)
o
Belimumab (Benlysta ®)
o
Cetolizumab (Cimzia ®)
o
Efalizumab (Raptiva ®)
o
Etanercept (Enbrel ®)
o
Golimumab (Simponi ®)
o
Infliximab (Remicade ®)
o
Natalizumab (Tysabri ®)
o
Rituximab (Rituxan ®)
o
Tocilizumab (Actemra ®)
o
Ustekinumab (Stelara ®)

Live virus vaccines (during the study and for 70 days after the last dose of 
study drug)

Investigational agents other than bermekimab

Oral or injectable corticosteroids for treatment of HS except those listed in 
section 2.11.3 Lesion Intervention

Oral Analgesics not listed in Section 2.11.1 Analgesic Therapy

New prescription topical therapies for HS

Over-the-counter topical washes, creams, soaps, ointments, gels and liquids containing 
antibacterial agents to treat HS not listed in Section 


24

2.10.2 Wound Care

Surgical or laser intervention for an HS lesion except as outlined in Section 2.11.3 Lesion 
Intervention
2.10 CONCOMITANT THERAPY
2.10.1  Concomitant Corticosteroid use for Conditions Other than HS
The use of systemic corticosteroids for indications other than HS 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.
2.10.2 Wound Care
Subjects are required to use a daily antiseptic wash on their HS lesions. Allowable antiseptic washes are 
limited to one of the following: soap and water, chlorhexidine gluconate, triclosan, benzoyl peroxide, or 
dilute bleach in bathwater. Concomitant use of wound care dressings on HS wounds is allowed, however 
options are limited to alginates, hydrocolloids and hydrogels.
2.11 RESTRICTED THERAPY
2.11.1 Analgesic Therapy
Antihistamine/NSAID use is permitted in this study including those to prevent or treat injection site 
reaction(s). Most subjects will be required to washout of all opioid analgesics for 14 days prior to baseline
or, in the case of non-opioid analgestics, for 24 hours prior to baseline. However, if a subject is on a stable 
dose of a opioid analgesic medication (PRN is not considered stable), the subject may continue the 
analgesic, provided the dose is stable for 14 days prior to baseline and is anticipated to remain stable
throughout study participation. If a subject's pain (HS-related or non-HS-related) worsens after baseline, 
they may initiate analgesic therapy at any time as follows:


25

Ibuprofen (at a dose of up to 800 mg po every 6 hours) not to exceed 3.2 grams/24 hours; 
AND/OR acetaminophen as per local labeling.

If pain is uncontrolled with ibuprofen or acetaminophen at the above dosing regimens after the 
baseline visit, subjects can be prescribed tramadol (at a dose of up to 100 mg po every 4 hours), 
not to exceed 400 mg/24 hours.
Dose adjustments of ibuprofen, acetaminophen, or tramadol, and use of these analgesics on an "as needed" 
(PRN) basis for HS-related pain up to the maximum permitted dose and frequency, are allowed during the 
study.
From Screening through the end of their study participation, subjects will be required to report to site staff 
any analgesics taken since their last visit . All analgesics and doses will be captured in the source and on 
the concomitant medications eCRF.
2.11.2 Antibiotic Rescue Therapy
Concomitant use of oral antibiotic therapy for treatment of HS is not allowed. At Week 4 or Week 8, if a 
subject experiences an increase in their AN count such that the total count is greaterthanor equalto 150% 
of their Baseline AN count, antibiotic rescue medication may be initiated. Subjects who qualify may initiate 
treatment with minocycline or doxycycline up to 100 mg bid. The dosing regimen must remain stable 
throughout study participation. Otherwise, concomitant use of oral antibiotic therapy for treatment of HS 
is not allowed. Rescue antibiotic therapy should be captured in the source and on the appropriate eCRF.
2.11.3 Lesion Intervention
In the event that an acutely painful lesion occurs that requires an immediate intervention, physicians will 
have the option to perform protocol-allowed interventions. Only two types of interventions are allowed: 
injection with intralesional triamcinolone acetonide suspension (at a concentration of up to 5 mg/mL, up to 
1 cc) and incision and drainage.
If incision and drainage is performed, the required over-the-counter antiseptic wash should continue to be 
used. New systemic and topical therapies following incision and drainage (including antibiotics), are 
prohibited. Concomitant use of wound care dressings is allowed however options are limited to alginates, 
hydrocolloids, and hydrogels. Subjects should continue using any ongoing oral and topical therapies (with 


26
the constraints as described in Section 2.11 RESTRICTED THERAPY during the study. See Section 9.8 
TOXICITY MANAGEMENT for additional discussion on the use of concomitant medications if 
medically necessitated. Concomitant medications associated with the lesion intervention(s) must be 
captured in the source and on the appropriate eCRF.
A total of two protocol-allowed interventions are permissible. An intervention can occur on maximally two 
different lesions at the same visit or on the same lesion at two different study visits. The same lesion cannot 
be treated two times at the same visit. If a subject requires more than two interventions within the 32 week
treatment period, then they must be discontinued from the study treatment.
All study visit evaluations must occur before any interventions are performed. Any lesion that undergoes 
an intervention will be documented in the source. The site will be required to count any lesion that 
undergoes an intervention as permanently present from the date of the intervention and must account for it 
in the source and on the appropriate eCRF.
3. STUDY DESIGN AND OBJECTIVES
This is a 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 
HS. Approximately 50% of patients enrolled will have failed prior targeted biologic therapy(ies) 
and approximately 50% will be naïve to these forms of biologic therapy in each arm. 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. 
Patients who meet eligibility criteria at screening will be randomized in a 1:1:1 fashion to one of 
three treatment arms:


27

Arm 1: 800 mg loading dose of bermekimab (2 x 400 mg SC injections) at weeks 0 and 
1 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 weeks 0 and 
1 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 weeks 0 and 1 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 1, followed 
by weekly injections from weeks 2 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 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.
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. The primary endpoint data will be collected at week 12.
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 


28
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 study protocol 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.  The trial will be conducted in 
compliance with the protocol, GCP, and all applicable regulatory requirements.
3.1 STUDY ENDPOINTS
Primary Endpoint:

Proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at  
week 12
Secondary Endpoints:

Change from baseline to week 32 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score

Change from baseline to week 16 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score

Change from baseline to week 12 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score


29

Change from baseline to week 8 in Numeric Rating Scale for Pain & Itch (NRS Pain & 
Itch) score

Proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at 
week 32

Proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at 
week 16

Change in Modified Hidradenitis Suppurativa Score (mHSS), Hidradenitis Suppurativa 
Physician’s Global Assessment (HS-PGA) and Hurley Stage from baseline to week 32

Change in Modified Hidradenitis Suppurativa Score (mHSS), Hidradenitis Suppurativa 
Physician’s Global Assessment (HS-PGA) and Hurley Stage from baseline to week 16

Change in Modified Hidradenitis Suppurativa Score (mHSS), Hidradenitis Suppurativa 
Physician’s Global Assessment (HS-PGA) and Hurley Stage from baseline to week 12

Change in patient reported outcomes from baseline to week 32, including: Hospital 
Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), Health 
Status Questionnaire (EQ-5D-3L), Patient Global Impression of Change (PGI-c), Patient 
Global Impression of Severity (PGI-s) and Hidradenitis Suppurativa Symptom Diary 
(HSSD) HS related Pain Symptom Score in the past 24 hours and total symptom score 

Change in patient reported outcomes from baseline to week 16, including: Hospital 
Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), Health 
Status Questionnaire (EQ-5D-3L), Patient Global Impression of Change (PGI-c), Patient 
Global Impression of Severity (PGI-s) and Hidradenitis Suppurativa Symptom Diary 
(HSSD) HS related Pain Symptom Score in the past 24 hours and total symptom score 

Change in patient reported outcomes from baseline to week 12, including: Hospital 
Anxiety and Depression Scale (HADS), Dermatology Life Quality Index (DLQI), Health
Status Questionnaire (EQ-5D-3L), Patient Global Impression of Change (PGI-c), Patient 
Global Impression of Severity (PGI-s) and Hidradenitis Suppurativa Symptom Diary 
(HSSD) HS related Pain Symptom Score in the past 24 hours and total symptom score

Assessment of Pharmacokinetics (PK)

Reduction in serum IL-6 from baseline to week 32

Reduction in serum IL-6 from baseline to week 16

Reduction in serum IL-6 from baseline to week 12

Reduction in serum IL-6 from baseline to week 8


30
Exploratory Endpoints:

Change from baseline to week 32 in International Hidradenitis Suppurativa Severity 
Score System (IHS4)

Change from baseline to week 16 in International Hidradenitis Suppurativa Severity 
Score System (IHS4)

Change from baseline to week 32 in Hidradenitis Suppurativa Quality of Life Measure 
(HiSQOL)

Change from baseline to week 16 in Hidradenitis Suppurativa Quality of Life Measure 
(HiSQOL)

Change from baseline to week 32 in Physician’s Global Assessment of Inflammatory Skin 
Disease (PGA-ISD)

Change from baseline to week 16 in Physician’s Global Assessment of Inflammatory Skin 
Disease (PGA-ISD)
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, age ≥18 years. 

Naïve to OR failure of prior targeted biologic therapy for HS (including anti-TNF, anti-IL-17, 
or JAK inhibitor therapy). 

Must agree to daily use (throughout the entirety of the study) of one of the following over-the-
counter treatments to the body areas affected with HS lesions: either soap and water, or a topical 
antiseptic wash containing chlorhexidine gluconate, triclosan, or benzoyl peroxide, or a dilute 
bleach bath.

Diagnosis of HS for at least 1 year prior to screening. 

HS affecting at least two distinct anatomic areas, one of which is Hurley II or III stage. 

A total body count of abscesses and inflammatory nodules (A+N) of at least 3. 

Full understanding of the procedures of the study protocol and willingness to comply with 
them. 


31

In case of female patients of childbearing potential, willingness to use one method of 
contraception of high efficacy during the entire study period. This method can be hormonal 
contraceptives or one of the following: condoms, diaphragm, or an intrauterine device. Women 
of non-childbearing potential include those considered to have a medical history that indicates 
that pregnancy is not a reasonable risk, including post-menopausal women and those with a 
history of hysterectomy or surgically sterilized. 

Males participating in this clinical research study should not get a sexual partner pregnant 
during participation in this research study as the effect of the study drug on sperm is not known. 
4.2 EXCLUSION CRITERIA
Subjects with ANY of the following will be excluded from the study: 

Age below 18 years.

History of treatment with bermekimab for any reason. 

Receipt of oral antibiotic treatment for HS within 28 days prior to baseline.

Receipt of prescription topical therapies for the treatment of HS within 14 days prior to baseline 

Receipt of systemic non-biologic therapies for HS (immunosuppressants, corticosteroids, 
retinoids, or hormonal therapies) within 28 days prior to screening.

Subject has been treated with any 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.

History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine 
monoclonal antibodies.

Has received a live (attenuated) vaccine over the 28 days prior to screening.

If entering the study on a dose of opioid analgesics that has not been stable for at least 14 days 
prior to baseline visit (PRN is not considered a stable dose).

Subject received non-opioid analgesics within 24 hours of baseline visit. 

Subject has a draining fistula count of greater than 20 at baseline.

Major surgery (requiring general anesthesia or respiratory assistance) within 28 days prior to 
Day 0 of start of study drug.

Hepatic dysfunction defined as any value of transaminases, of γ-glutamyl transpeptidase (γGT) 
or of total bilirubin > 3x upper normal limit.


32

Known or suspected history of immunosuppression, including history of invasive opportunistic 
infections 
(e.g. 
tuberculosis 
[TB], 
histoplasmosis, 
listeriosis, 
coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution.

Stage C Child-Pugh liver cirrhosis.

History of human immunodeficiency virus (HIV) or active infection with hepatitis B virus 
(HBV) or hepatitis C virus (HCV).

Neutropenia defined as <1,000 neutrophils/mm3.

Pregnancy or lactation.
5. TREATMENT PLAN
5.1 STUDY PROCEDURES
PLACEBO-CONTROLLED PERIOD
Screening (maximum 30 days):  The screening period begins once the informed consent is 
signed. 

Informed Consent

Inclusion/ Exclusion

Medical History/ Demographics

Height, Weight, Body Mass Index (BMI) [BMI= weight (kg)/height (m2)]

Concomitant Medications/treatments

Provide subject copies of the patient take home diary, which will consist of NRS pain 
(worst moment, average & current) and itch (worst moment & average) assessments to be 
completed by patients daily. 

Lesion Counts (HiSCR), mHSS, HS-PGA, PGA-ISD, IHS4, Hurley Staging 

DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL

Physical Exam 

Electrocardiogram

Vital Signs (blood pressure, pulse, oxygen saturation, respiratory rate and body 
temperature)

Urinalysis: pH, protein, glucose and blood cells (RBCs and WBCs)

Blood Draw:
o
Chemistry panel: Albumin, Alkaline Phosphatase, ALT, AST, GGT, 


33
Bicarbonate (CO2), Calcium, Chloride, Creatinine, Glucose, Potassium, 
Sodium, Total Bilirubin, Total Protein, Urea Nitrogen (BUN)
o
Hematology Panel:  Complete Blood Count (CBC) with differential and 
platelets
o
Infectious disease panel: HIV antibody, Hepatitis C antibody, Hepatitis B 
panel (HBsAg, anti-HBc, anti-HBs), and interferon gamma release assay 
(IGRA) for TB
o
Serum pregnancy test for WOCBP
o
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 (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. Do not heat

Pre-injection
o
Verify patient still meets inclusion/exclusion criteria 
o
Height, Weight, Body Mass Index (BMI) [BMI= weight (kg)/height (m2)]
o
Patient Diary
o
Baseline Lesion Counts (for future HiSCR assessments), mHSS, HS-PGA, PGA-
ISD, IHS4 and Hurley Staging
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL
o
Physical Exam, Vital signs, Urine pregnancy
o
Urinalysis
o
Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6,
PD, biomarker and research analysis

Bermekimab/placebo subcutaneous injections (To deliver a loading dose to subjects in the 
bermekimab groups while maintaining blinding, all subjects will receive two injections)

Post-injection
o
Adverse event monitoring


34
o
Concomitant medications/treatments
Visit 2 (Week 1) (day 7 +/-3); Visit 4 (Week 3) (day 21 +/-3); Visit 6 (Week 5) (day 35 +/-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
o
Patient Diary
o
HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL
o
Physical Exam, Vital signs, Urine pregnancy
o
Blood draw for PK/ADA, IL-6, PD, biomarker and research analysis

Bermekimab/placebo subcutaneous injections (To deliver a loading dose to subjects in the 
bermekimab groups while maintaining blinding, all subjects will receive two injections)

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 3 (Week 2) (day 14 +/-3); Visit 5 (Week 4) (day 28 +/-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
o
Patient Diary 
o
Vital signs, Urine pregnancy
o
Blood draw for PK/ADA, IL-6, PD, biomarker and research analysis

Bermekimab/placebo subcutaneous injection

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 7 (Week 6) (day 42 +/-3); Visit 11 (Week 10) (day 70 +/-3); Visit 14 (Week 13) (day 91 
+/-3); Visit 15 (Week 14) (day 98 +/-3); Visit 16 (Week 15) (day 105 +/-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


35
o
Patient Diary
o
Vital signs, Urine pregnancy

Bermekimab/placebo subcutaneous injection

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 8 (Week 7) (day 49 +/-3); Visit 10 (Week 9) (day 63 +/-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
o
Patient Diary
o
HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL
o
Physical Exam, Vital signs, Urine pregnancy

Bermekimab/placebo subcutaneous injection

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 9 (Week 8) (day 56 +/-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
o
Patient Diary
o
Vital signs, Urine Pregnancy
o
Urinalysis
o
Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6,
PD, biomarker and research analysis

Bermekimab/placebo subcutaneous injection

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments


36
Visit 12 (Week 11) (day 77 +/-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
o
Patient Diary
o
Physical Exam, Vital signs, Urine pregnancy

Bermekimab/placebo subcutaneous injection

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 13 (Week 12) (day 84 +/-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
o
Patient Diary
o
HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL
o
Physical Exam, Vital signs, Urine pregnancy
o
Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6,
PD, biomarker and research analysis

Bermekimab/placebo subcutaneous injection 

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
BLINDED ACTIVE DOSING PERIOD
Visit 17 (Week 16) (day 112 +/-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
o
Patient Diary
o
HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL


37
o
Physical Exam, Vital signs, Urine pregnancy
o
Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6, 
PD, biomarker and research analysis
o
Urinalysis

Bermekimab/placebo subcutaneous injection

Post-injection
o
Adverse event monitoring
o
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
o
Patient Diary
o
Vital signs 
o
Urine pregnancy

Bermekimab/placebo subcutaneous injection 

Post-injection
o
Adverse event monitoring
o
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
o
Patient Diary
o
HiSCR, mHSS, HS-PGA, PGA-ISD and IHS4 
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL
o
Vital signs, Urine pregnancy

Bermekimab/placebo subcutaneous injection 

Post-injection


38
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 25 (Week 24) (day 168 +/-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
o
Patient Diary
o
HiSCR, mHSS, HS-PGA, PGA-ISD and IHS4 
o
DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL
o
Vital signs, Urine pregnancy
o
Urinalysis
o
Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6, 
PD, biomarker and research analysis

Bermekimab/placebo subcutaneous injection 

Post-injection
o
Adverse event monitoring
o
Concomitant medications/treatments
Visit 33 (Week 32) (day 224 +/-3):

Patient Diary

HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging

DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL

Physical Exam, Vital signs, Urine pregnancy

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6, PD, 
biomarker and research analysis

Urinalysis

Adverse event monitoring 

Concomitant medications/treatment
FOLLOW-UP PERIOD
Visit 34 (Week 36) (day 252 +/-3):

HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging

DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL

Physical Exam, Vital signs, Urine pregnancy


39

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6, PD, 
biomarker and research analysis

Urinalysis

Adverse event monitoring 

Concomitant medications/treatment
UNSCHEDULED VISIT (if applicable) 

Patient Diary

HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging

DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL

Physical Exam, Vital signs, Urine or Serum pregnancy

Electrocardiogram

Blood draw for infectious disease panel, chemistry, hematology, inflammation markers, 
PK/ADA, IL-6, PD, biomarker and research analysis

Urinalysis

Adverse event monitoring 

Concomitant medications/treatment
EARLY TERMINATION VISIT (if applicable) 

Patient Diary

HiSCR, mHSS, HS-PGA, PGA-ISD, IHS4 and Hurley Staging

DLQI, HADS, PGI-c, PGI-s, EQ-5D-3L, HSSD, HiSQOL

Physical Exam, Vital signs, Serum pregnancy

Blood draw for chemistry, hematology, inflammation markers, PK/ADA, IL-6, PD, 
biomarker and research analysis

Urinalysis

Adverse event monitoring 

Concomitant medications/treatment








43
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.

Initiating treatment with prohibited therapies (see section 2.9)….
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:


44

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)/ ANTI-DRUG ANTIBODY (ADA)/ PHARMACODYNAMICS
(PD)/ BIOMARKER, RESEARCH SAMPLE COLLECTION
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 flowchart 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 (PK) in human plasma. The PK 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, 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 (week 0) (post-injection) 
through visit 33 (week 32) as well as during the 4-week follow up period (visit 34 at week 36). Any serious 
adverse events whether related or not to study drug 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, 3, 
17, 18 & 19 (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.    


45
Any grade 3 or greater adverse event or 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, height, weight, and BMI) 
medical history, medication history, and prior biologic use for each patient. Characteristics of the patients
with hidradenitis suppurativa, including duration of disease, baseline disease severity scores (HiSCR, 
Modified Hidradenitis Suppurativa Score, Hurley Staging and Hidradenitis Suppurativa Physician’s Global 
Assessment, Physician’s Global Assessment of Inflammatory Skin Disease), and baseline patient reported 
outcomes (PGI-c, PGI-s, NRS Pain, NRS Itch, EQ-5D-3L, HADS, HSSD, HiSQOL, IHS4 and DLQI), will 
be collected. Baseline is defined as the visit 1 (week 0), pre-injection assessment.
8.2 STUDY ENDPOINTS
Primary Endpoint 

The proportion of subjects achieving Hidradenitis Suppurativa Clinical Response (HiSCR). For this 
score patients are defined as achievers or non-achievers. The positive HiSCR score is defined as a 
≥50% reduction in inflammatory lesion AN count (sum of abscesses and inflammatory nodules), and 
no increase in abscesses or draining fistulas in HS compared with the lesions counted on visit 1 (week 
0)32. 
Secondary Assessments

Numerical Rating Scale (NRS) for Pain & Itch [take home patient diary]. 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. 

HS Related Pain Symptom Score in the past 24 hours based on Hidradenitis Suppurativa Symptom 
Diary (HSSD). HSSD is a 7-item patient self-reported questionnaire that assesses 5 HS-related 
symptoms including pain, tenderness, hot skin feeling, odor, and itchiness. The participants are asked 
to rate the severity of each symptom on a 0 to 10 numerical rating scale, with 0 indicating no symptom 
experience and 10 indicating the worst possible symptom experience. 

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 


46
three 6 ml collection tubes at each research draw collection time point. 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 
CRP33,34. 

Hidradenitis Suppurativa Physician’s Global Assessment (HS-PGA). This is defined as: a) clear when 
the total number of abscesses is 0, the total number of draining fistulas is 0, the total number of 
inflammatory nodules is 0 and the total number of non-inflammatory nodules is 0; b) minimal when 
the total number of abscesses is 0, the total number of draining fistulas is 0, the total number of 
inflammatory nodules is 0 and there is presence of non-inflammatory nodules; c) mild when the total 
number of abscesses is 0, the total number of draining fistulas is 0, and the total number of inflammatory 
nodules is 1-4, or when there is presence of one abscess or draining fistula and absence of any 
inflammatory nodules; d) moderate when the total number of abscesses is 0, the total number of draining 
fistulas is 0 and the total number of inflammatory nodules is at least 5; or when there is presence of one 
abscess or draining fistula and at least one inflammatory nodule; or when there are 2-5 abscesses or 
draining fistulas and fewer than 10 inflammatory nodules; e) severe when the total number of abscesses 
or draining fistulas is 2-5 and the total number of inflammatory nodules is at least 10; and f) very severe 
when there are more than 5 abscesses or draining fistulas35.  

The modified Hidradenitis Suppurativa score (mHSS). The Sartorius Scale is used to quantify the 
severity of HS. Points are awarded for 12 body areas (left and right axillae, left and right 
sub/inframammary areas, intermammary area, left and right buttocks, left and right inguino-crural folds, 
perianal area, perineal area, and other): points were awarded for nodules (2 points for each); abscesses 
(4 points); fistulas (4 points); scars (1 point); other findings (1 point); and longest distance between two 
lesions (2-6 points, 0 if no lesions); and if lesions are separated by normal skin (yes-0 points; no-6 
points). The total Sartorius score is the sum of the 12 regional scores.

Hurley Stage. The Hurley stage is used to qualify the severity of HS. Affected anatomic regions are 
individually scored. Hurley Stage I is defined as localized formation of single or multiple abscesses 
without sinus tracts and scarring. Hurley Stage II is defined as recurrent abscesses with sinus tract 
formation and scarring; single or multiple lesions. Hurley Stage III is defined as diffuse involvement 
with interconnected tracts and abscesses.

Dermatology Life Quality Index (DLQI). 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 


47
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.

Hospital Anxiety Depression Scale (HADS). The HADS is an instrument for screening anxiety and 
depression in non-psychiatric populations; repeated administration also provides information about 
changes to a patient’s emotional state. 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. 

Health Status Questionnaire (EQ-5D-3L). The EQ-5D-3L consists of 2 pages: the EQ-5D descriptive 
system and the EQ visual analogue scale (EQ VAS).The EQ-5D-3L descriptive system comprises the 
following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked 
to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 
five dimensions. This decision results into a 1-digit number that expresses the level selected for that 
dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the 
patient’s health state. The EQ VAS records the patient’s self-rated health on a vertical visual analogue 
scale where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst imaginable health 
state’. The VAS can be used as a quantitative measure of health outcome that reflects the patient’s own 
judgement. 

Patient Global Impression of Change (PGI-c). The PGI-c is a single item patient reported outcome that 
assesses change in severity of skin pain due to HS. Participants will rate how his/her HS has changed 
since the beginning of the study using a 7-point scale ranging from 1 which indicates "very much better" 
to 7 which indicates "very much worse" with a neutral center point 4 which indicates ("no change"). 

Patient Global Impression of Severity (PGI-s). The PGI-s is a single item patient reported outcome that 
assesses change in a patient’s impression of their disease severity. The PGI-s item asks the respondent 
to best describe how his/her HS symptoms are now (“check the one number that best describes how 
your HS symptoms are now”) on a 4-point scale scored as: “normal” (1), “mild” (2), “moderate” (3), 
or “severe” (4)”. 

HSSD Symptom Scale Score (Other Than Pain in the Past 24 Hours). HSSD is a 7-item patient self-
reported questionnaire that assesses 5 HS-related symptoms including pain, tenderness, hot skin feeling, 
odor, and itchiness. The participants are asked to rate the severity of each symptom on a 0 to 10 
numerical rating scale, with 0 indicating no symptom experience and 10 indicating the worst possible 


48
symptom experience. Change from baseline in each individual tenderness, hot skin feeling, odor and 
itchiness symptom score (rated on a scale of 0-10) will be determined. 

HSSD Total Symptom Score. HSSD is a 7-item patient self-reported questionnaire that assesses 5 HS-
related symptoms including pain, tenderness, hot skin feeling, odor, and itchiness. The participants are 
asked to rate the severity of each symptom on a 0 to 10 numerical rating scale, with 0 indicating no 
symptom experience and 10 indicating the worst possible symptom experience. All 5 symptoms have 
a recall period of the past 7 days, except for 2 additional questions on pain which evaluate current pain 
and pain in the past 24 hours. Each individual symptom scale score, ranging from 0-10 will be 
summarized. A total symptom score, which will also range from 0-10, will be derived by averaging the 
5 individual scale scores that utilize the past 7-day recall period with higher score indicates more severe 
disease. 
Exploratory Assessments

Hidradenitis Suppurativa Quality of Life Measure (HiSQOL). HiSQOL is an outcome 
measurement instrument specficially developed for HS. HiSQOL is a patient self-reported 
questionnaire that assesses various HS-related quality of life measures. 

International Hidradenitis Suppurativa Severity Score System (IHS4). IHS4 is a dynamic severity 
assessment of HS. IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the 
number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A 
total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe 
disease.

Physician’s Global Assessment of Inflammatory Skin Disease (PGA-ISD). The PGA-ISD is a tool 
developed by the International Dermatology Outcome Measures (IDEOM) organization to serve as 
a potential standardized outcome measure for assessment of inflammatory skin diseases.
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, 


49
including intermittent or episodic conditions.  

A significant or unexpected worsening of the condition/indication under investigation.  

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;

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 a 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 


50
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.
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 adverse event and 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 


51
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
More than 900 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.  Repeat dose toxicity in relevant species, safety pharmacology, 
genotoxicity, carcinogenic potential, and toxicity to reproduction studies have not been performed. A repeat 
dose toxicity study in mice did not reveal any unspecific toxicity related to bermekimab. Over 5000 doses 
of bermekimab were administered intravenously (50 mg/mL) at 7.5 mg/kg and over 900 doses of 
bermekimab were administered subcutaneously with 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 True Human monoclonal antibody derived immune plasma B cells derived from a natural 
human immune response against IL-1α. 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 


52
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.
For the purposes of expedited safety reporting in clinical trials, the following should be considered 
expected events:

Infusion Related Reactions

Injection Site Reactions
9.8 TOXICITY MANAGEMENT
Subjects who develop a new infection while undergoing treatment with bermekimab should be monitored 
closely. Administration of study injections should be interrupted if a subject develops an infection requiring 
IV anti-infective treatment or if an infection meets the definition of "serious" (refer to Section 9.2
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) for definition). Study medication may be 
restarted once the physician determines that the infection has been successfully treated. Otherwise 
prohibited concomitant medications may be given if medically necessitated. Specifically, if a patient 
develops an intercurrent infection, then topical and/or oral antibiotic usage is permitted. If a patient 
experiences an intercurrent illness associated with pain for which oral analgesia is required, then otherwise-
prohibited oral analgesics are permitted. Topical and/or oral antibiotic usage are not permitted for 
worsening of HS (except as specified in Section 2.11.2 Antibiotic Rescue Therapy. Prior to use, every 
attempt should be made to contact the Sponsor’s Medical Director for direction on re-introduction of 
bermekimab therapy after prohibited medication administration.
If the subject must undergo elective surgery, the study injections must be interrupted 2 weeks prior to the 
surgery. If the subject must undergo emergency surgery, the study injections must be interrupted at the time 
of the surgery. The injectable study medication can recommence at least 2 weeks after surgery once the 
physician has examined the surgical site and determined that it has healed and there is no sign of infection.


53
10. STATISTICAL PLAN
This section provides the basis for the statistical analysis plan (SAP) for the study. The SAP may be revised 
during the study to accommodate amendments to the clinical study protocol, and to make changes to adapt 
to unexpected issues in study execution and data that may affect planned analyses.  Analysis variables are 
listed in Section 8.
10.1 DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint is percent of patients who have a positive HiSCR score (achiever) at week 
12. The positive HiSCR score is defined as a ≥50% reduction in inflammatory lesion AN count (sum of 
abscesses and inflammatory nodules), and no increase in abscesses or draining fistulas in HS compared 
with the lesions counted at baseline.   The sample size is calculated for the bermekimab weekly injection 
group (Treatment Arm 1) versus placebo group (Treatment Arm 3) comparison (the primary comparison).
Assuming a positive HiSCR score is achieved in 60% of intent-to-treat (ITT) patients treated in the 
bermekimab weekly injection group (Treatment Arm 1) versus 30% in placebo treated patients (Treatment 
Arm 3), then, for a randomization ratio of 1:1:1, a sample size of 126 patients (42 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 150 
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 Arms 1, 2, or 3. The randomization schedule 
will be stratified by two factors: prior biologic use (yes/no) and Hurley Stage (II/III). 
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.


54
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 populations)

The total number of patients who complete the study and 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.  
10.5.2 Safety Analysis
The primary objective of this study is to evaluate the safety and efficacy of bermekimab. 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. 


55
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
Vital sign parameters (blood pressure, pulse, oxygen saturation, respiratory rate and body temperature) will 
be summarized descriptively by treatment group using actual values and change from baseline values.  
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 descriptively 
by treatment group using actual values and change from baseline values.  A 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 and treated patients (mITT population) and will 
be analyzed based on the randomized treatment groups, regardless of the treatment they actually received.
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 


56
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 DBL 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.
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 (Treatment Arm 1) will be compared to the placebo group 
(Treatment Arm 3) first.  If this test is significant at the 0.05 level, then the bermekimab every other week 
injection group (Treatment Arm 2) will be compared to the placebo group (Treatment Arm 3). Otherwise, 
the P-value for Treatment Arm 2 vs Treatment Arm 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 who have a positive HiSCR score (achiever) at week 12 will be 
presented by treatment group.  Patients who terminate from the study early prior to week 12 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 prior anti-tumor necrosis factor 
or IL-17 inhibitor therapy use (yes/no) and Hurley Stage (II/III) 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 efficacy endpoints (NRS pain & itch, HiSCR, mHSS, HS-PGA, PGA-ISD, HADS, DLQI, EQ-
5D-3L, PGI-c, PGI-s, HiSQOL, IHS4 and HSSD) will be summarized using descriptive statistics on actual 
and change from baseline values over time by treatment group. 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 factors (prior anti-tumor necrosis factor, IL-17 inhibitor therapy 


57
use (yes/no) and Hurley Stage (II/III)), baseline score, baseline score by week interaction, and the treatment-
by-week interaction, if applicable.  The impact of the stratification factors will also be assessed.  Hurley 
Stage, PGI-c, and PGI-s categories will also be summarized descriptively.
Responder analyses will also be performed for select efficacy variables including NRS pain (categorized 
as ≥30% reduction on pain score among patients with baseline score of ≥3), NRS itch (3 point improvement 
in patients with ≥3 itch score at baseline as well as 4 point improvement in patient with ≥4 itch score at 
baseline) at each week.  The number and percentage of patients who meet these criteria will be summarized 
by treatment group.  Additional responder analyses may be performed for other efficacy variables.  Full 
details will be provided in the statistical analysis plan.   
10.5.4 Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis
Descriptive statistics of PK and PD concentrations and parameters will be presented. 
10.5.5 Treatment Exposure
The number and percentage of patients exposed to study drug along with duration of exposure will be 
summarized descriptively by treatment group.
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 (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013), the guidelines of ICH GCP E6 (R2), 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 


58
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 an agreement by the study Sponsor and 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(ies) as required by the applicable 
regulatory requirement(s).
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, 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. Subjects 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.


59
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, 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), if applicable, 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-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. 
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 (E3). 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 


60
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 captured electronically in an Electronic Data Capture (EDC) system.  
Designated study personnel will be provided unique usernames and passwords. Each study personnel will 
have 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


61
11.10 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 
CRAs will establish and maintain regular contact between the Investigator and the Sponsor. CRAs will 
evaluate the competence the study center, informing the Sponsor about any problems relating to facilities, 
technical equipment or medical staff. During the study, CRAs will check that written informed consent has 
been obtained from all subjects correctly and that data are recorded correctly and completely. CRAs are 
also entitled to compare entries in eCRFs with corresponding source data and to inform the Investigator of 
any errors or omissions. CRAs will also monitor adherence to the protocol at the Investigator site. They 
will arrange for the supply of investigational product and ensure appropriate storage conditions are 
maintained. 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. During monitoring visits, entries in 
the eCRFs will be compared with the original source documents. The Investigator must agree to meet with 
the CRA at regular intervals and to cooperate in resolving any queries or findings made during the 
monitoring process. 
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 or/institution, as specified 
by the applicable regulatory requirement(s).


62
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63
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13 Udechukwu NS, Fleischer AB Jr. Higher Risk of Care for Hidradenitis Suppurativa in African
American and Non-Hispanic Patients in the United States. J Natl Med Assoc 2017; 109: 44-48
14 van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Elevated levels of 
tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: a 
rationale for targeting TNF-α and IL-1β. Br J Dermatol 2011; 164: 1292-1298
15 Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two phase 3 trials of 
adalimumab for hidradenitis suppurativa. N Engl J Med 2016; 375: 422-434
16 Adalimumab efficacy in hidradenitis suppurativa patients is sustained at least three years with weekly dosing: 
results from a phase 3 open-label extension study (PIONEER). American Academy of Dermatology 75th Annual 
Meeting, March 2017, Orlando, Florida (abstract 5085)
17 Kanni T, Tzanetakou V, Savva A, Kersten B, Pistiki A, van de Veerdonk FL, et al. Compartmentalized cytokine 
responses in hidradenitis suppurativa. PLoS One 2015; 10: e0130522
18 Tzanetakou V, Kanni T, Giatrakou S, Katoulis A, Papadavid E, Netea MG, et al. Safety and efficacy of anakinra 
in severe hidradenitis suppurativa: a randomized clinical trial. JAMA Dermatol 2016; 152: 52-59
19 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.
20 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.
21 Kurzrock R et al. Inteleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-
class true human interleukin-1α antibody, in a phase III randomized study of advanced colorectal cancer. 
Oncoimmunology. 2018 Dec 12;8(3):1551651. doi: 10.1080/2162402X.2018.1551651. eCollection 2019.
                                                


64
                                                                                                                                                            
22 Hong DS et al. MABp1, a fi rst-in-class true human antibody targeting interleukin-1α in refractory cancers: an 
open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 2014 May;15(6):656-66. doi: 
10.1016/S1470-2045(14)70155-X. Epub 2014 Apr 17.
23 Miossec. Anti-interleukin 1α autoantibodies. Ann Rheum Dis 2002; 61: 577-579.
24 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.
25 Suzuki et al. Anti- IL-1α autoantibodies in patients with rheumatic diseases and in healthy subjects. Clin Exp 
Immunol 1991; 85: 407-412.
26 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.
27 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.
28 Miossec. Anti-interleukin 1autoantibodies. Ann Rheum Dis 2002; 61: 577-579.
29 Gallay et al. Characterization and detection of naturally occurring antibodies against IL-1and IL-1in normal 
human plasma. Eur Cytokine Network 1991; 2: 329-338.
30 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
31 Svenson et al. Distribution and characterization of autoantibodies to interleukin 1 alpha in normal human sera. 
Scand J Immunol. 1990: 32 (6): 695-701
32 Kimball AB, Jemec GB, Yang M, Kageleiry A, Signorovitch JE, Okun MM, et al. Assessing the validity, 
responsiveness and meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical 
endpoint for hidradenitis suppurativa treatment. Br J Dermatol 2014; 171: 1434-1442
33 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.
34 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.
35 Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe hidradenitis 
suppurativa. Ann Intern Med 2012; 157: 846-855.


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 Hidradenitis Suppurativa
Protocol 77474462HDS2002; 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-37346 version 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
77474462HDS2002
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.


COVID-19 Appendix
JNJ-77474462 (bermekimab)
Clinical Protocol 77474462HDS2002
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 77474462HDS2002
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.




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 Hidradenitis Suppurativa
Protocol 77474462HDS2002; 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-37346 version 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
77474462HDS2002
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.
NCT04019041


COVID-19 Appendix
JNJ-77474462 (bermekimab)
Clinical Protocol 77474462HDS2002
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 77474462HDS2002
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
Approved, Date: 5 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 Hidradenitis Suppurativa
Protocol 77474462HDS2002; Phase 2  
JNJ77474462  (Bermekimab)
Status:
Approved
Date:
5 June 2020
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-206032357
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.
NCT04019041


JNJ77474462  (Bermekimab)
Statistical Analysis Plan 77474462HDS2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Approved, Date: 5 June 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 9
1.4.
Sample Size Justification ................................................................................................................. 9
1.5.
Randomization and Blinding ............................................................................................................ 9
1.5.1.
Procedures for Randomization and Stratification ......................................................................... 9
1.5.2.
Maintenance of Blind .................................................................................................................... 9
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11
2.1.
Imputation Rules for Partial or Missing AE Dates.......................................................................... 11
2.2.
Visit Windows................................................................................................................................. 12
2.3.
Pooling Algorithm for Analysis Centers.......................................................................................... 12
2.4.
Analysis Sets.................................................................................................................................. 12
2.4.1.
Efficacy Analysis Set(s) .............................................................................................................. 12
2.4.1.1.
Full Analysis Set ...................................................................................................................... 12
2.4.1.2.
Per Protocol Analysis Set........................................................................................................ 13
2.4.2.
Safety Analysis Set..................................................................................................................... 13
2.4.3.
Pharmacokinetics Analysis Set .................................................................................................. 13
2.4.4.
Pharmacodynamics Analysis Set ............................................................................................... 13
2.4.5.
Immunogenicity Analysis Set...................................................................................................... 13
2.5.
Definition of Subgroups.................................................................................................................. 13
2.6.
Study Day and Relative Day .......................................................................................................... 14
2.7.
Baseline and Endpoint ................................................................................................................... 14
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 15
4.
SUBJECT INFORMATION................................................................................................................ 15
4.1.
Demographics and Baseline Characteristics ................................................................................. 15
4.1.1.
Demographic .............................................................................................................................. 15
4.1.2.
Baseline Disease Characteristics ............................................................................................... 16
4.1.3.
Medical History ........................................................................................................................... 16
4.2.
Disposition Information................................................................................................................... 16
4.3.
Treatment Compliance................................................................................................................... 16
4.4.
Extent of Exposure......................................................................................................................... 16
4.5.
Protocol Deviations ........................................................................................................................ 17
4.6.
Prior and Concomitant Medications/Surgeries............................................................................... 17
5.
EFFICACY ......................................................................................................................................... 17
5.1.
General Method of Analysis........................................................................................................... 17
5.2.
Analysis Specifications................................................................................................................... 18
5.2.1.
Level of Significance................................................................................................................... 18
5.2.2.
Data Handling Rules................................................................................................................... 18
5.2.3.
Treatment Groups....................................................................................................................... 19
5.3.
Primary Efficacy Endpoint(s).......................................................................................................... 20
5.3.1.
Definition..................................................................................................................................... 20
5.3.2.
Estimands ................................................................................................................................... 20
5.3.3.
Data Handling ............................................................................................................................. 21
5.3.4.
Analysis Methods........................................................................................................................ 21
5.3.5.
Analysis Corresponding to Supplement Estimand ..................................................................... 22
5.3.5.1.
Supplementary Analysis 1 (Hypothetical Estimand)................................................................ 22
5.3.5.2.
Supplementary Analysis 2 (Treatment Policy Estimand) ........................................................ 22


JNJ77474462  (Bermekimab)
Statistical Analysis Plan 77474462HDS2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Approved, Date: 5 June 2020
5.3.6.
Subgroup Analysis...................................................................................................................... 22
5.3.7.
Per-protocol Analysis.................................................................................................................. 23
5.4.
Secondary Efficacy Variable(s)...................................................................................................... 23
5.4.1.
Analysis Methods........................................................................................................................ 23
5.4.1.1.
At Week 12 and Week 16........................................................................................................ 24
5.4.1.2.
Over Time Summaries............................................................................................................. 24
5.4.2.
Data Handling Rule..................................................................................................................... 25
5.4.3.
Secondary Efficacy Endpoints.................................................................................................... 25
5.4.3.1.
Hidradenitis Suppurativa Clinical Response (HiSCR)............................................................. 25
5.4.3.1.1.
Definition .............................................................................................................................. 25
5.4.3.1.2.
Analysis Related to HiSCR .................................................................................................. 25
5.4.3.2.
Lesion Count............................................................................................................................ 25
5.4.3.2.1.
Definition .............................................................................................................................. 25
5.4.3.2.2.
Analysis Related to Lesion Count ........................................................................................ 26
5.4.3.3.
Modified Hidradenitis Suppurativa Score (mHSS) (Modified Sartorius Score) ....................... 27
5.4.3.3.1.
Definition .............................................................................................................................. 27
5.4.3.3.2.
Analysis Related to Modified Hidradenitis Suppurativa Score (mHSS)............................... 28
5.4.3.4.
Hidradenitis Suppurativa Physician’s Global Assessment (HS-PGA)..................................... 28
5.4.3.4.1.
Definition .............................................................................................................................. 28
5.4.3.4.2.
Analysis Related to HS-PGA................................................................................................ 28
5.4.3.5.
Patient Reported Outcome...................................................................................................... 28
5.4.3.5.1.
Numerical Rating Scale (NRS) for Pain and Itch [take home diary] .................................... 28
5.4.3.5.1.1.
Definition ........................................................................................................................... 28
5.4.3.5.1.2.
Analysis Related to NRS (Pain & Itch) Score................................................................... 29
5.4.3.5.2.
DLQI..................................................................................................................................... 30
5.4.3.5.2.1.
Definition ........................................................................................................................... 30
5.4.3.5.2.2.
Analysis related to DLQI ................................................................................................... 30
5.4.3.5.3.
Hidradenitis Suppurativa Symptoms Diary (HSSD)............................................................. 30
5.4.3.5.3.1.
Definition ........................................................................................................................... 30
5.4.3.5.3.2.
Analysis Related to Hidradenitis Suppurativa Symptoms Diary (HSSD).......................... 31
5.4.3.5.4.
Hospital Anxiety and Depression (HADS)............................................................................ 31
5.4.3.5.4.1.
Definition ........................................................................................................................... 31
5.4.3.5.4.2.
Analysis Related to Hospital Anxiety and Depression...................................................... 32
5.4.3.5.5.
EuroQol Health Status Questionnaire (EQ-5D-3L)............................................................... 32
5.4.3.5.5.1.
Definition ........................................................................................................................... 32
5.4.3.5.5.2.
Analysis Related to Health Status Questionnaire (EQ-5D-3L)......................................... 32
5.4.3.5.6.
Patient’s Global Impression of Change (PGI-c)................................................................... 33
5.4.3.5.6.1.
Definitions ......................................................................................................................... 33
5.4.3.5.6.2.
Analysis Related to PGI-c ................................................................................................. 33
5.4.3.5.7.
Patient Global Impression of Severity (PGI-s)..................................................................... 33
5.4.3.5.7.1.
Definition ........................................................................................................................... 33
5.4.3.5.7.2.
Analysis Related to PGI-s ................................................................................................. 33
5.4.3.6.
Exploratory Endpoints ............................................................................................................. 33
5.4.3.6.1.
International Hidradenitis Suppurativa Severity Score System (IHS4)................................ 33
5.4.3.6.1.1.
Definition ........................................................................................................................... 33
5.4.3.6.1.2.
Analysis Related to IHS4 .................................................................................................. 34
5.4.3.6.2.
Hidradenitis Suppurativa Quality of Life Measure (HiSQOL) ............................................ 34
5.4.3.6.2.1.
Definition ........................................................................................................................... 34
5.4.3.6.2.2.
Analysis Related to HiSQOL............................................................................................. 34
5.4.3.6.3.
Physician’s Global Assessment of Inflammatory Skin Disease (PGA-ISD)......................... 34
5.4.3.6.3.1.
Definition ........................................................................................................................... 34
5.4.3.6.3.2.
Analysis Related to PGA-ISD ........................................................................................... 35
6.
SAFETY............................................................................................................................................. 35
6.1.
Adverse Events .............................................................................................................................. 36
6.2.
Clinical Laboratory Tests................................................................................................................ 37
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 37


JNJ77474462  (Bermekimab)
Statistical Analysis Plan 77474462HDS2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Approved, Date: 5 June 2020
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 38
7.1.
Pharmacokinetics........................................................................................................................... 38
7.1.1.
Bermekimab Concentrations ...................................................................................................... 38
7.1.1.1.
Data Handling Rules................................................................................................................ 39
7.1.2.
PK vs Efficacy............................................................................................................................. 40
7.1.3.
Population PK Analysis............................................................................................................... 40
7.2.
Immunogenicity.............................................................................................................................. 40
7.2.1.
Antibodies to Bermekimab.......................................................................................................... 40
7.2.2.
Antibody vs PK/Efficacy/Safety .................................................................................................. 40
7.3.
Biomarkers ..................................................................................................................................... 41
REFERENCES............................................................................................................................................ 42


JNJ77474462  (Bermekimab)
Statistical Analysis Plan 77474462HDS2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Approved, Date: 5 June 2020
ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
ALT/SGPT
alanine aminotransferase
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
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CRP
C-reactive protein 
CSR
Clinical Study Report
CV
coefficient of variation
DBL
Database Lock
DLQI
Dermatology Life Quality Index
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 
ESR
Erythrocyte Sedimentation Rate
FAS
full analysis set
FCS
Full Conditional Specification 
FDA
Food and Drug Administration
HADS
Hospital Anxiety and Depression Scale
HiSCR
Hidradenitis Suppurativa Clinical Response
HiSQOL
Hidradenitis Suppurativa Quality of Life Measure 
HS
Hidradenitis Suppurativa
HS-PGA
Hidradenitis Suppurativa Physician’s Global Assessment
HSSD
Hidradenitis Suppurativa Symptom Diary
ICH
International Conference on Harmonization
IHS4
International Hidradenitis Suppurativa Severity Score System 
IQ
interquartile
ITT
intent-to-treat 
IWRS
interactive web response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LS means
Least square means
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mHSS
Modified Hidradenitis Suppurativa Score
MMRM
Mixed-Effect Model Repeated Measure
NAb
neutralizing antibodies
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
NONMEM
nonlinear mixed-effects modeling 
NRS
Numeric Rating Scale
PD
pharmacodynamic
PGA-ISD
Physician’s Global Assessment of Inflammatory Skin Disease 
PGI-c
Patient’s Global Impression of Change
PGI-s
Patient Global Impression of Severity 
PK
pharmacokinetic(s)
PP
per protocol


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q2w
every other week
qw
every week
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation
SUSAR
suspected, unexpected, serious adverse reaction 
TEAE
treatment-emergent adverse event
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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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 JNJ-77474462PT047 study.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate initial efficacy, safety of different dose regimens 
of bermekimab in adult participants with moderate to severe hidradenitis suppurativa (HS).
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 HS.

To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of 
bermekimab therapy in adult participants with moderate to severe HS.
1.2.
Trial Design
This is a 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 
HS. It is anticipated that approximately 50% of patients enrolled will have failed prior targeted 
biologic therapy(ies) and approximately 50% will be naïve to these forms of biologic therapy in 
each arm. 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 participant. 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 participants.
A diagram of the study flow (Figure 1) is provided below. Approximately 150 patients who meet 
eligibility criteria at screening will be randomized in a 1:1:1 fashion to one of three treatment arms:
Bermekimab 400 mg SC (qw) (Treatment Arm 1): 800 mg loading dose of bermekimab (2 x 
400 mg SC injections) at weeks 0 and 1 followed by weekly (qw) subcutaneous (SC) injections of 
400 mg bermekimab through week 31


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Bermekimab 400 mg SC (q2w) (Treatment Arm 2): 800 mg loading dose of bermekimab (2 x 
400 mg SC injections) at weeks 0 and 1 followed by subcutaneous (SC) injections of 400 mg 
bermekimab every other week (q2w) alternating with matching placebo q2w through week 31.
Placebo (Treatment Arm 3): 4mL loading dose of placebo (2 x 2mL SC injections) at weeks 0 
and 1 followed by weekly placebo injections from week 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.
Efficacy assessments (Hidradenitis Suppurativa Clinical Response (HiSCR), Hidradenitis 
Suppurativa Physician’s Global Assessment (HS-PGA), Modified Hidradenitis Suppurativa Score 
(mHSS), lesion counts, International Hidradenitis Suppurativa Severity Score System (IHS4), 
Hurley staging, Hidradenitis Suppurativa Symptom Diary [HSSD], Numeric Rating Scale (NRS) 
for Pain and Itch, Dermatology Life Quality Index [DLQI], Hospital Anxiety and Depression Scale 
[HADS], Patient’s Global Impression of Change [PGI-c], Physician’s Global Assessment of 
Inflammatory Skin Disease (PGA-ISD), Patient Global Impression of Severity (PGI-s),  
Hidradenitis Suppurativa Quality of Life Measure (HiSQoL), and Health Status Questionnaire 
(EQ-5D-3L) will be performed according to the Schedules of Activities. Serum samples for PK,
immunogenicity, and biomarker analyses will be collected at the timepoints shown in 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.
Figure 1:
Study Flow Diagram
Visit(V)
Week(W)
Day (D)
After completion of the 36-week study period, data will be locked and analyzed for safety and 
efficacy. 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 to help 
plan potential future development activities.
Screening
TreatmentPeriod
Follow-up
Baseline WeeklyDosing
Endpoint
Assessment
D -30 to -1
V1
W0
D0
V2 to V32
W1 to W31
D7 to D217
V33
W32
D224
V34
W36
D252


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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 Hidradenitis Suppurativa Clinical Response (HiSCR) at 
Week 12.

HiSCR is defined as at least 50% reduction in total abscess and inflammatory nodule 
counts (AN count) with no increase in abscess count and no increase in draining fistula 
count relative to baseline.
1.4.
Sample Size Justification
The primary efficacy endpoint is percent of patients who achieve HiSCR at week 12.  The sample 
size is calculated for the bermekimab weekly injection group (Arm 1) versus placebo group
(Arm 3) comparison.
Assuming HiSCR is achieved in 60% of intent-to-treat (ITT) patients treated in the bermekimab 
weekly injection group (Arm 1) versus 30% in placebo treated patients (Arm 3), then, for a 
randomization ratio of 1:1:1, a sample size of 126 patients (42 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 150 
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 Arms 1, 2, or 3. The 
randomization schedule will be stratified by two factors: prior biologic use (yes/no) and Hurley 
Stage (II/III).
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 and 1, followed by weekly 
injections from weeks 2 to 31.  Additionally, to ensure that no unintentional unblinding occurs during 
study drug administration, 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.


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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 
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 for the purposes of performing data analysis 
and review.  Identification of sponsor personnel who will have access to the unblinded data at 
participant-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 
participant 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 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. The documentation received from the EDC indicating the code break must be retained 
with the participant's source documents in a secure manner.


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Participants who have had their intervention assignment unblinded by the investigator will not be 
eligible to receive further study intervention, but should continue to complete early termination 
visit specified in the Study Calendars section (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:

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.


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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 participant 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. 
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 and safety data through Week 16 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 HS. The selected efficacy and safety 
data include but not limited to following:
1.
Lesion count [includes Hidradenitis Suppurativa Clinical Response (HiSCR)]   
2.
Numeric Rating Scale for Pain & Itch (NRS Pain & Itch) score
3.
HS Symptom Diary (HSSD) HS related Pain Symptom Score
4.
Baseline Disease Characteristics for 1-3 above
5.
Demography 
6.
AE
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) 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.  


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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 7 in the protocol as listed below:

A total body count of abscesses and inflammatory nodules (A+N) of at least 3.

who met the exclusion criteria 10 in the protocol as listed below:

Has a draining fistula count of >20 at the baseline visit.

who did not receive all scheduled study agent administrations prior to Week 12. 
However, for those who discontinued the study agent prior to Week 12 will be included in the per-
protocol analysis and the data handling rule specified in Section 5.2.2 will apply. Participants who 
were excluded from the per protocol analyses will also be summarized.
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 complete 
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(including IL-6) 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 HiSCR at Week 12) over demographics, baseline disease characteristics, and prior HS
medication use, subgroup analyses will be performed when sample sizes are permitted.  The 
subgroups include, but are not limited to, the following:


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Baseline demographics:

Sex (male, female)

Race 

Baseline Age (<40 years, 40 to <65 years, 65 years)

Baseline weight (< median, ≥ median) 

BMI (Normal [<25], Overweight [25 -<30], Obese [≥ 30])
Baseline disease characteristics:

Baseline Hurley stage status (II, and III)

Age at diagnosis (years) (< median, ≥ median)

HS disease duration (years) (< median, ≥ median)

Baseline AN count category (3 to 5, 6 to 10, ≥11) 

Baseline AN count (< median, ≥ median)

Baseline HS-PGA (<3, 3, 4, 5)

Baseline C-reactive protein (CRP) level (< median, ≥ median)

Baseline Erythrocyte Sedimentation Rate (ESR) (< median, ≥ median)
HS medication:

Prior biologic therapy used

Never used

Ever used
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.


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3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis and 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 at Week 0, 
regardless of the treatment they actually received. The number of participants in FAS 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, participant listings will also be used to present the 
data.
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) (≤95 kg, > 95 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])


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4.1.2.
Baseline Disease Characteristics
Baseline disease severity measurements (e.g., duration of HS disease, baseline Hurley stage status,
baseline AN count, inflammatory nodule count, abscess count, and draining and non-draining 
fistula count, HS-PGA, Modified Hidradenitis Suppurativa Score) and baseline patient reported 
outcomes (e.g, DLQI, HSSD, NRS Pain, NRS Itch, EQ-5D-3L, HADS) will be summarized by 
treatment group. 
4.1.3.
Medical History
Summaries of participants’  surgical history, alcohol intake, and smoking status will be provided 
by treatment group. Medical history will be listed including body systems and condition/non-drug 
allergy as captured on the eCRF.
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 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 through Week 16 and through Week 36 will be summarized. 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 


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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.
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 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.
Prior and Concomitant Medications/Surgeries
Prior and concomitant medications 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 continue on after the first dose 
of study agent.
Prior biologic used that was captured in eCRF, summary of concomitant medications with 
potential to improve HS and summary of concomitant analgesic therapy will be summarized by 
randomized treatment group for the FAS. a listing of participants who received a  concomitant 
treatment that could improve HS, a listing of participants who received concomitant analgesic 
therapy, and a listing of participants who received concomitant corticosteroids 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
(400 mg SC qw, 400 mg SC q2w) and the placebo treatment group.


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In general, for response efficacy endpoints, treatment comparisons will be performed using a 
Cochran-Mantel-Haenszel (CMH) test stratified by the prior biologic use (yes/no) and  screening 
Hurley stage (II/III). For continuous efficacy endpoints, treatment comparisons will be performed 
using either a Mixed-Effect Model Repeated Measure (MMRM) model. All of the models will 
have treatment group, prior biologic use (yes/no), screening Hurley stage (II/III), and baseline 
value for the corresponding efficacy endpoint as explanatory factors. The MMRM model will also 
include visit, treatment group by visit interaction, prior biologic use by visit, screening Hurley 
stage by visit, and baseline value by visit interaction as additional explanatory factors. In addition, 
treatment differences and their associated 95% confidence intervals will be presented.
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.
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. Nominal p-values will be reported for other secondary analyses. 
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 controlled 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 HiSCR at Week 12, participants 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 participant 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 


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2 supplementary analyses) will also be applied for HiSCR 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 participant who 
discontinued treatment will be considered as a non-responder from that point onward. The 
remaining missing data will be imputed as non-responder. 
Continuous secondary endpoints:

If a participant 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.

In addition, supplementary analyses will be performed for the analyses related to 
(a) change from baseline in AN count (Section 5.4.3.2.2) and (b) change from baseline in 
HSSD past 24 hours pain (Section 5.4.3.5.3.2) endpoints using

Observed data regardless of whether the subject discontinued treatment or have 
missing data.
o
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, full analysis set 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 at Week 0:
o
Placebo:  Participants randomized to placebo group at Week 0.
o
Bermekimab 400 mg q2w:  Participants randomized to bermekimab 400 mg SC 
q2w group at Week 0.
o
Bermekimab 400 mg qw: Participants randomized to bermekimab 400 mg qw group 
at Week 0.
o
Combined Column: Combined column which combines the data from the 
randomized and treated participants who are assigned to bermekimab treatment 
groups at baseline.


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
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 at week 0 who crossed over to receive Bermekimab 400 mg qw at Week 16. 

Only placebo participants crossover to bermekimab 400 mg SC 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 SC q2w
group at Week 0.
o
Bermekimab400 mg qw: Participants randomized to bermekimab 400 mg SC qw
group at Week 0.
o
Combined Column: Combined column which combines the data from the 
randomized and treated participants who are assigned to bermekimab 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 participants achieve a HiSCR at Week 12. 
HiSCR  is defined as a ≥ 50% reduction in inflammatory lesion AN count (sum of abscesses and 
inflammatory nodules), and no increase in abscesses or draining fistulas in HS compared with the 
lesions counted at baseline.
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

Placebo
Note: treatment regimen include protocol specified antibiotic rescue therapy/lesion 
intervention as needed. 

Population:  Adult participants with moderate to severe Hidradenitis Suppurativa for at 
least 1 year.

Variable: HiSCR binary responder variable at Week 12, where a participant who 
discontinues treatment is considered as non-responder after discontinuation.


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
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 proportion of participants achieving HiSCR
at Week 12 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, the data of HiSCR status 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, the data of HiSCR status after treatment discontinuation 
will also be used in analysis.
5.3.3.
Data Handling
Participants who discontinued treatment prior to Week 12 will be considered HiSCR non-
responder at Week 12. In addition, participants with missing lesion count evaluations at Week 12 
will be considered as HiSCR non-responders at Week 12.
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 12 based on the composite strategy
(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.
In this primary analysis, the number and proportion of participants who achieve a HiSCR at 
Week 16 will be summarized for each treatment group. To address the primary objective, a CMH 
chi-square statistic stratified by stratified by prior biologic use (yes/no) and screening Hurley stage
(II/III) at an alpha level of 0.05 will be used.


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The proportion of participants who achieve HiSCR at Week 12 will be compared between each of 
the 2 bermekimab treatment groups and the placebo group. 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 prior biologic use (yes/no) and 
screening Hurley stage (II/III).
The study would be claimed 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. 
5.3.5.
Analysis Corresponding to Supplement Estimand
5.3.5.1.
Supplementary Analysis 1 (Hypothetical Estimand)
The first supplementary analysis will be performed utilizing the Hypothetical Estimand by using 
multiple imputations (MI)1 by treatment group based on HiSCR responses respectively. For 
participants who do not return for evaluation at Week 12 after discontinuation of study treatment 
for any reason, the data will be considered missing. The fully conditional specification (FCS) 
method will be used to impute the missing data for the HiSCR response at Week 12.
More specifically, the missing HiSCR response status will be imputed using FCS method with 500
imputed data sets with seed = 1231 to fill in the missing HiSCR responses through Week 12 in 
each of the 500 copies of datasets. The proportion difference of HiSCR at Week 12 adjusted for 
prior biologic use (yes/no) and screening Hurley stage (II/III) using Mantel-Haenszel weight 
between the bermekimab groups and the placebo group and its 95% CI combining multiple 
datasets will 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.
5.3.5.2.
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 at Week 12, the analysis will be performed using observed data 
regardless of study treatment discontinuation.
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 HiSCR at Week 12
and its 95% continuity adjusted confidence interval (when the number of participants permits) will 
be calculated.  Subgroup analyses will not be stratified by prior biologic use (yes/no) and screening 
Hurley stage (II/III). 
In addition, the proportion of participants achieving HiSCR at Week 12 by investigator site/region 
will be summarized. The same data handling rules specified in Section 5.2.2 will apply for 
subgroup analysis.


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5.3.7.
Per-protocol Analysis
The primary analyses for primary endpoint will also be performed on per-protocol analysis set 
(Section 2.4.1.2). Similar data handling rules specified in Section 5.2.2 will apply.
5.4.
Secondary Efficacy Variable(s)
In addition to the primary, the analyses for secondary efficacy endpoints will be performed and 
nominal p-values will be provided. Other efficacy endpoints include the endpoints related to 

HiSCR

Lesion Count

Modified Hidradenitis Suppurativa Score (mHSS)

HS-PGA 

Patient-reported Outcomes 

Numerical Rating Scale (NRS) for Pain & Itch [take home patient diary]

DLQI

HSSD

HADS

Health Status Questionnaire (EQ-5D-3L)

Patient’s Global Impression of Severity (PGI-s)

Patient’s Global Impression of Change (PGI-c) 

Exploratory endpoints

International Hidradenitis Suppurativa Severity Score System (IHS4)

Hidradenitis Suppurativa Quality of Life Measure (HiSQOL)

Physician’s Global Assessment of Inflammatory Skin Disease (PGA-ISD)
5.4.1.
Analysis Methods
The secondary efficacy analyses outlined in the following sections in general will be carried out 
at key endpoints (Week 12 and Week 16) and over time.
Most of the secondary efficacy analyses described in sections below will be based on FAS. 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.


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5.4.1.1.
At Week 12 and Week 16
For continuous endpoints where longitudinal data were collected prior to the analysis visits;
treatment comparisons will be performed using Mixed-Effect Model Repeated Measure (MMRM) 
model, with fixed effects for treatment, week, stratification factors (prior biologic use (yes/no), 
screening Hurley stage (II/III)) when sample size in each category of the stratification variables is 
permitted, and baseline value in the model. The MMRM model will also include prior biologic use 
by visit, screening Hurley stage by visit, and baseline value by visit interaction and   the treatment-
by-week interaction as additional explanatory factors. 
The model will be performed based on all available data from the 3 treatment groups through 
Week 16. The treatment difference between a guselkumab group and the placebo group will be 
estimated by the difference in the least squares means (LSmeans). The 95% CIs for the differences 
in LSmeans and p-values will be calculated.
For binary response endpoints treatment comparisons will be performed using a Cochran-Mantel-
Haenszel (CMH) test stratified by the prior biologic use (yes/no) and screening Hurley stage 
(II/III) with missing data imputed with Non-Responder Imputation (NRI) defined in Section 5.2.2.
For the PRO endpoints with ordinal scale, the Cochran-Mantel-Haenszel (CMH) mean scores test 
stratified by prior biologic use (yes/no) and screening Hurley stage (II/III) will be used to compare
bermekimab and placebo. The distribution of ordinal scale category will also be provided.
5.4.1.2.
Over Time Summaries
In general, all endpoints with over time analyses will be descriptively summarized by treatment 
groups using descriptive statistics, such as mean, median, standard deviation, interquartile range, 
minimum and maximum for continuous variables, and counts and percentages for categorical 
variables.
For continuous secondary endpoints, the change from baseline at each week will be analyzed 
using a restricted maximum likelihood (REML)-based mixed model for repeated measures 
(MMRM) with fixed effects for treatment, visit, stratification factors (prior biologic use (yes/no) 
and screening Hurley stage (II/III)), baseline value, prior biologic use by visit, screening Hurley 
stage by visit, baseline value by week interaction, and the treatment-by-week interaction. Least 
Square means (LSmeans), LS means differences and their corresponding 95% confidence interval 
will be provided over time through Week 16 by visit and treatment group in addition to the 
descriptive summary statistics. For over time summaries from Week 16 through Week 36. Least 
Square means (LSmeans) and their corresponding 95% confidence interval will be provided.
Additionally, graphical data displays may also be used to summarize the over time data if 
applicable.


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5.4.2.
Data Handling Rule
Unless otherwise specified, data handling rules specified in Section 5.2.2 will be applied to these
secondary analyses. For binary endpoints, participants with missing response status will be 
considered non-responders for the over time analyses.
5.4.3.
Secondary Efficacy Endpoints
5.4.3.1.
Hidradenitis Suppurativa Clinical Response (HiSCR)
5.4.3.1.1.
Definition

HiSCR75 is defined as a ≥ 75% reduction in inflammatory lesion AN count (sum of 
abscesses and inflammatory nodules) from baseline and no increase in abscesses or 
draining fistulas in HS compared with the lesions counted at baseline.

HiSCR90  is defined as a ≥ 90% reduction in inflammatory lesion AN count (sum of 
abscesses and inflammatory nodules) from baseline and no increase in abscesses or 
draining fistulas in HS compared with the lesions counted at baseline.
Please also refer to Section 5.3.1 for the definition of the HiSCR responder status.
5.4.3.1.2.
Analysis Related to HiSCR

The proportion of participants who achieved  HiSCR at Week 16 will be compared 
between each of the bermekimab groups and the placebo group.

The proportion of participants who achieved  HiSCR75 and HiSCR90 at Week 12 and 
Week 16 will be compared between each of the bermekimab groups and the placebo group.

The proportion of participants who achieved HiSCR, the proportion of participants who 
achieved HiSCR by baseline weight category (≤ 95 kg, > 95 kg), and the proportion of 
participants who achieved HiSCR by baseline Hurley stage  (II/III) will be summarized 
by treatment group over time.

The proportion of participants who achieved  HiSCR75 and HiSCR90 will be summarized 
by treatment group over time.
Subgroup analyses specified in Section 5.3.6 will also be performed at Week 16. In addition, for 
participants who discontinued study treatment or have missing data, the proportion of participants 
who achieve HiSCR through Week 16 will be analyzed utilizing the hypothetical estimand
(i.e. MI method) and treatment policy estimand (i.e. observed data).
5.4.3.2.
Lesion Count
5.4.3.2.1.
Definition
Lesion counts are defined as the number of abscesses, inflammatory nodules, non-inflammatory 
nodules, draining fistulas, and non-draining fistulas. Lesions will be counted during each visit.

AN count is defined as total abscess and inflammatory nodule count.

AN50 is defined as at least a 50% reduction in AN count relative to baseline.


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
AN75 is defined as at least a 75% reduction in AN count relative to baseline.

AN90 is defined as at least a 90% reduction in AN count relative to baseline.

AN100 is defined as a 100% reduction in AN count relative to baseline (ie, AN count = 0).
5.4.3.2.2.
Analysis Related to Lesion Count
AN Count

The change from baseline in total AN count at Week 12 and Week 16 will be compared 
between each of the bermekimab groups and the placebo group respectively.

The change from baseline in total AN count will be summarized by treatment groups over
time.

The proportion of participants achieving at least 50%, 75%, 90%, and 100% reduction in 
total AN count at Week 12 and Week 16 will be compared between each of the 
bermekimab groups and the placebo group.

The proportion of participants achieving at least 50%, 75%, 90%, and 100% reduction in 
total AN count will be summarized by treatment group over time. In addition, the 
proportion of participants achieving at least 50%, 75%, 90%, and 100% reduction in total 
AN count will be summarized in subgroups of baseline weight category (≤ 95 kg, > 95 kg) 
and baseline Hurley stage  (II/III) by treatment group over time.

The proportion of participants achieving AN count of 0/1 and 0/1/2 respectively at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group.

The proportion of participants who experienced at least one flare (defined as at least a 25% 
increase in AN count with a minimum increase of 2 AN count relative to baseline) over 
16 weeks will be compared between each of the bermekimab groups and the placebo group
at Week 12 and Week 16. Furthermore, the proportion of participants who experience at 
least one flare over 36 weeks will be summarized at Week 36 by treatment groups.
In addition, two supplementary analyses will be performed for the analyses  (a) change from 
baseline in AN count at Week 12 and week 16 and (b) change from baseline in AN count overtime
(Section 5.2.2) by using 

Observed data regardless of whether the subject discontinued treatment or have missing 
data.

Data after treatment discontinuation will be considered as missing, missing data will be 
addressed by MMRM model.
Abscess

The proportion of participants who achieved complete elimination of abscesses at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group among participants who had any abscess at baseline.


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
The change from baseline in number of abscesses at Week 12 and Week 16 will be 
compared between each of the bermekimab groups and the placebo group respectively.

The change from baseline in number of abscesses will be summarized by treatment group 
over time.
Fistulas

The proportion of participants who achieved complete elimination of draining fistulas at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group among those with draining fistulas at baseline.

The change from baseline in number of draining fistulas at Week 12 and Week 16 will be 
compared between each of the bermekimab groups and the placebo group respectively.

The change from baseline in number of draining fistulas and non-draining fistula will be 
summarized by treatment group over time.
Inflammatory Nodules non-inflammatory Nodules

The proportion of participants who achieved complete elimination of inflammatory 
nodules at Week 12 and Week 16 will be compared between each of the bermekimab
groups and the placebo group among those with inflammatory nodules at baseline.

The change from baseline in number of inflammatory nodules at Week 12 and Week 16 
will be compared between each of the bermekimab groups and the placebo group
respectively.

The change from baseline in number of inflammatory nodules will be summarized by 
treatment group over time.

The change from baseline in number of non-inflammatory nodules will be summarized by 
treatment group over time.
5.4.3.3.
Modified Hidradenitis Suppurativa Score (mHSS) (Modified Sartorius
Score)
5.4.3.3.1.
Definition
The Sartorius Scale is used to quantify the severity of HS. Points are awarded for 12 body areas 
(left and right axillae, left and right sub/inframammary areas, intermammary area, left and right 
buttocks, left and right inguino-crural folds, perianal area, perineal area, and other): points were 
awarded for nodules (2 points for each); abscesses (4 points); fistulas (4 points); scars (1 point); 
other findings (1 point); and longest distance between two lesions (2-6 points, 0 if no lesions); and 
if lesions are separated by normal skin (yes-0 points; no-6 points). The total Sartorius score is the 
sum of the 12 regional scores.


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5.4.3.3.2.
Analysis Related to Modified Hidradenitis Suppurativa Score (mHSS)

The change from baseline in modified Hidradenitis Suppurativa score at Week 12 and 
Week 16 will be compared between each of the bermekimab groups and the placebo group
respectively.

The change from baseline in modified Hidradenitis Suppurativa score will be summarized 
by treatment group over time.
5.4.3.4.
Hidradenitis Suppurativa Physician’s Global Assessment (HS-PGA)
5.4.3.4.1.
Definition
HS-PGA is defined as: a) clear when the total number of abscesses is 0, the total number of 
draining fistulas is 0, the total number of inflammatory nodules is 0 and the total number of non-
inflammatory nodules is 0; b) minimal when the total number of abscesses is 0, the total number 
of draining fistulas is 0, the total number of inflammatory nodules is 0 and there is presence of 
non-inflammatory nodules; c) mild when the total number of abscesses is 0, the total number of 
draining fistulas is 0, and the total number of inflammatory nodules is 1-4, or when there is 
presence of one abscess or draining fistula  and absence of any inflammatory nodules; d) moderate 
when the total number of abscesses is 0, the total number of draining fistulas is 0 and the total 
number of inflammatory nodules is at least 5; or when there is presence of one abscess or draining 
fistula and at least one inflammatory nodule; or when there are 2-5 abscesses or draining fistulas 
and fewer than 10 inflammatory nodules; e) severe when the total number of abscesses or draining 
fistulas is 2-5 and the total number of inflammatory nodules is at least 10; and f) very severe when 
there are more than 5 abscesses or draining fistulas1.
5.4.3.4.2.
Analysis Related to HS-PGA

The proportion of participants who achieved HS-PGA of clear (0), clear (0) or minimal 
(1) or HS-PGA score of mild or better (≤ 2) with at least a 2-grade improvement relative 
to baseline at Week 12 and Week 16 will be compared between each of the bermekimab
groups and the placebo group respectively.

The proportion of participants with 1-grade and 2-grade improvement in HS-PGA scores 
from baseline will be summarized over time respectively.

The proportion of participants who achieved HS-PGA of clear (0), clear (0) or minimal 
(1) or HS-PGA score of mild or better (≤ 2) with at least a 2-grade improvement relative 
to baseline will be summarized over time by treatment group.
5.4.3.5.
Patient Reported Outcome
5.4.3.5.1.
Numerical Rating Scale (NRS) for Pain and Itch [take home diary]
5.4.3.5.1.1.
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). Both pain and itch rating scale will be averaged into 


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a weekly score respectively (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. The baseline is defined as the average score of last 7 days prior 
to Week 0 study agent administration. Similarly, If there are more than 3 days missing data, then 
baseline is set as missing. Missing baseline will not be imputed.

NRS30 for numerical rating pain score (weekly average): at least 30% reduction from 
baseline in numerical rating scale for pain.
5.4.3.5.1.2.
Analysis Related to NRS (Pain & Itch) Score

Proportion of participants who achieved NRS30 for pain score – at worst (weekly average) 
at Week 12 and Week 16 among participants with baseline NRS pain score ≥ 3 will be 
compared between each of the bermekimab groups and the placebo group respectively.

Proportion of participants who achieved NRS30 for pain score – on average (weekly 
average) at Week 12 and Week 16 among participants with baseline NRS pain score ≥ 3
will be compared between each of the bermekimab groups and the placebo group
respectively.

Proportion of participants who achieved NRS30 – at worst (weekly average) and on 
average (weekly average) will be summarized over time by treatment group among 
participants with baseline NRS score ≥ 3 respectively.

Proportion of participants who achieve ≥3-point and ≥4-point improvement (reduction) in 
NRS itch score – at worst (weekly average) from baseline at Week 12 and Week 16 will 
be compared between each bermekimab group and the placebo group among participants
with baseline NRS itch score ≥ 3 and ≥4 respectively.

Proportion of participants who achieve ≥3-point and ≥4-point improvement (reduction) in 
NRS itch score – on average (weekly average) from baseline at Week 12 and Week 16 
will be compared between each bermekimab group and the placebo group among 
participants with baseline NRS itch score ≥ 3 and ≥4 respectively.

Proportion of participants who achieve ≥3-point and ≥4-point improvement (reduction) in 
NRS itch score – at worst (weekly average) and on average  (weekly average) from 
baseline will be summarized over time by treatment group among participants with 
baseline NRS itch score ≥ 3 and ≥ 4 respectively.

Change from baseline in NRS pain score and itch score – at worst (weekly average) at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group respectively.

Change from baseline in NRS pain score and itch score – on average (weekly average) at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group respectively.

Change from baseline in NRS pain and itch score -at worst (weekly average) and on 
average (weekly average) will be summarized over time by treatment group.


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5.4.3.5.2.
DLQI
5.4.3.5.2.1.
Definition
The DLQI is a dermatology-specific quality of life instrument designed to assess the impact of the 
disease on a participant’s quality of life.  It is a 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 participant’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):

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.
5.4.3.5.2.2.
Analysis related to DLQI

The change from baseline in DLQI scores at Week 12 and Week 16 will be compared 
between each of the bermekimab groups and the placebo group respectively. In addition, 
the change from baseline in DLQI scores will also be summarized over time.

The proportions of participants with DLQI score of 0 and 1 at Week 12 and Week 16 for 
the participants with baseline DLQI score >1 will be compared between each of the 
bermekimab groups and the placebo group respectively and will also be summarized by 
treatment groups over time.

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 12 and Week 16 will be compared 
between each of the bermekimab groups and the placebo group and will also be 
summarized by treatment groups over time.

The change from baseline in DLQI component scores at Week 12 and Week 16 will be 
compared between each of the bermekimab groups and the placebo group.
5.4.3.5.3.
Hidradenitis Suppurativa Symptoms Diary (HSSD)
5.4.3.5.3.1.
Definition
The HSSD is a 7-item patient self-reported questionnaire that assesses 5 HS-related symptoms 
including pain, tenderness, hot skin feeling, odor, and itchiness. The participants are asked to rate 
the severity of each symptom on a 0 to 10 numerical rating scale, with 0 indicating no symptom 


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experience and 10 indicating the worst possible symptom experience. All 5 symptoms have a recall 
period of the past 7 days, except for 2 additional questions on pain which evaluate current pain 
and pain in the past 24 hours. Each individual symptom scale score, ranging from 0-10, will be 
summarized. A total symptom score, which will also range from 0-10, will be derived by averaging 
the 5 individual scale scores that utilize the past 7-day recall period.
5.4.3.5.3.2.
Analysis Related to Hidradenitis Suppurativa Symptoms Diary
(HSSD)

The change from baseline in HS-related skin pain in the past 24 hours based on HSSD at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group respectively.

The change from baseline in each HSSD symptom scale score (7 days recall) and the 
change from baseline in current pain at Week 12 and Week 16 will be compared between 
each of the bermekimab groups and the placebo group.

The change from baseline in HSSD total symptom score at Week 12 and Week 16 will be 
compared between each of the bermekimab groups and the placebo group.

Number of participants with a reduction of ½ SD or more from baseline in HSSD total 
symptom score at Week 12 and Week 16 will be compared between each of the 
bermekimab groups and the placebo group.

The change from baseline in each HSSD symptom scale score (7 days recall), the change 
from baseline for the past 24 hours pain and current pain, and the change from baseline in 
HSSD total symptom score will be summarized over time.
In addition, two supplementary analyses will be performed for the analyses  (a) change from 
baseline in HS-related skin pain in the past 24 hours based on HSSD at Week 12 and week 16 and 
(b) change from baseline in HS-related skin pain in the past 24 hours based on HSSD overtime 
(Section 5.2.2) by using 

Observed data regardless of whether the subject discontinued treatment or have missing 
data.

Data after treatment discontinuation will be considered as missing, missing data will be 
addressed by MMRM model.
5.4.3.5.4.
Hospital Anxiety and Depression (HADS)
5.4.3.5.4.1.
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.


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If one or more of the items within each domain are left unanswered, that HADS component score 
will be considered missing.
5.4.3.5.4.2.
Analysis Related to Hospital Anxiety and Depression

The change from baseline in Hospital Anxiety and Depression scale (HADs) at Week 12 
and Week 16 will be compared between each of the bermekimab groups and the placebo 
group.

The change from baseline in Hospital Anxiety and Depression scale will be summarized 
over time by treatment groups.

The proportion of participants with hospital anxiety scale <8 and depression scale <8 at 
Week 12 and 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 with respect to the hospital 
anxiety and depression scale category (<8, >=8) will be summarized over time.
5.4.3.5.5.
EuroQol Health Status Questionnaire (EQ-5D-3L)
5.4.3.5.5.1.
Definition
The EQ-5D-3L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue 
scale (EQ VAS).The EQ-5D-3L descriptive system comprises the following five dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 
3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate 
his/her health state by ticking the box next to the most appropriate statement in each of the five 
dimensions. This decision results into a 1-digit number that expresses the level selected for that 
dimension. The digits for the five dimensions can be combined into a 5-digit number that describes 
the patient’s health state. The EQ VAS records the patient’s self-rated health on a vertical visual 
analogue scale where the endpoints are labelled ‘Best imaginable health state (scale of 100) ’ and 
‘Worst imaginable health state (scale of 0)’. The VAS can be used as a quantitative measure of 
health outcome that reflects the patient’s own judgement.
5.4.3.5.5.2.
Analysis Related to Health Status Questionnaire (EQ-5D-3L)

The change from baseline in EQ VAS scale at Week 12 and Week 16 will be compared 
between each of the bermekimab groups and the placebo group.

The change from baseline in EQ VAS scale will be summarized over time by treatment 
group. 

Number of participants with a reduction of ½ SD or more from baseline in EQ VAS scale
at Week 12 and Week 16 will be compared between each of the bermekimab groups and 
the placebo group.

The distribution of health state scale for each of the EQ-5D-3L dimension at Week 12 and 
Week 16 will be compared between each of the bermekimab groups and the placebo 
group; and will also be summarized over time.


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5.4.3.5.6.
Patient’s Global Impression of Change (PGI-c)
5.4.3.5.6.1.
Definitions
The PGI-c is a single item patient reported outcome that assesses change in severity of skin pain 
due to HS. Participants will rate how his/her HS has changed since the beginning of the study using 
a 7-point scale ranging from 1 which indicates "very much better" to 7 which indicates "very much 
worse" with a neutral center point 4 which indicates ("no change").
5.4.3.5.6.2.
Analysis Related to PGI-c

The distribution of the PGI-c scale will be summarized over time by treatment group.
5.4.3.5.7.
Patient Global Impression of Severity (PGI-s)
5.4.3.5.7.1.
Definition
The PGI-s is a single item patient reported outcome that assesses change in a patient’s impression 
of their disease severity. The PGI-s item asks the respondent to best describe how his/her HS 
symptoms are now (“check the one number that best describes how your HS symptoms are now”) 
on a 4-point scale scored as: “normal” (1), “mild” (2), “moderate” (3), or “severe” (4)”.
5.4.3.5.7.2.
Analysis Related to PGI-s

The distribution of the PGI-s scale at Week 12 and Week 16 will be compared between 
each of the bermekimab groups and the placebo group.

The proportion of participants who achieved PGI-s of normal (0), normal (0) or mild (1) 
at Week 12 and Week 16 will be compared between each of the bermekimab groups and 
the placebo group respectively.

Summary of PGI-s symptom status will be summarized over time.
5.4.3.6.
Exploratory Endpoints
In addition to the above efficacy analyses, the follow efficacy analyses and summaries will be 
explored :
5.4.3.6.1.
International Hidradenitis Suppurativa Severity Score System (IHS4)
5.4.3.6.1.1.
Definition
IHS4 is a dynamic severity assessment of HS. IHS4 score is arrived at by the number of nodules 
(multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining 
tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 
or higher signifies severe disease.


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5.4.3.6.1.2.
Analysis Related to IHS4

The change from baseline in international hidradenitis suppurativa severity score at 
Week 12 and Week 16 will be compared between each of the bermekimab groups and the 
placebo group.

The change from baseline in international hidradenitis suppurativa severity score will be 
summarized over time by treatment group.
5.4.3.6.2.
Hidradenitis Suppurativa Quality of Life Measure (HiSQOL)
5.4.3.6.2.1.
Definition
HiSQOL is a patient self-reported questionnaire that assesses various HS-related quality of life 
measures. This instrument includes 17 items that are categorized into 3 subscales as ‘Symptom’, 
‘Psychosocial’, and ‘Activities’. A five‐point item response scale incorporating ‘extremely’, ‘very 
much’, ‘moderately’, ‘slightly’ or ‘not at all’ was used for all items. The point values assigned to 
these responses were 4, 3, 2, 1 and 0, respectively. For some items, respondents were given the 
additional option of ‘unable to do, due to my HS’ and/or ‘I do not normally do this, HS did not 
influence’. The former option was assigned a score of 4 to indicate the severity of the impact of 
HS, whereas the latter option was assigned a score of 0 to indicate that HS did not impact it.
5.4.3.6.2.2.
Analysis Related to HiSQOL

The change from baseline in HiSQOL and HiSQOL subscales at Week 12 and Week 16 
will be compared between each of the bermekimab groups and the placebo group.

The change from baseline in HiSQOL and HiSQOL subscales will be summarized over 
time by treatment group.
5.4.3.6.3.
Physician’s Global Assessment of Inflammatory Skin Disease (PGA-
ISD)
5.4.3.6.3.1.
Definition
The PGA-ISD is a tool developed by the International Dermatology Outcome Measures (IDEOM) 
organization to serve as a potential standardized outcome measure for assessment of inflammatory 
skin diseases.

PGA-ISD score of 0: No inflammatory activity

PGA-ISD score of 1: Barely discemible inflammatory activity 

PGA-ISD score of 2: Mild inflammatory activity

PGA-ISD score of 3: Moderate inflammatory activity

PGA-ISD score of 4: Severe inflammatory activity

PGA-ISD score of 5: Extremely severe inflammatory activity


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5.4.3.6.3.2.
Analysis Related to PGA-ISD

The distribution of the PGA-ISD score at Week 12 and Week 16 will be compared between 
each of the bermekimab groups and the placebo group and will be summarized over time.

The proportion of participants who achieved PGA-ISD score of no inflammatory activity 
(0), no inflammatory activity (0) or barely discemible inflammatory activity (1) or PGA-
ISD score of mild inflammatory activity or better (≤ 2) at Week 12 and Week 16 will be 
compared between each of the bermekimab groups and the placebo group respectively.

The proportion of participants who achieved PGA-ISD score of no inflammatory activity 
(0), no inflammatory activity (0) or barely discemible inflammatory activity (1) or PGA-
ISD score of mild inflammatory activity or better (≤ 2) will be summarized over time by 
treatment group.
6.
SAFETY
Safety will be assessed by summarizing the incidence and type of AEs and examining changes in 
laboratory parameters (hematology, chemistry, and inflammatory markers), and vital signs.
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 400 mg q2w
3. Bermekimab 400 mg 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 400 mg qw
2. Bermekimab 400 mg q2w
3. Bermekimab 400 mg qw
4. Combined Bermekimab


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This allows safety comparisons between each bermekimab regimen through Week 36 based on the 
similar follow-up time in each group. 
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 at Week 0 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 at 
Week 0 started treatment with placebo only and later crossed over to receive treatment with 
bermekimab 400 mg SC (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 q2w: all participants who were randomized to bermekimab 400 mg SC 
(q2w) at Week 0 and received bermekimab. All the safety events/measurements from these 
participants that occurred from Week 0 will be included in this group.
4.
Bermekimab 400 mg qw: all participants who were randomized to bermekimab 400 mg SC 
(qw) at Week 0 and received bermekimab. All the safety events/measurements from these 
participants that occurred from Week 0 will be included in this group.
6.1.
Adverse Events
The verbatim terms used in the eCRF 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 to be 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 to be 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 also be used to assess the safety of participants in the study:

The incidence and type of AEs.

The incidence and type of SAEs.


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
AEs of severe intensity

AEs that led to permanent discontinuation of study agent administration

The incidence and type of reasonably related AEs.
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.
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, infusions 
and injections for each treatment group. A listing of participants who died will be provided.
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: Complete Blood Count (CBC) with differential, platelets, and hemoglobin.

Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, blood urea nitrogen/urea, calcium, chloride, creatinine, 
GGT, glucose, potassium, total protein, sodium, bicarbonate.
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
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 


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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
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
Blood samples for measuring bermekimab concentrations will be collected from all participants 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. Samples must 
be collected before study agent administration at visits when a study agent administration is 
scheduled.  
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.

Proportion of participants without detectable bermekimab concentration (below the lower 
limit of quantification) at each visit by treatment group.


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
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 
Hurley stage status .

Summary of bermekimab concentrations at each visit by treatment group and prior 
biologic use status.

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 participant 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 participant 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 visit
± 7 days from scheduled visit day


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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 HiSCR and change from baseline in AN count.
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 antibodies to bermekimab at the 
specified visits as shown in the schedule of activities in the protocol. Samples will also be collected 
at the final visit from participants who terminate study participation early. 
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. 
7.2.2.
Antibody vs PK/Efficacy/Safety
To explore the relationship between antibodies to bermekimab status and serum bermekimab
concentrations, efficacy and safety, the following analysis may be performed if sufficient numbers 
of participants are positive for antibodies:  


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
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 HiSCR and 
change from baseline in AN count) 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 HS 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 (eg, IL-17A, IL-17F, IL-23, TNFα, IL-6, IL-22), and other categories of biomarkers 
potentially associated with the development and progression of HS or related to the bermekimab
mechanism of action. These analyses are considered exploratory and will be summarized in a 
separate biomarker technical report.


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REFERENCES
1.
Rubin DB, Multiple Imputations for Nonresponse in Surveys. New York: John Wiley & Sons. 1987.