A Randomized, Subject and Investigator Blinded, Placebo-controlled and Multi-center Platform Study, to Assess Efficacy and Safety of Different Investigational Drugs in Patients With Moderate to Severe Hidradenitis Suppurativa
Phase: PHASE2
Conditions: Hidradenitis Suppurativa
Sponsor: Novartis Pharmaceuticals

 
 
 
Novartis Research and Development 
PLATFORM 
Clinical Trial Protocol CCFZ533H12201BC 
A randomized, subject and investigator blinded, placebo-
controlled and multi-center platform study, to assess 
efficacy and safety of different investigational drugs in 
patients with moderate to severe hidradenitis suppurativa 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2018-002757-30 
Version number: 
v10 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
24-May-2024 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 

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Site Operations Manual (SOM) 
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report. 

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Table of contents 
Site Operations Manual (SOM) ........................................................................................... 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 8 
List of abbreviations .......................................................................................................... 10 
Glossary of terms ............................................................................................................... 15 
Amendment 10 (May 2024) .............................................................................................. 17 
Amendment 9 (November 2023) ....................................................................................... 18 
Amendment 8 (July 2023) ................................................................................................. 20 
Amendment 7 (March 2023) ............................................................................................. 22 
Amendment 6 (June 2022) ................................................................................................ 25 
Amendment 5 (January 2022) ........................................................................................... 26 
Amendment 4 (December 2021) ....................................................................................... 28 
Amendment 3 (February 2021) ......................................................................................... 31 
Amendment 2 (June 2020) ................................................................................................ 35 
Amendment 1 (July 2019) ................................................................................................. 38 
Protocol summary .............................................................................................................. 41 
1 
Introduction ....................................................................................................................... 45 
1.1 
Background ............................................................................................................ 45 
1.1.1 
Hidradenitis suppurativa ....................................................................... 45 
1.1.2 
Platform study design ............................................................................ 46 
1.1.3 
Iscalimab summary ............................................................................... 47 
1.1.4 
LYS006 summary ................................................................................. 48 
1.1.5 
MAS825 summary ................................................................................ 48 
1.1.6 
Remibrutinib summary.......................................................................... 49 
1.1.7 
Ianalumab summary .............................................................................. 51 
1.2 
Purpose .................................................................................................................. 52 
2 
Objectives and endpoints ................................................................................................... 52 
3 
Study design ...................................................................................................................... 56 
3.1 
Cohort A (iscalimab) ............................................................................................. 60 
3.2 
Cohort B (LYS006) ............................................................................................... 60 
3.3 
Cohort C (MAS825) .............................................................................................. 60 
3.4 
Cohort D (Remibrutinib) ....................................................................................... 61 
3.5 
Cohort E (Ianalumab) ............................................................................................ 61 
4 
Rationale ............................................................................................................................ 62 

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4.1 
Rationale for study design ..................................................................................... 62 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 63 
4.2.1 
Cohort A (iscalimab) ............................................................................. 64 
4.2.2 
Cohort B: LYS006 ................................................................................ 67 
4.2.3 
Cohort C (MAS825) .............................................................................. 68 
4.2.4 
Cohort D (remibrutinib) ........................................................................ 72 
4.2.5 
Cohort E (Ianalumab) ............................................................................ 74 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 77 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 77 
4.5 
Risks and benefits .................................................................................................. 78 
4.5.1 
Cohort A (Iscalimab) ............................................................................. 78 
4.5.2 
Cohort B (LYS006) ............................................................................... 79 
4.5.3 
Cohort C (MAS825) .............................................................................. 80 
4.5.4 
Cohort D (remibrutinib) ........................................................................ 81 
4.5.5 
Cohort E (Ianalumab) ............................................................................ 84 
4.5.6 
Study related/ non cohort specific risks and benefits ............................ 88 
5 
Population .......................................................................................................................... 89 
5.1 
Inclusion criteria .................................................................................................... 89 
5.2 
Exclusion criteria ................................................................................................... 90 
6 
Treatment ......................................................................................................................... 100 
6.1 
Study treatment .................................................................................................... 100 
6.1.1 
Investigational and control drugs ........................................................ 100 
6.1.2 
Additional study treatments ................................................................ 102 
6.1.3 
Treatment arms/group ......................................................................... 103 
6.2 
Other treatment(s) ................................................................................................ 104 
6.2.1 
Concomitant therapy ........................................................................... 104 
6.2.2 
Prohibited medications and non-drug therapies .................................. 104 
6.2.3 
Other medications having potential interactions with remibrutinib 
(Cohort D only) ................................................................................... 108 
6.2.4 
Rescue medications and non-drug therapies ....................................... 109 
6.2.5 
Restrictions for study subjects ............................................................ 109 
6.3 
Subject numbering, treatment assignment, randomization .................................. 110 
6.3.1 
Subject numbering .............................................................................. 110 
6.3.2 
Treatment assignment, randomization ................................................ 110 
6.4 
Treatment blinding ............................................................................................... 111 
6.5 
Dose escalation and dose modification ................................................................ 112 

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6.6 
Additional treatment guidance ............................................................................. 112 
6.6.1 
Treatment compliance ......................................................................... 112 
6.6.2 
Recommended treatment of adverse events ........................................ 113 
6.6.3 
Emergency breaking of assigned treatment code ................................ 115 
6.7 
Preparation and dispensation ............................................................................... 116 
7 
Informed consent procedures .......................................................................................... 118 
8 
Visit schedule and assessments ....................................................................................... 119 
8.1 
Screening ............................................................................................................. 136 
8.1.1 
Information to be collected on screening failures ............................... 136 
8.2 
Subject demographics/other baseline characteristics ........................................... 136 
8.2.1 
Hurley score ........................................................................................ 137 
8.3 
Efficacy ................................................................................................................ 137 
8.3.1 
Hidradenitis suppurativa lesion count ................................................. 137 
8.3.2 
Hidradenitis suppurativa clinical response (HiSCR) .......................... 138 
8.3.3 
Anatomical HS regions involved ........................................................ 139 
8.3.4 
 139 
8.3.5 
 140 
8.3.6 
 140 
8.3.7 
 140 
8.3.8 
Appropriateness of efficacy assessments ............................................ 140 
8.4 
Safety ................................................................................................................... 141 
8.4.1 
Laboratory evaluations ........................................................................ 141 
8.4.2 
Electrocardiogram (ECG) ................................................................... 143 
8.4.3 
Pregnancy and assessments of fertility ............................................... 144 
8.4.4 
Other safety evaluations ...................................................................... 144 
8.5 
Additional assessments ........................................................................................ 145 
8.5.1 
Patient Reported Outcomes (PROs) .................................................... 145 
8.5.2 
Pharmacokinetics ................................................................................ 147 
8.5.3 
Biomarkers .......................................................................................... 150 
8.5.4 
Immunogenicity (Cohort A, C and E only) ......................................... 152 
8.5.5 
Target engagement - Soluble CD40 in plasma (Cohort A only) ......... 153 
8.5.6 
Target engagement - IL-ȕ, IL-18, and IL-18BP in serum (Cohort 
C only) ................................................................................................. 153 
9 
Study discontinuation and completion ............................................................................ 153 
9.1 
Discontinuation .................................................................................................... 153 
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9.1.1 
Discontinuation of study treatment ..................................................... 154 
9.1.2 
Withdrawal of informed consent ......................................................... 155 
9.1.3 
Lost to follow-up ................................................................................. 156 
9.1.4 
Study stopping rules ............................................................................ 156 
9.1.5 
Early study termination by the sponsor ............................................... 157 
9.2 
Study completion and post-study treatment ........................................................ 157 
10 Safety monitoring and reporting ...................................................................................... 158 
10.1 
Definition of adverse events and reporting requirements .................................... 158 
10.1.1 
Adverse events .................................................................................... 158 
10.1.2 
Serious adverse events ........................................................................ 160 
10.1.3 
SAE reporting...................................................................................... 162 
10.1.4 
Pregnancy reporting ............................................................................ 163 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 163 
10.2 
Additional Safety Monitoring .............................................................................. 164 
10.2.1 
Liver safety monitoring ....................................................................... 164 
10.2.2 
Renal safety monitoring ...................................................................... 165 
10.2.3 
Data Monitoring Committee ............................................................... 165 
11 Data Collection and Database management .................................................................... 166 
11.1 
Data collection ..................................................................................................... 166 
11.2 
Database management and quality control .......................................................... 167 
11.2.1 
 ..................................................................... 167 
11.3 
Site monitoring .................................................................................................... 168 
12 Data analysis and statistical methods .............................................................................. 168 
12.1 
Analysis sets ........................................................................................................ 169 
12.2 
Subject demographics and other baseline characteristics .................................... 169 
12.3 
Treatments ........................................................................................................... 169 
12.4 
Analysis of the primary endpoint(s) .................................................................... 170 
12.4.1 
Definition of primary endpoint(s) ....................................................... 170 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 170 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 170 
12.4.4 
Sensitivity and Supportive analyses .................................................... 171 
12.5 
Analysis of secondary endpoints ......................................................................... 172 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 172 
12.5.2 
Safety endpoints .................................................................................. 172 
12.6 
Analysis of exploratory endpoints ....................................................................... 173 
12.6.1 
Exploratory efficacy endpoints ........................................................... 173 
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12.6.2 
Exploratory safety ............................................................................... 174 
12.6.3 
Pharmacokinetics ................................................................................ 174 
12.6.4 
Pharmacodynamics ............................................................................. 175 
12.6.5 
Exposure-response relationship .......................................................... 176 
12.6.6 
Immunogenicity (Cohort A, C and E) ................................................. 176 
12.6.7 
Exploratory biomarkers ....................................................................... 176 
12.6.8 
Other optional exploratory endpoints .................................................. 177 
12.7 
Interim analyses ................................................................................................... 178 
12.8 
Sample size calculation ........................................................................................ 179 
12.8.1 
Primary endpoint(s) ............................................................................. 179 
12.8.2 
Secondary endpoint(s) ......................................................................... 181 
13 Ethical considerations and administrative procedures .................................................... 181 
13.1 
Regulatory and ethical compliance ...................................................................... 181 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 181 
13.3 
Publication of study protocol and results............................................................. 182 
13.4 
Quality Control and Quality Assurance ............................................................... 182 
14 Protocol adherence .......................................................................................................... 182 
14.1 
Protocol Amendments ......................................................................................... 183 
15 References ....................................................................................................................... 184 
16 Appendices ...................................................................................................................... 191 
16.1 
Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ....................................................................................................... 191 
16.2 
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up .... 195 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 52 
Table 6-1 
Overview of study medication ............................................................ 101 
Table 6-2 
Additional study treatment .................................................................. 103 
Table 6-3 
Prohibited medications and non-drug therapies .................................. 105 
Table 6-4 
Other medications having potential interactions with remibrutinib .... 108 
Table 6-5 
Blinding and unblinding plan .............................................................. 111 
Table 8-1 
Assessment Schedule: Screening ........................................................ 121 
Table 8-2 
Assessment Schedule, Cohort A: iscalimab ........................................ 122 
Table 8-3 
Assessment Schedule, Cohort B: LYS006 .......................................... 124 
Table 8-4 
Assessment Schedule, Cohort C: MAS825 ......................................... 127 
Table 8-5 
Assessment Schedule, Cohort D: Remibrutinib .................................. 129 

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Table 8-6 
Assessment Schedule, Cohort E: Ianalumab Treatment and 
Mandatory Follow-up periods ............................................................. 131 
Table 8-7 
Assessment Schedule, Cohort E: Ianalumab Conditional Follow-up 
period ................................................................................................... 134 
Table 8-8 
Hurley score ........................................................................................ 137 
Table 8-9 
Safety Assessments ............................................................................. 141 
Table 8-10 
Laboratory Assessments ...................................................................... 142 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 164 
Table 16-1 
Liver Event and Laboratory Trigger Definitions ................................ 191 
Table 16-2 
Follow Up Requirements for Liver Events and Laboratory Triggers . 192 
Table 16-3 
Specific Renal Alert Criteria and Actions ........................................... 195 
List of figures 
Figure 3-1 
Cohort A, B and C study design............................................................ 56 
Figure 3-2 
Cohort D study design ........................................................................... 57 
Figure 3-3 
Cohort E study design ........................................................................... 57 
Figure 4-1 
Study CCFZ533X2203 in pSS patients: preliminary iscalimab 
plasma concentration-time profiles from Cohort 1 (3 mg/kg s.c. 
regimen) demonstrating the efficient pre-systemic CD40-mediated 
elimination of iscalimab after s.c. if CD40 receptors are not fully 
saturated ................................................................................................ 65 
Figure 4-2 
Study CCFZ533X2203 in pSS subjects: preliminary iscalimab 
plasma concentration-time profiles in Cohort 3 demonstrating that 
a s.c. loading and maintenance regimen has the ability to overcome 
CD40-mediated elimination of iscalimab ............................................. 66 
Figure 4-3 
Predicted time-course of plasma iscalimab concentrations in HS 
patients .................................................................................................. 67 
Figure 4-4 
.. 69 
Figure 4-5 
.. 70 
Figure 4-6 
.. 71 
Figure 4-7 
.. 73 
Figure 4-8 
Dose-response modelling (MCP-Mod) for ESSDAI at Week 24 
(study CVAY736A2201) ...................................................................... 75 
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Figure 4-9 
Exposure-response relationship for ESSDAI (study 
CVAY736A2201) ................................................................................. 76 
Figure 8-1 
 139 
Figure 8-2 
 ................................................................ 147 
Figure 12-1 
Operating characteristics for 
 at interim and final 
analysis ................................................................................................ 179 
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List of abbreviations 
A 
Abscesses 
AD 
atopic dermatitis 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AIH 
autoimmune hepatitis 
ALOX5/5-LO 
Arachidonate 5-lipoxygenase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AN 
Abscess and inflammatory nodule counts 
aPTT 
activated Partial Thromboplastin Time 
AST 
aspartate aminotransferase 
AxMP 
Auxiliary Medicinal Product 
BAFF(-R) 
B cell activating factor (receptor) 
BCRP 
Breast cancer resistance protein (also known as ABCG2) drug transporter 
BDR 
Bioanalytical Data Report 
b.i.d. 
twice a day 
BMX 
Bone Marrow kinase gene on the X chromosome 
BTK(i) 
Bruton’s tyrosine kinase (inhibitor) 
BUN 
blood urea nitrogen 
CD40 (L) 
Cluster of differentiation 40 (ligand) 
CDC 
complement dependent cytotoxicity 
CFR 
U.S. Code of Federal Regulation 
CL 
Clearance 
cm 
Centimeter 
CMV 
Cytomegalovirus 
CNS 
central nervous system 
COVID-19 
Corona virus disease 2019 
(e)CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CS 
Corticosteroid 
CSF 
cerebro-spinal fluid 
CSU 
Chronic Spontaneous Urticaria 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CXCL 
Chemokine (C-X-C motif) ligand 
DAMPs 
Damage Associated Molecular Patterns 
DDE 
Direct Digital Entry 
dL 
Deciliter 
 
 
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DMC 
Data Monitoring Committee 
DNA 
Deoxy-ribonucleic acid 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EoS 
End of Study 
ePPND 
enhanced pre-and postnatal development 
eSource 
Electronic Source 
ESSDAI 
EULAR Sjögren's syndrome disease activity index 
EU CTR 
European Union Clinical Trial Regulation 536/2014 
F 
Draining fistulae 
Fc 
Fragment crystallizable 
)Fİ5 
Fc epsilon receptor 1, high-affinity receptor for the Fc region of immunoglobulin E  
)FȖ5 
Fc gamma receptor, receptor for the FC portion of Immunoglobulin G 
FDA 
Food and Drug Administration 
FiH 
First in human 
GCP 
Good Clinical Practice 
(e)GFR 
(estimated) Glomerular Filtration Rate 
GGT 
Gamma-glutamyl transferase 
*52Į 
Growth regulated oncogen alpha 
h 
Hour 
HbcAb 
Hepatitis B core Antibody 
HbsAg 
Hepatitis B surface antigen 
HDL 
High Density Lipoprotein 
HHV-6 
Human Herpes Virus-6 
HiSCR 
Hidradenitis suppurativa clinical response 
HIV 
human immunodeficiency virus 
HS 
Hidradenitis suppurativa 
hsCRP 
High sensitivity C-reactive protein 
HV 
Healthy volunteers 
Kg 
Kilogram 
IA 
Interim Analysis 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization (of Technical Requirements for 
Registration for Pharmaceuticals for Human Use) 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
IgG(1) 
immunoglobulin G (1) 
IgM 
Immunoglobulin M 
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IL-1ß/IL-1beta 
Interleukin 1 beta 
IL-18 
Interleukin-18 
IL-18BP 
Interleukin-18 binding protein 
INR 
International Normalized Ratio 
IP-10 
Interferon-gamma inducible Protein-10 
IPF 
Idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITK 
IL2-inducible T-cell kinase 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
i.v. 
Intravenous 
L 
Liter 
LDL 
Low Density Lipoprotein 
LFT 
Liver function test 
LIVI 
Liquid in Vial 
LLOQ 
lower limit of quantification 
LTA4H 
leukotriene A4 hydrolase 
LTB4 
Leukotriene B4 
LXA4 
Lipoxin A4 
m2 
meters squared 
mAb 
monoclonal antibody 
MCH 
Mean Corpuscular Hemoglobin 
MCII 
minimal clinically important change 
MCP-Mod 
Dose-response modelling 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
μg 
microgram(s) 
mg 
milligram(s) 
min 
Minute 
mL 
milliliter(s) 
MPO 
Myeloperoxidase 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple sclerosis 
N 
Inflammatory nodules 
ng 
nanogram(s) 
nM 
nanoMolar 
NN 
Non-inflammatory Nodules 
NOAEL 
no observable adverse effect level 
NOEL 
no observable effect level 
NRS 
Numerical Rating Scale 
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NRS30 
At least 30% reduction and at least 1 unit reduction from baseline in Skin Pain 
NRS  
PAMP 
Pathogen Associated Molecular Patterns 
PCOS 
Polycystic ovary syndrome 
PD 
pharmacodynamic(s) 
 
 
PK 
pharmacokinetic(s) 
 
 
PML 
progressive multifocal leukoencephalopathy 
p.o. 
Oral 
PoC 
proof of concept 
PRO 
Patient Reported Outcome 
pSS 
primary Sjögren's Syndrome 
PT 
prothrombin time 
RA 
Rheumatoid arthritis 
RCT 
Randomized Clinical Trial 
RNA 
Ribonucleic Acid 
s.c. 
Subcutaneous 
SAE 
serious adverse event 
 
 
sCr 
serum creatinine 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
sHISCR 
Simplified Hidradenitis Suppurativa Clinical Response 
sIL2R 
Serum soluble Interleukin-2 Receptor 
SLE 
Systemic lupus erythematosus 
SOM 
Site Operations Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
TBNK 
T and B Lymphocyte and Natural Killer 
TEC 
Tyrosine kinase Expressed in hepatocellular Carcinoma 
71)Į 
Tumor Necrosis Factor alpha 
TXK 
T and X cell expressed Kinase 
UAS7 
weekly urticaria activity score 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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WoC 
Withdrawal of Consent 
WoCBP 
women of child-bearing potential 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Auxiliary medicinal 
product (AxMP) 
Medicinal product used for the needs of a clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g., rescue 
medication, challenge agents, background treatment or medicinal products 
used to assess end-points in the clinical trial). 
Concomitant therapy is not considered as AxMP. 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 
 
once a day, 
 twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces.  
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Epoch 
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up) which applies 
across all arms of a study. 
eSource 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate. 
Flare 
An exacerbation of a chronic disease. Sometimes referred to as a flare-up, a 
flare occurs when symptoms of a disease that has been present for a time 
suddenly worsen. A flare is a transient worsening in severity of a disease or 
condition that eventually subsides or lessens.  
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Investigational drug 
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance” 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest 
Personal data 
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.  
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Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Study treatment 
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date 
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc. 
Treatment number 
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study 
Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
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Amendment 10 (May 2024) 
Amendment rationale 
As of the 23 May 2024, this study has enrolled 229 patients, of which 45 were assigned to 
Cohort A, 40 to Cohort B, 43 to Cohort C, 77 to Cohort D and 24 to Cohort E. Last Patient Last 
Visit was achieved for Cohort A, B, C and D.  
The main purpose of this amendment is to introduce the Auxiliary Medicinal Products (AxMP) 
definition and related safety reporting rules, to comply with EU Clinical Trial Regulation 
536/2014 (EU CTR). In addition, clarifications on 
 sampling process and AE causality 
assessment were added. 
Editorial changes have been made throughout the protocol for increased clarity and consistency. 
Changes to the protocol 
The following sections in the protocol were updated: 
x Section 6.1.2, Additional Treatments: AxMP details Table 6-2 was added for 
predniso(lo)ne or equivalent 
x Section 8, Visit Schedule and Assessments 
x Table 8-2, Table 8-3, Table 8-4, Table 8-5 and Table 8-6, Cohorts A to E, Schedule of 
Activities: 
x Inclusion/Exclusion Criteria documentation was clarified as recorded in the source 
(not eCRF) 
x Section 8.5.3.7, Exploratory 
 the site of collection and few more details were 
described more in details 
x Section 10.1.1 Adverse Events: causality assessment was clarified and AE reporting was 
updated to include AxMP related text 
x Section 10.1.3.2 Serious Adverse Events:  SAE reporting requirements were updated to 
include AxMP related text 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein do not affect the Informed Consent. 
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Amendment 9 (November 2023) 
Amendment rationale 
As of the 20 November 2023, this study has enrolled 205 patients, of which 45 were assigned 
to Cohort A, 40 to Cohort B, 43 to Cohort C and 77 to Cohort D. Last Patient Last Visit was 
achieved for Cohort A, B, C and D.  
The main purpose of this amendment is to revise the exclusion criteria no. 30, specific to Cohort 
E. In error, the wash-out period was missing in exclusion criterion no. 30. This criterion has 
been deleted and content incorporated into exclusion criterion no. 2a. Additionally, further 
clarifications were added to exclusion criteria no. 2a and 3. 
Other updates include revisions to align with the latest version of Investigator Brochure with a 
cut-off date of 24-Sep-2023. The number of patients exposed to ianalumab, the number of 
clinical trials conducted with ianalumab and the number of Covid-19 cases were updated. In 
addition, a summary statement on no observation of opportunistic infections was included.  
The US FDA recommendations for expedited reporting of potential Hy’s Law cases were also 
included in this amendment. 
Editorial changes have been made throughout the protocol for increased clarity and consistency. 
Changes to the protocol 
The following sections in the protocol were updated: 
x Protocol summary: skin tape stripes assessment in Cohort E was deleted for consistency 
with the other sections of the protocol. 
x Section 1.1.7 Ianalumab summary: the number of subjects that have been exposed to 
ianalumab and number of clinical studies with ianalumab were updated. 
x Table 2-1 Objectives and related endpoints: 
 endpoint was added for Cohort E 
for consistency with the other sections of the protocol.  
x Section 4.5.5.2 Potential risks associated with exposure to ianalumab: the information on 
number of Covid-19 cases was updated and a summary statement on no observation of 
opportunistic infections was included. 
x Section 5.2 Exclusion criteria has been updated by deleting the exclusion criteria no. 30 
and inserting its content into exclusion criteria no. 2a. Additionally, further clarifications 
were added to exclusion criteria no. 2a and 3. 
x Table 8-6 Assessment Schedule, Cohort E: Ianalumab Treatment and Mandatory Follow-
up periods was updated by adding a foot note to clarify that PK sample on Day 88 should 
be taken 3 days +/- 1 day after the dose on Day 85. 
x Section 10.1.2 Serious adverse events and Table 16-2 were updated to comply with FDA 
requirement for expedited reporting of potential Hy’s Law cases. 
x Table 16-2 was updated with regards to appropriate CRFs to be used for recording of liver 
events. 
Minor typographical errors have been corrected. 
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Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein do not affect the Informed Consent.  

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Amendment 8 (July 2023) 
Amendment rationale 
As of the 12 June 2023, this study has enrolled 205 patients, of which 45 were assigned to 
Cohort A, 40 to Cohort B, 43 to Cohort C and 77 to Cohort D. Last Patient Last Visit was 
achieved for Cohort A, B, C and D. 
The main purpose of this amendment is to update the dosage form for Cohort E (ianalumab) 
from pre-filled syringe to liquid in vials. 
Other updates include revisions to update the number of patients exposed to ianalumab and the 
associated risks, additions to the eligibility criteria to further align with other ianalumab trials 
and an update to the statistics section reflecting that Cohort E will be the only ongoing cohort. 
Changes to the protocol 
Changes made to the protocol relating to change of drug supply for Cohort E (ianalumab): 
• Protocol summary has been updated. 
• Section 1.1.7 ianalumab summary has been updated. 
• Section 4.5.5.2.1 and Section 4.5.5.2.2 has been updated to reflect the latest potential risks 
associated with exposure to ianalumab. 
• Section 4.5.6.2: blood sample volume for cohort E has been updated. 
• Section 5.2 has been updated to further align with other ianalumab protocols. 
• Section 6.1.1 and Table 6.1 has been updated to reflect the dosage form that will be used. 
• Table 6-2 has been updated to include iscalimab in the prohibited medications list for 
Cohort E. 
• Table 8-10 laboratory assessments have been updated. 
• Section 8.5.3.6 title updated. 
• Section 9.1.1 has been updated to include a statement regarding patients that discontinue 
treatment should continue with follow up visits. 
• Section 9.2 has been updated to clarify the wording regarding B cell recovery and study 
completion/post study treatment. 
• Figure 12-1 updated for iscalimab and LYS006 cohorts. 
• Section 13.4 Update of retention period. 
• Section 16.2 Appendix 2: Renal event follow up and actions have been updated to align 
with the current Novartis template. 
Minor typographical errors have been corrected. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Amendment 7 (March 2023) 
Amendment rationale 
As of the 8 February 2023, this study has enrolled 205 patients, of which 45 were assigned to 
Cohort A, 40 to Cohort B, 43 to Cohort C and 77 to Cohort D. Last Patient Last Visit was 
achieved for Cohort A, B and C and recruitment into Cohort D has now been completed. 
The main purpose of this amendment is to introduce an additional cohort (Cohort E) into this 
platform study. Ianalumab (VAY736) is a human IgG1/N mAb which targets the B cell 
activating factor BAFF receptor, (BAFF-R), expressed on the surface of immature and mature 
B cells up to the lymphoblast stage. Ianalumab has dual mechanisms of action: i) enhanced 
antibody dependent cellular cytotoxicity (ADCC) mediated B cell depletion and ii) blocking 
BAFF-mediated activation through the BAFF-R thereby inhibiting B cell activation, 
proliferation, maturation and survival.   
The rationale for targeting BAFF-R in HS is based on the emerging role for both B cells and 
plasma cells both present in HS lesions and autoantibodies correlating with disease severity and 
duration. Little is known about the survival factors supporting the persistence of immune cells 
in HS but increased BAFF expression correlating with lesional B cell and plasma cell presence 
has recently been demonstrated. 
 have been removed from the protocol due to limited 
uptake by sites (only a single site taking part) and subject interest of this optional assessment 
(zero out of five patients consented to this optional assessment). As there are fewer subjects 
required in Cohort E, it is unlikely that having this assessment in the protocol will yield any 
significant data.  
Changes to the protocol 
Changes made to the protocol relating to the addition of Cohort E (Ianalumab): 
x Protocol summary has been updated. 
x Updates have been made to Platform study design in Section 1.1.2 
x Section 1.1.7 Ianalumab summary section has been created 
x Updates have been made to the purpose in Section 1.2 
x Objectives have been updated in Table 2-1 to include Cohort E 
x Updated text and new study design Figure 3-3 for Cohort E have been added in Section 3 
x Section 3.5 has been created for Cohort E describing the specifics of the cohort such as 
number of patients and dose levels used.  
x Section 4.1 has been updated for Cohort E with respect to the clinical endpoints being 
evaluated 
x Section 4.2.5 has been created describing the rationale for the dose/regimen and duration 
of treatment for Cohort E. 
x Section 4.4 has been updated 
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• Section 4.5.5 and subsections Section 4.5.5.1 and Section 4.5.5.2 have been added to 
describe the risk and benefits of ianalumab 
• Section 4.5.6.2 on Blood sample volume was updated for Cohort E 
• Updates have been made to Section 5 incorporating Cohort E into the description of the 
population of the study 
• Eligibility criteria have been updated for Cohort E in Section 5.1 and Section 5.2 
• Section 6.1 and sub-sections Section 6.1.1, Section 6.1.2 and Section 6.1.3 have been 
updated to include Cohort E study treatment information. 
• Update to Section 6.2 and sub-sections to link information about vaccinations to an early 
section in the protocol and state concomitant and prohibited medications. 
• Cohort E has been added to the treatment assignment and randomization information in 
Section 6.3.2 
• Treatment blinding information for Cohort E has been added to Section 6.4 
• Treatment compliance information for Cohort E have been added Section 6.6.1 
• Recommended treatment of adverse events for Cohort E have been added with the 
creation of Section 6.6.2.6 
• Information on preparation and dispensation of ianalumab have been added to Section 6.7 
• The assessment schedule for Cohort E (Table 8-1, Table 8-6 and Table 8-7) has been 
added to Section 8  
• Update of Section 8.4.1 and subsection Section 8.4.1.2, together with Table 8-10 that has 
been updated to include analysis of TBNK panel, CD19 B cell count and B cell subset 
panel and additional test (IgG, IgM, sBAFF). 
• Section 8.4.3 on Pregnancy and assessments of fertility was updated for Cohort E. 
• Pharmacokinetic information for Cohort E has been added in Section 8.5.2.5 
• Biomarker information has been added for Cohort E in Section 8.5.3 and all corresponding 
subsections 
• Section 8.5.4 on Immunogenicity was updated for Cohort E 
• Rules for discontinuation of study treatment has been updated to include Cohort E in 
Section 9.1.1 
• Rules for putting Cohort E on hold have been added to Section 9.1.4 
• Additional information regarding study completion and post study treatment has been 
added to Section 9.2 
• Adverse event monitoring timeline has been updated to include Cohort E in Section 10.1.1 
• Ianalumab has been added to data analysis and statistical methods in Section 12 and 
subsections. 
• Rationale for pooling placebo data from Cohort E despite the use of 
prednisone/prednisolone has been added to Section 12. 
• Section 12.6.3.5 has been added to include Cohort E PK analysis information 

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x Section 12.6.4.5 has been added to include Cohort E pharmacodynamic analysis 
information 
x Exploratory biomarker information has been updated in Section 12.6.7 to add information 
regarding Cohort E 
x Section 12.7 on Interim analyses has been updated 
x Sample size information for the primary endpoint has been added to Section 12.8.1 for 
Cohort E 
Other changes made to the protocol: 
x List of abbreviations has been updated to add new abbreviations 
x Removal of ‘If additional cohorts are added, the Sponsor will strive to further limit the 
number of subjects exposed to placebo, based on the learnings from previous cohorts and / 
or published studies.’ paragraph from Section 4.3. 
x Clarification regarding AE analysis for infections (all cohorts) vs renal events (LYS006) 
in Section 12.5.2.1. 
x 
 have been removed (previously Section 8.5.4 and 
Section 12.6.8.2. 
x Section 12.7 on Interim analyses has been updated 
x Section 15 has been updated to include all new and updated references  
Minor typographical errors have been corrected. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
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Amendment 6 (June 2022) 
Amendment rationale 
As of the 03rd May 2022, this study has enrolled 128 patients, of which 45 were assigned to 
Cohort A, 40 to Cohort B and 43 to Cohort C. Last Patient Last Visit was achieved for Cohort 
A and B and recruitment into cohort C has now been completed. 
The purpose of this amendment is to address comments raised by the Health Authority in 
Germany (PEI) on the study protocol amendment 5, pertaining to eligibility criteria and 
stratification planned for Cohort B. It is clarified that the group size of patients with 3-4 lesions 
is limited to 15 patients and that this stratification only applies for Cohort B. Indeed, the interim 
analysis showed that in terms of response to placebo, patients with lower severity as compared 
with higher severity had a similar response in the primary endpoint, the simplified HiSCR or 
sHiSCR. Thus, no further stratification is deemed needed for cohort D.  
It has been re-emphasized that inclusion criterion providing disease severity definition by 
number of inflammatory lesions is unchanged between Cohort B and D as outlined in 
chapter 5.1. There is a difference of minimally required lesions counts between oral cohorts (at 
least 3 abscesses and/or nodules) and injectable biologics cohorts (at least 5 abscesses and / or 
nodules), that reflect that biologics are usually reserved for more severe patients, but still both 
populations have been considered as moderate to severe hidradenitis suppurativa (HS) (see 
Section 4.1. Rationale for study design). 
The scientific rationale of the newly proposed cohort has been updated. 
Changes to the protocol 
• Purpose and rationale have been updated in Protocol summary section 
• Section 3 has been modified to clarify overall eligibility criteria 
• Section 4.5.4.1 has been modified to clarify and update the potential benefit of treatment 
with remibrutinib  
• Absence of stratification for Cohort D has been clarified in Section 6.3.2 
• Section 12.4: Primary objective of the study has been clarified  
• References have been added in the references list Section 15  
A minor typographical error has been corrected. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The non-substantial changes described in this amended protocol do NOT require IRB/IEC and 
Health Authority approval.  
The changes herein do NOT affect the trial specific model ICF. 

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Amendment 5 (January 2022) 
Amendment rationale 
As of the 14th January 2022, this study is registered in 11 countries, ongoing in 10 countries 
and has enrolled 112 patients, of which 45 were assigned to Cohort A, 40 to Cohort B and 27 
to Cohort C. Recruitment into both cohorts A and B have now been completed. 
The purpose of this amendment is to add a blood sample for coagulation parameters to Cohort 
D, visits 101, 103, 105 and 199 for safety monitoring reasons. In cohort D, remibrutinib, A BTK 
inhibitor, will be tested and BTK is a signaling molecule in one of several platelet activation 
pathways. The blood volume is still within the previously communicated volume of 
approximately 200 mL for Cohort D. 
In addition, after comments received from the US FDA, physical treatments, including 
photodynamic therapy, laser and intense light treatments will be considered prohibited 
treatment and a with a wash-out period of 4 weeks as part of exclusion criterion 2.6. 
Changes to the protocol 
• Inconsistency corrected in the protocol summary to ensure the highly effective 
contraception duration post treatment is consistent with the body of the protocol. 
• Reference to prohibited physical treatments for HS added in Section 4.2. 
• The title of Section 4.5.4.2.3 has been updated from ‘Bleeding risk’ to ‘Risk for bleeding’ 
in order to align with the wording in the IB. 
• Exclusion criterion 2.6 in Section 5.2 has been updated from ‘Surgical treatment for HS in 
the last 4 weeks prior to randomization’ to ‘Surgical and physical treatment for HS in the 
last 4 weeks prior to randomization’.  
• In Table 6-2 the row ‘Photodynamic therapy or laser therapy’ will be changed to ‘Physical 
treatment for HS, including laser, intense light and photodynamic therapy’ and will 
continue to lead to discontinuation of study treatment.  
• IgA samples added to Table 8-5 Assessment Schedule, Cohort D: Remibrutinib along with 
hsCRP to be consistent with the text in the body of the protocol. No additional samples 
will be added to Cohort C as the enrolment will likely be concluded before this protocol is 
approved and there will be no baseline data. 
• IgE samples will no longer be taken and the reference to this has been removed from the 
protocol in Table 8-8 Laboratory Assessments. 
• Coagulation panel added to Table 8-5 Assessment Schedule, Cohort D: Remibrutinib at 
visits 101, 103, 105 and 199 (after 4 weeks and 12 weeks of treatment and at the end of 
the treatment period) for safety monitoring. 
• Correction to footnote 5 in Table 8-5 Assessment Schedule, Cohort D: Remibrutinib. 
Fasting on PK days should be 12 hours as already indicated in Section 6.7. 
• Addition of non-draining fistulas in Section 8.3.3. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
If the changes herein affect the Informed Consent, sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  

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Amendment 4 (December 2021) 
Amendment rationale 
As of the 27th October 2021, this study is registered in 11 countries, ongoing in 10 countries 
and has enrolled 92 patients, of which 45 were assigned to Cohort A, 40 to Cohort B and 7 to 
Cohort C. Recruitment into both cohorts A and B have now been completed. 
The main purpose of this amendment is to introduce an additional cohort (Cohort D) into this 
platform study. LOU064, also called remibrutinib, is an oral covalent binding Bruton’s tyrosine 
kinase (BTK) inhibitor (or BTKi), currently in active clinical development for the treatment of 
chronic spontaneous urticaria (CSU), primary Sjögren’s Syndrome (pSS) and multiple sclerosis 
(MS). BTK is in the central node in the Fc epsilon receptor 1, high-affinity receptor for the Fc 
region of immunoglobulin E (FcİR) as well as B cell receptor (BCR) signaling and thus could 
block B cell driven effects. 
Recently B cells and more so, the BTK-pathway activation has been shown to be a central signal 
transduction network in hidradenitis suppurativa (HS) and thus provides a solid scientific 
rationale for testing a BTKi such as remibrutinib, in patients with HS (Gudjonsson et al 2020).  
30 subjects will receive remibrutinib 
mg
 and 10 subjects will receive corresponding 
placebo in Cohort D, however unlike previous cohorts, an additional dose regimen of 
remibrutinib (
 mg 
.) will be evaluated in a further 30 subjects to explore a dose response 
relationship in patients with HS. In addition, selected exploratory objectives have been updated 
as below:  
Changes to the protocol 
Changes made to the protocol relating to the addition of Cohort D (remibrutinib): 
x Updates have been made to Background in Section 1.1.1 
x Section 1.1.6 Remibrutinib summary section has been created 
x Updates have been made to the purpose in Section 1.2 
x Objectives have been updated in Table 2-1 to include Cohort D and the Hidradenitis 
Suppurativa – 
 
x Updated text and new study design figure for Cohort D have been added in Section 3 
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• Section 3.4 has been created for Cohort D describing the specifics of the cohort such as 
number of patients and dose levels used.  
• Section 4.1 has been updated with respect to the clinical endpoints being evaluated 
• Section 4.2.4 has been created describing the rationale for the dose/regimen 
• Additional information relevant to Cohort C has been added to Section 4.3 describing the 
number of placebo subjects needed for this cohort and the ratio of active to placebo 
subjects. 
• Section 4.5.4 and subsections have been added to describe the risk and benefits of 
remibrutinib 
• Updates have been made to Section 5 incorporating Cohort D into the description of the 
population of the study 
• Eligibility criteria have been updated for Cohort D in Section 5.1 and Section 5.2 
• Section 6.1 and sub-sections have been updated to include Cohort D study treatment 
information. 
• Update to Section 6.2 and sub-sections to link information about vaccinations to an early 
section in the protocol and state concomitant and prohibited medications. 
• Cohort D has been added to the treatment assignment and randomization information in 
Section 6.3.2 
• Treatment blinding information for Cohort D has been added to Section 6.4 
• Treatment compliance information for Cohort D have been added Section 6.6.1 
• Recommended treatment of adverse events for Cohort D have been added with the 
creation of Section 6.6.2.5 
• Information on preparation and dispensation of remibrutinib have been added to 
Section 6.7 
• The assessment schedule for Cohort D (Table 8-5) has been added to Section 8  
• Pharmacokinetic information for Cohort D has been added in Section 8.5.2.4 
• Biomarker information has been added for Cohort D in Section 8.5.3 and subsections 
• Rules for discontinuation of study treatment has been updated to include Cohort D in 
Section 9.1.1 
• Rules for putting Cohort D on hold have been added to Section 9.1.4 
• Adverse event monitoring timeline has been updated to include Cohort D in Section 10.1.1 
• Remibrutinib has been added to data analysis and statistical methods in Section 12 and 
subsections. 
• Section 12.6.3.4 has been added to include Cohort D PK analysis information 
• Section 12.6.4.4 has been added to include Cohort D pharmacodymanic analysis 
information 
• Exploratory biomarker information has been updated in Section 12.6.7 to add information 
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x Sample size information for the primary endpoint has been added to Section 12.8.1 for 
Cohort D 
Other changes made to the protocol: 
x List of abbreviations has been updated to add new abbreviations 
x Updates have been made to the objectives in Table 2-1 to add additional biomarker 
objectives and additional objectives for lesion counts relating to abscesses and nodules.  
x Section 4.5.4.2 has been deleted as the 
 sub-study has been stopped due to very low 
enrolment. 
x Exclusion criterion 23 has been removed Section 5.2 due to the stopping of the 
 sub-
study 
x Clarification on how to proceed after a dose interruption has been added to Section 6.5 
x Treatment compliance information formatting has been updated in Section 6.6.1 
x The 
assessments have been removed from Table 8-2  (Cohort A), Table 8-3  (Cohort 
B) and Table 8-4  (Cohort C) 
x Additional information has been added to Section 8.3.1 regarding the review of reduction 
of abscesses and nodules. 
x Table 8-8 has been updated to include analysis of IgA. 
x Section 8.4.1.2 has been updated to clarify that 
 panel will be carried out 
on both on-site and at-home urine samples. 
x Section 8.5.1.2 has been added to include the
 into the study. 
x Section 8.5.3.5 has been updated to include 
assessments. 
x Section 8.5.4.1 has been removed due to the cessation of the optional 
 assessments. 
x Wording has been updated regarding reporting of SAEs in Section 10.1.3.2 
x Section 12.6.8.2 has been deleted due to removal of optional 
sub-study 
x References section has been updated to include all new and updated references 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  
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Amendment 3 (February 2021) 
Amendment rationale  
As of 17th February 2021, this study is ongoing in 10 countries and has enrolled 61 patients, of 
which 32 were assigned to Cohort A and 29 to Cohort B.  
The main purpose of this amendment is to introduce an additional cohort (Cohort C) into this 
platform study, with MAS825, a 
 antibody targeting the key inflammasome effector 
cytokines interleukin-1 beta (IL-1ß) and interleukin-18 (IL-18). Kelly et al 2015 described that 
IL-1ß and IL-18 expression was increased in lesional and perilesional hidradenitis suppurativa 
(HS) skin, suggesting that the upregulation of both cytokines may play a role in the pathogenesis 
of HS. Tzanetakou et al 2016 has shown efficacy of interleukin-1 (IL-1) blockade in HS 
patients, as significant differences were noted between anakinra and placebo treated patients in 
the Hidradenitis suppurativa clinical response (HiSCR) and in HS exacerbations. Thus, 
MAS825 may show efficacy in HS patients and it is proposed to be added in Cohort C into this 
protocol. 
In Cohort C, 30 subjects will receive MAS825 and 10 subjects placebo, a further reduced 
proportion of subjects exposed to placebo, as the placebo groups across cohorts will be pooled 
while maintaining the ability to have the treatments blinded within the same cohort. MAS825 
is in early clinical development for the treatment of IL-1ß and IL-18 driven inflammatory 
diseases. A clinical proof of concept study has started in the treatment of COVID-19.  
The protocol was also updated to remove unnecessary text which is detailed in other documents 
such as the current versions of the Investigator’s Brochures (IB).  
Inhibitors of BCRP are no longer excluded in Cohort B since no effect on the PK of LYS006 is 
expected based on new in vitro data as per the IB version 6 dated 05-Oct-2020. In addition, 
some wording has been adapted and/or harmonized between cohorts.  
Optional 
 has been reinstated in the protocol (was present 
in protocol version 00 but removed in protocol version 01). This will be conducted at a limited 
number of sites only and is an exploratory assessment. 
Changes to the protocol 
Changes made to the protocol relating to the addition of Cohort C (MAS825): 
x Randomization ratio of active to placebo added in Section 1.1.2 
x Background added in Section 1.1.5. 
x Purpose updated in Section 1.2. 
x Objectives updated in Table 2-1 to include Cohort C. Objectives have been moved to 
group together by type e.g. clinical outcomes, PK and immunogenicity etc. but no 
objectives have been deleted. Exploratory objective added for 
 
 for all cohorts. 
x Figure 3-1 study design graphic updated to include the new cohort. 
x Updates made to the study design in Section 3 and Section 3.3. 
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x Updates made to the rationale in Section 4.1, the rationale for does/regimen and duration 
of treatment in Section 4.2.3 and information about placebo in Section 4.3. 
x Benefit and risk information for MAS825 has been added in Section 4.5.3.  
x Approximate blood volume has been added in Section 4.5.4.3 
x Cohort C information has been added in Section 5 and eligibility criteria updated to 
include Cohort C (Section 5.1 and Section 5.2) 
x Various updates made to study treatment in Section 6.1 and subsections Section 6.1.1, 
Table 6-1 and Section 6.1.3 incorporating information about MAS825. 
x Updated to include Cohort C into prohibited medication in Table 6-2. 
x Randomization ratio of active to placebo added in Section 6.3.2. 
x Cohort C blinding information added in Section 6.4. 
x Cohort C information has been added in Section 6.6.1 regarding treatment compliance. 
x A new section on the recommended treatment of adverse events added in Section 6.6.2.4. 
x Cohort C information added to preparation and dispensation (Section 6.7). 
x Visit and assessment schedule for Cohort C added in Table 8-4. 
x Cohort C added to the 
 specimen section regarding central 
 panel in 
Section 8.4.1.2 
x Specific information regarding pregnancy testing added in Section 8.4.3. 
x Assessments relating to Cohort C added to Section 8.5 and subsections. 
x Discontinuation of treatment criteria updated for Cohort C in Section 9.1.1. 
x Added text confirming no specific study stopping rules for MAS825 in Section 9.1.4. 
x Adverse event monitoring timeline added for MAS825 in Section 10.1.1. 
x Reference to MAS825 added in Section 12.3 (Treatments) and the analysis of primary 
endpoint information in Section 12.4 and subsections of Section 12.4. 
x PK analysis section created for Cohort C (Section 12.6.3.3). 
x Pharmacodynamic analysis section created for Cohort C (Section 12.6.4.3). 
x Cohort C added to the immunogenicity information in Section 12.6.6. 
x Cohort C exploratory biomarkers added in Section 12.6.7. 
x Updates made in Section 12.8.1 to include the total subjects required in Cohort C and the 
study as a whole. 
Other changes made to the protocol: 
x References to patient or subject has been harmonized throughout the protocol. Patient is a 
term used to refer to a person suffering with HS whereas a subject is a HS patient taking 
part in the study. 
x The List of Abbreviations has been updated to remove abbreviations that were not present 
in the protocol and add new abbreviations. 
x Protocol summary updated to align with changes in the body of the protocol. 
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x Clarification of the term ‘PD’ provided in Section 3.1 (Cohort A) and Section 3.2 (Cohort 
B). 
x Information duplicated from the Investigator’s Brochure regarding the risks of CFZ533 
and LYS006 have been removed from Section 4.5.1.2 and Section 4.5.2.2 respectively. 
Readers are directed to the current version of the respective IB. Also updated is the 
information about vaccinations in Section 4.5.1.2.1, Section 4.5.2.2.3. 
x New wording added to exclusion criterion 9 regarding SARS-CoV-2 infection, exclusion 
10 regarding live/attenuated vaccines and exclusion 16, point 5 regarding haematological 
abnormalities (Section 5.2). 
x Wording to direct readers to vaccination sections added to Section 6.2.1 Concomitant 
therapy. 
x BCRP inhibitors removed from Table 6-2 as this requirement is no longer applicable to 
LYS006 base on new information in the IB. 
x Duplicate information removed from Section 6.2.2 and Table 6-2 revised to aid clarity (no 
changes other than in the bullet above). 
x Reference to IB made in relation to treatment of adverse events in Section 6.2.3. 
x The blinding and unblinding plan has been updated to include the scenario when a cohort 
is complete before the completion of the study in Table 6-3 (Final analysis per cohort). It 
has also been clarified that appropriate external consultants and DMC members may be 
unblinded. 
x In Section 6.7 (preparation and dispensation), wording has been added to allow outpatient 
injections for Cohort A and C in the case of a pandemic and if local regulations allow. 
x COVID-19 testing added when in line with health and governmental authority guidance to 
exclusion criterion 9 in Section 5.2. 
x Table 8-1 updated to reflect changed made in rest of the protocol. 
x Optional 
 assessments added back into the 
assessment schedules for all three cohorts in Table 8-2, Table 8-3 and Table 8-4. 
Additional information added in Section 8.5.4.2. 
x Clarification to CMV testing added in Section 8.4.4.2. 
x Clarifications made to the tests laboratory evaluations performed and calculated from 
those evaluations in Table 8-6. 
x Clarification made to the CMV discontinuation criterion in Section 9.1.1. 
x Text relating to discontinued subjects deleted from Section 12.4.1 and added to 
Section 12.4.3. 
x Updates made to the sensitivity analysis description in Section 12.4.4.1. 
x Updates made to the supportive analyses in Section 12.4.4.2. 
x Updates to the analysis of secondary endpoints for ECGs and vital signs in 
Section 12.5.2.2 and Section 12.5.2.3. 
x Section added detailing the analysis of 
 in 
Section 12.6.8.3. 
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• Clarification made to Section 12.7 regarding the communication of interim results. 
• Wording updated in Section 12.8.1 to allow subjects to be replaced if required to preserve 
the statistical power, unless treatment was stopped for safety reasons. 
• References updated in Section 15. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  

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Amendment 2 (June 2020) 
Amendment rationale 
The main purpose of this amendment is to address requests from Health Authorities and Ethics 
Committees, as well as to correct some inconsistencies in the protocol discovered during 
implementation. 
Eligibility criteria have been updated. In the inclusion criteria the maximum number of fistula 
have been increased in order to be in line with other clinical studies in HS (such as 
Kimball et al 2016, Tzanetakou et al 2016), where more fistulae were allowed.  
The sponsor has updated the exclusion criteria relating to levels of bilirubin, lipase and amylase. 
Only values above the upper limit of normal will now be exclusionary, instead of values outside 
normal range, as only abnormal high levels should be avoided. This will not impact on patient 
safety. 
At the request of Health Authorities, we are implementing a precautionary CMV serology test 
at screening, in particular for patients participating in cohort A (CFZ533). An acute CMV 
infection will lead to a discontinuation of treatment in patients in Cohort A. For the same 
purpose, history of antiphospholipid syndrome is now specified and will lead to an exclusion 
(for patients in cohort A, CFZ533).  
One assessment of skin pain was added for cohort A to align with cohort B (V199).  
At the time of this amendment, the study has randomized 11 patients in cohort A and 5 in cohort 
B. 2 patients are currently in treatment period, while 9 have completed the study and 5 have 
completed the treatment period and are in follow up. There have been no Serious Adverse 
Events reported. The recruitment of the study is currently halted until the ease of the lock down 
measures due to COVID-19 permits it to continue but may restart prior to the implementation 
of this amendment. Additional information has been added regarding handling of missed visits 
or patients in lockdown but this is not specific to COVID-19. Some patients may discontinue 
due to the impact of the lockdown measures. To reflect this specific case, the statistical handling 
has been adapted, as has the analysis of pain in patients with pain medication.  
Other changes include clarification of prohibited medication and/or therapies, extending the 
screening period to 35 days (previously 30) and widening some visit windows to provide more 
flexibility for patients. This does not impact on patient safety or data integrity but will avoid 
unnecessary protocol deviations. 
The protocol was also updated to correct typographical errors and inconsistencies also 
incorporating changes requested by IEC/IRBs.  

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Changes to the protocol 
The following sections of the protocol were changed:  
• Updates to abbreviation list and protocol summary to reflect changes to the main body of 
the protocol. 
• Section 1.1.4 reference and additional information about metabolites derived from skin 
lesions added in the LYS006 summary. 
• Section 4.5.1.2.2: Updated risk text to include fatal SAE in a different CFZ533 study in a 
lupus nephritis patient treated with CFZ533. 
• Section 4.5.3.3: Blood volumes have been updated (reduced) in line with the actual blood 
volumes from the central lab for the study. 
• Section 5.1 and Section 5.2: Eligibility criteria have been tabulated to add clarity around 
which criteria apply to which cohort. 
• Section 5.1: Inclusion criterion 5 reworded 
• Section 5.2: Addition of wording in exclusion criterion 8 for positive IgM for CMV at 
screening 
• Section 5.2: Addition of wording in exclusion criterion 15 for patients with 
antiphospholipid syndrome. 
• Section 5.2: Update to exclusion criterion 16 for lipase, amylase and bilirubin 
exclusionary values 
• Section 6.2 (and sub-sections): Removed duplicative wording, added references to non-
drug therapies.  
• Section 6.2.2: added list of non-prohibited medications and non-drug therapies, from 
section 6.2.3 
• Table 6-2: Systemic corticosteroids added to the list of prohibited medication. 
• Table 6-2: Wording for surgery, photodynamic therapy and laser clarified in list of 
prohibited medication. 
• Table 6-2: Wording for surgery, photodynamic therapy and laser clarified in list of 
prohibited medication. 
• Table 6-2: Consolidated rows for systemic immunosuppressants and immunomodulators 
• Table 6-2: Added row for other investigational drugs 
• Table 6-2: Clarified wording for use of spironolactone and other anti-androgens 
• Table 6-2: Clarified “systemic” antibiotic row 
• Table 6-2: Reworded “other systemic treatments for HS” row 
• Table 6-2: Live/attenuated vaccines added for Cohort C 
• Section 6.2.3: Moved text regarding conservative treatment of skin infections / HS lesion 
exacerbations with non-prohibited medications from Section 6.2.3 and further clarified.  
• Section 6.7: Wording has been added regarding the shipment of IMP to a patient in certain 
circumstances. 

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x Section 7: Text regarding informed consent in the case of home nursing has been added. 
x Section 8: Guidance text added for how to deal with missed visits and the any potential 
future issue in which patients would be unable to travel to the site due to local restrictions. 
x Table 8-1: Screening period extended to 35 days from 30 days. 
x Table 8-2 and Table 8-3: Visit windows updated for both cohorts to avoid unnecessary 
protocol deviations. 
x Table 8-3, footnote 6 updated to allow for central lab 
analysis where local analysis is 
not available.  
x Table 8-3, footnote 10 updated: 
 collection for PK assessment on the day prior to the 
visits has been removed for non-treatment visits. The samples can be taken on the day of 
the visit by the site. 
x Section 8.1: Additional wording added that will allow patients that were screen failed due 
to the temporary halt in enrolment to be screened like a new patient. 
x Section 8.4: Text added regarding the use remote communication for safety monitoring in 
case patients are unable to travel to the site. 
x Section 8.3.2 the primary endpoint has been clarified as the HiSCR50. The addition of the 
HiSCR75 and HiSCR90 has also been included. 
x Table 8-6 has been updated to include the assessments done by the laboratory as per the 
assessment schedule and statement of work. 
x Section 8.4.1.2 has been updated to include the assessments done by the laboratory as per 
the assessment schedule and statement of work. 
x Section 8.4.4.2 added to give clarity around CMV and SARS-CoV-2 (COVID-19) 
assessments. 
x Section 8.5.1 added wording regarding completion of PROs in case of epidemic or 
pandemic. 
x Section 8.5.2: additional wording regarding the collection of PK samples in case patient 
travel is restricted.  
x Section 12.3: Addition of analysis to explore pain medication use across cohorts and 
treatment groups.  
x Wording included in Section 12.4.4 stating how surgical incisions/excisions will be 
handled. 
x Section 12.6.1: Addition of details of analysis of exploratory endpoints in relation to the 
HiSCR 50, 75 and 90.  
x Removal of Section 17 (Information on Investigational treatments) as this data is in the IB 
and will be updated as necessary.  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol: strike through red font for deletions and red underline for insertions. 
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Amendment 1 (July 2019) 
Amendment rationale 
The main purpose of this amendment is to remove the requirement for male contraception in 
the LYS006 cohort given that completed preclinical safety studies with LYS006 showed there 
was no teratogenic or genotoxic potential observed with LYS006, reflected in the last update of 
the investigator’s brochure (Ed. 4). However, in order to harmonize eligibility criteria between 
cohorts, highly effective contraception for women of childbearing potential (WOCBP) will be 
kept as requirement for both cohorts.  
Further, the eGFR exclusion criterion (<80 ml/min/1.73 m2) is proposed to be updated, as the 
eGFR assessment is not performed with strict hydration and meat restriction prior to the test, 
resulting in a frequent underestimation of kidney function. Thus, a minimal threshold of 
60 ml/min/1.73 m2 is proposed to exclude patients with potential moderate or severe kidney 
damage. 
Two additional Hidradenitis Suppurativa (HS) scores have been added:  
x 
 an exploratory 
endpoint derived from the other lesion counts, has been added to the analysis without 
adding a new clinical assessment.  
x Hurley score has been added at Day 1 only to document patient population and disease 
severity.  
This protocol amendment also adds clarifications per recent comments received from HAs and 
ECs, e.g. the rationale for pooling placebo.  
A Data Monitoring Committee (DMC) has been set up and will function independently of the 
individuals associated with the conduct of this clinical trial. 
Additionally, in an effort to reduce site and patient burden, the following updates were made: 
x The baseline visit has been removed from the study. However, the term “baseline” is 
maintained and used throughout the protocol to refer to “prior to study treatment”. 
Eligibility criteria will be confirmed based on the evaluations that take place during the 
screening visit and at randomization (pre-dose on Day 1). 
x LYS006 quantification of 
 has been removed, as this assessment presented 
a major operational hurdle and sufficient information can be gathered from the other 
LYS006 
 assessment.  
x 
 (exploratory endpoints) have been removed.  
x Some exploratory sample time points have been removed (such as for 
 
. 
In order to provide more accurate qualitative and quantitative assessment of HS lesions, the 
.  
The protocol was also updated to correct typographical errors and inconsistencies.  
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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol: strike through red font for deletions and red underline for insertions. 
The following sections of the protocol were changed:  
x List of Abbreviations and Glossary updated 
x Protocol summary updated 
x Section 3 and Figure 3-1 updated to reflect changes in design. Baseline visit was removed.  
x Section 4.5.2.2 
 
 assessment removed 
x Section 4.5.2.2 Teratogenicity data updated with most recent findings from animal studies 
x Section 4.5.3.2 
 added 
x Section 5.1 wording of some of the inclusion criteria clarified. 
x Section 5.2 wording of some of the exclusion criteria clarified:  
x Criterion #3: Period of using of highly effective methods of contraception for 
WOCBP in Cohort A changed from 12 subsequent weeks after dosing to 14 weeks 
subsequent weeks after dosing.  
x Criterion #8: Testing for Hepatitis B and Hepatitis C was specified.  
x Criterion #12 was updated to remove laboratory assays to assess drug abuse since this 
was inadvertently added in the protocol.  
x Criterion #17: History of hypersensitivity or allergy now specified to any constituent 
of the investigational compounds. 
x Criterion #19 was removed following LYS006 IB update. 
x Criterion #21: Change of eGFR from 80 ml/min/1.73 m2 to 60 ml/min/1.73 m2. 
x Criterion #23: Hypersensitivity to any constituent of the gadolinium contrast agent 
was added.  
x Section 6.7 study treatment preparation and dispensation updated 
x Prior Section 8.1.1 removed 
x Section 8.2.1 Added Hurley score 
x Section 8.3.6 Added 
 
x Section 8.4.1.1 Blood specimens updated 
x Section 8.4.1.2 Urine specimens updated 
x Section 8.5.3.5 Exploratory 
 specified for both cohorts 
x Section 8.5.4 The administration of a
 procedure has been 
added. 
 removed.  
x Section 10.1.1 Adverse events reporting updated. 
x Section 10.2.3 Added a Data Monitoring Committee. 
x Section 12 Added rationale for pooling placebo data. 
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x Section 12.6 Added an exploratory endpoint, 
 
. 
x Section 12.6.8 
 details removed 
The following tables were changed: 
x Table 2-1 Exploratory objectives and endpoints updated  
x Table 6-2 Medications requiring wash out have been removed from the table to remove 
duplication of information and discrepancy with Exclusion Criteria. 
x Table 8-1 Baseline visit removed. 
x Table 8-1, Table 8-2, and Table 8-3 
 exploratory 
endpoints removed. Footnotes updated. 
x Table 8-2 
sampling removed at Day 113. 
x Table 8-3 
 assessment removed at EOS. 
x Other minor updates were made in the document to align different document sections and 
to improve readability. 
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Protocol summary 
Protocol number 
CCFZ533H12201BC 
Full Title 
A randomized, subject and investigator-blinded, placebo-controlled and 
multi-center platform study, to assess efficacy and safety of different 
investigational drugs in patients with moderate to severe hidradenitis 
suppurativa 
Brief title 
Study of efficacy and safety of investigational treatments in patients with 
moderate to severe hidradenitis suppurativa 
Sponsor and Clinical 
Phase 
Novartis 
II 
Investigation type 
Drug and Biological 
Study type 
Interventional  
Purpose and rationale 
This study is designed to assess the efficacy, safety, tolerability, PK of 
various selected systemic investigational treatments for 16 weeks in 
moderate to severe hidradenitis suppurativa (HS) subjects in comparison 
to placebo. Data from this study will enable determination of whether the 
clinical profile of these investigational treatments support further clinical 
development in moderate to severe HS. 
Primary Objective(s)  
The primary objective of this study is to assess the efficacy of the 
investigational treatments when compared to placebo, in moderate to 
severe inflammatory HS patients by comparing the proportion of patients 
achieving clinical response defined by the simplified Hidradenitis 
Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment 
Secondary Objectives 
To assess the safety and tolerability of the investigational treatments in 
patients with moderate to severe hidradenitis suppurativa (HS) by 
(i) number and severity of AEs and (ii) physical examination, vital signs, 
safety laboratory measurements and ECGs at baseline and repeatedly 
until study completion visit 
Study design 
This is a non-confirmatory, randomized, subject and investigator-blinded, 
placebo-controlled, multi-center and parallel-group study to assess 
efficacy, safety and tolerability of several active investigational drugs, 
iscalimab, LYS006, MAS825, remibrutinib and ianalumab, in patients with 
moderate to severe hidradenitis suppurativa. The maximum duration of 
any subject's participation in a Cohorts A, B and C may not exceed 
33 weeks, 25 weeks for Cohort D; remibrutinib, and 121 weeks for Cohort 
E; ianalumab and will consist of a 35 day screening period, a 16 week 
treatment period and will be concluded by a 12 week safety follow-up 
(4 week safety follow up for remibrutinib). For ianalumab there will be a 
mandatory follow up period of 16 weeks, followed by a conditional follow 
up period for up to 84 weeks. Subjects will be allocated to either of the 
cohorts (based on the eligibility criteria for each cohort). Within each 
cohort, subjects will be randomized 2:1 (Cohort A and B) or 3:1 (Cohort C 
and E), or 3:3:1 (Cohort D) to either investigational treatment or matching 
placebo. The study will be set up as a platform study to allow early 
discontinuation of cohorts and inclusion of new cohorts. 
Population 
Adult male and female participants, 18 to 65 years of age, presenting with 
moderate to severe hidradenitis suppurativa, diagnosed with recurrent 
inflammatory lesions for at least 12 months prior to screening. 

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Key Inclusion criteria 
• 
Male and female subjects, 18 to 65 years of age (inclusive), with 
clinically diagnosed HS for at least 12 months prior to screening 
• 
Patients with moderate to severe HS, as per evaluation at screening 
and randomization (pre-dose on Day 1):  
• 
For Cohort A, C and E ONLY:  
• 
A total of at least 5 inflammatory lesions, i.e., abscesses 
and/or inflammatory nodules, and 
• 
No more than 15 fistulae, and 
• 
At least two anatomical areas need to be involved with HS 
lesions 
• 
For Cohort B and D ONLY:  
• 
A total of at least 3 inflammatory lesions, i.e., abscesses 
and/or inflammatory nodules, and 
• 
No more than 15 fistulae, and 
• 
At least two anatomical areas need to be involved with HS 
lesions 
• 
Minimal body weight of 50 kg (inclusive) at screening 
• 
Able to communicate well with the investigator and understand and 
comply with the requirements of the study, and the ability and 
willingness to conduct study visits as per the study schedule. 
Key Exclusion criteria 
These criteria are applicable for all subjects across all cohorts. Please also 
refer to the cohort-specific eligibility criteria for any additional factors to 
consider. 
• 
Use of other investigational drugs at the time of screening, or within 
30 days or 5 half-lives of randomization, whichever is longer; or 
longer if required by local regulations. 
• 
WoCBP (defined as all women physiologically capable of becoming 
pregnant), unless they are using highly effective methods of 
contraception during dosing and for a minimum of 14 weeks after the 
last study drug administration for Cohort A (iscalimab) and a 
minimum of 2 weeks after the last study drug administration for 
Cohort B (LYS006). In Cohort C (MAS825), WoCBP will be asked to 
adhere to highly effective contraception from at least 3 months prior 
to first drug administration and until 5 months after the final dose 
(Day 225 to Day 253), when a pregnancy test will be conducted. In 
Cohort D (remibrutinib), WoCBP will be asked to adhere to highly 
effective contraception while receiving study medication and for 
2 weeks after stopping study medication. In Cohort E (ianalumab), 
WoCBP will be asked to adhere to highly effective contraception 
while on study treatment and for 6 months after the final dose 
(Day 253 to Day 281) 
• 
Pregnant or nursing (lactating) women at screening or randomization, 
where pregnancy is defined as the state of a female after conception 
and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
• 
For Cohort D: significant bleeding risk or coagulation disorders e.g.: 
• 
History of gastrointestinal bleeding, e.g. in association with use 
of nonsteroidal anti-inflammatory drugs (NSAID), that was 
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x 
Use of anticoagulant medication [for example, warfarin or Novel 
Oral Anti-Coagulants (NOAC)] within 2 weeks prior to 
randomization 
x 
International Normalized Ratio (INR) of more than 1.5 at 
screening 
x 
Use of anti-platelet medication [including dual anti-platelet 
therapy (e.g. acetylsalicylic acid + clopidogrel)] within two weeks 
prior to randomization.  
x 
Note: monotherapy with acetylsalicylic acid (up to 100 mg/day) 
or clopidogrel is not exclusionary. 
x 
Major surgery within 8 weeks prior to screening or planned 
surgery the during study treatment period. 
x 
For Cohort E: Subjects with evidence of existing hematological 
abnormalities at screening: 
x 
Hemoglobin below 8.0 g/dL 
x 
White blood cell count: below 2 x 109/L 
x 
Absolute Neutrophil count: below 1.5 x 109/L  
x 
Platelets: below 50 x 109/L 
x 
History of hypersensitivity to drugs of similar chemical classes to 
ianalumab (e.g. mAb of IgG1 class) or to any of the constituents of 
the study drug 
 
x 
Prior use of any B cell depleting therapy (e.g., rituximab or other anti-
CD20 mAb, anti-CD22 mAb or anti-CD52 mAb) within 1 year prior to 
dosing. 
x 
History of major organ, hematopoietic stem cell or bone marrow 
transplantation 
Study treatment 
x 
CFZ533 (iscalimab), 600 mg, s.c. or matching placebo as follows: 
weekly from Day 1 (Week 1) to Day 29 included (Week 5) and then 
bi-weekly from Day 43 (Week 7) to Day 99 included (Week 15). 
x 
LYS006, 20 mg, p.o. or matching placebo as follows: b.i.d. from 
Day 1 (Week 1) to Day 113 included (Week 17). 
x 
MAS825, 
 mg, s.c. or matching placebo as follows: 
 
(
) from Day 1 (week 1) to Day 29 (Week 5) and then 
 
(
) until Day 85 included (Week 13).  
x 
LOU064 (remibrutinib), 
mg 
. p.o or 
 mg 
. p.o or 
placebo from Day 1 (Week 1) to Day 113 included (Week 17). 
x 
VAY736 (ianalumab), 
 mg s.c. or matching placebo: 
 
) from Day 1 (week 1) until Day 85 included (Week 13) 
Key efficacy 
assessments 
x 
Simplified and original Hidradenitis Suppurativa clinical response 
(HiSCR) rate 
x 
 
 
 
 
 
 
 
 
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Key safety 
assessments 
x 
Number and severity of Adverse Events (CTCAE v5.0 grading) 
x 
Physical examination, incl. vital signs, safety laboratory 
measurements, and ECGs 
Other assessments 
x 
PK  
x 
 (optional), skin tape strips (Cohort B and C) 
x 
 
x 
Patient reported outcomes including Skin Pain Numerical Rating 
Scale (NRS), 
 
For Cohort E: 
x 
 
 
 
Data analysis 
In each treatment group, the primary variable, the proportion of subject with 
simplified HiSCR after 16 weeks of treatment, will be modeled with 
a binomial distribution. A neutral non-informative Beta (1/3, 1/3) distribution 
will be used for the prior for the response rate all treatment groups. 
Based on the priors and the observed primary outcome, posterior 
distributions for the response rate in investigational treatment and pooled 
placebo groups will be computed respectively. The posterior distribution of 
the 
difference 
of 
response 
rates, 
investigational 
treatment 
(iscalimab/LYS006/MAS825/each remibrutinib regimen/ianalumab) minus 
placebo, will be obtained by simulations, i.e. sampling from the posterior 
distributions of the corresponding treatment groups. The posterior 
probabilities for the difference of response rates will be assessed according 
to the dual efficacy criteria as a guide to decision making. 
Each investigational treatment will be assessed separately in comparison 
to the pooled placebo group. Subjects who do not complete the 16-week 
treatment due to lack of efficacy or adverse events due to worsening of 
disease, or subjects who discontinue before 12 weeks of treatment (if 
10% of the PD analysis set population) will be considered as non-
responders. If subjects who discontinue before 12 weeks of treatment 
constitute >10% of the PD analysis set population, multiple imputation 
methods will be used. 
Key words 
Hidradenitis suppurativa, acne inversa, platform study 
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1 
Introduction 
1.1 
Background 
1.1.1 
Hidradenitis suppurativa 
Hidradenitis suppurativa (HS), also called “acne inversa” or “maladie de Verneuil”, is a chronic, 
recurrent, and debilitating inflammatory skin condition that typically presents with deep, 
inflammatory, painful lesions in apocrine gland-bearing parts of the body. The most common 
areas affected are the axillae, the groin, and the anogenital region (Jemec 2012;  
Fimmel, Zouboulis 2010). 
HS is currently considered to be an inflammatory disease of the pilosebaceous follicle with an 
underlying immune system imbalance that occurs in genetically predisposed individuals  
(Sabat 2022, Kelly et al 2014). While it is considered a disease primarily triggered by follicular 
occlusion, HS is an inflammatory skin disease characterized by large numbers of neutrophils 
and macrophages in inflammatory lesions (Lima et al 2016, Shah et al 2017). While HS 
SDWKRSK\VLRORJ\LVVWLOOODUJHO\XQNQRZQWKHEHQHILWRIWXPRXUQHFURVLVIDFWRUDOSKD71)Į
blockade have been described in larger studies (Kimball et al 2016). 
Evidence of the efficacy of anti-Interleukin (IL)1 treatment using the IL-1 receptor blocker 
anakinra (Tzanetakou et al 2016), or with an antibody against anti-IL-Į EHUPHNLPDE 
(Gottlieb et al 2020), or an IL-1ß blocker, 
 have been described.  
Blocking IL-17A (Thorlacius et al 2018, Schuch et al 2018, Giuseppe et al 2018,  
Jørgensen et al 2018, Reguiaï et al 2020, Casseres et al 2020) or anti IL-23 treatment  
(Sharon et al 2012, Blok et al 2016) has also been successful in smaller studies and/or in case 
reports. Interestingly, Blok observed that a low serum LTA4H at baseline and low severity was 
correlated with efficacy of ustekinumab. More recently, investigational approaches using the 
oral PDE4 inhibitor apremilast (Weber et al 2017) or an anti-complement 5a compound  
(Kanni et al 2018; Giamarellos-Bourboulis 2020) have been described. Other innovative 
approaches to tackle the high medical need in HS include treatment with JAK inhibitors or more 
specific kinase inhibitors, such as TYK2 or IRAK4 inhibitors.  
A more recent study has identified Bruton’s tyrosine kinase (BTK) pathway activation as a 
central signal transduction network in HS (Gudjonsson et al 2020). 
The disease starts after puberty and women are more frequently affected than men (3:1). 
Risk factors include obesity and smoking. Although epidemiological prevalence estimates vary 
widely (0.03-4.3%; Jemec 2012, Jemec, Kimball 2015), and geographical differences exist, a 
prevalence of approximately 0.1-1% is accepted by the scientific community (Garg et al 2018). 
The clinical manifestations of HS are heterogeneous, but the disease tends to manifest with 
chronic, relapsing, deep, painful, inflammatory skin lesions, mostly inflammatory nodules and 
abscesses, leading to possible drainage and suppuration. Inflammatory lesions are complicated 
during disease progression by sinus tract formation and fistulization, and may lead to 
hypertrophic scarring with a possible impact on functional use. Generally, the inflammatory 
burden of HS is considered high (Riis et al 2015) and specifically inflammatory markers such 
as CRP are increased and correlate with disease severity (Hessam et al 2015, 
Akdogan et al 2020). 
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HS is associated with pain, malodorous discharge from the wounds, and scarring, and does 
frequently have devastating psychosocial effects. HS is a profoundly debilitating disease with 
a high negative impact on 
 with multiple studies confirming that the impact 
is greater than that seen with other dermatologic diseases (Deckers, Kimball 2016). 
Patients with HS also often suffer from depression, social isolation, have impaired sexual 
health, and may have difficulty performing their work duties (Esmann, Jemec 2011,  
Fimmel, Zouboulis 2010, Janse et al 2017). 
HS is difficult to treat. Official European treatment guidelines were only developed in 2015 and 
suggest that patients should be provided with adjuvant, medical and surgical therapy  
(Zouboulis et al 2015). 
While topical antibiotics can be used for mild cases, long courses of multiple systemic antimicrobial 
therapies are preferred for moderate to severe HS, generally with tetracyclines or a combination of 
clindamycin and rifampicin, which can be followed by maintenance with chronic antibiotic treatment 
for months or even years (Bettoli et al 2016, Dessinioti et al 2016, Zouboulis et al 2015). 
However, it is widely recognized that HS is a chronic inflammatory condition, not an infectious 
disease (Jemec 2012). Therefore, anti-inflammatory agents are an alternative and probably 
more appropriate approach than antibiotics. Over time, the consequence of chronic, recurrent, 
inadequately treated inflammation is irreversible fibrosis, which manifests as scarring and 
tunnels, or sinus tracts, which often do not respond to medical therapy. Once lasting anatomical 
changes occur, the only therapeutic option to reduce the volume of fibrotic tissue and improve 
functionality in the areas of affected skin is surgery (Andersen, Jemec 2017). One of the future 
treatment goals should be to reduce persistent scarring and to avoid surgery, which may be 
achieved by prevention of inflammatory lesions or may need a specific treatment. 
In 2015, adalimumab (Humira®), a recombinant human monoclonal immunoglobulin G1 
(IgG1) antibody to soluble and membrane bound TNF-ĮUHFHLYHGUHJXODWRU\DSSURYDOIRUWKH
treatment of moderate to severe HS. Efficacy has been seen with adalimumab, with HiSCR 
(Hidradenitis Suppurativa clinical response) response rates over placebo of approximately 16% 
(41.8% adalimumab vs 26% placebo) and 31% (58.9% adalimumab vs 27.6% placebo) as 
reported in PIONEER I and II studies, respectively (Kimball et al 2016). As captured in 
the adalimumab labels, adalimumab is associated with an increased safety risk for serious 
infections including tuberculosis, invasive fungal infections and other opportunistic infections. 
An increased incidence of malignancies has also been reported with adalimumab. 
There is, therefore, an unmet need for systemic therapies that effectively reduce inflammation 
while having a favorable safety profile for patients suffering from moderate to severe HS. 
No oral drug is currently approved, though oral antibiotics are used. 
1.1.2 
Platform study design 
This study uses a platform study design to investigate multiple targeted investigational 
treatments in the context of a single disease. An adaptive platform design offers flexible features 
such as dropping treatment cohorts for futility, declaring one or more investigational treatments 
superior, or adding new investigational treatments to be tested during the course of a trial. 
As a result, platform studies may find beneficial treatments with fewer subjects, fewer subject 
failures, less time, and with greater probability of success than a traditional two-arm strategy. 
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In addition, the results are based on very similar conditions and can be compared. This platform 
design also limits placebo exposure, with an overall 2:1 investigational drug:placebo 
randomization rate in Cohorts A and B, 3:1 in Cohort C and E, and 3:3:1 Cohort D. 
1.1.3 
Iscalimab summary 
Iscalimab (CFZ533) is a non-agonistic, fully human, Fc-silent, antagonistic IgG1 anti-CD40 
antibody that binds to the CD40 ligand (CD40L) binding site on CD40 and prevents the binding 
of CD40L to CD40. Since it is Fc-silent, iscalimab binding is able to block the CD40/CD40L 
costimulatory pathway and inhibit cellular proliferation and other effector functions, but does 
not cause antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent 
cytotoxicity (CDC). Iscalimab inhibits CD40L-induced activation in vitro and T cell-dependent 
antibody formation and germinal center formation in vivo. Iscalimab was able to prolong non-
human primate renal allograft survival alone or in combination with sub-therapeutic doses of 
cyclosporine. In addition, iscalimab was able to completely suppress primary and secondary 
antibody responses to immunization with a T cell-dependent antigen. Iscalimab has been tested 
in Phase 1 and is currently in Phase 2 trials in various immune-mediated conditions. Based on 
human data (approximately 295 subjects in the development program to date), iscalimab has 
shown a favorable safety and tolerability profile. More information can be found in the chapters 
below dedicated to iscalimab and in the Iscalimab Investigator's Brochure (IB). Overall, these 
results suggest that inhibition of the CD40/CD40L pathway by iscalimab may represent a safe 
and efficacious novel therapeutic approach for the treatment of HS. 
The presence and upregulation of B cells has been observed previously in HS lesions  
(Hunger et al 2008, van der Zee et al 2012). B cells and plasma cells were detected in HS lesions 
and 
in 
particular 
in 
chronic 
lesions 
(as 
opposed 
to 
early-stage) 
by  
van der Zee et al 2012, as compared to perilesional and healthy skin. In some samples, lymphoid 
follicles with CD20+ B cells were detected in chronic lesions. In a recent study 
 involving moderate to severe HS subjects, 
 samples showed a 
 
 in lesional skin as well as several 
 in the lesional 
tissue. In the same study, 
 in 
 data from 
 showed not 
only a clear 
 but also a 
 based on transcriptomics (data on file). 
In line with these observations, abnormalities and upregulation in 
 
in HS patients were observed by 
). 
In addition, and perhaps more importantly, macrophages are abundantly found in chronic HS 
lesional skin (Shah et al 2017). Recently, these macrophages were identified as potentially M2 
CD163+ macrophages (Byrd et al 2018). In the 
 HS samples, 
 was 
expressed on 
 present in HS lesions and is abundantly expressed in HS 
lesional 
 while the 
 was expressed by 
 in HS lesional 
. 
The 
 confirmed the pathway engagement seen with signatures on the 
transcriptional level (data on file). Thus, iscalimab could be the first treatment for HS 
that targets the 
 pathophysiology recently observed in HS. 
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1.1.4 
LYS006 summary 
LYS006 is a highly potent and selective oral inhibitor of the enzyme leukotriene A4 Hydrolase 
(LTA4H). LYS006 inhibits the biosynthesis of pro-inflammatory leukotriene B4 (LTB4) and 
increases the generation of anti-inflammatory, resolution-enhancing lipoxin A4 (LXA4). 
Both lipid mediators are known to play an important role in the orchestration of neutrophilic 
inflammation. LTA4H inhibition therefore represents a relevant mechanism for treatment of 
neutrophil-driven inflammatory conditions (Zouboulis 2009). LTB4 inhibitors, however, have 
not been developed for these indications yet, and no LTA4H inhibitor is currently marketed. 
LYS006 would therefore constitute a new therapeutic approach for this chronic inflammatory 
skin disease. In preclinical pharmacological models, inhibition of LTB4 generation by LYS006 
in peripheral blood correlated well with the anti-inflammatory efficacy of LYS006 observed in 
inflamed tissues in different mechanistic models. LYS006 inhibited neutrophil influx and 
swelling in an acute 
 skin inflammation model. The first-in-human study (FiH, 
CLYS006X2101) showed that LYS006 was well tolerated in healthy volunteers (HV) after a 
single dose (up to
 mg 
 administered 
) and multiple dose for 
 (up 
to 
mg 
). The pre-clinical signal of 
, observed in dogs and 
rodents at high doses, was not observed in any of the active treated subjects with ~4 fold higher 
doses used in the FiH, than proposed in the present study. In the same study,  mg 
 had an 
effect on 
 after 
 stimulation (
% suppression at 
) 
and the dose of 
mg 
 exhibited a 
) throughout the 
day. 
The dose used in this study, 
 mg 
 is 4 times lower than the highest multiple dose tested 
in controlled conditions over 12 days in HV and was well tolerated. No 
 were 
observed in any LYS006 treated subject in the FiH study. Laboratory events were without 
significant findings. However, sporadic, transient and isolated elevations of lipase without clear 
correlation to the dose or treatment duration have been observed. No signs of pancreatitis were 
observed and the transient elevations of lipase resolved even with continuation of treatment. 
More information can be found in the current edition of the LYS006 IB. 
As described above, neutrophils and macrophages are involved in HS lesions and are the main 
producers and target cells of LTB4 and LXA4 (Serhan et al 2008). Relevance of LTB4 was 
clinically demonstrated in related skin pathology inflammatory acne (Zouboulis et al 2003). 
As a sign for pathway activation, perinuclear localization of ALOX5 (5-LO) in lesional 
leukocytes has been previously described (Christmas et al 1999). Penno et al 2020 report that 
lesional HS skin displays an enrichment of 5-lipoxygenase (5-LO) derived metabolites, in 
particular leukotriene B4 (LTB4), which is the target of LYS006. Hyper-activation of the 5-LO 
pathway in lesional macrophages, identified these cells as potential source of LTB4, which may 
cause neutrophil influx and activation. In addition, LXA4 elevation may have impact on fibrosis 
in addition to the anti-inflammatory effect of the drug (Börgeson et al 2011). 
1.1.5 
MAS825 summary 
MAS825 is an 
 monoclonal antibody (mAb) containing a 
 
part that 
 neutralizes the key inflammasome effector cytokines interleukin-1 beta 
(IL-1ß) and interleukin-18 (IL-18). MAS825 has 
 affinities to both cytokines 
and inhibits IL-ȕ DQG ,/-18 signaling in cellular in vitro assays at 
 
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concentrations. IL-ȕ DQG ,/-18 are the two pro-inflammatory cytokines secreted after 
inflammasome activation in response to the recognition of damage associated molecular 
patterns (DAMPs) and pathogen associated molecular patterns (PAMPs). The combined 
inhibition of IL-ȕDQG,/-18 is expected to result in a more effective down-modulation of the 
inflammasome-driven pro-inflammatory responses compared to the inhibition of either 
cytokine alone. 
Kelly et al 2015 pointed out that in HS both cytokines, IL-1ß and IL-18 are upregulated and 
could thus play a role in its pathogenesis. Witte-Händel et al 2019 has confirmed these findings 
and showed specifically that IL-1ß signature was present in HS lesions and could be reversed 
by application of IL-1 receptor antagonist. Tzanetakou et al 2016 in a small proof of concept 
study was able to show promising clinical efficacy results versus placebo with anakinra, a 
recombinant IL-1R antagonist, while case reports or series have as well confirmed these 
findings (Leslie et al 2014, Zarchi et al 2013, André et al 2019). Case reports have shown that 
 using 
 may be of benefit in moderate to severe HS  
(Houriet et al 2017) or to associated syndromes such as PASH (pyoderma gangraenosum, acne 
and suppurative hidradenitis (Jaeger et al 2013). However, some observed failures in HS 
 
 and with anakinra (van der Zee, Prens 2013, 
Russo, Alikhan 2016) hint possibly to the fact that only subpopulations may be responsive to 
anti-IL-1 blockade or that this blockade alone may not be sufficient to achieve results in most 
patients.  
By targeting both inflammasome effector cytokines, IL-1ß and IL-18, MAS825 has therefore 
the potential for superior clinical efficacy in (auto)-inflammatory conditions or where both 
IL-ȕDQG,/-18 independently contribute to disease pathophysiology, such as HS. MAS825, a 
anti-IL-ȕP$ELVH[SHFWHGWRUDSLGO\QHXWUDOL]HDOOLQIODPPDVRPHGHSHQGHQWDV
well as inflammasome independent sources of IL-ȕDQG,/-18.  
MAS825 was well tolerated when administered to 
 s.c. up to 
 mg/kg, 
 for 26 weeks (No Observed Effect Level (NOEL) 
 mg/kg; Cmax,ss of 
 ȝJP/$8&-KVVRI
ȝāKP/DQGGLGQRWVKRZDQ\VDIHW\SKDUPDFRORJ\
(central nervous, cardiovascular and respiratory systems), toxicology (including 
 
) or local tolerability effects. No effects were also seen 
after 
 intravenous (i.v.) dosing at 
 mg/kg for 26-weeks (Cmax,ss of 
ȝJP/ $8&-KVV RI
ȝJāKP/)XUWKHUPRUHQRWUHDWPHQW-related effects 
were noted 
 in the peripheral blood as well as on primary and secondary 
humoral immune responses upon foreign antigen challenge.  
A Phase 2 study in adult patients who are hospitalized, and diagnosed with COVID-19 
pneumonia, impaired respiratory function and evidence of hyperinflammation (increased CRP 
and/or Ferritin; CMAS825F12201) has started. In this study, MAS825 is administered as single 
dose of 
 mg/kg.  
1.1.6 
Remibrutinib summary  
Remibrutinib (LOU064) is a selective, potent, covalent inhibitor of BTK. It has the potential of 
being one of the first oral treatments approved in HS. BTK is a member of the TEC-family 
kinases (TEC=Tyrosine protein kinase), such as TEC, Bone Marrow kinase gene on the 
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X chromosome (BMX), IL2-inducible T-cell kinase (ITK), T and X cell expressed Kinase 
(TXK). It plays a crucial role in B cell development, as it is downstream from the B cell receptor 
signaling and also downstream of the Fc gamma receptor, receptor for the FC portion of 
Immunoglobulin G ()FȖ5) which can be found on macrophages. BTK is selectively expressed 
in cells of the adaptive and innate immune system including B cells, macrophages, mast cells, 
basophils and thrombocytes. BTK is indispensable for signaling through the Fc epsilon receptor 
()Fİ5IRU,PPXQRJOREXOLQ(DQGWKHDFWLYDWLQJ)FJDPPDUHFHSWRUV)FȖ5IRU,J*DVZHOO
as the B cell antigen receptor (BCR). It is hypothesized that inhibition of BTK may be an 
attractive therapeutic concept to treat various autoimmune and chronic inflammatory diseases 
and clinical development programs with various BTK inhibitors have been initiated or are 
ongoing in, Sjögren´s syndrome, rheumatoid arthritis, asthma, CSU and other immune-
mediated diseases (Rip et al 2018). 
The scientific rationale of inhibiting BTK to treat HS is based on several observations: 
In HS lesional skin, several authors have demonstrated that macrophages, plasma and B cells 
are present and predominant in HS skin Shah 2017, Altman, Criswell 2021, 
Gudjonsson et al 2020, Frew et al 2020, Musilova 2020. Recently, Gudjonsson at al 2020 
described that B cells and plasma cells are pivotal players in HS pathogenesis and they 
constitute the predominant infiltrating leucocyte population in HS. While )Fİ5)FȖ5DQG%&5
signaling was detected in HS lesional skin, BTK besides SYK and STAT1 or Jun pathway 
activation constitute a central signal transduction network (Gudjonsson et al 2020). In addition, 
BTK pathway activation is shown in HS lesions (Gudjonsson et al 2020, Rumberger 2020). 
Remibrutinib has been and is being tested in several indications (Mar 2021): at least 
650 subjects (including healthy volunteers (HVs) and patients suffering from atopic dermatitis 
(AD), chronic spontaneous urticaria (CSU), asthma, and primary Sjögren’s Syndrome (pSS) 
have received remibrutinib in doses between 
 mg and 
 mg or placebo in 10 clinical 
studies. Pharmacodynamics (PD) of remibrutinib in healthy volunteers (HV) were characterized 
by assessing target occupancy (i.e.: BTK occupancy), distal pathway inhibition in basophils and 
B cells, and inhibition of a response to a known allergen in the skin prick test of atopic HV in 
the first-in-KXPDQ),+VWXG\&/28;$VLQJOHGRVHRI
 mg remibrutinib results 
in complete BTK occupancy in blood for >24 h. The B cell activation marker CD69 was 
LQKLELWHGE\DWGRVHVRI
PJ&RQVLVWHQWZLWKLWVFRYDOHQWPRGHRIDFWLRQUHPLEUXWLQLE
provided prolonged PD effect in targeted cells. In the skin, remibrutinib showed a dose-
dependent reduction of the wheal diameter of the allergen induced skin prick test, (for more 
details please refer to the IB). 
In the Phase 1 studies, the frequency and distribution of AEs observed did not appear to be dose 
dependent, with the majority of AEs occurring as single events. Given the non-serious and 
generally mild nature of AEs reported, they were not considered as clinically relevant safety 
concerns and they did not prevent dose escalation. A maximal tolerated dose (MTD) has not 
been defined. There were no clinically relevant changes in any of the cohorts with regards to 
ECG, vital signs, coagulation parameters or clinical signs of bleeding, clinical chemistry, 
hematology, or urinalysis following the administration of remibrutinib. Furthermore, 
remibrutinib showed encouraging blood and skin pharmacodynamics with a favorable safety 
profile, fully supporting further development for diseases driven by B cells, mast cells, or 
basophils (Kaul et al 2021). Beyond that, the Phase 2b CSU clinical trial CLOU064A2201 
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primary endpoint analysis demonstrated clinical efficacy and a fast onset of action of 
remibrutinib in the treatment of CSU patients as well as a favorable safety profile with no dose-
dependent safety concerns (for detailed information please refer to the IB). 
1.1.7 
Ianalumab summary 
Ianalumab (VAY736) is a human IgG1/N mAb which targets the B cell Activating Factor of the 
TNF-alpha Family (BAFF) receptor, BAFF-R (Syn:BR3), expressed on the surface of immature 
and mature B cells up to the lymphoblast stage. BAFF-R is not expressed by precursor B cells 
in the bone marrow or on long-lived plasma cells therefore there is no risk of inducing 
hypogammaglobulinemia. 
Ianalumab works through two distinct mechanisms.  
Enhanced antibody dependent cellular cytotoxicity (ADCC): afucosylation of the 
ianalumab Fc (fragment cystallizable) part enhances binding to human FcȖRIIIa/CD16 resulting 
in an enhanced ability to mediate CD16-dependent ADCC of BAFF-R+ B cells.  
Blocking BAFF-mediated activation of BAFF-R: Through its antigen binding region, 
ianalumab efficiently competes with BAFF for binding to BAFF-R on B cells, thereby 
inhibiting BAFF:BAFF-R signaling. BAFF-R signaling is critically involved in activation of 
B cell effector functions such as antibody production, isotype class switching 
(Mackay, Schneider 2009) and B cell proliferation, and also for BAFF-mediated B cell 
maturation of transitional B cells and B cell survival. Provided that ianalumab can access 
peripheral tissues in the same way as native immunoglobulins and existing therapeutic 
antibodies, it is expected to block BAFF:BAFF-R-mediated activation and survival of tissue 
B cells. 
The rationale for targeting BAFF-R in HS is based on the emerging role for both B cells and 
plasma cells both present in HS lesions (Gudjonsson et al 2020) and autoantibodies correlating 
with disease severity and duration (Macchiarella et al 2022). Little is known about the survival 
factors supporting the persistence of immune cells in HS but increased BAFF expression 
correlating with lesional B cell and plasma cell presence has recently been demonstrated 
(Sabat 2022). As of 24-Sep-2023 an estimated total of 905 subjects have been exposed to 
ianalumab, at various doses, in 22 clinical studies across multiple indications (rheumatoid 
arthritis (RA), chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Sjögren’s syndrome, 
multiple sclerosis, pemphigoid vulgaris, idiopathic pulmonary fibrosis (IPF), systemic lupus 
erythematosus (SLE), autoimmune hepatitis (AIH), lupus nephritis (LN). A phase 2b dose-
range study in Sjögren’s syndrome explored three ianalumab doses ( mg, 
mg and 
mg) 
administered 
 compared to placebo at Week 24.
 
 
 
has 
an acceptable safety profile with no dose-dependent safety observations other than local 
injection site reactions (which were mostly mild-to-moderate). For detailed information please 
refer to the IB. 
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1.2 
Purpose 
The purpose of this proof of concept platform study is to determine whether selected systemic 
investigational treatments, mostly in early stage clinical development, have an adequate clinical 
profile to support further clinical development in moderate to severe hidradenitis suppurativa 
(HS). This proof of concept study is designed as a platform study. This platform design allows 
several investigational drugs to be tested in an adaptive way under the same conditions in one 
study. This study started initially with two investigational drugs (iscalimab and LYS006), was 
extended to include a third cohort using MAS825, a fourth cohort using remibrutinib and now 
a fifth cohort using ianalumab.  
Cohorts A, B, C, D and E will assess safety and efficacy of three injectable drugs (iscalimab - 
Cohort A; MAS825- Cohort C; ianalumab – Cohort E) and two orally administered drugs 
(LYS006 - Cohort B; remibrutinib – cohort D). No further cohorts, investigating additional 
drugs, may be included via substantial protocol amendment(s). 
2 
Objectives and endpoints 
NOTE: the term “baseline” is used throughout this protocol to refer to “prior to study 
treatment”. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
x 
To assess the efficacy of the 
investigational treatments, compared 
to placebo in moderate to severe 
inflammatory HS patients 
x 
Proportion of patients achieving clinical response 
evaluated by the simplified Hidradenitis 
Suppurativa Clinical Response (HiSCR) after 
16 weeks of treatment 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
x 
To assess the safety and tolerability 
of the investigational treatments in 
patients with moderate to severe HS 
x 
Number and severity of AEs 
x 
Physical examination, vital signs, safety laboratory 
measurements, ECGs at baseline and repeatedly 
until study completion visit 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
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Objective(s) 
Endpoint(s) 
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Objective(s) 
Endpoint(s) 
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Objective(s) 
Endpoint(s) 
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3 
Study design
Figure 3-1 
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Figure 3-2 
Cohort D study design  
  
Figure 3-3 
Cohort E study design  
This is an exploratory, randomized, subject and investigator-blinded, placebo-controlled, multi-
center and parallel-group non-confirmatory study to assess the efficacy, safety and tolerability 
of five investigational drugs, iscalimab, LYS006, MAS825, remibrutinib and ianalumab in 
subjects with moderate to severe HS. The study will be set up as a platform study to allow early 
discontinuation of cohorts and inclusion of new cohorts. The study will consist of a screening 
period of up to 35 days, a treatment period of 16 weeks and a safety follow-up of 12 weeks
For ianalumab, following the last 
treatment on Day 85 and the End of treatment visit on Day 113, there will be a mandatory follow 
up period of 16 weeks, followed by a conditional follow up period for up to 84 weeks. 
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Eligibility criteria will be confirmed based on the evaluations that take place during the 
screening visit and at randomization (pre-dose on Day 1), as specified in Section 5. 
Randomization may be performed only after a subject’s study eligibility is confirmed on Day 1. 
With the exception of the urine pregnancy test, Day 1 laboratory and ECG results are not 
required to be available prior to randomization. 
Subjects will be allocated to either Cohort A, B, C, D or E based on the cohort-specific 
eligibility criteria. Should a subject be eligible for more than one cohort, they will be 
randomized to any suitable cohort. HS disease severity at Day 1 will be used to determine 
cohort eligibility.  
Subjects will be allocated to either: 
x Cohort A: consisting of an investigational treatment arm, iscalimab, 600 mg (2 injections 
of 2 mL) s.c. weekly for 4 weeks then biweekly, or its corresponding placebo (2 x 2 mL) 
s.c. weekly for 4 weeks then biweekly 
or 
x Cohort B: consisting of an investigational treatment arm, LYS006, 
mg 
 or its 
corresponding placebo b.i.d. p.o. 
or 
x Cohort C: consisting of an investigational treatment arm, MAS825, 
mg s.c. 
 
injections of 
mL) 
 then 
 or its corresponding placebo s.c. 
 mL) 
 
or 
x Cohort D: consisting of two investigational treatment arms and placebo 
. p.o.: 
x 
mg 
 remibrutinib plus placebo to 
 mg remibrutinib 
 
x 
 mg 
. remibrutinib plus placebo to 
mg remibrutinib
 
x Placebo to 
 mg remibrutinib and placebo to 
 mg remibrutinib 
. 
or 
x Cohort E: consisting of an investigational treatment arm, ianalumab, 
 mg 
 
 injections of  mL) 
 or its corresponding placebo s.c. 
 injections of  mL) 
. 
Within each cohort, subjects will be randomized to either the investigational treatment arm or 
its corresponding placebo in a 2:1 ratio for Cohorts A and B, 3:1 for Cohort C and Cohort E or 
3:3:1 for Cohort D. Cohort allocation will be performed by the IRT system. If a subject is only 
eligible for one open cohort, they will be allocated 100% to that cohort. If the subject is eligible 
for more than one open cohort, the IRT will randomly allocate the subject to a cohort. The 
sponsor can set the cohort allocation ratio to favor any of the cohorts but this favoring to any 
one cohort will not exceed 80%. 
In the event that enrolment into any cohort is not possible e.g. due to pending approvals, vendor 
readiness or study supply availability enrolment may continue into other available cohorts. 
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This platform study is set up to allow for further addition of cohorts of similar size and 
population, for other investigational treatments in early clinical phase for subjects with 
moderate to severe HS. These additional cohorts may include orally administered or injectable 
compounds. Inclusion of cohorts, to up to 5 in total, will only be proposed via substantial 
protocol amendments and will depend on the following criteria: 
x at least one study cohort still ongoing or communication has been provided to HAs, 
IRBs/ECs to confirm that further cohorts may be included. 
x 
scientific rationale 
x perceived favorable benefit-risk profile 
x pre-requisites that allow for at least 12, ideally 16 weeks of treatment duration 
It is expected that additional cohorts will be subject and investigator-blinded and include a 
placebo. 
Adult subjects with confirmed HS and with moderate to severe disease severity will be enrolled.  
Subjects with a minimum of 5 or more lesions at randomization (pre-dose on Day 1) will be 
eligible for all cohorts (A, B, C, D and E). 
For Cohort B only, a stratification factor will be utilized. Subjects with a minimum of 3 but less 
than 5 lesions (i.e. 3 - 4 lesions) at randomization (pre-dose on Day 1) will be capped at a 
maximum number of 15 subjects in Cohort B (up to 15 subjects with 3-4 lesions). 
For Cohort D, all subjects must have 3 or more lesions. Interim analysis in Cohort A and Cohort 
B showed that in terms of response to placebo, patients with lower severity as compared with 
higher severity had a similar response in the primary endpoint simplified HiSCR. Thus, no 
further stratification was used for cohort D. Randomization to the cohorts and respective arms 
will be done using a centralized Interactive Response Technology (IRT) system. 
The primary clinical endpoint is the simplified HiSCR (Hidradenitis Suppurativa Clinical 
Response) after 16 weeks of treatment. 
On Day 113 (Week 17), after safety and other assessments have been performed, all subjects 
will enter the follow-up period and will not receive any further study drug administrations. 
If medically justified, and if no potential safety concerns have been identified (after discussion 
with the sponsor), subjects may receive previously prohibited medication during this follow-up 
period. 
Safety and efficacy assessments will be conducted at follow-up visits as specified in the 
assessment schedule. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity 
(IG; Cohorts A, C and E only) and biomarker samples will also be collected. The end of study 
(EOS) visit will occur on Day 197 (Week 29) for Cohorts A, B and C, Day 141 (Week 21) for 
Cohort D and up to Day 813 (Week 121) for Cohort E, and will include study completion 
evaluations followed by discharge from the study. Blinding will be maintained for the 
investigator and the subject until the study is completed. 
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3.1 
Cohort A (iscalimab) 
This cohort will comprise approximately 45 subjects, 30 will receive the investigational 
treatment and 15 will receive placebo. 
x On Day 1, a dose of 600 mg iscalimab or matching placebo (2 injections of 2 mL) will be 
administered by subcutaneous injection (s.c.) by trained site personnel. 
Clinical assessments will be performed as well as PK, target engagement, IG, pathway and 
disease biomarkers and safety assessments. Subjects will be discharged from the site on 
the same day after completion of all assessments, provided there are no safety concerns. 
Following the first administration, subjects should be observed for immediate injection 
site reactions for at least one hour at the site, or longer at the discretion of the Investigator. 
x Subjects will return to the study center to receive weekly s.c. doses of either 600 mg 
iscalimab or matching placebo (same as they have received on Day 1) on Day 8 (Week 2), 
Day 15 (Week 3), Day 22 (Week 4) and Day 29 (Week 5). 
x After Week 5, subjects will receive 600 mg s.c. iscalimab every other week, on Day 43 
(Week 7), Day 57 (Week 9), Day 71 (Week 11), Day 85 (Week 13), and Day 99 (Week 
15; last dose). 
Safety and selected efficacy assessments will be conducted during these visits and PK/target 
engagement/IG/pathway and disease biomarker samples will be collected. 
3.2 
Cohort B (LYS006) 
This cohort will comprise approximately 40 to 45 subjects, approximately 30 subjects will 
receive the investigational treatment and approximately 15 subjects will receive matching 
placebo. 
x On Day 1, LYS006 20 mg or its corresponding placebo will be provided to the subjects at 
the site. The subject will be instructed by the site personnel how to take the drug (b.i.d.), 
including the need for sufficient fluid intake (preferably water) and to take the drug during 
or shortly after their morning and evening meal. Clinical assessments will be performed as 
well as PK, target engagement, pathway and disease biomarkers, and necessary safety 
assessments. Subjects will be discharged from the site on the same day after completion of 
all assessments provided there are no safety concerns. 
x Subjects will return to the study center on the days specified in the assessment schedule. 
Safety and selected efficacy assessments will be conducted during these visits 
and PK/biomarker samples will be collected. 
3.3 
Cohort C (MAS825) 
This cohort will comprise approximately 
 subjects; 
 subjects will receive the 
investigational treatment and 
 subjects will receive matching placebo. 
x On Day 1, MAS825 
 mg or its corresponding placebo (  injections of 
mL) will be 
administered by subcutaneous injection (s.c.) by trained site personnel. 
Clinical assessments will be performed as well as PK, target engagement, 
immunogenicity, pathway and disease biomarkers and safety assessments. Subjects will be 
discharged from the site on the same day after completion of all assessments, provided 
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there are no safety concerns. Following the first administration, subjects should be 
observed at the site for immediate injection site reactions for at least one hour, or longer at 
the discretion of the Investigator. 
x Subjects will return to the study center during the 
 (from Day 1 
(Week 1) to Day 29 (Week 5)) to receive MAS825 
 s.c. (
; 3 doses). 
x Then during the maintenance phase of the study (from Day 29 (Week 5) to Day 85 
(Week 13)) MAS825 will be administered at 
mg s.c. 
 (
 
doses). 
Safety and selected efficacy assessments will be conducted during these visits and PK, target 
engagement, immunogenicity and pathway/disease biomarker samples will be collected. 
3.4 
Cohort D (Remibrutinib) 
This cohort will comprise approximately 
 subjects. Approximately 
 subjects will receive 
the investigational treatment: 
 will receive 
 mg 
, 30 will receive 
 mg 
., 
approximately 
subjects will receive matching placebos. 
x On Day 1, remibrutinib 
 mg, 
 mg or their corresponding placebo will be provided to 
the subjects at the site. The study medication may be taken with or without a meal on non-
PK assessment days, but subjects should adhere to their choice throughout the study. If 
taken without food, the study medication should be taken with a glass of water (250 mL) 
at least 2 hours after the last meal and 1 hour before the next meal. Clinical assessments 
will be performed as well as PK, target engagement, pathway and disease biomarkers, and 
necessary safety assessments. Subjects will be discharged from the site on the same day 
after completion of all assessments provided there are no safety concerns. 
x Subjects will return to the study center on the days specified in the assessment schedule. 
Safety and selected efficacy assessments will be conducted during these visits 
and PK/biomarker samples will be collected. 
x After the treatment period of 16 weeks, the subjects will enter a follow-up period of 
4 weeks prior to the End of Study visit. 
3.5 
Cohort E (Ianalumab) 
This cohort will comprise approximately 40 subjects; 30 subjects will receive the 
investigational treatment and 10 subjects will receive matching placebo. 
x On Day 1, ianalumab 
 mg or its corresponding placebo ( injections of  mL) will be 
administered by 
injection (
) by trained site personnel. Prior to the first 
administration of study treatment, study subjects must receive pre-medication 
 
or equivalent administered orally. See Section 6.1.2 for more details. 
Clinical assessments will be performed as well as PK, target engagement, 
immunogenicity, pathway and disease biomarkers and safety assessments. Subjects will be 
discharged from the site on the same day after completion of all assessments, provided 
there are no safety concerns. Following the first administration, subjects should be 
observed at the site for potential injection related reactions for at least hours, or longer at 
the discretion of the Investigator. 
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x Subjects will return to the study center (from Day 29 (Week 5) to Day 85 (Week 13) to 
receive 
 mg s.c. 
 
Safety and selected efficacy assessments will be conducted during these visits and PK, target 
engagement, immunogenicity and pathway/disease biomarker samples will be collected. 
4 
Rationale 
4.1 
Rationale for study design 
This proof of concept study in moderate to severe HS subjects is designed as an adaptive 
platform study to allow ineffective treatment cohorts to be closed early and avoid unnecessary 
exposure of subjects. In addition, it will allow the inclusion of new innovative treatments which 
can be directly compared, in a field with high medical need. This may result in an improved 
and more efficient inclusion of subjects. The slightly different inclusion criteria per study cohort 
permit a coordinated screening, and thus subjects may benefit from different therapeutic 
approaches and more opportunities to participate in investigational research and earlier access 
to potentially beneficial therapies (see Woodcock, LaVange 2017). Despite the lack of 
universally recognized severity criteria, a minimum of 3 inflammatory lesions has been 
accepted in the past to describe moderate to severe HS patients (Kimball et al 2016). 
This threshold has been used for defining the minimal inclusion criteria for Cohort B and D 
with an oral treatment LYS006 or remibrutinib respectively, since there is no regulatory 
precedent for oral treatments. Injectables are generally used in patients with higher severity as 
compared to oral treatments. Thus, a minimum of 5 inflammatory lesions is selected for Cohort 
A with iscalimab,  Cohort C with MAS825 and Cohort E with ianalumab. 
The primary objective is to show efficacy of the selected investigational treatments, in HS 
subjects after 16 weeks of treatment in comparison to placebo. After the 16-week treatment 
period, a follow up period of 12 weeks is included to observe whether the effect can be sustained 
or increased after 16 weeks of treatment. This period also covers the safety follow-up period of 
iscalimab, LYS006, MAS825 and ianalumab. For ianalumab there will be a mandatory follow 
up period of 16 weeks (20 weeks from the last treatment), followed by a conditional follow up 
period for up to 84 weeks for a total maximum follow up period of 2 years. 
The EoS visit will be performed 2 years after the last dose of the study treatment have passed. 
After achieving the B cell recovery, conditional follow-up may be stopped and the EOS visit 
performed at any point. If B cell counts have not recovered at 2 years after the last dose of the 
study treatment, the follow-up may stop and the EOS visit may be performed. 
%FHOOUHFRYHU\LVGHILQHGDVZKHQ&'%FHOOFRXQWVUHWXUQWRRIEDVHOLQHYDOXHRU
50 cells/μL (Genovese et al 2008), whichever occurs earlier. 
 
 An additional urine pregnancy test will also be done for women of 
childbearing potential 5 months after the last treatment in Cohort C (MAS825). 
Blinding of subjects and investigators allows for an unbiased assessment of subjective readouts 
such as lesion counts in HS or global 
 scores, as well as adverse events.  
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Clinical assessments available for HS are not universally recognized. A recent Cochrane review 
(Ingram et al 2016) stated that 12 randomized prospective trials included in the review utilized 
16 physician-reported instruments. The study includes multiple clinical endpoints, to better 
evaluate the properties of these selected endpoints: 
x For this study, the simplified HiSCR was selected as the primary endpoint. The original 
HiSCR used in the phase 3 clinical trials conducted with adalimumab (Kimball et al 2016) 
has been validated, but may include some potential limitations, notably as it has been 
shown recently that investigators have difficulties in reliably assessing abscesses and sinus 
tracts and that the inter-rater variability is high (presentation at IDEOM meeting, 
Washington, USA 2018). The simplified HiSCR is defined as 50% decrease in the total 
number of abscesses plus inflammatory nodules, without any increase in draining fistulae. 
However, in contrast to the original HiSCR, increases in abscesses are allowed to 
constitute a clinical response, if the previous conditions are met. 
x The inflammatory lesions of HS will be counted as individual lesions (inflammatory 
nodules, abscesses and draining fistulae) in the typical anatomical areas. In addition to the 
count, a global assessment scale (Hidradenitis Suppurativa - 
 
 or 
 as well as a composite score 
 
 or 
 will be used. Abscesses and nodules will also be 
presented as AN Counts. 
x Several patient reported outcomes will be used, including the 
 
 and the 
 (at selected 
sites). Finally, as from a subject's perspective skin related pain is the most important 
symptom, the numerical rating scale (NRS) for pain is included.  
x As 
 is now recognized as a symptom in HS patients, 
 has been included 
in Cohort D and E 
 
x In addition, in Cohorts D and E a new scale the 
 
 will be used as described by 
  
4.2 
Rationale for dose/regimen and duration of treatment 
The median treatment duration of comparative HS trials in a recent Cochrane review was 
16 weeks (Ingram et al 2016). This was also the duration of a similar placebo-controlled phase 
2 study with adalimumab, recently approved for the treatment of HS (Kimball et al 2012) while 
another placebo-controlled trial was up to 24 weeks in a very similar HS population 
(Tzanetakou et al 2016). Placebo treatment may have some effect on the disease, reflecting the 
natural history, regression to the mean effects or a tighter clinical management of the subjects 
in part also due to concomitant medication. In this trial, use of topicals for wound care is 
allowed, as well as short term (< 2 weeks) antibiotics, which can be used if medically justified 
(as outlined in Section 6.2).  
Clinically significant worsening of HS necessitating a prohibited medical, surgical or physical 
treatment may lead to premature discontinuation of the concerned subject (as outlined in 
Section 9.1).  
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4.2.1 
Cohort A (iscalimab) 
At each dosing visit, HS subjects will receive 600 mg iscalimab s.c. (2 injections of 2 mL). 
During the loading phase of the study (from Day 1 (Week 1) to Day 29 inclusive (Week 5)), 
iscalimab will be administered weekly s.c. (Q1W; 5 doses). 
HS subjects present with a high inflammatory status which is likely to be associated with high 
CD40 expression and therefore the loading phase is justified to overcome the efficient 
CD40-mediated elimination of iscalimab when iscalimab is administered s.c. in conditions 
where CD40 expression in tissues is likely to be elevated. 
This has been demonstrated in Study CCFZ533X2203 in pSS subjects. In Cohort 1 
(s.c. regimen; Figure 4-1) most subjects demonstrated lower than expected PK profiles due to 
efficient pre-systemic CD40-mediated elimination, likely in the interstitium, lymphatic 
capillaries and/or lymph nodes. As CD40 receptors have been reported to be upregulated on 
parenchyma in inflamed tissues, an increased level of CD40 receptors is likely to be the origin 
of the efficient pre-systemic CD40-mediated elimination of iscalimab. As mentioned before, 
iscalimab is subject to target mediated elimination, and elevated CD40 expression is associated 
with high elimination rate of iscalimab if CD40 receptors are not fully saturated. 

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Figure 4-1 
Study CCFZ533X2203 in pSS patients: preliminary iscalimab plasma 
concentration-time profiles from Cohort 1 (3 mg/kg s.c. regimen) 
demonstrating the efficient pre-systemic CD40-mediated elimination 
of iscalimab after s.c. if CD40 receptors are not fully saturated 
 
In Study CCFZ533X2203-Cohort 1, iscalimab was administered at 3 mg/kg s.c. on Study Day 1, 15, 
29, and 57 in the placebo-controlled period, and on Study Day 85, 99, 113, and 141 in the open-
labelled period. Most subjects demonstrated lower than expected PK profiles. Only a few subjects had 
LVFDOLPDEFRQFHQWUDWLRQVȝJP/DQGDOORIWKHPKDGLVFDOLPDEFRQFHQWUDWLRQVZHOOEHORZ
40 ȝJP/DWKUHVKROGDVVRFLDWHGZLWKFRPSOHWHVXSSUHVVLRQRIJHUPLQDOFHQWHUGHYHORSPHQWDQG7
cell dependent antibody response in non-human primates (more details in the Investigator's Brochure). 
Individual (gray dots and lines) and mean data (red and purple lines) are presented. Red line: 
Subjects received iscalimab during the placebo-controlled and the open labelled periods. Purple line: 
Subjects received iscalimab only during the open-labelled period. 
In HS subjects, the 
 mg s.c. weekly regimen during the loading period is expected to provide, 
at start of treatment, rapid and complete CD40-CD40L pathway blockade in target tissues. 
In Study CCFZ533X2203, to demonstrate that an s.c. regimen was able to deliver steady state 
trough plasma concentrations similar to Cohort 2 (i.v. regimen; positive PoC) and had the ability 
to overcome the CD40-mediated elimination of iscalimab, Cohort 3 was introduced: 
 mg s.c. weekly on 4 occasions (loading), followed by 
mg s.c. weekly on 9 occasions 
(maintenance; Figure 4-2). Preliminary data indicated that this regimen was safe and well 
tolerated. 
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Figure 4-2 
Study CCFZ533X2203 in pSS subjects: preliminary iscalimab plasma 
concentration-time profiles in Cohort 3 demonstrating that a s.c. 
loading and maintenance regimen has the ability to overcome 
CD40-mediated elimination of iscalimab
In Study CCFZ533X2203-Cohort 3 (interim/preliminary data), iscalimab was administered at 
mg 
s.c. on Study Day 1, 8, 15 and 22 for the loading phase (red vertical bars), and at 
 mg s.c. 
y 
from Study Day 29 to Study Day 85. Individual (blue dots) and mean (thick blue line) plasma 
concentration data are presented.
During the maintenance phase of the study (from Day 43 (Week 7) to Day 99 (Week 15)) 
iscalimab will be administered at 
 mg s.c. 
The
 mg 
 maintenance regimen is expected to deliver steady state trough plasma 
concentrations of about 160-170 μg/mL (Figure 4-3), which is slightly above those observed in 
Study CCFZ533X2203-Cohort 2 (10 mg/kg IV regimen) in pSS subjects. In Study 
CCFZ533X2203-Cohort 2, steady state iscalimab trough plasma concentrations of 
ȝJP/ZHUHDVVRFLDWHGZLWKFOLQLFDOHIILFDF\VXFh as clinical improvement of the 
EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), and suppression of a 
biologically relevant biomarker CXCL13 (chemokine CXC ligand 13 protein; a marker of 
germinal center activity).
In HS (a follicular skin disease with deep dermal nodules/boils (in apocrine gland-bearing skin) 
and abscesses), tissue penetration of iscalimab is key and is likely to require higher plasma 
exposure as compared to pSS. 
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Figure 4-3 
Predicted time-course of plasma iscalimab concentrations in HS 
patients 
  
The line represents the predicted time-course of plasma iscalimab concentrations for the typical 
patient; the band represents the 90% prediction interval (90% of the patients’ concentration is 
expected in that area). 
4.2.1.1 
Target engagement after last dose 
Based on the predicted median iscalimab plasma concentration-time profile in HS subjects 
(Figure 4-3), about 10 weeks after the last dose (administered on Day 99), iscalimab plasma 
FRQFHQWUDWLRQVDUHH[SHFWHGWREH
ȝJP/ZLWKQRH[SHFWHGSKDUPDFRG\QDPLFDFWLYLW\LQ
target tissues like germinal centers (more details in the Investigator Brochure). A 14-week 
washout period after the last dose (EOS on Day 197) is acceptable considering the uncertainties 
in the predicted PK profiles. 
4.2.2 
Cohort B: LYS006 
In this cohort, a dose of 
 mg 
 is proposed to explore the efficacy and safety of LYS006 
in HS. 
The main potential safety risk identified in LYS006 preclinical safety studies, was 
and 
; these adverse effects 
determined the NOAEL selection for both preclinical species. In 16-week toxicity studies, the 
NOAEL was established at 100 mg/kg/day in the dog and 15 mg/kg/day in the rat, with total 
drug Cmax-based safety margins of 34 and 29, respectively, as compared with the proposed 
dose of 20 mg b.i.d. in this study. At this dose, a 
 is expected as 
suggested by the data from healthy volunteers of the first in human study (CLYS006X2101). 
In this FiH study, 80 mg b.i.d. was well tolerated over 12 days without detection of 
 
. This clinical safety margin of at least 4 should allow for potentially higher variability 
in pharmacokinetics and urinary excretion in the trial population. 
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A dose-dependent increase in incidence and severity of 
 was seen in a 16-week dog 
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of 
 mg 
.). Mildly decreased 
 in dogs 
administered 100 mg/kg/day (at Cmax-based exposure multiples of 34) were suggestive of 
decreased 
 formation, but not considered adverse due 
to the absence of correlating microscopic findings in 
. 
Steady-state leukotriene A4 hydrolase (LTA4H) target inhibition assessed ex-vivo in trough 
blood samples was on average 
% at 
mg 
, 
% at 
 mg 
 and 
% at 
mg 
.. 
Therefore, 
 mg 
. is selected as a pharmacodynamically active dose hypothesised to 
generate a maximal clinical response. Whilst the degree of LTA4H target inhibition may be 
lower in skin and other tissues, there is no specific reason such as slow or restricted drug 
distribution or high LTA4H turnover currently hypothesised to cause a major difference from 
the blood compartment. Selection of a dose higher than 
 mg 
. appears unjustified 
considering the high degree of target inhibition at this dose level and the increasing risk of 
 
 at higher dose levels. 
In the FiH trial, a very high fluctuation between peak and trough concentrations was observed. 
High peak plasma concentrations are associated with 
 and may 
constitute a potential safety concern. The present study applies a b.i.d. posology to reduce peak 
concentrations whilst maintaining high levels of LTA4H target inhibition. Moreover, as seen in 
the FiH trial, dosing together with food intake (standard breakfast, tested at 10 mg) decreased 
Cmax of LYS006 by approximately 40% with little impact on AUC. Thus, dosing with food, 
as proposed in this study, is expected to reduce peak plasma and 
 concentrations to a 
similar extent and will therefore further decrease the likelihood of 
 
, which was not observed at higher doses up 80 mg b.i.d. in the FiH study. 
4.2.3 
Cohort C (MAS825) 
During the 
 mg of MAS825 will be administered s.c. 
 
(from Day 1 (Week 1) to Day 29 (Week 5)) (
;  doses). 
During the maintenance phase of the study (from Day 29 (Week 5) to Day 85 (Week 13)) 
MAS825 will be administered at 
 mg s.c. 
 doses). 
The model used to predict the dynamics of the anti-IL-ȕ,/-18 
 antibody and its 
targets in serum consists of a general competitive binding model for the IL-18 arm  
) and the previously published model of 
 adjusted to 
 
DUPZLWKDQRYHOPRGHOGHVFULELQJWKHIUHHDQGWRWDO
. To predict the dynamics of 
LQUHVSRQVHWRWKHDSSOLFDWLRQRI

the model established in the clinical 
 study was used (
) and 
the 
 PK parameters and binding affinities were updated accordingly. To adjust 
the 
FRQFHQWUDWLRQVLQ
SDWLHQWVZHXVHGWKHV\QWKHVLVDQGFOHDUDQFHSDUDPHWHUVRI
this 
 listed in the 
 clinical study 
 The model is 
based on in-house in vitro and published human data from free and total IL-18 serum 
concentrations from patients across several autoimmune diseases (Weiss et al 2018). Based on 
this, a dosing schedule of 
 s.c. is predicted to result in the simultaneous 
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reduction of 
 IL-ȕDQG,/-18 levels in serum and effective neutralization of IL-ȕDVZHOO
as IL-18 is expected.
Figure 4-4 
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Figure 4-5 
MAS825 is evaluated in a FiH single dose ascending study up to 
mg/kg i.v. in healthy 
volunteers without any drug related SAEs. The pharmacokinetics (PK) of MAS825 in human 
follows human 
 based on 
data and is 
to soluble ligand cytokine target(s). MAS825 showed a 
in exposure matching the predicted human PK (evaluated up to
 mg/kg i.v.). The predicted 
human PK parameters of MAS825 are: clearance (CL) = 
 L/d, volume of distribution (Vd) 
= 
 L (for a 70-kg human subject) or 
L/kg; half-life (T1/2) =
 days. Preliminary 
analysis of PK profiles from the FiH study has 
 of 
of MAS825 due to the formation of anti-drug antibodies (ADA). 
Based on recent subcutaneous data from the FiH study, bioavailability and absorption rate 
constants were adjusted due to these findings and used in the prediction of the subcutaneous 
PK.
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Figure 4-6 
The MAS825 dose of 
 mg 
 s.c. is further justified by: 
The dose is predicted to lead to rapid and simultaneous neutralization of all systemic free IL-ȕ
and IL-18. The exposure after 
 mg s.c. 
IC90 for IL-ȕDQG,/-18 for 
more than 
 days after a single dose.  
The dose and the projected Cmax is lower than the well tolerated MAS825 dose 
administered to healthy volunteers and COVID-19 patients with no identified safety 
concerns (
mg/kg i.v.). 
The predicted exposure for humans for 
 mg s.c. 
 of MAS825 is 
approximately 
-fold lower for AUC and approximately 
-fold lower for Cmax to the 
non-clinical NOEL of 
mg/kg s.c. in 
. 
 has been administered to healthy subjects in doses up to 
mg/kg 
 and was 
well tolerated. PoC studies in pulmonary sarcoidosis and atopic dermatitis patients with 
mg/kg i.v. 
are currently ongoing. In the atopic dermatitis study an arm with 
a roughly three fold lower dose of 
 mg s.c. 
is included. 
 is approved in doses up to 
 mg every 
In the 26-week 
toxicology study in 
), 
 mg/kg, twice a week had no 
adverse events with no observed effect level. 
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4.2.4 
Cohort D (remibrutinib) 
In this cohort, two doses, 
mg 
. and 
mg 
., are proposed to explore the efficacy 
and safety of remibrutinib in adult HS patients. 
Based on the safety data from the completed and ongoing remibrutinib trials, the clinical safety 
profile of remibrutinib is favorable and fully supports the selected doses of 
 mg 
. and 
 mg 
. The dose of 
 mg 
 has been used in several studies in different indications, 
such as AD, asthma, pSS, as well as in CSU. In the primary endpoint analysis of the dose-range 
finding Phase 2b study CLOU064A2201 in CSU, where the dose range of 
 mg 
. to 
 mg
 was tested, most adverse events (AEs) were mild in severity, without any patterns 
of clustering or dose-dependency. Ongoing clinical safety review of CLOU064A2201E1, the 
ongoing long-term extension study of CLOU064A2201, which has a 52-week treatment period 
with 
 mg remibrutinib 
., was consistent with the core study CLOU064A2201 safety 
profile and did not reveal any safety signals. In addition, the clinical safety data from the 
completed Phase 1 studies, which tested doses of remibrutinib up to 
 mg 
 and 
 mg
 was favorable and did not raise any concerns. For more detailed information on 
the safety profile of remibrutinib, please see Section 4.5 and the IB. 
In the dose-range finding study CLOU064A2201 with 311 adult CSU patients, the efficacy of 
remibrutinib was assessed versus placebo for the following dose regimens: 
 mg 
., 
 mg 
., 
 mg 
., 
mg 
., 
 mg 
., 
 mg 
The treatment duration was 
12 weeks and the primary endpoint was change in weekly urticaria activity score (UAS7) from 
baseline at Week 4. At the time of the primary endpoint analysis, there were 301 participants 
(40-47 per arm) in the full analysis set with a UAS7 score at Week 4, and 233 participants 
(29-37 per arm) with a UAS7 score at Week 12. The treatment groups were overall well 
balanced in terms of demography and baseline disease characteristics. 
The study demonstrated clinical efficacy of remibrutinib in the treatment of CSU, with all tested 
doses showing superior efficacy over placebo at Week 4. A dose-response relationship was 
established for the 
. and 
 remibrutinib dosing regimens compared to placebo with 
respect to the change from baseline in UAS7 score at Week 4, with the dose-response plateau 
already achieved at 
 mg for 
. dosing (
mg total daily exposure) and at 
mg for 
 
dosing 
mg total daily exposure). 
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Figure 4-7 
 
A 
 dosing regimen is supported from a pharmacokinetics, pharmacodynamics and mode-
of-action perspective, in order to ensure sustained BTK inhibition over 24 hours, considering 
the relatively fast turn-over of the covalent BTK-remibrutinib complex in tissue (see 
Investigator´s Brochure for details). Furthermore, 
 dosing leads to a faster onset of action 
and steady state. 
Taken together, all tested remibrutinib dosing regimens demonstrated superior efficacy in 
treating signs and symptoms of CSU compared to placebo, when assessing the mean change 
from baseline in UAS7. Based on the data from CLOU064A2201, 
mg 
 was selected as 
the optimal dosing regimen for the treatment of CSU, a disease primarily driven by mast cell 
activation and degranulation. However, the mechanism of action and primary target may be 
different in HS as compared to CSU. We hypothesize that the scientific rationale of BTK 
inhibition in HS is related to B cell and plasma cells, as these can be found in tertiary lymphoid 
organs in lesional tissue (Gudjonsson et al 2020). BTK turn-over is potentially higher in B cells 
located in tertiary lymphoid organs of HS lesions compared to skin mast cells and sufficient 
target tissue penetration might be more difficult to achieve in HS compared to CSU, due to the 
fibrotic tissue remodeling as well as abscess and fistula tract formation typically present in HS. 
Thus, for Cohort D, we will explore not only the dose of 
 mg 
., which was selected for 
the CSU indication but also 
 mg 
, which, as mentioned above, is well covered from a 
safety perspective and can potentially offer higher tissue penetration with higher tissue BTK 
occupancy (see IB). 
Translational PK/PD model simulations were used to predict human peripheral tissue 
occupancy (e.g. spleen and lymph node) of remibrutinib assuming absence of relevant inter-
species differences in turn-over and drug-potency. The PK/PD model was focused on B cells, 
which are, as described above, hypothesized to be the relevant primary target of remibrutinib 
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in HS. B cells are typically residing in lymph nodes and in the spleen, besides a circulating 
fraction. In HS, B cells are also present in so called ‘tertiary lymphoid organs’ in HS lesional 
tissue, resembling key lymph node and germinal center characteristics. It can be assumed that 
B cells residing in spleen, lymph nodes or tertiary lymphoid organs in HS lesions show a faster 
BTK turn-over compared to circulating B cells in peripheral blood. The model predicts that 
overall significantly higher BTK occupancy can be achieved using a 
 dosing regimen. 
While a trough BTK occupancy of approximately 70-95% is predicted in human tissue for the 
PJ
GRVLQJUHJLPHQWKH
PJ
GRVLQJUHJLPHQLVSUHGLFWHGWRDFKLHYH
trough BTK occupancy (for more information refer to the IB). 
While B cells are hypothesized to be the leading target of BTK inhibition in HS, there are also 
other relevant immune cells types present in HS lesions, in which BTK is expressed and 
LQGLVSHQVDEOHIRU)FHSVLORQUHFHSWRU)Fİ5RU)FJDPPDUHFHSWRU)FȖ5 signaling, such as 
macrophages or mast cells. BTK inhibition in these cells might further contribute to a potential 
efficacy of remibrutinib in the treatment of HS. 
Single doses lower than 
 mg did not elicit high, sustained (>24h), near complete (>90%) BTK 
occupancy in all subjects in a first in human study (see the IB).  Thus, based on multiple dosing 
and experience in CSU, another skin disease, both doses of 
mg 
. 
mg 
 
remibrutinib could have the potential to elicit a therapeutic response in HS patients.  
In total, approximately 771 adult subjects have been enrolled into clinical studies with 
remibrutinib (as of March 2021), out of which at least 650 subjects were exposed to at least one 
dose of remibrutinib. The clinical safety profile fully supports both dosing regimens, 
mg 
 as well as 
 mg 
(see Section 4.5 and the IB), with a favorable safety profile and 
no dose-dependent safety signals.  
4.2.5 
Cohort E (Ianalumab) 
In this cohort, ianalumab 
mg s.c. 
is proposed to explore the efficacy and safety of 
ianalumab in adult HS patients. 
The rationale for the proposed dose regimen relies on the safety profile of completed and on-
going clinical studies with ianalumab in pSS, SLE, RA, AIH, IPF and results of a Phase 2b 
study in patients with pSS (CVAY736A2201), where three ianalumab doses 
 mg, 
 mg and 
mg) administered
 over 6 months were studied and compared to placebo. 
 
 
 
 
 
 has a favorable safety profile and no dose-related safety observations other than mostly 
mild to moderate, local injection site reactions have been observed. These clinical results in 
ianalumab-treated patients with pSS suggest that additional therapeutic benefits are obtained by 
maintaining sustained BAFF-R blockade over the dosing interval in addition to rapid and 
sustained depletion of circulating B cells, justifying the 
 regimen for treatment in 
this Phase 2 study in HS patients. In the paragraphs below, we describe dose-response 
modelling, exposure-response exploration based on data from patients with pSS, and additional 
evidence to support the proposed dose. 
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Dose-response relationship for ESSDAI based on phase 2b data at Week 24 
(CVAY736A2201)
The primary objective of study CVAY736A2201 was met and a statistically significant dose 
response relationship was observed in ESSDAI change from baseline at Week 24 (Figure 4-8).
The best clinical efficacy and best benefit/risk for patients was seen at the highest dose level of 
mg s.c. administered 
 
Figure 4-8 
Dose-response modelling (MCP-Mod) for ESSDAI at Week 24 (study
CVAY736A2201)
Placebo-adjusted change from baseline of ESSDAI versus dose (open circles and associated 
confidence interval) and model mean curve at Week 24 (blue dashed line). Solid horizontal line 
represents baseline; dashed horizontal line represents minimal clinically important change (MCII) of 
3 points. The simulated dose-response is based on model average method through 
bootstrappingtechnique.
Exposure-response relationship for ESSDAI based on phase 2b data at 
Week 24 (CVAY736A2201)
Due to the high placebo effect and variability in the ESSDAI response, it was not possible to
establish a robust exposure-response model. Hence, an exploratory cross-sectional exposure-
response analysis of ESSDAI change from baseline at Week 24 was performed. Individual 
patient data at Week 24 (including placebo, 
 and 
 mg dose levels) were used to 
characterize the relationship between observed trough ianalumab concentrations and ESSDAI 
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change from baseline (Figure 4-9). Despite the large variability of ESSDAI responses, there 
was a clear trend towards a sigmoid exposure-response relationship, which appears to plateau 
DWH[SRVXUHVDERYHaȝJP/7KHUHZDVHYLGHQFHWKDWH[SRVXUHVKLJKHUWKDQWKRVHDFKLHYHG
with 
mg
 will not translate into additional clinical benefit. Acknowledging that the dose 
level of 
mg 
 was not part of the primary efficacy analysis, our PK simulations suggest 
that the maximum clinical efficacy won’t be reached with 
 mg
 for a substantial number 
of patients, whereas 
 mg 
 is most likely to achieve maximum clinical efficacy. 
Figure 4-9 
Exposure-response relationship for ESSDAI (study CVAY736A2201)
Exposure-response relationship for ESSDAI (difference from baseline) at Week 24 based on 
data from dose levels Placebo, 
 and 
 mg from study CVAY736A2201. The exposure 
was split into six bins (equally sized ranges on log-scale, delimited by vertical dashed lines), 
with "n" showing the number of data points in each bin. Data are given as mean +/- standard 
error within each bin. Dashed line and grey area indicate loess smooth on individual data. 
Concentrations at zero refer to placebo patients. ConcentUDWLRQVDW
ȝJPL are below the 
limit of quantification (LOQ).
Further support for the choice of dose and regimen: The pharmacokinetic properties of 
ianalumab support a fixed dose for all patients
.In the phase 2b dose-range study 
in Sjögren's syndrome the primary endpoint ESSDAI was maximized with ianalumab 
mg 
 and stimulated salivary flow showed greater improvement on ianalumab 
 mg 
 as 
compared to lower doses. 
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Ianalumab
 mg
 provides B cell depletion, suggestive of sustained BAFF-R blockade 
based on biomarker results. Ianalumab 
mg 
 has a favorable safety profile; there are no 
dose-related safety observations other than mostly mild-to-moderate, local injection site 
reactions. 
Hidradenitis Suppurativa patients have higher body weight compared to patients with Sjögren's 
syndrome and tend to have lower exposure of therapeutic mAbs compared to other patient 
categories supporting the ianalumab 
mg 
dose to be tested in HS. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Adalimumab (Humira®D71)ĮLQKLELWRUIRUVFLQMHFWLRQLVWKHRQO\GUXJFXUUHQWO\DSSURYHG
for HS. No oral drug is currently approved for the treatment of HS and/or has clearly proven its 
efficacy. This study does not include a direct active comparator per cohort but instead compares 
investigational treatments to a corresponding placebo. While topical treatments and short term 
antibiotics are allowed, relevant systemic treatments used for HS are not allowed during the 
treatment phase, in line with what was done previously (Kimball et al 2016). The inclusion of 
placebo allows for a direct and unbiased estimate of the effect of the investigational treatment, 
which is important when no objective clinical assessment scores are available and clinical 
endpoints are rather subjective and can thus be influenced by beliefs or convictions. The use of 
a placebo arm also ensures an unbiased comparison of safety data with that of the actively 
treated population, and better reflects the natural history of the disease, which is still largely 
unknown and is thus difficult to predict (since only relatively few RCT data are available in this 
specific HS subject population). Inclusion of a placebo group clearly helps with establishing 
the efficacy and thus the usefulness of the proposed investigational treatments, specifically in 
early proof of concept trials (Singer 2004). Placebo controlled trials have been conducted 
previously in HS subjects for a duration up to 16 weeks (Tzanetakou et al 2016, 
Kimball et al 2012, Kimball et al 2016). The overall randomization ratio for investigational 
treatment to placebo is 2:1 in Cohorts A and B and 3:1 for Cohort C and E, which limits the 
number of subjects who will receive a placebo in this trial. For Cohort D, since a second dose is 
added, a randomization of 3:3:1 (active: active: placebo) is proposed. Only 10 patients will be exposed 
to placebo to ensure a double blind design, with 60 patients exposed to active. Both active doses will 
be compared to the pooled placebo group.  
4.4 
Purpose and timing of interim analyses/design adaptations 
Two interim analyses (IA) are planned for each cohort:  
x One IA to assess efficacy and safety, to avoid unnecessary exposure of subjects to 
compounds that have no, or marginal, chances to be effective (Section 12.4.2). This IA 
will be conducted when approximately half the planned subjects have completed 16-weeks 
of treatment, and 
x One IA after all subjects have completed all planned assessments of the concerned cohort, 
because it is possible that different cohorts may complete enrolment at different times. 
These end-of-cohort interim analyses are intended to help with the planning of later steps 
in the development program of each treatment. 
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Additional IAs may be conducted to support decision making, concerning the current clinical 
study, the sponsor’s clinical development projects in general, or in case of any safety concerns. 
If the recruitment rate is higher than expected, the first planned IA can be missed and only the 
end of cohort IA will be conducted.  
Additional information is presented in Section 12.7 (Interim Analyses). 
4.5 
Risks and benefits 
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
stopping rules, are included in this protocol. Recommended guidelines for supportive 
management of study-drug induced adverse events are provided in Section 16. 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and adequate post-treatment safety follow-up to capture any potential 
late occurring AEs. Refer to the IBs for more detailed information of the investigational 
treatments used in this trial. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
be excluded from participation in the study. 
4.5.1 
Cohort A (Iscalimab) 
4.5.1.1 
Potential benefit of treatment with iscalimab 
To date, only one drug (adalimumab) has been approved for the treatment of HS where a high 
unmet medical need still exists. Current standard of care therapies comprise topical care, 
conventional antibiotics, and immunosuppressive therapies, which are not fully efficacious in 
most subjects. Based on the scientific rationale for targeting the CD40 pathway in HS and the 
data available for iscalimab, CD40 inhibition by iscalimab has a potential to treat subjects with HS. 
4.5.1.2 
Potential risks associated with exposure to iscalimab 
Currently, limited data exists regarding the use of agents that block the CD40/CD40L pathway. 
Preclinical and data from the Phase 1 and 2 programs for iscalimab and data from compounds 
acting on the same pathway (CD40/CD40L) have been taken into account to estimate the 
potential risks associated with iscalimab. The current edition of the IB also provides detailed 
instructions regarding the risks and their mitigation. 
4.5.1.2.1 Vaccinations 
Vaccination of subjects during iscalimab treatment and prior to clearance of the antibody is 
likely to result in therapeutic failure (i.e., non-protective antibody titers) due to the 
pharmacologic activity of the antibody. Reduced or absent immunization effectiveness may be 
expected during treatment and for 14 weeks post treatment For subjects participating in this 
study, all vaccinations should be up to date based on local guidelines and an appropriate 
duration to illicit an immune response, prior to inclusion. Administration of live vaccines or 

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attenuated agents will be prohibited within a 2-month period before first dosing with iscalimab 
in the current study, during study treatment and for at least 14 weeks after the last dose.  
4.5.1.2.2 Teratogenicity 
As iscalimab's reprotoxicity potential is not fully characterized yet (see current IB of CFZ533), 
women of child bearing potential are only to be included if they follow highly effective 
contraception. Women will be monitored during the trial participation with serum pregnancy 
tests at screening and EoS, and urine pregnancy tests during the trial. If the subject is confirmed 
to become pregnant, the treatment must be discontinued. 
4.5.2 
Cohort B (LYS006) 
4.5.2.1 
Potential benefit of treatment with LYS006 
Currently, limited data exists regarding the use of agents that block LTA4H. Another LTA4H 
inhibitor, acebilustat from Celtaxsys, is in a clinical study in 200 cystic fibrosis subjects 
(NCT02443688), where preliminary summary results became available recently, referring to a 
successful outcome and move to phase 3 (Celtaxsys Inc. Press-release 2018). Another study in 
124 acne subjects was earlier completed (NCT02385760), though results are not yet available. 
Zileuton is an upstream acting oral 5-Lipoxygenase (5-LO) inhibitor, approved for treating 
asthma with similar but less selective pharmacology. Neutrophils, the main cellular target for 
LYS006, are abundant in HS lesions. Internal data show that the LTA4H pathway, in particular 
5-LO, is observed and shows signs of activation in HS histological samples. In the absence of 
predictive preclinical disease tests, it seems likely that the inhibiting chemoattraction of 
neutrophils may exhibit a potential clinical effect in HS.  
4.5.2.2 
Potential risks associated with exposure to LYS006 
Overall, LYS006 was well tolerated in the single and multiple ascending dose cohorts in a total 
of 121 enrolled healthy volunteers. Doses up to 80 mg b.i.d. were well tolerated, while for this 
present study, daily dosing of 
 mg 
. is planned. The current edition of the IB also provides 
detailed instructions regarding the risks and their mitigation. 
4.5.2.2.1
 
 was observed with increasing 
doses in preclinical studies. From these preclinical studies, it can be reasonably assumed that 
the risk of LYS006 
 increases when 
 
 It is expected that 
will 
precede 
 damage. 
 were not observed in LYS006 treated subjects 
in the FIH despite close monitoring with doses up to 80 mg b.i.d. and under stressed conditions 
(
.. Thus, it is not anticipated that any 
 induced 
by LYS006 will be observed during the present trial at the dose of 
 mg 
. 
Nevertheless,
 and LYS006 
 
 assessment will be performed on samples collected. Any 
 event or changes 
in 
 will also be monitored closely. 
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To lower the peak concentration of LYS006 in the 
, LYS006 capsules are to be taken 
twice daily (b.i.d.), in the morning and in the evening. In addition, during the FiH study, the 
administration of LYS006 with food was associated with decreased maximal concentrations of 
LYS006 in plasma 
. Therefore, LYS006 should be always taken with a glass of fluid 
(typically water) during or shortly after a meal and subjects instructed to drink at least 
1.5 liter (L) /day during the duration of the trial. 
4.5.2.2.2 Teratogenicity 
As per CTGF recommendation related to contraception and pregnancy testing in clinical trials 
(Clinical Trial Facilitation Group September 2014. Recommendations related to contraception 
and pregnancy testing in clinical trials), LYS006 is considered unlikely to cause human 
teratogenicity/ fetotoxicity in early pregnancy. However, in order to harmonize eligibility 
criteria between cohorts, highly effective contraception for women of childbearing potential 
(WoCBP) will be kept as a requirement for both cohorts in this study. 
No induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 was observed in human 
hepatocytes in vitro, therefore no human drug-drug interaction with oral or systemic hormonal 
contraception is anticipated.  
The use of condoms for male participants is not required. 
4.5.2.2.3 Vaccinations 
There is currently no clear evidence that blockade of LTA4 hydrolase would interact 
significantly with vaccination responses. Thus, the impact of LYS006 on vaccine response is 
expected to be low. However, studies investigating vaccine response in the presence of LYS006 
have not been conducted.  
4.5.3 
Cohort C (MAS825) 
4.5.3.1 
Potential benefit of treatment with MAS825 
To date, only one drug (adalimumab) has been approved for the treatment of HS where a high 
unmet medical need still exists. Current standard of care therapies comprise topical care, 
conventional antibiotics, and immunosuppressive therapies, which are not fully efficacious in 
most subjects. Based on the scientific evidence of upregulation of both IL-1ß and IL-18 in HS 
lesions (Kelly et al 2015), as well as the encouraging data in a small proof of concept trial with 
an anti-IL-1R antagonist (Tzanetakou et al 2016), there is some evidence that blockade of IL-1ß 
and IL-18 
may be beneficial to patients with HS. However, as this is the first time that 
MAS825 is tested in HS patients, it is unknown if a benefit and its extent can be confirmed.  
4.5.3.2 
Potential risks associated with exposure to MAS825 
Currently, limited data exists regarding the use of agents that 
 agents IL-1ß 
and IL-18. The current edition of the IB for MAS825 also provides detailed instructions 
regarding the risks and their mitigation. 
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4.5.3.2.1 Vaccination 
Data are lacking to confirm immunization effectiveness during treatment and for 14 weeks post 
treatment with MAS825, however interference is not expected. For subjects participating in this 
study, all vaccinations should be up to date based on local guidelines and an appropriate 
duration to illicit an immune response, prior to inclusion. 
Administration of live vaccines or attenuated agents will be prohibited within a 2-month period 
before first dosing with MAS825, during study treatment, and for at least 14 weeks after the 
last dose. 
4.5.3.2.2 Women of Child bearing potential (WoCBP) 
There is no available reproductive toxicity data for MAS825 nor clinical experience with the 
mAb in human pregnancies. 
Similar to other IgG antibodies, MAS825 may have FcRn-mediated, cross-placental transfer. 
The potential of placental transfer can be influenced by many factors (maternal level of the total 
IgG and specific antibodies and their subclasses, gestational age and placental integrity) 
(Palmeira et al 2012).  
Women of child-bearing potential (WoCBP) can be included in the MAS825 patient trials 
where the risk-benefit is considered favorable (i.e., studies in which there is potential benefit 
from 
), if they fulfil the following criteria: 
x Practice highly effective contraception for at least 3 months prior to study enrollment; 
x Have a negative pregnancy test at the time of enrollment; 
x Practice highly effective contraception during treatment with MAS825; and 
x Practice highly effective contraception for 5 months following treatment with MAS825, 
when it is predicted that 
 have come back to the values prior to treatment. 
Pregnant women are excluded from all MAS825 clinical trials. 
4.5.4 
Cohort D (remibrutinib) 
4.5.4.1 
Potential benefit of treatment with remibrutinib 
BTK inhibition is a new therapeutic principle for the treatment of HS that significantly differs 
from currently available treatment options in terms of its mode of action and route of 
administration. Because of its central role in B cell receptor (BCR) signaling and pro-
inflammatory Fc-receptor function, BTK inhibition has recently emerged as an attractive 
approach for selective immune modulation (Kaul et al 2021). BTK is expressed in selected cells 
of the adaptive and innate immune system, including B cells, macrophages, mast cells, 
basophils, and thrombocytes. 
The role of BTK in regulating BCR signaling strength is the rationale to explore BTK inhibitors 
in B cell driven diseases, such as rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus 
erythematosus (SLE), as well as B cell lymphomas, like chronic lymphocytic leukemia, leading 
to the approval of ibrutinib, acalabrutinib, and zanubrutinib by several regulatory agencies, 
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including the US Food and Drug Administration (Kaul et al 2021). Hidradenitis suppurativa is 
a potential candidate to be included in this list.  
Indeed, in HS lesional skin, several authors have demonstrated that macrophages, plasma and 
B cells are present and predominant in HS skin Shah 2017, Altman, Criswell 2021, 
Gudjonsson et al 2020, Frew et al 2020, Musilova 2020. In particular B cells seem to be more 
prominent in chronic lesions and around tunnel structures, where tertiary lymphoid structures 
are found as well (van Straalen et al 2022, Frew et al 2020). B cells and B cell signature are 
present in HS (Frew et al 2020, Musilova 2020, Rumberger 2020) and BCR was considered 
activated through the detection of pBTK and pSYK in HS lesional skin (Gudjonsson et al 2020). 
In an in vitro model in IgG/IgM stimulated B cells, Gudjonsson et al 2020 showed that BTK 
induced changes could be decreased with BTKi, such as acalabrutinib or ibrutinib.  
In several publications, autoantibodies have been detected and more commonly observed in 
patients with HS (Ross and Ballou 2021, Roediger 2022), which may hint to an increased B cell 
activity. Carmona-Rivera et al 2022 identified specific IgG autoantibodies that recognize 
circulating and tissue antigens in HS and suggest an autoimmune mechanism. Presence of 
autoantibodies was correlated with HS disease severity.  
In addition to the above that may apply to the BCR- DQG)FȖ5PHGLDWHGVLJQDOLQJRIWKH%7.
pathway, List et al 2019, but as well van der Zee et al 2012 showed that mast cells are 
upregulated in HS patients. 
Thus, a 
 scientific rationale exists to test a BTK inhibitor, such as remibrutinib, in HS 
patients, where no approved oral treatment is currently available and alternatives include 
adalimumab or surgery.  
Remibrutinib did show promising results in CSU patients in a recent phase 2b study as 
compared to placebo and will proceed to larger phase 3 program in CSU and as well in MS. 
Based on the above described scientific rationale and its efficacy on B cells, macrophages 
possibly mast cells and the promising clinical efficacy in CSU, 
 that remibrutinib 
may show a reduction of HS lesions over time.   
4.5.4.2 
Potential risks associated with exposure to remibrutinib 
Based on the mode of action of remibrutinib, pre-clinical safety information, drug-drug-
interaction studies, and the review of currently available literature as well as safety information 
of approved BTK inhibitors (e.g. ibrutinib, acalabrutinib and zanubrutinib), the following 
potential risks of remibrutinib have been identified (see below). Of note, several safety risks 
noted for ibrutinib and acalabrutinib, two BTK inhibitors approved for the treatment of B cell 
malignancies (mantle cell lymphoma, chronic lymphatic leukemia, Waldenstroem´s disease), 
are less likely related to the pharmacology of BTK inhibition, but rather to the underlying 
hemato-oncologic diseases being treated and their associated comedications and complications, 
such as tumor lysis syndrome, second primary malignancies etc. Therefore, when comparing 
the safety risks between the approved BTK inhibitors and remibrutinib, the underlying 
condition of the treated patient population must be taken into consideration. Furthermore, 
ibrutinib and acalabrutinib have a different target selectivity profile compared to remibrutinib 
(Angst et al 2020). The current edition of the IB also provides detailed instructions regarding 
the risks and their mitigation. 
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4.5.4.2.1 Infections 
BTK is an important signaling kinase downstream of cell surface receptors and expressed in a 
number of cell types of the adaptive and innate immune system, including B cells, macrophages, 
basophils and mast cells. In the completed and ongoing clinical trials with remibrutinib, 
infections were well balanced between the remibrutinib and placebo arms. Most of the 
infections observed were mild to moderate and did not lead to a change in study treatment. In 
the primary endpoint analysis of the Phase 2b study CLOU064A2201, infections rates were 
comparable between any remibrutinib arm (22.8%) and the placebo arm (21.4%). Most 
infections reported in the remibrutinib arms were mild in severity and did not lead to treatment 
discontinuation.  
All participants in remibrutinib clinical trials are monitored closely for signs and symptoms of 
infections while in the trial. Patients with a known history of chronic recurrent or active ongoing 
infections are excluded from the trial (refer to Section 5.2 for details).  
4.5.4.2.2 Vaccination 
Immune modulation of B cells via BTK inhibition is expected to affect the response to 
vaccination, and thus during treatment with remibrutinib, vaccination may be less effective. 
Therefore, it is recommended to have any necessary vaccinations completed 2 weeks prior to 
enrollment in the study. However, the use of live attenuated vaccines should be avoided 
2 months before, during, and for 4 weeks after the last dose of remibrutinib (see Section 6.2.2). 
4.5.4.2.3 Risk for bleeding 
In patients with B cell malignancies (chronic lymphatic leukemia, Waldenstroem´s disease, 
mantle cell lymphoma) treated with the BTK inhibitors ibrutinib or acalabrutinib, major 
bleeding events (i.e. serious events, gastrointestinal bleeding) were reported. However, the 
underlying hemato-oncologic diseases of these patients, the prevalence of anti-coagulant/anti-
platelet comedication use and the association with such complications should be taken into 
consideration. No relevant increase in bleeding risk has been observed in patients with X-linked 
agammaglobulinemia (XLA), an inborn genetic deficiency of BTK (Quek et al 1998, 
Futatani et al 2001, von Hundelshausen, Siess 2021). Furthermore, BTK inhibition does not 
have any impact on the plasmatic coagulation system and plasmatic coagulation was not 
affected in the human Phase 1 study up to the highest tested dose of 
 mg remibrutinib. In 
the completed and ongoing trials with remibrutinib only few mild and moderate bleeding events 
were reported. In the primary analysis of the Phase 2b study CLOU064A2201, 13 (4.9 %) non-
serious bleeding events were reported on any remibrutinib dose compared to one event on 
placebo (2.4 %). None of the events reported on remibrutinib was serious or severe. There was 
a single mild event (petechiae) leading to treatment discontinuation. Blood cell counts 
(including thrombocytes), hemoglobin and coagulation status will be closely monitored 
throughout the trial. Patients with a known history of bleeding disorders, or with a history of 
clinically relevant gastrointestinal bleeding and patients requiring anti-platelet or anticoagulant 
therapy (other than aspirin up to 100 mg/day or clopidogrel) are excluded from the trial; the use 
of dual anti-platelet therapy (e.g. acetylsalicylic acid + clopidogrel) is prohibited (see details in 
Section 5.2 and Section 6.2.2). In case of a significant bleeding event, remibrutinib must be 
discontinued immediately. 
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4.5.4.2.4 Other potential risks 
For detailed information on potential risks and other effects on QT intervals, myelomodulation, 
drug-drug interaction and reproductive toxicity associated with remibrutinib, please refer to the 
current IB of remibrutinib. 
4.5.5 
Cohort E (Ianalumab) 
For the latest information on benefit risk of ianalumab please see the latest version of the 
ianalumab Investigators Brochure (IB). 
4.5.5.1 
Potential benefits of treatment with ianalumab 
With currently only one drug (adalimumab) approved for HS there is a high unmet medical 
need in HS and among HS patients who do not respond to adalimumab lesional B cells and 
plasma cells are enriched compared non-responders (Hambly 2023). Indeed, in lesional HS skin 
plasma cells and B cells are predominantly present (Shah 2017, Altman, Criswell 2021, 
Gudjonsson et al 2020, Frew et al 2020, Musilova 2020). In particular B cells seem to be more 
prominent in chronic lesions and around tunnel structures, where tertiary lymphoid structures 
are found as well (van Straalen et al 2022, Frew et al 2020). B cells and B cell signature are 
present in HS (Frew et al 2020, Musilova 2020, Rumberger 2020) with BCR-activation 
demonstrated through the detection of pBTK and pSYK (Gudjonsson et al 2020, 
Rumberger 2020) and recently autoantibodies correlating with disease severity and duration 
have been demonstrated in HS patients (Macchiarella et al 2022). Little is known about the 
survival factors supporting the persistence of immune cells in HS lesions but increased B cell 
activating factor (BAFF) expression has recently been demonstrated. In HS lesions, BAFF 
receptor expression is most prominent in B cells and plasma cells with a strong correlation 
between BAFF expression and B cells and plasma cells (Sabat 2022). Taken together, targeting 
BAFF receptors with ianalumab in HS seems to be justified based on the scientific rationale 
above and the promising clinical efficacy seen in primary Sjögren's patients. 
4.5.5.2 
Potential risks associated with exposure to ianalumab 
The identified safety risks of ianalumab are injection-related reactions (systemic and local) and 
upper respiratory tract infections. Potential risks that have been observed with different B Cell 
depleting agents include infections (hepatitis B reactivations, opportunistic infections, such as 
progressive multifocal leukoencephalopathy (PML)), neutropenia, allergic reactions, 
immunogenicity, lower response to vaccinations, malignancies and reproductive toxicity. Since 
B cell depletion can last several months or even years after last treatment with B cell depleting 
agents, monitoring requirements are put forth to be adhered to during the post-treatment safety 
follow-up period and are detailed below. 
4.5.5.2.1 Injection-related reactions (systemic and local reactions) 
These reactions are anticipated based on the mode of action of ianalumab, whereby B cell killing 
leads to release of intracellular cytokines by antibody-dependent cellular cytotoxicity (ADCC).  
Mild-to-moderate, systemic injection-related reactions including symptoms such as headache, 
fever/pyrexia, shivering/chills, mild nausea, dizziness, rash, flushing, myalgia, fatigue and 

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tachycardia have occurred in ianalumab single dose and multiple dose studies. Reactions 
typically occur within 30 minutes and up to 24 hours after the first administration of ianalumab. 
Symptoms were most often observed after the first ianalumab dose but new-onset and recurrent 
reactions after repeated dosing have occasionally been reported. Symptoms either did not 
require any treatment or were manageable with paracetamol, antihistamines and corticosteroids. 
In the current study, mandatory premedication with a fixed dose of predniso(lo)ne prior to the 
first dose of the study treatment will be given to attenuate development and intensity of potential 
injection-related reactions (local and systemic). Patients are required to stay at the clinic until 
at least 4 hours after first dose of the study treatment. Patients must be observed/clinically 
monitored during this period for symptoms of possible injection-related reactions. Patients must 
be instructed to promptly report symptoms occurring within 24 hours after study treatment 
administration. 
In the dose-ranging study CVAY736A2201, participants with Sjögren’s syndrome received pre-
medication with methylprednisolone i.v. (
 mg or 
 mg) prior to the first dose of the study 
treatment. In the ianalumab 
 mg arm, systemic reactions were observed in 8.5% (4/47) of 
patients treated with ianalumab compared to 4.1% (2/49) of patients in placebo arm. Majority 
of the systemic reactions reported (4/47) in patients dosed with ianalumab 
 mg were of mild 
intensity (6.4%, 3/47). There was no severe systemic reaction in the patients dosed with 
ianalumab 
 mg. Symptoms included dizziness, headache, fever, chills, rash, flushing, 
nausea, myalgia, fatigue, tachycardia, and hypotension. As in the previous studies, symptoms 
either did not require treatment or were manageable with paracetamol, antihistamines and 
steroids. The site reactions were dose-dependent, with approximately 60% of participants 
experiencing a reaction at the 
 mg dose. Most were mild or moderate in severity (46.8%, 
10.6%, respectively). There was a single case of a severe local injection-related reaction in a 
participant who received ianalumab 
 mg which led to study treatment discontinuation. 
Symptoms included erythema, swelling, pain, itching/pruritus, rash and tenderness around the 
injection site. Some local injection reactions have been reported with a delayed onset and lasting 
up to several weeks. The majority of local reactions did not require treatment or were managed 
symptomatically as warranted. 
4.5.5.2.2 Infections 
The potential of ianalumab to increase the risk of infections has been identified (see IB 
Section 7). The risk of infection may increase if ianalumab is combined with corticosteroids or 
strong immunosuppressive drugs. In this study, predniso(lo)ne is prohibited except for the 
mandatory pre-medication administered at the first IMP administration. The Investigator should 
remind the patient of the risk of infections and ask them to promptly report any symptoms of 
infections. Subjects in this study will be monitored regularly and carefully for signs and 
symptoms which might indicate an infection.  
In the 
 the incidence of the Infections and 
Infestations System Organ Class during the double-blind, placebo-controlled period (first 
blinded treatment period up to Week 24) was comparable between the all-exposed ianalumab 
group (51.8%, 73/141) and placebo (59.2%, 29/49). Overall, during the entire study period 
(including the post-treatment follow up period), the combined incidence across all ianalumab 
doses (all-exposed) of the Infections and Infestations System Organ Class was 74.5%. The most 
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FRPPRQO\UHSRUWHGLQIHFWLRQVRFFXUULQJE\SUHIHUUHGWHUPVZHUHQDVRSKDU\QJLWLVXSSHU
respiratory tract infection, urinary tract infection, sinusitis, bronchitis, oral herpes and 
conjunctivitis, with no relation to dose. The majority of the events were non-serious, mild to 
moderate events that were self-limiting or responded promptly to treatment and did not lead to 
study drug discontinuation. There were three infection AEs that led to study treatment 
discontinuation (non-serious bronchitis, herpes zoster and a serious event of wound infection). 
The proportion of patients with serious infections was small and showed no dose-response 
relationship: mg (2.1%, 1/47), 
 mg (4.3%, 2/47), 
 mg (6.4% 3/47), 
 mg (4.3%, 2/47). 
COVID-19 
has 
similar 
impact 
on 
the 
risk-benefit 
as 
other 
infections. 
Any 
immunosuppressive/immunomodulatory agent may be associated with an increased risk of 
infections. Therefore, the risk of becoming infected or potentially developing a severe 
respiratory illness may be further increased in patients who are treated with ianalumab. 
During the COVID-19 pandemic, there have been serious and non-serious events of COVID-
19 infections reported. As of 24-Sep-2023, 8 SAEs of confirmed COVID-19 infections were 
reported. Of these, four were fatal (reported from the CVAY736A2101, CVAY736B2201, 
CVAY736Y2102 and CVAY736J12101 studies) with other potential contributory factors were 
present (e.g. obesity, diabetes, hypertension, or cancer). All SAEs of COVID-19 infections were 
assessed as not related to ianalumab by the investigator. Based on review of all COVID-19 
cases, no new safety signals were detected. 
As of 24-Sep-2023, there were no disseminated opportunistic infections in patients treated with 
ianalumab. 
4.5.5.2.3 Allergic reactions 
Although no allergic reactions following i.v. or s.c. administration were observed so far, the 
potential to develop an allergic reaction in a predisposed subject cannot entirely be ruled-out. 
Routine monitoring as for other biological treatments is warranted, as described in the 
ianalumab IB. 
4.5.5.2.4 Immunogenicity 
Anti-drug antibodies (ADAs) are assessed in all participants across all clinical trials with 
ianalumab. Only limited signs and symptoms of immunogenicity have been observed thus far 
in participants exposed to ianalumab. Administration of any mAb, independent of the antibody 
specificity for antigen, carries the risk of immune reactions such as acute anaphylaxis, serum 
sickness and the generation of neutralizing ADAs. Other potential clinical manifestations can 
include local skin reactions at the injection site, pyrexia and an influenza-like syndrome. In 
study 
 the incidence of treatment emergent 
 was 
%, 
%, 
% and 
% in the , 
, 
 and 
 mg dose groups 
respectively. 
 participants with treatment emergent 
 in the  mg dose group 
had none-or-no sustained B cell depletion. 
participants with treatment emergent 
 in the other dose groups had 
. 
There was no evidence of a relationship between development of treatment emergent 
 
and AEs as referred to preferred terms in the Standardized Medical dictionary for regulatory 
activities (MedDRA) Query 'Hypersensitivity' and preferred term 'Injection site reaction'. 
Especially, there was no trend observed towards a higher frequency of injection-related 
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reactions (both local and systemic) in participants with treatment emergent ADAs. Most of the 
patients with injection related reactions had no signal of ADAs. 
 
 
4.5.5.2.5 Vaccinations 
In immune suppressed patients, live vaccinations may cause serious adverse events and 
vaccination success may be attenuated. No data exists on the effect of ianalumab on response 
to vaccinations. It is recommended that patients receive appropriate vaccinations in accordance 
with current immunization guidelines, at least 2 weeks prior to the first administration. After a 
live vaccine is administered, exposure to the first dose of ianalumab (randomization) should not 
occur within 4 weeks. For further information please refer to the Vaccination Guidance for 
ianalumab (provided to study sites). 
4.5.5.2.6 Malignancies 
There is a risk of malignancies in immunocompromised patients in general, including patients 
receiving immunosuppressive therapies and/or patients who were immunocompromised from 
prior therapies. Patients with autoimmune disorders are also prone to develop specific types of 
cancer, depending on type of autoimmune disease. (Jung et al 2020, Ju et al 2023, 
Liang et al 2014, Brito-Zerón et al 2017, Zintzaras et al 2005, Nocturne, Mariette 2015,  
Tansel et al 2017, Jensen et al 2022, Danielsson Borssén et al 2015, Rees et al 2016, 
Clarke et al 2021). Based on the description of individual cases of malignancies reported from 
clinical trials with ianalumab, and the confounding factors present (e.g. underlying disease, 
prior/concomitant treatment with immunosuppressants), a causal association with ianalumab 
cannot be established at this time. However, given that patients receiving immunosuppressive 
therapies are at increased risk of malignancies and based on the safety information from other 
anti-CD20 mAb and BAFF inhibitor therapies, ‘Malignancy’ is considered as a potential risk 
for ianalumab. Based on overall data analysis to date, the benefit-risk profile of ianalumab 
remains unchanged. In ongoing non-oncology studies, there exists long-term treatment-free 
safety follow-up of patients until B cell count recovery thresholds are met (up to 2 years post-
treatment). During this time, all SAEs including any malignant neoplasm, are collected allowing 
for further evaluation of this important potential risk of malignancy. 
4.5.5.2.7 Reproductive toxicity  
Based on a reproductive toxicity study (enhanced pre-and postnatal development; ePPND) in 
cynomolgus monkeys, there was no teratogenicity observed over 6 months monitoring after 
birth. However, there was reported an increased number of abortions, as well as one stillbirth 
and two postnatal deaths of infant monkeys. The stillbirth and one perinatal death were likely 
attributed to immunosuppression in mother animals and associated infections. Some outcomes 
were considered secondary to effects specific to the animal species being tested, while there 
may have been a contributory effect from ianalumab in some other outcomes relevant to humans 
resulting from the pharmacologically intended immunosuppression (B cell depletion).  
In humans, transient peripheral B cell depletion and lymphocytopenia have been reported in 
infants born to mothers exposed to anti-CD20 antibodies during pregnancy. The potential 
duration of B cell depletion in infants following maternal exposure to ianalumab in utero and 
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the impact of B cell depletion on the safety and effectiveness of vaccines, are unknown 
(Sangle et al 2013).  
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy occurs during the study, and of the importance of 
contraceptive measures. Before enrollment, they must agree that in order to participate in the 
study, they must adhere to highly effective contraception requirements for the duration of the 
study treatment and 6 months after its discontinuation, as outlined in the protocol’s exclusion 
criteria Section 5.2. If there is any question that the subject will not reliably comply, she should 
not be entered or continue in the study. 
4.5.6 
Study related/ non cohort specific risks and benefits 
Additional risks are related to the procedures of the trial, such as blood sampling and 
 
 sampling. During the collection of blood samples, subjects may experience pain and/or 
bruising at the injection site. In addition, although rare, localized clot formation, infections and 
nerve injuries may occur. Lightheadedness or fainting may also occur during or after the blood 
draw.
 
 
 
 
4.5.6.1 
Treatment of Adverse Events 
Treatment for adverse events should follow general guidelines for standard-of-care, and is at 
the discretion of the investigator or treating physician (please refer to Section 16). Please also 
refer to Section 6.6.2. 
Subjects with clinically significant worsening of their disease are to be discontinued from study 
treatment (see Section 9.1.1) if prohibited treatments (Table 6-3) are needed to treat their 
symptoms. 
4.5.6.2 
Blood sample volume 
Approximately 250mL (Cohort B), 300 mL (Cohort A), 405 mL (Cohort C), 200 mL 
(Cohort D) or 500 mL (Cohort E) of blood is planned to be collected over a period of 33 weeks 
(up to 121 weeks for Cohort E), from each subject as part of the study. Additional samples for 
monitoring of any safety findings would be in addition to this. This is not considered to be a 
risk for this population. 
Timings of blood sample collection are outlined in Section 8 (Assessment Schedules). 
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and Central Laboratory Manual. 
See Section 8.5.3.9 on the potential use of residual samples. 
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5 
Population 
Subjects included in this study are adult male and female subjects of 18 to 65 years of age 
(inclusive), presenting with moderate to severe HS diagnosed with recurrent inflammatory 
lesions for at least 12 months. At randomization (pre-dose on Day 1), subjects need to have at 
least 5 inflammatory lesions (abscesses and nodules) in at least 2 anatomical areas to be 
included in Cohort A (iscalimab), Cohort C (MAS825) and Cohort E (ianalumab) and at least 
3 inflammatory lesions in at least two anatomical areas to be included in Cohort B (LYS006) 
and Cohort D (remibrutinib). Most of the other eligibility criteria are the same or very similar 
between the cohorts. Differences in eligibility criteria are based on the differences in the 
pharmacological profiles of the respective drugs, such as the need to monitor 
 and 
 for LYS006.  
A total of approximately 240 subjects will be enrolled in the study. Approximately 45 subjects 
will be enrolled in Cohort A (iscalimab) and approximately 40 to 45 subjects will be enrolled 
in Cohort B (LYS006) with approximately 40 subjects being enrolled in Cohort C (MAS825), 
approximately 70 subjects being enrolled into Cohort D (remibrutinib) and approximately 
40 subjects being enrolled into Cohort E (ianalumab). Within each cohort approximately 
30 subjects will receive the investigational treatment and approximately 15 subjects will receive 
the matching placebo in Cohorts A and B, with approximately 10 receiving placebo in 
Cohort C, D and E. However, in Cohort D an additional arm is included for a second dose level, 
therefore approximately 60 subjects in Cohort D will receive remibrutinib: approximately 
30 patients will receive 
 mg 
. and approximately 30 patients will receive 
mg 
 
The investigator must ensure that all subjects being considered for the study meet the eligibility 
criteria. Subject selection is to be established by checking through all eligibility criteria as 
specified below. A relevant record (e.g. checklist) of the eligibility criteria must be stored with 
the source documentation at the study site. Deviation from any entry criterion excludes a subject 
from enrollment into the study. Waivers for deviations from these criteria are not allowed to be 
given or granted. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
# 
Detail of Inclusion 
Cohort 
1 Written informed consent must be obtained before any 
assessment is performed. 
A B C D 
E 
2 Male and female patients, 18 to 65 years of age (inclusive), 
with clinically diagnosed HS for at least 12 months prior to 
Screening. 
A B C D 
E 
3 Patients with moderate to severe HS, as per evaluation at 
screening and randomization (values obtained pre-dose on 
Day 1 are used to determine cohort eligibility): 
 
 
 
 
 
 
x A total of at least 5 inflammatory lesions, i.e., 
abscesses and/or inflammatory nodules. 
A 
 
C 
 
E 
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# 
Detail of Inclusion 
Cohort 
 
• A total of at least 3 inflammatory lesions, i.e., 
abscesses and/or inflammatory nodules. 
 
B 
 
D 
 
 
• No more than 15 fistulae. 
A B C D 
E 
 
• At least two anatomical areas need to be involved with 
HS lesions. 
A B C D 
E 
5 Able to communicate well with the investigator, able to 
understand and comply with the requirements of the study 
and: 
A B C D 
E 
 
1. 
able and willing to participate in Cohort A and 
conduct study visits as per the Cohort A visit 
schedule. 
A 
 
 
 
 
 
2. 
able and willing to participate in Cohort B and 
conduct study visits as per the Cohort B visit 
schedule. 
 
B 
 
 
 
 
3. 
able and willing to participate in Cohort C and 
conduct study visits as per the Cohort C visit 
schedule. 
 
 
C 
 
 
 
4. 
able and willing to participate in Cohort D and 
conduct study visits as per the Cohort D visit 
schedule. 
 
 
 
D 
 
 
5. 
able and willing to participate in Cohort E and 
conduct study visits as per the Cohort E visit 
schedule. 
 
 
 
 
E 
6 Subjects must have a minimal body weight of 50 kg 
(inclusive) at screening. 
A B C D 
E 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
# 
Detail of Exclusion 
Cohort 
1 
Use of other investigational drugs at the time of 
screening, or within 30 days or 5 half-lives of 
randomization, whichever is longer; or longer if required 
by local regulations. 
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# 
Detail of Exclusion 
Cohort 
2 
Use/receipt of the following treatments during the 
specified time frames: 
1. Use of IL12 and IL23 blocking biologics such as 
ustekinumab or guselkumab within the last 
6 months prior to randomization. 
2. Use of B cell targeting or B cell depleting biologics 
or similar such as rituximab or belimumab within 
12 months prior to randomization; For patients who 
received these drugs earlier, B cell count must be 
within normal range at screening. 
3. Use of biological immunomodulating agents other 
than above (e.g., adalimumab, secukinumab, 
etanercept, infliximab, etc.) within 3 months or 
5 half-lives (whichever is longer) prior to 
randomization. 
4. If spironolactone or other anti-androgens (such as 
finasteride, cyproterone acetate, etc.) are used (for 
HS or other conditions, such as PCOS), only 
patients who have been on a stable dose for the last 
3 months prior to randomization and who are 
planning to continue for the duration of the study 
are eligible. 
5. Use of systemic antibiotics for HS in the last week 
prior to randomization. 
6. Surgical and physical treatment (such as laser, 
intense light and photodynamic therapy) for HS in 
the last 4 weeks prior to randomization. 
Surgical treatment does not include sporadic 
excisional biopsies.  
7. Use of any other systemic treatment for HS in the 
last 4 weeks prior to randomization (such as 
retinoids or other immunmodulating therapies, e.g., 
methotrexate, cyclosporine A, corticosteroids, PDE4 
inhibitors).  
8. Receipt of any high-dose injected corticosteroid 
bolus (>1mg/kg) within 3 months prior to 
randomization.  
9. Use of cyclophosphamide within the last 6 months 
prior to randomization 
10. Use of any systemic JAK inhibitors (such as 
tofacitinib or upadacitinib) or BTK inhibitors (such 
as ibrutinib and acalabrutinib) within 4 weeks or 5 
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# 
Detail of Exclusion 
Cohort 
half-lives (whichever is longer) prior to 
randomization. 
2a 
Use/receipt of the following treatments during the 
specified time frames: 
1. Use of IL12, IL23 or TNF-α blocking biologics such 
as ustekinumab, guselkumab, adalimumab, 
etanercept and infliximab within the last 6 months 
prior to randomization. 
2. Any B-cell depleting therapies, other than 
ianalumab (e.g., rituximab, other anti-CD20 mAb, 
anti-CD22 mAb, or anti-CD52 mAb) administered 
within 1 year prior to randomization, or as long as B 
cell count is less than the lower limit of normal or 
baseline value prior to receipt of B cell-depleting 
therapy (whichever is lower). 
3. Use of IL-17 blocking biologicals such as 
secukinumab within 3 months or 5 half-lives 
(whichever is longer) prior to randomization. 
4. If spironolactone or other anti-androgens (such as 
finasteride, cyproterone acetate, etc.) are used (for 
HS or other conditions, such as PCOS), only 
patients who have been on a stable dose for the last 
3 months prior to randomization and who are 
planning to continue for the duration of the study 
are eligible. 
5. Use of systemic antibiotics for HS in the last week 
prior to randomization. 
6. Surgical and physical treatment (such as laser, 
intense light and photodynamic therapy) for HS in 
the last 4 weeks prior to randomization. 
Surgical treatment does not include sporadic 
excisional biopsies. 
7. Use of any other systemic treatment for HS (such as 
retinoids or other immunomodulating therapies, e.g., 
methotrexate, corticosteroids, PDE4 inhibitors) in 
the last 4 weeks prior to randomization. Patients 
receiving methotrexate at a weekly dose more than 
25 mg or hydroxychloroquine more than 400 mg 
daily or leflunomide at a non-stable dose, in the last 
3 months prior to randomization.  
 
 
 
 
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8. Receipt of any high-dose injected corticosteroid 
bolus (>1mg/kg) or cyclosporine A within 3 months 
prior to randomization.  
9. Use of CTLA4-Fc Ig (abatacept), 
cyclophosphamide, intravenous IgG, 
plasmapheresis, iscalimab (anti-CD40) or 
belimumab (anti-BAFF mab) within the last 6 
months prior to randomization 
10.  Use of any systemic JAK inhibitors (such as 
tofacitinib or upadacitinib) or BTK inhibitors (such 
as ibrutinib and acalabrutinib) within 4 weeks or 5 
half-lives (whichever is longer) prior to 
randomization. 
3 
WoCBP, defined as all women physiologically capable 
of becoming pregnant, unless they are using highly 
effective methods of contraception during dosing and for 
the subsequent 14 weeks after the last study drug 
administration for Cohort A (iscalimab) and the 
subsequent 2 weeks after the last study drug 
administration for Cohort B (LYS006) and D 
(remibrutinib). In Cohort C, WoCBP will be asked to 
adhere to highly effective contraception from at least 3 
months prior to first drug administration and until 5 
months after the final dose (Day 225 to Day 253), 
when a pregnancy test will be conducted. 
In Cohort E, WoCBP will be required to adhere to 
highly effective contraception during dosing and for 6 
months after the final dose (Day 253 to Day 281). 
Highly effective contraception methods include: 
• Total heterosexual abstinence (when this is in line 
with the preferred and usual lifestyle of the subject). 
Periodic abstinence (i.e., calendar, ovulation, 
symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of 
contraception. 
• Female sterilization (surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, 
or tubal ligation) at least 6 weeks prior to 
randomization. In case of oophorectomy alone, only 
when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
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• Male sterilization (at least 6 months prior to 
screening). The vasectomized male partner should 
be the sole partner for that subject 
• Use of oral, injected or implanted hormonal methods 
of contraception or placement of an intrauterine 
device (IUD) or intrauterine system (IUS) or other 
forms of hormonal contraception that have 
comparable efficacy (failure rate <1%). For 
example, hormone vaginal ring or transdermal 
hormone contraception. In case of use of oral 
contraception, women should have been treated with 
the same pill and dose for a minimum of 3 months 
prior to randomization.  
Women are considered post-menopausal and not of child 
bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
If local regulations are more stringent than the 
contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described 
in the ICF. 
4 
Pregnant or nursing (lactating) women at screening or 
randomization, where pregnancy is defined as the state of 
a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test. 
A B C D 
E 
5 
Any severe, progressive or uncontrolled medical or 
psychiatric condition or other factors at randomization 
that in the judgment of the investigator prevent the 
patient from participating in the study. 
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6 
At screening, history or symptoms of malignancy of any 
organ system, treated or untreated, within the past 5 
years, regardless of whether there is evidence of local 
recurrence or metastases with the following exceptions: 
1. 
history of basal cell carcinomas and/or up to 3 
squamous cell carcinomas of the skin, if 
successful treatment has been performed, with no 
signs of recurrence;  
2. 
actinic keratoses, if present at screening, should 
be treated according to standard therapy before 
randomization. 
A B C D 
E 
7 
History of auto-immune or immunodeficiency diseases, 
or a positive HIV (ELISA and Western blot) test result at 
screening. 
A B C D 
E 
8 
Positive serology for: 
 
 
 
 
 
 
1. 
hepatitis B surface antigen (HBsAg) or hepatitis 
B core antibody (anti-HBc) or hepatitis C 
antibodies at screening 
A B C D 
E 
 
2. 
IgM for Cytomegalovirus (CMV) in the absence 
of positive CMV IgG, or quantifiable CMV DNA 
by PCR (patients with detectable but NOT 
quantifiable DNA test result may be eligible for 
the study) at screening 
A 
 
 
 
 
9 
Signs or symptoms of a clinically significant systemic 
viral, bacterial or fungal infection within 30 days of 
randomization. 
Infections are considered controlled if appropriate 
therapy has been instituted and, at the time of Screening, 
no signs of infection progression are present. Progression 
of infection is defined as hemodynamic instability 
attributable to sepsis, new symptoms, worsening physical 
signs or radiographic findings attributable to infection. 
1. 
COVID-19 specific: If in line with health and 
governmental authority guidance, it is highly 
recommended during a pandemic, that PCR or 
comparable approved methodology for COVID-
19 is completed within 1 week prior to first 
dosing. The physician needs to consider whether 
or not to do the test and/or interpret test results, 
in case the patients would have received a 
vaccine for SARS-CoV-2. If testing is 
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performed, negative test results are required prior 
to enrolment into the study. Additional testing 
may occur at the discretion of the investigating 
physician. COVID-19 testing should be 
completed via nasal or throat swabs or other 
approved route. If testing is not performed, the 
investigator must document their discussion with 
the patient/ parent/ caregiver regarding testing, 
and the rationale for not testing, in the source 
documentation.  
10 
Any condition, that would result in a significantly 
elevated risk for infections, as judged by the investigator, 
e.g.: 
 
 
 
 
 
 
1. 
Receipt of live/ attenuated vaccinations within the 
2 month period before randomization and willing 
to withhold any future live/attenuated vaccines 
until 14 weeks after the last dose  
A 
 
C 
 
 
 
2. 
Receipt of live/attenuated vaccinations within the 
2 month period before randomization until 4 
weeks after the last dose 
 
 
 
D 
 
 
3. 
Any other current, active or latent infection 
susceptible to reactivation, at randomization 
A B C D 
E 
 
4. 
Receipt of live/attenuated vaccinations within the 
4 week period before randomization until the end 
of the follow up period. 
 
 
 
 
E 
11 
Evidence of active or latent tuberculosis as assessed by 
Quantiferon testing at screening  
A B C D 
E 
12 
History of drug abuse or unhealthy alcohol use within the 
12 months prior to randomization. In the case of drug 
use, the Investigator must determine if a subject’s drug 
use qualifies as drug abuse. Unhealthy alcohol use is 
defined as five or more drinks on the same occasion on 
each of 5 or more days in the past 30 days. 
A B C D 
E 
13 
Donation or loss of 400 mL or more of blood within 8 
weeks prior to randomization, or longer if required by 
local regulation. 
A B C D 
E 
14 
Inability or unwillingness to undergo repeated 
venipunctures (e.g., due to poor tolerability or lack of 
access to veins). 
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15 
Patients who are at significant risk for thromboembolic 
events based on their medical history and as judged by 
the investigator, and who are not under appropriate 
treatment at randomization, in particular patients with 
antiphospholipid syndrome or with a history of a positive 
test for antiphospholipid antibodies. 
A 
 
 
 
 
16 
Any surgical or medical condition which might 
significantly alter the absorption, distribution, 
metabolism, or excretion of drugs, or which may 
jeopardize the subject in case of participation in the 
study. The investigator should make this determination in 
consideration of the subject’s medical history and/or 
clinical or laboratory evidence of any of the following: 
 
 
 
 
 
 
1. 
Inflammatory bowel disease, peptic ulcers, 
gastrointestinal bleeding including rectal bleeding 
 
B 
 
D 
 
 
2. 
Major gastrointestinal tract surgery such as 
gastrectomy, gastroenterostomy, or bowel 
resection) 
 
B 
 
D 
 
 
3. 
Pancreatic injury or pancreatitis  
Lipase and amylase must not be above the 
upper limit of normal at screening 
 
B 
 
 
 
 
4. 
Liver disease or liver injury as indicated by 
clinical symptoms and clinically relevant 
abnormal liver function tests at screening. As a 
guidance, abnormal values for ALT (SGPT), AST 
(SGOT), and alkaline phosphatase are considered 
those exceeding 1.5ULN, in particular if two or 
more liver values are increased.  
Serum total bilirubin must not be above 1.2 x the 
upper limit of normal at screening 
A 
 
 
 
 
A 
B 
 
 
 
 
B 
 
D 
 
 
 
E 
 
5. 
Subjects with evidence of existing hematological 
abnormalities at screening: 
 
Hemoglobin levels below 8.0 g/dL 
White blood cell count below 2.0 x 109/L 
Absolute Neutrophil Count below 1.5 x 109/L, 
and/or 
Platelet count below 100 x 109/L  
 
 
C 
 
 
 
6. 
Subjects with evidence of existing hematological 
abnormalities at screening: 
Hemoglobin below 10 g/dl 
 
 
 
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White blood cell count: below 3 x 109/L 
Absolute Neutrophil count: below 1.5 x 109/L  
Platelets: below 100 x 109/L 
 
7. 
Subjects with evidence of existing hematological 
abnormalities at screening: 
Hemoglobin below 8.0 g/dL 
White blood cell count: below 2 x 109/L 
Absolute Neutrophil count: below 1.5 x 109/L  
Platelets: below 50 x 109/L 
 
 
 
 
E 
17 
History of hypersensitivity or allergy to any constituent 
of the investigational compounds or related compounds 
of the respective cohort. 
A B C D 
E 
 
In addition, history of hypersensitivity or allergy to 
inhibitors of LTA4H or LTB4. 
 
B 
 
 
 
 
History of hypersensitivity to drugs of similar chemical 
classes to ianalumab (e.g., mAb of IgG1 class) or to any 
of the constituents of the study drug (
 
 
 
 
 
 
E 
18 
Patients receiving concomitant medication(s) that is/are 
known to inhibit OAT3 (see Table 6-3) and that cannot 
be discontinued or replaced by safe alternative 
medication at least 5 half-lives or 1 week (whichever is 
longer) prior to randomization and for the duration of the 
study. 
 
B 
 
 
 
19 
Intentionally blank - removed by Protocol Amendment 1. 
 
 
 
 
 
20 
 
 
 
B 
 
 
 
21 
Subjects with eGFR <60 mL/min/1.73 m2 (estimated by 
MDRD) at screening. 
 
B 
 
 
 
22 
Difficulty in urination and/or obstructive urine outflow 
symptoms at screening or randomization; history or 
presence of impaired renal function as indicated by 
clinically significant abnormal creatinine or BUN and/or 
urea values, or clinically significant abnormal urinary 
constituents (e.g. albuminuria) at screening. 
 
B 
 
 
 
23 
x Intentionally blank - removed by Protocol 
Amendment 4. 
 
 
 
 
 
24 
Evidence of clinically significant cardiovascular (such as 
but not limited to myocardial infarction, unstable 
 
 
 
D 
 
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ischemic heart disease, NYHA Class III/IV left 
ventricular failure, arrhythmia and uncontrolled 
hypertension within 12 months prior to Visit 1), disease 
that in the investigator's opinion, would compromise the 
safety of the subject, interfere with the interpretation of 
the study results or otherwise preclude participation or 
protocol adherence of the subject 
25 
Uncontrolled disease states, such as asthma, where flares 
are commonly treated with oral or parenteral 
corticosteroids 
 
 
 
D 
 
26 
Significant bleeding risk or coagulation disorders e.g.: 
• Use of anti-platelet medication [including dual 
anti-platelet therapy (e.g. acetylsalicylic acid + 
clopidogrel)] within two weeks prior to 
randomization.  
• Note: monotherapy with acetylsalicylic acid up to 
100 mg/day or clopidogrel is not exclusionary. 
• Use of anticoagulant medication [for example, 
warfarin or Novel Oral Anti-Coagulants 
(NOAC)] within 2 weeks prior to randomization 
• History of gastrointestinal bleeding, e.g. in 
association with use of nonsteroidal anti-
inflammatory drugs (NSAID), that was clinically 
relevant  
• International Normalized Ratio (INR) of more 
than 1.5 at screening 
• Major surgery within 8 weeks prior to 
randomization or planned major surgery for the 
duration of study treatment 
 
 
 
D 
 
27 
Use of any of the following within two weeks prior to 
randomization: 
• Strong CYP3A4 inhibitors 
• Moderate CYP3A4 inhibitors 
• Strong CYP3A4 inducers 
• Moderate CYP3A4 inducers 
 
 
 
D 
 
28 
History or current diagnosis of ECG abnormalities 
indicating significant risk of safety for subjects, such as: 
Concomitant clinically significant cardiac arrhythmias, 
e.g. sustained ventricular tachycardia or clinically 
 
 
 
D 
 

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significant second or third degree atrioventricular block 
without a pacemaker 
History of familial long QT syndrome or known family 
history of Torsades de Pointes.  
Cardiac arrythmias requiring anti-arrythmic treatment 
with Class Ia or Class III anti-arrhythmic drugs which 
prolong QT interval (See Table 6-3 for list).  
29 
5HVWLQJ47F)PVHFPDOHRUIHPDOHDW
screening or randomization  
 
 
 
D 
 
30 
Intentionally blank - removed by Protocol Amendment 9 
 
 
 
 
 
31 
History of major organ, hematopoietic stem cell or bone 
marrow transplant 
 
 
 
 
E 
6 
Treatment 
6.1 
Study treatment 
The investigational drugs, e.g. iscalimab, LYS006, MAS825, remibrutinib, ianalumab and their 
corresponding matching placebos, will be prepared by Novartis and supplied to the 
investigational site as double-blinded medication kits. Details on the requirements for storage 
and management of study treatment, and instructions to be followed for subject numbering, 
prescribing/dispensing and taking study treatment, are outlined in the Site Operations Manual. 
6.1.1 
Investigational and control drugs 
x For iscalimab, the dosage form of the supplied drug is a “ready to use” aqueous buffered 
sterile solution, also referred to as “CFZ533 150 mg/ml solution for injection (liquid in 
vial or “LIVI”)”. The 6 mL glass vial contains 1.2 mL of a “ready to use” 150 mg/mL 
solution of iscalimab and the excipients L-histidine, sucrose, and polysorbate 20, 
pH 6.0 ± 0.5. The placebo control, selected for this study, is a solution with a matching 
composition of inactive excipients.  
x For LYS006, the dosage form of the supplied drug is a capsule which contains 5 mg 
LYS006. The placebo control, selected for this study, has a matching composition of 
inactive excipients. Drug and matching placebo will be administered orally in accordance 
with the specified study procedures. 
x For MAS825, the dosage form of the supplied drug is a 
mg/mL concentrate for 
solution for injection. In addition to the active ingredient, the MAS825 drug product also 
contains
 and 
 
The placebo control, selected for this study, is a solution for injection without any active 
ingredients. 
x For remibrutinib, the dosage form of the supplied drug is a film-coated tablet with a 
strength of 
mg and 
 mg, respectively. The placebo control, selected for this study, 
has a matching composition of inactive excipients. As the tablet size depends on the 
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content, and
 mg and 
mg have different sizes, each patient in Cohort D will receive 
one large size tablet and one smaller size tablet to ensure a double blind design. Drug and 
matching placebos will be administered orally in accordance with the specified study 
procedures. 
x For ianalumab, the dosage form of the supplied drug is a ‘ready to use’ aqueous buffered 
sterile solution, also referred to as VAY736 
 mg/mL solution for injection (liquid in 
vial or ‘LIVI’). This formulation is stored in 6 mL glass vials and consists of ianalumab 
(VAY736)
 mg per 1 mL, 
 
The placebo control, selected for 
this study, is a solution for injection without any active ingredients. Drug and placebo will 
be administered s.c in accordance with the specified study procedures. 
Table 6-1 
Overview of study medication 
Study Drug 
Name/  
Unit dose 
Formulation 
Route of 
Administration 
Packaging 
Provided by 
Cohort A 
 
 
 
 
Iscalimab  
150 mg/mL* 
Solution for 
injection / infusion 
Subcutaneous 
6 ml, Type I glass 
vials, 
double blind 
Novartis 
Placebo  
0 mg/mL* 
Solution for 
injection / infusion 
Subcutaneous 
6 ml, Type I glass 
vials, 
double blind 
Novartis 
Cohort B 
 
 
 
 
LYS006 5 mg 
Hard 
Gelatin Capsule 
Oral 
Double blind 
subject kits 
Novartis 
Placebo 0 mg 
Hard Gelatin 
Capsule 
Oral 
Double blind 
subject kits 
Novartis 
Cohort C 
 
 
 
 
MAS825 
 mg/mL* 
Solution for 
injection / infusion 
Subcutaneous 
6 ml, Type I glass 
vials, 
double blind 
Novartis 
Placebo  
0 mg/mL* 
Solution for 
injection 
Subcutaneous 
6 ml, Type I glass 
vials, 
double blind 
Novartis 
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Study Drug 
Name/  
Unit dose 
Formulation 
Route of 
Administration 
Packaging 
Provided by 
Cohort D 
 
 
 
 
Remibrutinib 
 mg 
Tablet 
Oral 
Double 
blind/dummy 
subject kits 
Novartis 
Remibrutinib 
mg  
Tablet 
Oral 
Double 
blind/dummy 
subject kits 
Novartis 
Placebo to 
remibrutinib 
mg 
Tablet 
Oral 
Double 
blind/dummy 
subject kits 
Novartis 
Placebo to 
remibrutinib 
 mg 
Tablet 
Oral 
Double 
blind/dummy 
subject kits 
Novartis 
Cohort E 
 
 
 
 
Ianalumab  
 mg/1mL* 
Solution for 
injection / infusion 
Subcutaneous 
6 ml, Type I glass 
vials 
Double blind, 
subject kits 
Novartis 
Placebo  
0 mg/1mL* 
Solution for 
injection / infusion 
Subcutaneous 
6 ml, Type I glass 
vials 
Double blind, 
subject kits 
Novartis 
*The vials contain up to a 20% overfill to allow for a complete withdrawal of the labeled amount of 
Iscalimab/MAS825 or placebo. A pharmacist or authorized designee is required to prepare the study 
drug. Instructions for the storage and handling of study medication vials, and preparation of injection 
solution are described in the SOM (which is provided as a separate document). 
Clinical supplies are to be dispensed only in accordance with the specified study procedures 
6.1.2 
Additional study treatments 
For Cohorts A, B, C and D no additional treatment beyond investigational drugs and control 
drugs are included in this trial. 
For Cohort E: 
1 to 2 hours prior to the first administration of the study treatment, study subjects must receive 
pre-medication with 50 mg predniso(lo)ne or equivalent administered orally. The purpose of 
corticosteroid pre-medication is to mitigate potential cytokine release-related signs and 
symptoms associated with rapid depletion of circulating B cells. After the initial dose, 
corticosteroid pre-medication will not be required for subsequent injections of the study 
treatment. Predniso(lo)ne may be provided by the investigational site.  
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Table 6-2 
Additional study treatment 
Treatment Title 
Glucocorticoids (ATC code: H02AB)  
Treatment Description 
As pre-medication (refer to Section 6.1.2) 
Type 
Drug 
Dose Formulation 
Tablet/capsule according to locally approved label 
Unit Dose Strength(s) 
50 mg predniso(lo)ne or equivalent 
Dosage Level(s) 
According to locally approved label 
Route of Administration 
According to locally approved label 
Use 
Pre-medication 
Authorization status of the AxMP in 
EEA 
Yes 
Sourcing 
Provided centrally by or on behalf of the sponsor or 
locally by the study site 
Packaging and Labeling 
Locally available authorized product will be used 
At the investigator’s discretion, in addition to predniso(lo)ne, paracetamol (acetaminophen) at 
doses not exceeding 1000 mg p.o. and/or oral second generation antihistamines (e.g., loratadine) 
may be administered. 
After the first administration of the study treatment, all subjects must remain at the study 
site/doctor’s office for at least 4 hours to enable safety monitoring for potential injection-related 
reactions. Such monitoring will not be required at subsequent visits. 
6.1.3 
Treatment arms/group 
Subjects will be assigned to one of the following cohorts: 
x Cohort A: iscalimab, 600 mg (2 injections of 2 mL) s.c. weekly for 4 weeks then bi-
weekly, or its corresponding placebo (2 x 2 mL) s.c. weekly then bi-weekly  
or 
x Cohort B: LYS006, 
 mg 
 or its corresponding placebo b.i.d. p.o.  
or 
x Cohort C: MAS825, 
mg s.c. 
 
 for 4 weeks then 
, or its corresponding placebo (2 x 1.5 mL) s.c. 
and then 
 
or 
x Cohort D: remibrutinib, 
 mg 
. and matching placebo for 
 mg p.o., or 
mg 
 and matching placebo for 
mg p.o., or their matching placebo for 
 mg and 
matching placebo for 
 mg 
. p.o.  
x Cohort E: ianalumab, 
 
) s.c. 
 or its matching placebo 
 s.c. 
 
Within each cohort, subjects will be randomized to the investigational treatment arm or its 
corresponding placebo in a 2:1 ratio for Cohort A and B and a 3:1 ratio for Cohort C and E. As 
a second dose regimen will be used in Cohort D, the randomization will be 3:3:1 (remibrutinib 
mg 
: 
 mg 
: placebo). The maximum treatment duration will not exceed 
16 weeks. 
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Cohort allocation will be performed by the IRT system. If a subject is only eligible for one open 
cohort, they will be allocated 100% to that cohort. If the subject is eligible for more than one 
open cohort, the IRT will randomly allocate the subject to a cohort. The sponsor can set the 
cohort allocation ratio to favor any of the cohorts but this favoring to any one cohort will not 
exceed 80%. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including surgery, excision and incisions, laser therapy and photodynamic therapy, physical 
therapy and blood transfusions) administered or taken within 6 months prior to the start of the 
study and during the study, must be recorded on the CRF. Medication entries should be specific 
to trade name, the single dose and unit, the frequency and route of administration, the start and 
discontinuation date and the reason for therapy. 
Each concomitant therapy must be individually assessed against all exclusion criteria/prohibited 
medications and non-drug therapies. If in doubt, the investigator should contact the Novartis 
medical monitor before randomizing a subject or allowing a new therapy to be started. If the 
subject is already enrolled, contact Novartis to determine if the subject should continue 
participation in the study. 
For information regarding the potential impact of study treatment on vaccination success, please 
refer to Section 4.5.1.2.1 (Cohort A), Section 4.5.2.2.3 (Cohort B) Section 4.5.3.2.1 (Cohort C), 
Section 4.5.4.2.2 (Cohort D) and Section 4.5.5.2.5 (Cohort E). 
6.2.2 
Prohibited medications and non-drug therapies 
Use of the treatments displayed in the table below is NOT allowed after randomization, unless 
otherwise specified. If medically justified, the investigator can prescribe appropriate prohibited 
medication or non-drug therapy after the EOT visit.  A list of medications and non-drug 
therapies where caution needs to be exercised and certain action need to be taken are listed 
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Table 6-3 
Prohibited medications and non-drug therapies 
Medication or non-drug therapy 
Action taken (if taken during study treatment 
period) 
Use of other investigational drugs 
To be discussed with Sponsor on case by case 
basis 
Any systemic immunosuppressant or 
immunomodulator, such as but not limited to:  
• 
Corticosteroids 
• 
Cyclosporine A 
• 
Methotrexate 
• 
Cyclophosphamide 
• 
Biologics such as adalimumab, secukinumab, 
bimekizumab, bermekimab, etanercept, 
infliximab, ustekinumab, guselkumab, 
rituximab, belimumab, iscalimab (cohort E 
only), etc. 
• 
Systemic JAK inhibitors (such as tofacitinib 
or upadacitinib) or BTK inhibitors (such as 
ibrutinib and acalabrutinib)  
Discontinue study treatment 
Locally injected corticosteroids  
Acceptable, if sporadic use (other than in 
HS lesions). Discontinue treatment if more than 
3 injections are needed during study period 
Spironolactone or other anti-androgens (such as 
finasteride, cyproterone acetate, etc.)  
Can be used but must be on stable dose for the 
last 3 months prior to randomization and 
planning to continue for the duration of the 
study.  
To be discussed with Sponsor on case by case 
basis if new therapy is initiated or existing 
therapy is changed during the treatment period.  
Any long term (>2 weeks) treatment with 
systemic antibiotics 
Consider discontinuing study treatment if 
required antibiotic treatment is significantly 
longer than 2 weeks. 
To be discussed with Sponsor on case by case 
basis 
Other systemic treatments for HS, including but 
not limited to:  
• 
Retinoids (such as isotretinoin),  
• 
Dapsone 
• 
Metformin  
• 
Oral zinc  
To be discussed with Sponsor on case by case 
basis For metformin, a close monitoring of blood 
glucose is suggested   
Surgery for HS 
Acceptable, if localized, once during the 
treatment period.  
Discontinue study treatment if large excision 
(more than one lesion) and/or larger area 
treatment  
Other cases to be discussed with Sponsor on 
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Medication or non-drug therapy 
Action taken (if taken during study treatment 
period) 
For Cohort D:  
If major surgery is planned, which includes 
systemic or local anesthesia, please discontinue 
study drug treatment for 7 days prior to the 
intervention and until the risk for bleeding is 
considered over. 
Physical treatment for HS, including laser, 
intense light and photodynamic therapy 
Discontinue study treatment 
Only for Cohort A,C, D and E 
Live/ attenuated vaccines 
Discontinue study treatment 
Other 
approved 
(including 
HA 
conditional 
marketing authorization) vaccines e.g. killed, 
inactivated, subunit, nucleic acid (e.g. DNA, 
mRNA) 
may 
be 
permitted 
according 
to 
investigator’s discretion and per local guidance. 
Only for Cohort B 
Concomitant systemic medication inhibiting  
OAT3 such as: Probenecid, Gemfibrozil, 
Teriflunomide, Cimetidine and Diclofenac 
Discontinue study treatment 
Only for Cohort D 
Anti-platelet medication, except for 
monotherapy with acetylsalicylic acid up to 100 
mg per day or clopidogrel.  
Note: the use of dual anti-platelet therapy (e.g. 
acetylsalicylic acid + clopidogrel) is prohibited. 
Discontinue study treatment 
Only for Cohort D 
Anticoagulant medication such as warfarin or 
Novel Oral Anti-Coagulants (NOAC) 
Discontinue study treatment 
Only for Cohort D 
Strong or Moderate CYP3A4 inhibitors 
Examples (non-exhaustive)1: aprepitant, 
amprenavir, boceprevir, casopitant, ceritinib, 
clarithromycin, cimetidine, ciprofloxacin, 
cobicistat, conivaptan, crizotinib, darunavir, 
diltiazem, dronedarone, duvelisib, erythromycin, 
faldaprevir, fedratinib, fluconazole2, idelalisib, 
imatinib, indinavir, isavuconazole2, istradefylline, 
itraconazole2, josamycin, ketoconazole2, 
lefamulin, letermovir, Magnolia vine (Schisandra 
sphenanthera), mibefradil, mifepristone, 
nefazodone, nelfinavir, netupitant, nilotinib, 
posaconazole2, ravuconazole2, ribociclib, 
ritonavir, saquinavir, telaprevir, telithromycin, 
tofisopam, troleandomycin, tucatinib, verapamil 
voriconazole2, voxelotor 
Discontinue study treatment 

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Medication or non-drug therapy 
Action taken (if taken during study treatment 
period) 
Only for Cohort D 
Strong or Moderate CYP3A4 inducers  
Examples (non-exhaustive) 1: apalutamide, 
avasimibe, carbamazepine, enzalutamide, 
ivosidenib, lumacaftor, mitotane, phenobarbital, 
phenytoin, rifampicin, rifapentine, St. John’s wort 
(Hypericum perforatum), asunaprevir, 
beclabuvir, daclatasvir, bosentan, cenobamate, 
dabrafenib, elagolix, efavirenz, etravirine, 
lesinurad, lersivirine, lopinavir, nafcillin, 
primidone, rifabutin, talviraline, telotristat ethyl, 
thioridazine, 
Discontinue study treatment 
Only for Cohort D 
Class Ia or Class III anti-arrhythmic drugs which 
work by prolonging QT interval.   
Ia: qunidine, procainamide, disopyramide, 
hydroquinidine 
III: bretylium, amiodarone, ibutilide, sotalol, 
dofetilide, vernakalant, dronedarone 
Discontinue study treatment 
1The lists provided are not exhaustive. References: University of Washington Drug Interaction 
database (www.druginteractioninfo.org): Database search October, 2021.  
2Exclusions of concomitant antifungal treatment only apply to oral/parenteral administration. 
The following medications and non-drug therapies are NOT prohibited during the treatment 
period (if medically indicated):  
• Topical antibiotics (such as clindamycin) and antiseptics, standard wound care. 
• Oral antibiotics may be used, but for no longer than 2 weeks as rescue treatment in case of 
skin infection during the treatment period. 
• Incision OR excision of one HS lesion, if medically indicated to relieve the subject. 
• Pain medication, such as nonsteroidal anti-inflammatory drugs and opiates. 

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6.2.3 
Other medications having potential interactions with remibrutinib 
(Cohort D only) 
Note: use of the following medications may otherwise be excluded. Please consult Table 6-3. 
Table 6-4 
Other medications having potential interactions with remibrutinib 
Medication or non-drug therapy 
Action taken (if taken during study treatment 
period) 
Intestinal BCRP or P-gp substrates which have 
a narrow therapeutic index 
Examples (non-exhaustive)1: baricitinib, 
daunorubicin, doxorubicin, mitoxantrone, 
digoxin, docetaxel, eribulin, everolimus, 
pazopanib, sirolimus, sorafenib, tacrolimus, 
talazoparib, tolvaptan, venetoclax 
Use with caution. Co-administer in a staggered 
dosing approach (3hrs after remibrutinib). 
Substrates of systemic efflux and uptake 
transporters OAT3 or OATP1B1 
Examples (non-exhaustive):1 paclitaxel, 
pemetrexed, topotecan, carboplatin, cisplatin, 
oxyplatin, sorafenib 
Use with caution. Monitor patients and adjust the 
dose of the concomitant drug(s) as required.  
OCT1 substrates 
 
Examples (non-exhaustive)1: ranitidine, 
metformin 
Use with caution. Monitor patients and adjust the 
dose of the concomitant drug(s) as required. 
 
Metformin: subjects to monitor their blood 
glucose levels after co-administration with 
remibrutinib and discontinue remibrutinib 
treatment in case of uncontrolled glucose 
Drugs with known QT prolongation effect 
 
Examples (non-exhaustive)1: aclarubicin, 
anagrelide, arsenic trioxide, astemizole, 
azithromycin, bepridil, cesium chloride, 
chloroquine, chlorpromazine, chlorprothixene, 
cilostazol, cisapride, citalopram, cocaine,  
domperidone, donepezil, droperidol, 
escitalopram, flecainide, gatifloxacin, 
grepafloxacin, halofantrine, haloperidol,  
hydroxychloroquine, ibogaine, levofloxacin, 
levomepromazine (methotrimeprazine), 
levomethadyl acetate, levosulpiride, meglumine 
antimoniate, mesoridazine, methadone, 
moxifloxacin, nifekalant, ondansetron, 
oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, probucol, propofol,  
roxithromycin, sertindole, sevoflurane, 
sparfloxacin, sulpiride, sultopride, terfenadine, 
terlipressin, terodiline, vandetanib 
Use these drugs with caution keeping in mind 
these risk factors: 
1. QT effects of other co-prescribed drugs 
2. Electrolyte imbalances (such as 
hypokalemia, hypomagnesemia) 
3. Any impact on their clearance or 
metabolism (e.g. CYP450 inhibition) 
Subjects on these medications should be 
educated to report symptoms like palpitations, 
light-headedness, or dizziness and ECG should 
be conducted for such symptoms.  
1The lists provided are not exhaustive. References: University of Washington Drug Interaction 
database (www.druginteractioninfo.org): Database search October, 2021.  

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6.2.4 
Rescue medications and non-drug therapies 
If skin infections or an exacerbation of HS lesions occur, the investigator may choose to treat 
with permitted medications and non-drug therapies in order to avoid discontinuation of the 
subject from the study treatment. Examples include: 
• Conservative and topical wound care and dressings,  
• Oral treatment with antibiotics, which should target involved bacteria if known and be no 
longer than 2 weeks in duration 
No specific rescue medication is planned to be used for this trial. However, several standard of 
care (SOC) medications can be used to alleviate signs and symptoms of HS, such as antibiotics 
or 
biologics 
(Section 
6.2.4). 
According 
to 
the 
European 
Guidelines 
(Zouboulis et al 2015), locally recurring lesions can be treated by classical surgery or LASER 
techniques, whereas medical treatment either as monotherapy or in combination with radical 
surgery is more appropriate for widely spread lesions. Medical treatment in HS may include 
antibiotics (such as clindamycin plus rifampicine, tetracyclines), acitretin, biologics 
(adalimumab, infliximab), hormonal treatment, dapsone and other biologics such as IL-17A 
blockers.  
Please refer to Table 6-3 for prohibited treatments during the study. During the follow-up 
period, if medically indicated, SOC HS treatments, including surgery, may be used. 
See respective IB for recommended treatment of specific adverse events.  
6.2.5 
Restrictions for study subjects 
Highly strenuous physical exercise (e.g. weight training) should be avoided until after Study 
Completion evaluation, particularly prior to and during study visits. Subjects may otherwise 
continue with their usual level of physical activity. 
Whenever possible, excessive sweating such as sauna and/or visit to countries with very hot 
climate should be restricted in particular for subjects enrolled in Cohort B (LYS006). If not, the 
subjects should be reminded to drink sufficiently. Subjects enrolled in Cohort B should be 
reminded that the intake of the medication should always be with a glass of liquid and during 
or within 15 minutes after meals. Sufficient water intake should be ensured during the whole 
day.  
In addition, all subjects should not donate blood during the course of the study. 
6.2.5.1 
Dietary restrictions and smoking 
Standard of care recommendations should be applied with regards to smoking habits and weight 
loss. Smoking habits will be recorded throughout the study. 
Body weight will be recorded as indicated in the Assessment schedules. 
6.2.5.2 
Other restrictions 
Not applicable 

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6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see the ‘subject 
numbering’ section in the Site Operations Manual. 
6.3.2 
Treatment assignment, randomization 
Randomization may be performed only after a subject’s study eligibility is confirmed on Day 1.  
Subjects only eligible for one cohort will be assigned directly to the corresponding cohort; while 
subjects eligible for more than one cohort will be randomized to a cohort.  
In Cohort B, a stratification factor (baseline lesion count >=5 or 3-4) will be utilized, to cap the 
number of subjects with 3-4 lesions at randomization (pre-dose on Day 1) to a maximum 
number of 15 subjects, which is expected to minimize the impact of any potential differences 
in placebo response between cohorts due to different baseline lesion count. When the number 
of subjects allocated to one cohort reaches the planned 45, the enrollment for this cohort will 
be closed and subjects in screening afterwards will only be evaluated for eligibility into another 
cohort. 
Based on interim analysis data of the primary endpoint, placebo effect was observed to be 
similar between Cohort A (injectable) and Cohort B (oral compound). Due to this reason the 
stratification based on the number of baseline lesion count was not applied for Cohort D. 
After cohort allocation, subjects will be randomized to the investigational treatment or placebo 
arm with a ratio of 2:1 in Cohorts A and B, 3:1 in Cohort C and E and 3:3:1 in Cohort D. For 
any prematurely terminated cohort, all ongoing subjects in both treatment arms in this cohort 
will be discontinued and not be replaced. The enrollment into this cohort will also be stopped. 
The IRT system will be set up for the allocation of eligible subjects, and for distribution and 
assignment of the study medication (see Site Operations Manual for details). 
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. The randomization number is only used to identify which 
treatment the subjects have been randomized to receive. For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject to randomization numbers. These randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. 
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects. 

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6.4 
Treatment blinding 
Subjects and investigators will remain blinded to study treatment throughout the study, except 
where indicated below. However both subject and investigator will know to which cohort 
(Cohort A, B, C, D or E) the subject has been assigned. 
Within a cohort, the identity of the treatments will be concealed by the use of study drugs that 
are all identical in packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study. 
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.6.3). 
Sponsor staff or delegate 
The following unblinded sponsor roles are required for this study: 
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-5. 
For example, unblinded summaries and unblinded individual data can be shared with the team 
for interim analyses. 
Study programmers and other personnel involved in study data analysis (e.g. PK/PD modeler) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses. 
The clinical trial team is allowed to share unblinded results with other individuals (e.g. decision 
boards) as required for internal decision making on the study or the project at the time of interim 
analyses while the study is ongoing. 
Following final database lock all roles may be considered unblinded. 
Table 6-5 
Blinding and unblinding plan 
Role 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Interim 
Analysis 
Final analysis 
per cohort 
Subjects 
B 
UI 
B 
UI* 
Site staff 
B 
UI 
B 
UI* 
Field monitor 
B 
UI 
B 
UI* 
Unblinded 
Pharmacovigilance 
sponsor staff 
UI 
UI 
UI 
UI 
Statistician/statistical 
programmer/ data 
analysts (e.g. biomarker, 
PK) 
B 
UI 
UI 
UI 

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Role 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Interim 
Analysis 
Final analysis 
per cohort 
All other sponsor staff 
and external consultants 
not identified above (trial 
team, project team, 
management & decision 
boards (including DMC), 
support functions) 
B 
UI 
UI 
UI 
B Blinded ; UI Unblinded at individual level ; UI*For the respective closing cohort only 
6.5 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
Should this occur for any reason, the Investigator should discuss the option to restart treatment 
with the Sponsor. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Cohort A (iscalimab), Cohort C (MAS825) and Cohort E (ianalumab): 
Information about study medication administered to the subject should be captured in the source 
document at each visit and in the eCRF. 
Since the study treatment will be administered to the subject during the clinic visits by the 
investigator and/or designated study personnel only, it is the responsibility of the site staff to 
adequately capture all study treatment dispensed and used in the Drug Accountability Log. 
Cohort B (LYS006) and Cohort D (remibrutinib): 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable to take the study treatment as prescribed for any reason. 
Compliance will be assessed by the investigator and/or designated study personnel at each visit, 
using information provided by the subject. In addition, pill counts should be done at all drug 
dispensation and drug return visits. This information should be captured in the source document 
at each visit and in the eCRF. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. 

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6.6.2 
Recommended treatment of adverse events 
6.6.2.1 
HS related events 
6.6.2.1.1 Skin infections 
If skin infections or an exacerbation of HS lesions occur, the investigator may choose to treat 
with conservative topical wound care and dressings, or may also consider oral treatment with 
antibiotics, which should target the involved bacteria, if known, and be no longer than 2 weeks 
in duration, in order to avoid discontinuation of the subject from the study. Rescue treatments 
are detailed in Section 6.2.3. Medication used to treat AEs must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF. 
6.6.2.1.2 Inflammatory skin lesions 
If medically indicated, an HS lesion may be incised or excised once during the 16 week 
treatment period to relieve the subject. The surgery (incision or excision, etc.) needs to be 
recorded in the subject CRFs.  
For cohort D: if surgery is indicated, the Investigator should take into account a potential 
bleeding risk of remibrutinib, in particular in case of additional risk factors, such as inherent 
risk of bleeding, or concomitant therapy with anti-platelet or anti-coagulant therapies (see 
Section 6.6.2.5). 
6.6.2.2 
Cohort A (iscalimab) 
Parenteral administration of monoclonal antibodies can be associated with acute, severe 
reactions (occurring within the first few hours post dose) secondary to hypersensitivity, 
immunogenicity, or ADCC-mediated cell depletion. 
In this study, iscalimab will be administered as subcutaneous injections. No infusion or injection 
reactions have been noted in the Phase 1 and Phase 2 clinical program with iscalimab so far; 
however, investigators should be aware of the possibility and be prepared to treat such events. 
Subjects will be monitored after the first injection at the site for approximately 1 hour post dose 
or longer, if needed at the discretion of the Investigator, to ensure adequate safety monitoring. 
In case of any signs of an acute reaction, clinical treatment may be provided as determined by 
the treating physician on a case-by-case basis and depending on the severity, using symptomatic 
treatment, anti-histamines, NSAIDs, acetaminophen, intravenous fluids, corticosteroids, or 
adrenaline. 
For the management of allergic reaction, anaphylaxis and cytokine release, it is recommended 
to follow the guidelines by the National Cancer Institute Common Toxicity Criteria 
(NCI-CTCAE/v5, Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
Use of rescue medication must be recorded on the Concomitant medications / Significant 
non-drug therapies eCRF after start of study drug. 

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6.6.2.3 
Cohort B (LYS006) 
There are no known expected AEs associated with LYS006 that would warrant specific 
treatment. Necessary medication as well as surgical or physical treatment used to treat AEs 
must be recorded on the Concomitant medications/Significant non-drug therapies CRF. 
6.6.2.4 
Cohort C (MAS825) 
Parenteral administration of monoclonal antibodies can be associated with acute, severe 
reactions (occurring within the first few hours post dose) secondary to hypersensitivity, 
immunogenicity, or ADCC-mediated cell depletion. 
In this study, MAS825 will be administered as subcutaneous injections. Some injection site 
hemorrhage in 2 out of 6 subjects has been noted, but no dose related infusion site reactions 
have been noted after i.v. administration, thus injection site reactions may be observed. 
Subjects will be monitored after the first injection at the site for approximately 1 hour post dose 
or longer, if needed at the discretion of the Investigator, to ensure adequate safety monitoring. 
In case of any signs of an acute reaction, clinical treatment may be provided as determined by 
the treating physician on a case-by-case basis and depending on the severity, using symptomatic 
treatment, anti-histamines, NSAIDs, acetaminophen, intravenous fluids, corticosteroids, or 
adrenaline. 
For the management of hypersensitivity or allergic reaction, anaphylaxis and cytokine release, 
it is recommended to follow the guidelines by the National Cancer Institute Common Toxicity 
Criteria (NCI-CTCAE/v5, Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
Use of rescue medication must be recorded on the Concomitant medications / Significant 
non-drug therapies eCRF after start of study drug. 
6.6.2.5 
Cohort D (Remibrutinib) 
There are no dose related adverse event associated with remibrutinib that would need specific 
treatment. In case of a significant bleeding event, remibrutinib (LOU064) must be   discontinued 
immediately. Platelet transfusion may be considered in emergency. Although not yet 
established as a rescue therapy, platelet transfusion has been shown in a small pilot study to 
have beneficial effects on hemostasis when administered after elimination of ibrutinib (another 
BTK inhibitor) from blood (Levade et al 2014). Currently, there is no scientific evidence to 
support the use of fresh frozen plasma for the treatment of bleeding adverse events related to 
remibrutinib. 
In the same context, whenever surgery is needed, and a significant bleeding risk is identified, 
remibrutinib should be stopped. Please, refer to IB for additional details.  
As this risk is not considered major, some smaller surgical interventions such as incisions, it 
may not be necessary to stop the treatment in order to alleviate pain and or disease burden. The 
observation for the signs of bleeding is recommended post intervention. 

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6.6.2.6 
Cohort E (ianalumab) 
If warranted, mild-to-moderate local and systemic injection related reactions can be managed 
according to symptoms and their severity (e.g., cooling, topical creams/gels, patches, 
paracetamol, antihistamines etc.) at investigator discretion. It is recommended that sites of 
administration are alternated, avoiding any body areas where there has been a recent local 
reaction. If a study subject experiences a severe systemic or local injection related reaction, 
management should be guided by general principles of treating the respective condition, 
including intensive care admittance, if warranted.  
Subjects will be monitored after the first injection at the site for a minimum of 4 hours post dose 
or longer, if needed at the discretion of the Investigator, to ensure adequate safety monitoring. 
As with any biologic treatment, subjects should be monitored for signs and symptoms of 
anaphylaxis, including urticaria, rash, dyspnea, hypotension, chest pain, fever, and chills. 
Hypersensitivity reactions should be treated with antihistamines and glucocorticoids, and 
depending on severity, these subjects may also require 100% oxygen, volume expansion, 
catecholamines and transfer to an intensive care setting. Plasmapheresis to decrease the 
systemic concentration of ianalumab may be considered, depending on the subjects condition. 
The investigator should carefully assess for signs and symptoms which might indicate an 
infection, remind the participant of the risk of infections and ask them to promptly report any 
symptoms of infections. Subjects with bacterial skin infections should be monitored closely. 
When evaluating a subject with a suspected infection, it is recommended the most sensitive test 
should be used (e.g., culture, PCR for direct pathogen detection). If a subject is evaluated for 
unexpected neurological or psychiatric symptoms (e.g., cognitive deficit, behavioral changes, 
visual disturbances or any other neurologic signs and symptoms), infectious causes should be 
considered in consultation with infectious disease experts as appropriate, and brain MRI and/or 
CSF examinations including cellular, biochemical and microbiological analyses (e.g., herpes 
virus, John Cunningham virus) performed as needed. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.6.3 
Emergency breaking of assigned treatment code 
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject. 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Blinding codes may also be broken after a participant discontinues treatment due 
to disease progression if deemed essential to allow the investigator to select the participant’s 
next treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study subject who presents with an emergency condition. Emergency treatment code 
breaks are performed using the IRT. When the investigator contacts the system to break a 
treatment code for a subject, he/she must provide the requested subject identifying information 
and confirm the necessity to break the treatment code for the subject. The investigator will then 
receive details of the investigational drug treatment for the specified subject and a fax or email 

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confirming this information. The system will automatically inform the Novartis monitor for the 
site and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency.  
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. Please refer to the Study Operations Manual (SOM) for 
Cohort A (iscalimab) and Cohort C (MAS825) study drug preparation. No specific preparation 
for Cohort B (LYS006), Cohort D (remibrutinib) or Cohort E (ianalumab) study drug is 
necessary. 
A unique medication number is printed on the study medication label. Investigator staff will 
identify the study medication kits to dispense to the subject by contacting the IRT and obtaining 
the medication number(s). The study medication has a 2-part label (base plus tear-off label), 
immediately before dispensing the medication kit to the subject, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document. 
See the Site Operations Manual for further details. Sponsor qualified medical personnel will be 
readily available to advise on trial related medical questions or problems. 
If a subject will miss a visit and a home visit is not possible e.g. in the case of an epidemic or 
pandemic that limits or prevents on-site study visits (e.g. COVID-19 pandemic), delivery of 
IMP directly to a participant’s home is generally permitted for Cohort B and D only and on 
one occasion only, in the event that the Investigator has decided that: 
1. an on-site visit by the participant is not appropriate or possible, AND  
2. it is in the best interest of the participant’s health to continue administration of the study 
treatment even without performing an on-site visit. 
In the event that on site visits can be replaced by home visits, and key assessments are able to 
be performed, home delivery of IMP is also permitted, for either cohort. In such a case there 
are no restrictions on the permissible number of home deliveries.  See Section 8 for information 
regarding home visits. 
In either case implementation will need to be discussed with Novartis. The dispatch of IMP 
from the site to the participant’s home remains under the accountability of the Investigator. 
Each shipment/provisioning will be dispensed as per the IRT system.  

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Cohort A 
x Iscalimab and its matching placebo will be administered to the subject via two subcutaneous 
injections (2 x 2 mL) every one or two weeks during the subjects dosing visits at the study 
center. No dosing should occur on an outpatient basis except during an epidemic or pandemic 
(e.g. COVID-19 pandemic) that limits or prevents on-site study visits, visits by site staff to a 
patient’s home may be arranged in order to continue study treatment per protocol, as permitted 
by local regulations. 
Cohort B 
x LYS006 and its matching placebo will be taken orally by the subject twice daily, in the 
morning and in the evening.  
x It is recommended that LYS006 and its matching placebo are taken during or shortly after 
a meal with a glass of water. At dosing visits, a snack may substitute for a meal. 
x On treatment visit days, morning doses should be administered at the study site to enable 
pre-dose assessments. Every reasonable effort should be made to ensure that visits are 
held early enough in the day to enable on-site morning dose administrations. If a visit 
MUST be held after a subject’s morning dose administration, the following procedures 
should be followed: 
1. The morning dose should be taken by the subject with their morning meal prior to the 
visit. The subject should record the time of dose administration. 
2. No dose will be administered during the visit. At the visit, the subject will be asked to 
provide the time of morning dose administration, which will be entered into the CRF. 
3. No changes are to be made to the procedures performed at the visit. 
4. The evening dose should be administered outpatient at the normal time. 
x All other administrations will occur on an outpatient basis. 
x LYS006 or matching placebo doses should be taken approximately 12 hours apart, with 
morning and evening meals. Any missing dose should be taken as soon as possible unless 
the next dose is scheduled within the next 6 hours, in which case the missed dose should 
be skipped. 
Cohort C 
x MAS825 and its matching placebo will be administered to the subject via
 
subcutaneous injections 
 mL) every 
 during the subjects dosing 
visits at the study center. No dosing should occur on an outpatient basis except during an 
epidemic or pandemic (e.g. COVID-19 pandemic) that limits or prevents on-site study 
visits, visits by site staff to a patient’s home may be arranged in order to continue study 
treatment per protocol, as permitted by local regulations. 
Cohort D 
Every subject should take 
 film-coated tablets (
) in the 
 with an approximate 
 interval at 
approximately the same time 
 The study medication may be taken with or without a 
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meal but subjects should adhere to their choice throughout the study. If taken without food, the 
study medication should be taken with a glass of water (250 ml) at least 2 hours after the last 
meal and 1 hour before the next meal. Subjects should be instructed to swallow whole tablets 
and not to chew or break them. 
On treatment visit days, 
 doses should be administered at the study site to enable pre-
dose assessments. Every reasonable effort should be made to ensure that visits are held early 
enough in the day to enable on-site 
 dose administrations. If a visit MUST be held after 
a subject’s 
 dose administration, the following procedures should be followed: 
1. The 
 dose should be taken by the subject with their 
 meal prior to the 
visit. The subject should record the time of dose administration. 
2. No dose will be administered during the visit. At the visit, the subject will be asked to 
provide the time of 
 dose administration, which will be entered into the CRF. 
3. No changes are to be made to the procedures performed at the visit with the exception of 
the PK samples. In this situation, the PK sample should not be obtained if the patient has 
already taken their 
 dose before arriving at the study site. 
4. The 
dose should be administered outpatient at the normal time. 
On treatment visit days with PK assessments, doses should be administered at the study site 
after the subject has fasted for 12 hours. Fasting should continue until after the 90 minute PK 
sample has been obtained. 
Cohort E 
Ianalumab and matching placebo will be administered to the subject via  subcutaneous 
injections 
 mL) 
 at the study center. No dosing should occur on an 
outpatient basis except during an epidemic or pandemic (e.g. COVID-19 pandemic) that limits 
or prevents on-site study visits, visits by site staff to a patient’s home may be arranged in order 
to continue study treatment per protocol, as permitted by local regulations. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICH E6 (R2) GCP Guideline 2016 and regulatory requirements and is considered appropriate 
for this study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research. 
The procedures set out in the main consent form concerning the storage, maintenance of 
privacy, and release of the data or specimens for the main study will also be adhered to for any 
future research. Any changes to the proposed consent form suggested by the investigator must 
be agreed to by Novartis before submission to the IRB/IEC. 
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Information about common side effects already known about the investigational drugs can be 
found in the respective IB. This information will be included in the subject informed consent 
and should be discussed with the subject during the study as needed. Any new information 
regarding the safety profile of the investigational drugs that is identified between IB updates 
will be communicated as appropriate, for example, via an Investigator Notification or an 
Aggregate Safety Finding. New information might require an update to the informed consent 
and then must be re-discussed with the subject. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.  
Ensure subjects are informed of the contraception requirements outlined in Section 5.2 
(Exclusion criteria). 
The study includes an optional 
 component which requires a separate signature if the 
subject agrees to participate. It is required as part of this protocol that the investigator presents 
this option to the subject, as permitted by local governing regulations. The process for obtaining 
consent should be exactly the same as described above for the main informed consent. 
Declining to participate in these 
 will in no way affect the subject’s ability to 
participate in the main research study. 
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval. 
In case Home Nursing is implemented during an epidemic or pandemic, a separate Home 
Nursing consent document must be used in addition to the main ICF. 
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included in 
this study. 
8 
Visit schedule and assessments 
Subjects should be seen for all visits/assessments as outlined in the Assessment Schedules: 
x All Subjects (Table 8-1) 
x Cohort A (Table 8-2) 
x Cohort B (Table 8-3) 
x Cohort C (Table 8-4) 
x Cohort D (Table 8-5) 
x Cohort E (Table 8-6 and Table 8-7) 
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Missed or rescheduled visits should not lead to automatic discontinuation. The following should 
be considered: 
• If a subject cannot attend a visit as per the schedule, they should attend as soon as possible 
for the scheduled assessments that were due to be completed at the missed visit. 
• If a subject cannot attend the site until the next scheduled visit, consider contacting the 
subject by phone to determine if there have been any adverse events or changes to 
concomitant medications. See Section 8.5.1 for information on how to deal with PROs. 
If practically possible and allowed by local regulation, drug for Cohort B (LYS006) and 
Cohort D (remibrutinib) may shipped directly to a subject (see Section 6.7). If there is a 
possibility that the subject may miss more than one visit either consecutively or non-
consecutively, this should be discussed with the Sponsor. Every attempt must be made to 
have the subject on site for visits 102 (day 8), 199 (day 113) and 299 (day 197 – end of 
study). 
• If there are restrictions on travel in a county or region e.g. in the case of an epidemic or 
pandemic, that limits or prevents on-site study visits, alternative methods of providing 
continuing care may be implemented. Visits by site staff/home nursing service to the 
participant´s home depending on local regulations and capabilities, can replace on-site 
study visits, for the duration of the pandemic until it is safe for the participant to visit the 
site again. IMP should be provided to the subject by the site staff or shipped to the subject 
if permitted (see Section 6.7). Phone calls, virtual contacts (e.g. teleconsult) may also be 
considered where appropriate in addition to home visits by site staff/nursing service. 
Subjects who prematurely discontinue the study treatment for any reason should be scheduled 
for a visit as soon as possible. Where possible, they should return for the assessments as defined 
in their respective assessment table. If not possible, all of the assessments listed for the final 
visit should be performed. At this final visit, all dispensed investigational product should be 
reconciled, and the adverse event and concomitant medications recorded on the CRF. 
Specifications for and timing of each assessment are detailed in the protocol. The methods and 
recording of each assessment may be outlined in the Site Operations Manual. 

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Table 8-1 
Assessment Schedule: Screening 
Visit Name 
Screening 
Visit Number1 
1 
Days 
Up to Day -35 to Day -1 
Informed Consent Form(s) 
X 
consent 
X 
Inclusion / Exclusion criteria 
S 
Pregnancy test (blood test) 
X 
Demography 
X 
Physical Examination 
S 
Vital Signs 
X 
Body Height 
X 
Body Weight 
X 
Smoking habit 
X 
Medical history/current medical conditions 
X 
Hepatitis, CMV , Lupus anticoagulant and HIV Screen 
S 
Electrocardiogram (ECG) 
X 
Clinical Chemistry 
X 
Hematology 
X 
Urinalysis 
X 
Coagulation Panel (aPTT, PT, INR) 
X 
hsCRP, IgA, IgM, IgG, sBAFF 
X 
Quantiferon test 
X 
COVID-19 test3 
S 
Blood collection for B cell count (TBNK) 
X 
Concomitant medications 
X 
Adverse Events4 
X 
Serious Adverse Events 
X 
HS lesion count 
X 
 
X 
Anatomical HS regions involved 
X 
New or flared existing boils 
X 
Skin Pain NRS 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Removed in PA4 therefore N/A 
3 COVID test performed at a separate visit within 7 days of treatment if a COVID test is in line with 
health and governmental authority guidance 
4 Including HS lesion flares 
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Table 8-2 
Assessment Schedule, Cohort A: iscalimab 
Epoch 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Treatment 
Non-Treatment 
EOS 
Visit Numbers1 101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
199 
201 
202 
2992 
Days 
13 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±3 
57 
±3 
71 
±3 
85 
±3 
99 
±3 
113 
±3 
141 
±5 
169 
±5 
197 
±5 
Inclusion / Exclusion criteria 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test4 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
Physical Examination 
S 
  
  
  
S 
  
S 
  
  
  
S 
  
  
S 
Vital Signs 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
Body Weight 
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
X 
Smoking habit 
X 
 
 
  
X 
  
 
  
 
  
X 
 
  
X 
Hurley score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
X 
  
  
X 
  
X 
  
  
  
X 
  
  
X 
Clinical Chemistry 
X5 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
Hematology 
X 
X 
  
  
X 
  
X 
  
X 
  
X 
  
  
X 
Urinalysis 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
Coagulation Panel 
X 
 
 
  
 
  
X 
 
 
  
X 
  
  
  
hsCRP 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
Drug administration  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Concomitant medications 
X 
Adverse Events6 
X 
Serious Adverse Events 
X 
HS lesion count 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
Anatomical HS regions involved 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
New or flared existing boils 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
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Epoch 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Treatment 
Non-Treatment 
EOS 
Visit Numbers1 101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
199 
201 
202 
2992 
Days 
13 
8 
±2 
15 
±2 
22 
±2 
29 
±2 
43 
±3 
57 
±3 
71 
±3 
85 
±3 
99 
±3 
113 
±3 
141 
±5 
169 
±5 
197 
±5 
Skin Pain NRS 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
  
X 
PK blood collection8,9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity blood collection8,9 
X 
  
X 
  
  
  
X 
  
  
  
 
X 
X 
X 
PD blood collection - Soluble CD408 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
Biomarkers blood collection11 
X 
X 
  
  
X 
  
  
  
X 
  
X 
  
  
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Subjects who discontinue the study early should have the same assessments performed as for the end of study visit 299 (EOS). 
3 All Day 1 assessments should be performed/collected pre-dose (not required for Exploratory 
 
4 Blood test at EOS or last study visit; urine tests done at other indicated visits. 
5 Subject should be fasted for at least 6 hours prior to collection 
6 Including HS lesion flares 
7 Selected sites only 
8 Pre-dose sampling on dosing days - All subjects 
9 In case of suspected event due to immunogenicity, an additional (unscheduled) PK and an additional IG sample should be collected as close as possible to the event  
10 Optional 
 collection requires a separate consent and can be collected at or after D1 
11 Biomarkers blood collection including Serum and Plasma 
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Table 8-3 
Assessment Schedule, Cohort B: LYS006 
Epoch 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Treatment 
Non-
Treatment 
EOS 
Visit Numbers1 
101 
102 
103 
104 
105 
106 
199 
201 
2992 
Days 
13 
8 
±3 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
113 
±3 
141 
±5 
197 
±5 
Inclusion / Exclusion criteria 
S 
 
 
 
 
 
 
 
 
Pregnancy test4 
X  
X 
X 
X 
X 
X 
X 
X  
X 
Physical Examination 
S 
  
  
 S 
S  
S 
  
  
S 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
  
  
  
  
X 
  
  
X 
Smoking habit 
X 
 
 
 
X 
 
X 
 
X 
Hurley score 
X 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
X 
  
X 
X 
X 
  
  
X 
Hematology 
X 
X 
  
X 
X 
X 
X 
  
X 
Clinical Chemistry 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hsCRP 
X 
X 
X 
  
X 
X 
X 
  
X 
Drug administration  
X 
X 
X 
X 
X 
X 
X 
  
  
Concomitant medications 
X 
Adverse Events7 
X 
Serious Adverse Events 
X 
HS lesion count 
X 
  
X 
X 
X 
X 
X 
X 
X 
Anatomical HS regions involved 
X 
  
X 
X 
X 
X 
X 
X 
X 
New or flared existing boils 
X 
  
X 
X 
X 
X 
X 
X 
X 
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Epoch 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Treatment 
Non-
Treatment 
EOS 
Visit Numbers1 
101 
102 
103 
104 
105 
106 
199 
201 
2992 
Days 
13 
8 
±3 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
113 
±3 
141 
±5 
197 
±5 
Skin Pain NRS 
X 
  
X 
X 
X 
X 
X 
X 
X 
PK blood collection - pre-dose9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers urine collection11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Soluble biomarkers blood collection8,12 
X 
X 
  
X 
  
X 
  
X 
X 
Biomarkers blood collection15 
X 
X 
  
X 
  
X 
X 
  
X 
Randomization 
X 
 
 
 
 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Subjects who discontinue the study early should have the same assessments performed as for the end of study visit 299 (EOS). 
3 All Day 1 assessments should be performed/collected pre-dose (not required for Exploratory 
) 
4 Blood test at screening and EOS or last study visit; urine tests done at other indicated visits 
5 Subject should be fasted for at least 6 hours prior to collection 
6 Central lab: full micro panel on on-site samples and 
detection on at-home samples; Local lab may perform 
detection on on-site and/or at-home samples if 
deemed necessary and in consultation with the Sponsor. At-home 
 samples are only collected at the visits defined for the “
” assessment.  
7 Including HS lesion flares 
8 Selected sites only 
9 The sample volume will be immediately separated into 2 tubes: 1 tube for blood PK analysis and 1 tube for plasma preparation and plasma PK analysis. 
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10 For treatment visits, the
 sample will be collected at home the day prior to the visit, 2-4 h after study drug evening dose intake. The sample will be kept at room 
temperature. For post-treatment visits, the
 samples will be obtained on the day of the visit. 
11 Protein levels of potential kidney damage biomarkers.  
12 Analysis from ex-vivo stimulated and non-stimulated whole blood, including LTB4. 
13 Collection from region with inflammatory nodular skin lesions (peri-lesional). 
14 Optional 
 collection requires a separate consent and can be collected at or after D1  
15 Biomarkers blood collection including Serum and Plasma 
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Table 8-4 
Assessment Schedule, Cohort C: MAS825 
NOTE: Blood samples should be taken after the subject has been fasting for at least 6 hours. 
Epoch 
Treatment 
Post-Treatment Follow-Up 
Post study 
Visit Name 
Treatment 
Non-Treatment 
EOS 
Pregnancy test 
Visit Numbers1 
101 
102 
103 
104 
105 
199 
201 
202 
2992 
 
Days 
13 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
113 
±3 
141 
±5 
169 
±5 
197 
±5 
239 
±14 
Inclusion / Exclusion criteria 
S 
 
 
 
 
 
 
 
 
 
Pregnancy test4 
X 
X 
X 
X 
X 
X 
X 
  
X 
S 
Physical Examination 
S 
  
S 
S 
  
S 
  
  
S 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
Body Weight 
X 
  
  
X 
  
X 
  
  
X 
 
Smoking habit 
X 
 
X 
 
 
X 
 
  
X 
 
Hurley score 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
 
X 
X 
 
X 
 
  
X 
 
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
  
X 
 
hsCRP 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
Drug administration  
Concomitant medications 
X 
 
Adverse Events5 
X 
 
Serious Adverse Events 
X 
 
HS lesion count 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
Anatomical HS regions involved 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
New or flared existing boils 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
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Epoch 
Treatment 
Post-Treatment Follow-Up 
Post study 
Visit Name 
Treatment 
Non-Treatment 
EOS 
Pregnancy test 
Visit Numbers1 
101 
102 
103 
104 
105 
199 
201 
202 
2992 
 
Days 
13 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
113 
±3 
141 
±5 
169 
±5 
197 
±5 
239 
±14 
Skin Pain NRS 
X 
X 
X 
X 
X 
X 
X 
  
X 
 
PK blood collection7,8 
Immunogenicity blood collection7,8 
X 
X 
  
X 
  
 
X 
X 
X 
 
PD blood collection - target engagement BM7 
Biomarkers blood collection10 
 (optional) 
X 
  
  
  
  
X 
  
  
  
 
Biomarkers skin tape strips 
X 
  
X 
 
X 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Subjects who discontinue the study early should have the same assessments performed as for the end of study visit 299 (EOS). A urine pregnancy test should be 
performed 5 months after the last treatment of MAS825 
3 All Day 1 assessments should be performed/collected pre-dose (not required for Exploratory 
) 
4 Blood test at EOS or last study visit if subjects participation stops early; urine tests done at other indicated visits. Post study safety contact pregnancy test can be done 
by posting pregnancy test kit and a telephone follow up. 
5 Including HS lesion flares 
6 Selected sites only 
7 Pre-dose sampling on dosing days - All subjects 
8 In case of suspected event due to immunogenicity, an additional (unscheduled) PK and an additional IG sample should be collected as close as possible to the event  
9 Optional 
 collection requires a separate consent and can be collected at or after D1 
10 Biomarkers blood collection including Serum.  
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Table 8-5 
Assessment Schedule, Cohort D: Remibrutinib 
Epoch 
Treatment 
Post-Treatment 
Visit Name 
Treatment 
EOS 
Visit Numbers1 
101 
102 
103 
104 
105 
199 
Days 
13 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
113 
±3 
±5 
Inclusion / Exclusion criteria 
S 
 
 
 
 
 
 
Pregnancy test4 
X  
X 
X 
X 
X 
X 
X 
Physical Examination 
S 
  
 S 
S  
S 
  
S 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
  
  
  
 
X  
X 
Smoking habit 
X 
 
 
 
 
X 
X 
Hurley score 
X 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
 X 
X 
X 
X 
X  
X 
Hematology 
X 
 X 
X 
X 
X 
X 
X 
Clinical Chemistry 
X5 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
 
X 
 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
hsCRP, IgA 
X 
X 
  
X 
X 
X 
X 
Drug administration  
X 
X 
X 
X 
X 
X 
  
Concomitant medications 
                                                                             X 
Adverse Events6 
                                                                             X 
Serious Adverse Events 
                                                                             X 
HS lesion count 
X 
X 
X 
X 
X 
X 
X 
Anatomical HS regions involved 
X  
X 
X 
X 
X 
X 
X 
New or flared existing boils 
X  
X 
X 
X 
X 
X 
X 
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Epoch 
Treatment 
Post-Treatment 
Visit Name 
Treatment 
EOS 
Visit Numbers1 
101 
102 
103 
104 
105 
199 
Days 
13 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
113 
±3 
±5 
Skin Pain NRS 
 
X 
X 
X 
X 
X 
X 
X 
Biomarkers blood collection (BTK) 
X 
X  
X 
  
X 
X 
X 
Biomarkers blood collection (serum and plasma) 
X 
X 
X 
  
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Subjects who discontinue the study early should have the same assessments performed as for the end of study visit 299 (EOS). 
3 All Day 1 assessments should be performed/collected pre-dose (not required for Exploratory 
) 
4 Blood test at screening and EOS or last study visit; urine tests done at other indicated visits 
5 Subject should be fasted for at least 12 hours prior to collection. Samples to be taken pre-dose, then 45 and 90 minutes post dose. 
6 Including HS lesion flares 
7 Selected sites only 
8 Optional 
 collection requires a separate consent and can be collected at or after D1  
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Table 8-6 
Assessment Schedule, Cohort E: Ianalumab Treatment and Mandatory Follow-up periods 
Epoch 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Treatment 
Mandatory (non- treatment) 
Visit Numbers1 
101 
1022 
103 
104 
105 
106 
199 
201 
202 
203 
204 
Days 
1 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
8810 
±3 
113 
±3 
141 
±5 
169 
±5 
197 
±5 
225 
±5 
Inclusion / Exclusion criteria 
S 
 
 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Physical Examination 
S 
 
S 
S 
 
 
S 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
X 
 
 
X 
 
 
 
 
Smoking habit 
X 
 
 
 
 
 
X 
 
 
 
 
Hurley score 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Clinical Chemistry 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
X 
X 
 
X 
X 
 
 
X 
hsCRP, IgA, IgM, IgG,
 
X 
 
x 
 
X 
 
X 
 
 
X 
X 
Drug administration  
Corticosteroid induction 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
Adverse Events4 
X 
Serious Adverse Events9 
X 
HS lesion count 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Anatomical HS regions 
involved 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
New or flared existing boils 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
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Epoch 
Treatment 
Post-Treatment Follow-Up 
Visit Name 
Treatment 
Mandatory (non- treatment) 
Visit Numbers1 
101 
1022 
103 
104 
105 
106 
199 
201 
202 
203 
204 
Days 
1 
15 
±3 
29 
±3 
57 
±3 
85 
±3 
8810 
±3 
113 
±3 
141 
±5 
169 
±5 
197 
±5 
225 
±5 
Skin Pain NRS 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
PK blood collection6, 7 
Immunogenicity (ADA) 6, 7 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 All Day 1 assessments should be performed/collected pre-dose (not required for Exploratory 
) 
3 Blood test at screening and EOS or last study visit; urine tests done at other indicated visits 
4 Including HS lesion flares 
5 Selected sites only 
6 For both PK and IG Samples to be collected pre-dose unless otherwise stated. 
7 In case of hypersensitivity reaction, an unscheduled sample needs to be collected for PK and IG 
8 Optional 
 collection requires a separate consent and can be collected at or after D1 
9 All SAEs occurring until 30 days after the last study visit must be reported to Novartis safety immediately, without undue delay, but under no circumstances later than 
within 24 hours of obtaining knowledge of the events (Note: If more stringent, local regulations regarding reporting timelines prevail). See Section 10.1.3. 
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10 PK sample on Day 88 should be taken 3 days +/- 1 day after the dose on Day 85 

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Table 8-7 
Assessment Schedule, Cohort E: Ianalumab Conditional Follow-up period 
Epoch 
Post-Treatment Follow-Up 
Visit Name 
Conditional (B cell dependent) 
Visit Numbers1 
210 
220 
230 
240 
250 
260 
2992 (EOS) 
Days 
309 
±7 
393 
±7 
477 
±7 
561 
±7 
645 
±7 
729 
±7 
813 
±7 
Pregnancy test3 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
S 
S 
S 
S 
S 
S 
S 
Vital Signs 
X 
 
 
 
 
 
X 
Body Weight 
 
 
 
 
 
 
X 
Smoking habit 
 
 
 
 
 
 
X 
Electrocardiogram (ECG) 
 
 
 
 
 
 
X 
Hematology 
 
 
 
 
 
 
X 
Clinical Chemistry 
 
 
 
 
 
 
X 
Urinalysis 
 
 
 
 
 
 
X 
Concomitant medications 
X 
Adverse Events4 
X 
Serious Adverse Events6 
X 
HS lesion count 
X 
X 
X 
X 
X 
X 
X 
Anatomical HS regions 
involved 
X 
X 
X 
X 
X 
X 
X 
New or flared existing boils 
 
 
 
 
 
 
X 
Skin Pain NRS 
 
 
X 
X 
X 
X 
X 
X 
X 
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Epoch 
Post-Treatment Follow-Up 
Visit Name 
Conditional (B cell dependent) 
Visit Numbers1 
210 
220 
230 
240 
250 
260 
2992 (EOS) 
Days 
309 
±7 
393 
±7 
477 
±7 
561 
±7 
645 
±7 
729 
±7 
813 
±7 
Immunogenicity (ADA) 
 
X 
 
 
 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Subjects who discontinue the study early should have the same assessments performed as for the end of study visit 299 (EOS). 
3 Blood test at screening and EOS or last study visit; urine tests done at other indicated visits 
4 Including HS lesion flares 
5 Selected sites only 
6 All SAEs occurring until 30 days after the last study visit must be reported to Novartis safety immediately, without undue delay, but under no circumstances later than 
within 24 hours of obtaining knowledge of the events (Note: If more stringent, local regulations regarding reporting timelines prevail). See Section 10.1.3. 
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8.1 
Screening 
It is permissible to re-screen a subject if s/he fails the initial screening e.g. due to washout 
period- of concomitant medication; however, each case must be discussed and agreed with the 
Sponsor on a case-by-case basis. 
A new ICF will need to be signed if the investigator chooses to re-screen the subject after he/she 
has screen failed. All eligibility criteria must be re-checked, based on the most recent data 
available, and met prior to enrollment of the subject into the study. 
All required screening activities must be performed when the subject is re-screened for 
participation in the study. An individual subject may only be re-screened once for the study.  
An exception may be granted for those subjects who screen failed due to the temporary halts of 
enrolment due to epidemics or pandemics. If a subject fails screening but is re-screened, the 
subject will be assigned a new subject number. 
Once the number of subjects screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the subjects who screen failed 
will not be permitted to re-screen. 
For screening failures (initial or after re-screening), information on what data should be 
collected is outlined in the Site Operations Manual. 
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. See the SOM for the list of information to be collected for screening 
failures. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a serious adverse event during the screening phase 
(see Section 10.1.2, Section 10.1.3). If the subject fails to be randomized, the IRT must be 
notified within 2 days of the screen fail that the subject was not randomized. 
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data will be collected on all subjects. Data to 
be collected will include general subject demographics, relevant medical history and current 
medical conditions prior to study entry, diagnosis and other variables believed to influence HS 
severity or response to treatment, such as weight and smoking status, details of prior anti-HS 
treatment, and any other assessments that are done for the purpose of determining eligibility for 
inclusion in the study. 
All medications and significant non-drug therapies (including herbal medicines, physical 
therapy and blood transfusions) taken within 6 months prior to first dose of study drug must be 
recorded on the eCRF. Details are outlined in the Site Operations Manual. 
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature. 

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8.2.1 
Hurley score 
The Hurley score (Revuz 2009) will be collected to understand the characteristics of the patient 
population enrolled in this study. 
Table 8-8 
Hurley score 
Hurley’s classification 
Grade I 
Abscess formation, single or multiple without sinus tracts and cicatrization 
Grade II 
Recurrent abscesses with tract formation and cicatrization. Single or multiple, 
widely separated lesions 
Grade III 
Diffuse or near-diffuse involvement, or multiple interconnected tracts and 
abscesses across entire area 
8.3 
Efficacy 
Efficacy assessments are specified below, with the methods for assessment and recording, 
specified in the Study Operations Manual. Assessments will be performed and samples 
collected at the timepoint(s) defined in the Assessment schedule Section 8. As clinical efficacy 
measures are rater dependent, each evaluator should be appropriately trained and qualified for 
these assessments. 
Every effort should be made to ensure that the same evaluator should assess and count the 
lesions for a subject throughout the study. Clinical Outcome measures will assess the HS 
severity in different areas of the body and also the numbers and types of lesions in the different 
anatomical areas. Due to the inter- and intra- rater variability inherent to every subjective 
grading system, every effort should be made to keep the same evaluator per subject. As HS 
lesions are complex and difficult to distinguish, it is highly recommended that only experienced 
raters evaluate the subjects and that palpation on top of inspection is used to define the numbers 
of distinct lesions. 
The counting is to be done by lesion type and by counting area. For each assessment, the 
evaluator will be recorded in the source documentation and CRF and change of evaluator should 
be taken into account. 
8.3.1 
Hidradenitis suppurativa lesion count 
Individual lesions counts will be performed as outlined in the Assessment schedules. The lesion 
count will include all observed typical HS lesions at the given timepoint and in the typical 
anatomical areas and will be recorded in the CRFs. The HS lesions are: 
• Inflammatory nodules (N) that are typically tender, erythematous, possibly pyogenic 
granuloma lesions typically of more than 1 cm in diameter. 
• Abscesses (A) that are often inflammatory, fluctuant, with or without drainage, tender or 
painful. The fluctuant character must be confirmed by palpation.  
• Draining fistulae (F) are synonyms for sinus tracts or tunnels; draining fistulae have a 
visible communications to the skin surface, and visible drainage, such as purulent fluid or 
lymphatic liquid. 
• Non-draining fistulae (NF) are identified fistulae without visible drainage. 

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• Non-inflammatory nodules (NN) are dense lesions of more than 1 cm in diameter that are 
typically neither tender nor painful and lack peri-lesional or lesional redness. 
8.3.2 
Hidradenitis suppurativa clinical response (HiSCR) 
The HiSCR is defined by the status of three types of HS specific lesions, which are abscesses 
(fluctuant, with or without drainage, tender or painful), inflammatory nodules (tender, 
erythematous, pyogenic granuloma lesion), and draining fistulae (sinus tracts, with 
communications to the skin surface, draining purulent fluid, also called tunnel). The proposed 
definition of responders to treatment (HiSCR achievers) is at least a 50% reduction in abscesses 
and nodules (Ans), no increase in the number of abscesses, and no increase in the number of 
draining fistulas from baseline (Kimball et al 2014, Kimball et al 2018). 
A simplified HiSCR50 is proposed for this study as primary endpoint and is defined as 
follows:  
1. at least a 50% reduction in abscesses and inflammatory nodules (Ans), 
2. no increase in the number of draining fistulas from baseline 
This definition is used to reflect the difficulty in clinically distinguish abscesses reliably from 
inflammatory nodules. The score will be derived from the individual lesion counts of abscesses 
and nodules (and fistulae) at scheduled visits as indicated in Assessments schedule and as such 
will not be recorded in the CRF. 
Additionally to facilitate comparisons with other trials, the following HiSCRs will be derived: 
• The simplified HiSCR75 
a. at least a 75% reduction in abscesses and inflammatory nodules (Ans), 
b. no increase in the number of draining fistulas from baseline 
• The original HiSCR (or HiSCR50) 
c. at least a 50% reduction in abscesses and inflammatory nodules (Ans), 
d. no increase in the number of draining fistulas from baseline 
e. no increase in the number of abscesses 
• HiSCR75:  
f. at least a 75% reduction in abscesses and inflammatory nodules (Ans), 
g. no increase in the number of draining fistulas from baseline 
h. no increase in the number of abscesses 
• HiSCR90: 
i. at least a 90% reduction in abscesses and inflammatory nodules (Ans), 
j. no increase in the number of draining fistulas from baseline 
k. no increase in the number of abscesses 

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8.3.3 
Anatomical HS regions involved  
The following HS affected anatomical areas will be recorded in the CRF:  
x right and left axillary (armpit), 
x right and left gluteal (perianal), 
x right and left inguinal-femoral (groin), 
x right and left submammary (breast), 
x perineal, 
x others (any other HS-affected anatomical areas, to be identified by investigator) 
These anatomical areas are to be assessed for the location of HS lesions (abscesses, draining 
fistulas, non-draining fistulas, inflammatory nodules, and non-inflammatory nodules). 
8.3.4 
 
 
 
 
 
 
 
 
The scores will be recorded in the CRF. 
Figure 8-1 
 
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8.3.5 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
8.3.6 
 
 
 
 

 
8.3.7 
 
 
 
 
 
 
 
 
8.3.8 
Appropriateness of efficacy assessments 
As described in Section 4.1 several clinical efficacy parameters have been used in the past to 
assess HS, without a universally recognized endpoint. For this study, the simplified HiSCR 
(Hidradenitis Suppurativa Clinical Response) was selected as primary endpoint. 
In addition, since the main goal for a medical intervention is to reduce inflammation and 
consequent pain and HS severity and symptoms, the primary clinical endpoint focuses on 
inflammatory HS lesions (inflammatory nodules, abscesses and fistulae). 
Other clinical endpoints are used to examine
 
 
 Subjects will be asked to evaluate their own 
 while the skin pain NRS will assess the primary symptom of HS, skin 
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related pain. 
 
8.4 
Safety 
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedules (Section 8) detailing when each 
assessment is to be performed. 
During an epidemic or pandemic that limits or prevents on-site study visits regular phone or 
virtual calls will occur (as per the Assessment schedule or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until the participant can again visit 
the site. 
For details on AE collection and reporting, refer to Section 10.1. 
Table 8-9 
Safety Assessments 
Assessment 
Description 
Physical 
examination 
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. 
If indicated based on medical history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be performed. 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present 
prior to signing informed consent must be included in the Medical History part 
of the CRF. Significant findings made after first administration of 
investigational drug which meet the definition of an Adverse Event must be 
recorded on the Adverse Event section of the CRF. 
Vital sign 
Vital signs include body temperature (recorded in °C), BP and pulse 
measurements. After the subject has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured using an automated validated device, with an 
appropriately sized cuff. In case the cuff sizes available are not large enough 
for the subject's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured. 
Height information will be collected at screening only. 
The methods for each assessment and data recording details are specified in the SOM. 
8.4.1 
Laboratory evaluations 
Central laboratories will be used for the analysis of scheduled hematology, coagulation panel 
and clinical chemistry blood and urine specimens collected as part of screening and safety 
monitoring (as detailed in the Assessment schedule (Table 8-1, Table 8-2, Table 8-3, 
Table 8-4 ,Table 8-5, Table 8-6 and Table 8-7). With the exception of local 
 
results, only laboratory results from the central laboratory can be used to determine subject’s 
eligibility for the study. During the course of the study, unscheduled assessments can be 
performed if clinically indicated. 
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In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening, the assessment may be repeated once prior 
to randomization. If the repeat value remains outside of protocol specified ranges, the subject 
is excluded from the study. 
In the case where a laboratory range is not specified by the protocol but is outside the reference 
range for the laboratory at screening, a decision regarding whether the result is of clinical 
significance or not shall be made by the Investigator and shall be based, in part, upon the nature 
and degree of the observed abnormality. The assessment may be repeated once prior to 
randomization. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to continue in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted. 
Details on the collection, and shipment of samples and the reporting of results by the central 
laboratory are provided to the investigators in a separate Laboratory Manual. 
8.4.1.1 
Blood specimens 
Table 8-10 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils), 
MCH, MCHC, MCV, For Cohort E only: 
 
 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Creatinine, Creatine kinase, 
Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose, 
serum ketones (Cohort C only)  
eGFR will also be calculated for Screening and Cohort B and E subjects. 
If the total bilirubin concentration is increased above 1.5 times the upper 
limit of normal, direct and indirect reacting bilirubin should be differentiated 
Coagulation 
International normalized ratio [INR]), activated Partial thromboplastin time 
(aPTT), Prothrombin time (PT) 
Serology 
HbsAg, HbcAb, hepatitis C antibodies, HIV, CMV, Lupus anticoagulant, 
Quantiferon 
Additional tests 
 
Pregnancy Test 
Serum / Urine pregnancy test 
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8.4.1.2 
Urine specimens 
All Cohorts: 
During visits at the clinic, a midstream urine sample (approx. 30 ml) will be obtained, in order 
to avoid contamination with epithelial cells and sediments and allow proper assessments. 
Protein, creatinine, microalbumin, protein-creatinine ratio (PCR) and albumin-creatinine ratio (ACR) 
measurements will be performed at the Central Lab. 
A semi-quantitative “dipstick” evaluation for the following parameters will be performed at the 
central lab: Specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and 
blood. 
Screening, Cohort A, C, D and E: 
A microscopic panel will be performed by the central lab in the case of select dipstick results, 
as specified in the Central Laboratory Manual.  
 only: 
In 
 additional 
 samples will also be collected at home, the day prior to 
on-treatment visit days at the clinic, per the schedule outlined for 
” in the 
Assessment schedule (Table 8-3). These samples will be collected
 after study drug intake 
in the evening and will be sent to a central laboratory for 
 
 see Section 8.5.2.2) 
The following will be systematically performed for
 subjects, per the schedule outlined 
for “
 in the Assessment schedule (Table 8-3): 
x Central lab 
 panel, on on-site and at-home 
 samples 
If 
 are detected, additional analyses including exploratory biomarker analysis may be 
implemented (see Study Operations Manual/Laboratory Manual for details). 
All 
 samples should ideally be kept at body/room temperature until local and/or central 
analysis. 
8.4.2 
Electrocardiogram (ECG) 
A central reading of standard 12-lead ECGs will be implemented. Full details of all procedures 
relating to the ECG collection and reporting are contained in the core laboratory technical 
manual or in the Site Operations Manual. For cohort D, ECGs will be recorded in triplicates.  
PR interval, QRS duration, heart rate, RR, QT, QTcF (Fridericia QT) will be collected. 
Clinically significant abnormalities must be reported in the AE CRF. 
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8.4.3 
Pregnancy and assessments of fertility 
At screening and EOS (or last visit), a serum pregnancy test will be performed centrally. 
Throughout the study, local urine pregnancy test are sufficient. Additional urine pregnancy tests 
may be required, if a reason occurs such as subject reports delay in menstruation. 
A positive urine pregnancy test requires immediate interruption of study drug until serum 
β-hCG is performed and found to be negative. For Cohort C, all WoCBP are required to 
continue the highly effective contraception until 5 months after the last treatment with MAS825 
(refer to Chapter 7.9 of the MAS825 IB). Between Day 225 and 253 a urine pregnancy test will 
be conducted (pregnancy test can be provided to the subject at the EoS visit and the test 
completed at home) and results communicated to the site. See Section 10.1.4 for guidance on 
pregnancy reporting and follow-up. For Cohort E, all WoCBP are required to continue the 
highly effective contraception during treatment and until 6 months after the last treatment with 
ianalumab. Between Day 253 and 281 a urine pregnancy test will be conducted (pregnancy test 
can be provided to the subject at visit 204 and the test completed at home) and results 
communicated to the site. See Section 10.1.4 for guidance on pregnancy reporting and 
follow-up. 
8.4.4 
Other safety evaluations 
8.4.4.1 
Quantiferon test 
A QuantiFeron test will be performed and read at screening (or within 6 months prior to 
randomization) in order to evaluate the infection with tuberculosis (TB). The test may be 
repeated if test result is ambiguous. A positive QuantiFeron test at screening will exclude the 
subjects from participation in the study. 
T-SPOT or other types of ELISPOT assays based on interferon-gamma release may also be 
used for tuberculosis diagnosis as per local practice. 
Precautions against tuberculosis should be handled according to the best medical practice 
consistent with the local standards in each country with prior consultation with Novartis. 
Subjects requiring administration of antibiotics against latent tuberculosis should complete their 
treatment and should be considered cured prior to being re-considered for entry into this study 
(consultation with Novartis must occur before allowing the subject to enter the study). 
Results will be available as source data and will not be recorded within the eCRF. 
8.4.4.2 
CMV and SARS-CoV-2 (COVID-19) 
CMV 
Guidance to investigators: 
CMV infections will be recorded as Adverse Events and on the CMV-specific CRF. CMV 
infection is identified by assessments of laboratory and/or clinical sign/symptoms. 
Cytomegalovirus disease is defined according to published criteria (Ljungman et al 2017) as 
described below. 

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a. ACTIVE CYTOMEGALOVIRUS INFECTION is defined as a detectable 
cytomegalovirus viral load in the absence of signs or symptoms attributable to 
cytomegalovirus. Active cytomegalovirus infection can be the result of cytomegalovirus 
reactivation or primary cytomegalovirus infection. 
b. PROVEN DISEASE: For pneumonia, central nervous system (CNS) disease, 
gastrointestinal disease, hepatitis, nephritis, cystitis, myocarditis, pancreatitis, and disease 
in other organs, definite tissue-invasive disease requires the correct clinical syndrome 
combined with the detection of cytomegalovirus in tissue samples (or in bronchoalveolar 
lavage fluid for pneumonia) by virus isolation, immunohistochemical analysis, in situ 
hybridization, or conventional histologic features. Detection of cytomegalovirus by PCR 
alone is not sufficient. 
• Cytomegalovirus viral syndrome requires fever (oral temperature >38°C) for two or 
more days within a 4-day period, neutropenia or thrombocytopenia, and the detection 
of cytomegalovirus in the blood by culture or the detection of antigen, DNA, or RNA. 
Human herpes virus -6 (HHV-6) infection needs to be excluded. 
• For central nervous system (CNS) disease, detection of cytomegalovirus in 
cerebro-spinal fluid (CSF) samples by culture or PCR is sufficient. 
• For retinitis, typical cytomegalovirus lesions must be confirmed by an 
ophthalmolo-gist; detection of cytomegalovirus is not required. 
c. PROBABLE DISEASE requires the correct clinical syndrome but the detection of 
cytomegalovirus cannot be confirmed as outlined above. 
Detection during screening and treatment period (only Cohort A): 
1. At study screening, subjects with active viral infections (quantifiable CMV DNA by PCR 
or positive IgM in the absence of a positive IgG) will not be eligible for randomization in 
Cohort A. 
2. During treatment in Cohort A: In case of suspicion of CMV infection, CMV serology and 
PCR will be performed as soon as possible and the subject should not receive treatment 
until confirmed negative. Treatment will be discontinued if confirmed. 
SARS-CoV-2 (COVID-19) 
Local guidelines and regulations need to be strictly followed regarding the screening and 
monitoring of the new coronavirus called SARS-CoV-2 (COVID-19).  
8.5 
Additional assessments 
8.5.1 
Patient Reported Outcomes (PROs) 
During an epidemic or pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a participant’s home are not feasible the PRO data collection may be done by sending 
the subject the diaries/questionnaires by email or post or if possible, the PRO may be completed 
by telephone interview. 

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8.5.1.1 
Skin Pain Numerical Rating Scale (NRS) 
 
 
 
 
Results will be transcribed into the CRF by site personnel. 
8.5.1.2 
 
 
 
 
 
 
 
 
Results will be transcribed into the CRF by site personnel. 
8.5.1.3 
 
 
 
 
 
 
 
Results will be transcribed into the CRF by site personnel. 
8.5.1.4 
 
 
 
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Figure 8-2 
 
 
8.5.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.1.6 
New or flared existing boils 
The number of new boils or existing boils which flare up in the past four weeks, provides a 
good representation of the inflammatory load and disease-burden experienced by patients with 
HS that has a strong impact on the patients’ discomfort (Hessam et al 2018). Subjects will be 
asked at scheduled visits (as described in the Assessment schedules – see Section 8) to report 
this number for the past 4 weeks approximately. 
8.5.2 
Pharmacokinetics 
During an epidemic or pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a participant’s home are not feasible the collection of samples may be modified by 
Novartis and will be communicated to the Investigator. 
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8.5.2.1 
Cohort A (iscalimab) 
PK blood samples will be collected at the timepoints defined in the Assessment 
schedule (Table 8-2). Follow instructions outlined in the SOM and Central Laboratory Manual 
regarding sample collection, numbering, processing and shipment. 
PK samples will be obtained from all subjects (iscalimab-, and placebo-treated) to maintain 
blinding, but the analysis (free iscalimab concentration in plasma) will only be conducted for 
iscalimab-treated subjects. 
Iscalimab plasma concentrations will be determined using a validated target-based sandwich 
(/,6$PHWKRG7KHORZHUOLPLWRITXDQWLILFDWLRQ//24LVȝJP/LQXQGLOXWHGKXPDQ
plasma. The data and details of the analytical methods will be provided in the Bioanalytical 
Data Report. Concentrations below the LLOQ will be reported as ‘zero’ and missing data will 
be labeled as such in a Bioanalytical Data Report. 
8.5.2.2 
Cohort B (LYS006) 
PK samples will be collected at the timepoints defined in the Assessment schedule (Table 8-3). 
Follow instructions outlined in the Site Operations Manual and Central Laboratory Manual 
regarding sample collection, numbering, processing and shipment. 
The collection of enriched PK blood samples may be stopped once samples from approximately 
8 subjects randomized in the LYS006 cohort have been received by the unblinded PK 
bio-analyst. 
For pre-dose PK blood samples and enriched PK blood samples, the subjects should arrive with 
their study drug kits at the study center before the morning dose administration. Study drug 
administration will be done during, or shortly after meals as described in Section 6.7. 
 samples will be collected from all subjects, 
 
 during the treatment period (apart from Study Day 
 
The subjects will be asked to 
, take the evening dose 
as usual (Section 6.7), and 
. 
As with 
 samples collected at the study center, the 
 samples collected 
 should 
ideally be kept at room temperature until shipment to the central laboratory and its analysis. 
LYS006 concentrations will be determined in plasma 
 by a validated LC-MS/MS 
method. The anticipated lower limits of quantification (LLOQ) are 0.1 ng/mL for plasma and 
5.00 ng/mL for 
. In addition, LYS006 concentrations will be determined in blood samples 
in an exploratory way. 
Remaining plasma, 
 or blood from PK samples may be used for metabolite investigations 
/ exploratory work. 
Concentrations will be expressed in mass per volume units. Concentrations below the LLOQ 
will be reported as “zero” and missing data will be labeled as such in a Bioanalytical Data 
Report. Due to the b.i.d. dosage regimen, for enriched PK blood profiles, pre-dose concentration 
(Cmin,ss) will be used as 12 h post-dose concentration, for AUC calculation. 
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For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol. Pharmacokinetic parameters will be determined using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin 
(Version 6.4 or higher). The linear trapezoidal rule will be used for AUC calculation. 
8.5.2.3 
Cohort C (MAS825) 
PK blood samples will be collected at the timepoints defined in the Assessment 
schedule (Table 8-4). Follow instructions outlined in the SOM and Central Laboratory Manual 
regarding sample collection, numbering, processing and shipment. 
PK samples will be obtained from all subjects (MAS825 and placebo-treated) to maintain 
blinding, but the analysis (MAS825 concentration in serum) will only be conducted for 
MAS825-treated subjects. 
MAS825 serum concentrations will be determined using a validated target-based sandwich 
ELISA method. The lower limit of quantification (LLOQ) is 
 ng/mL in human serum. The 
data and details of the analytical methods will be provided in the Bioanalytical Data Report. 
Concentrations below the LLOQ will be reported as ‘zero’ and missing data will be labeled as 
such in a Bioanalytical Data Report. 
8.5.2.4 
Cohort D (remibrutinib) 
PK blood samples will be collected at the timepoints defined in the Assessment 
schedule (Table 8-5). Follow instructions outlined in the SOM and Central Laboratory Manual 
regarding sample collection, numbering, processing and shipment. 
PK samples will be obtained from all subjects (remibrutinib and placebo-treated) to maintain 
blinding, but the PK analysis and calculation of respective PK parameters will only be 
conducted for remibrutinib treated subjects. 
Remibrutinib blood concentrations will be determined using a validated LC-MS/MS method. 
The lower limit of quantification (LLOQ) is 
 ng/mL in human blood. The data and details of 
the analytical methods will be provided in the Bioanalytical Data Report. Concentrations below 
the LLOQ will be reported as ‘zero’ and missing data will be labeled as such in a Bioanalytical 
Data Report. 
8.5.2.5 
Cohort E (ianalumab) 
Pharmacokinetic (PK) samples will be collected at the visits defined in Table 8-6 and Table 8-7 
Schedule of Assessments. At each visit indicated, a blood sample will be taken prior to dosing 
by either direct venipuncture or an indwelling cannula inserted in a forearm vein. Follow 
instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment. See the potential use of residual samples for more information. 
PK samples will be obtained in all participants to maintain blinding but ianalumab 
concentrations will be evaluated only in the participants that receive ianalumab. 
A validated ELISA will be used to determine ianalumab serum concentrations in the clinical 
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The data and details of the analytical methods will be provided in the Bioanalytical Data Report 
(BDR). Concentrations below the LLOQ will be reported as ‘zero’ and missing data will be 
labeled as such in the BDR. 
8.5.3 
Biomarkers 
Biomarker samples will be collected at the time points defined in the Assessment schedules 
(Table 8-2, Table 8-3, Table 8-4, Table 8-5, Table 8-6 and Table 8-7). Instructions regarding 
sample collection, numbering, processing and shipment will be provided in the Site Operations 
Manual and Central Laboratory Manual. 
Detailed descriptions of the assays will be provided in the bioanalytical data reports. 
8.5.3.1 
Exploratory soluble biomarkers 
Plasma and serum samples will be collected for the analysis of pathway-related markers, 
including but not limited to 
 Cohort A, or 
in Cohort B and
 
in Cohort C and 
in Cohort D and 
 
in Cohort E. Whole blood samples will be collected and stored for the assessment of BTK 
occupancy (based on free BTK) if warranted by the outcome of clinical endpoints. 
These samples may also be used for the analysis of disease-related markers such as 
 
 
 which 
will be conducted depending on the overall study results, results obtained in other studies or 
new findings in the literature. 
If performed, data from profiling (hypothesis-free) platforms will be reported separately from 
the CSR (e.g. CSR addendum). 
8.5.3.2 
Skin tape strips samples (Cohort B and C) 
Skin tape strips samples will be collected using adhesive non-invasive tapes (D-Squame tape). 
Tape strips will be used to explore pathway activation and disease activity in skin. To do so, 
analyses will include soluble biomarkers related to state of inflammation, cell infiltrates and 
activation, such as but not limited to 
 
 
 
 or pathway and mechanistic markers such as 
and 
 (Cohort C). The 
final selection of markers will be based on assays availability at the time of analysis. 
8.5.3.3 
Soluble blood biomarkers (Cohort B only) 
The inflammatory leukotriene LTB4, as a product of LTA4H, directly related to the enzymatic 
activity inhibited by LYS006, will be measured in whole blood with and without stimulation 
by Calciumionophore S and N, mobilizing intracellular Ca2+-levels. Other related eicosanoid 
markers and other disease- or pathway-related markers will be also analyzed in the same 
samples. The sampling of whole blood with and without ex-vivo stimulation will be performed 
at selected, appropriately equipped and specifically trained centers only. 
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8.5.3.4 
Exploratory 
 biomarkers (Cohort B only) 
Protein levels of exploratory 
 may 
be assessed, in particular in case of suspicion of a 
, assessed by related clinical 
assessment (refer to Section 16.2) related to the presence of 
. The list of markers 
may be changed or expanded, if it is recognized that more relevant or additional biomarkers 
should be assessed during the conduct of the study. 
8.5.3.5 
Cellular Biomarkers Cohort E (Ianalumab) 
 
 
 
samples will be collected at each indicated visit in Table 8-1, Table 8-6 and Table 8-7 
Assessment Schedules. 
 are intended to be used for the exploratory 
assessment of the relationship of ianalumab exposure and PD 
 at visits after end of treatment may determine the end of the conditional 
follow up period and end of study. 
8.5.3.6 
 Cohort E  
Effects of ianalumab 
 
 may be assessed by 
. The assessment may include the assessment 
of the
 
8.5.3.7 
Exploratory 
 (optional) 
The study includes an optional 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
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 assessments may include analysis of specific panel of 
, such as 
 
 
For subjects in Cohort B (LYS006) soluble biomarkers in 
 will be measured to 
explore 
 
 and for Cohort C, specific markers may be considered such as 
 
The analysis of 
 samples will be triggered depending on the number of obtained 
samples. 
8.5.3.8 
Exploratory 
 (optional) 
The study includes an optional 
 
 
 
 
 
 
 
As technology changes over time, the most appropriate technology will be used at the time the 
exploratory 
 research is performed. This may include the study of the 
. 
8.5.3.9 
Use of residual biological samples 
Residual blood, skin tape strip or 
 samples may be used for another protocol 
specified endpoint. 
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis. This may include but is not limited to using residual 
samples for protein binding, metabolite profiling, biomarkers of transporters or metabolic 
enzyme activity or other bioanalytical purposes (e.g. cross check between different sites and/or 
stability assessment). Given the exploratory nature of the work, the analytical method used for 
those assessments will not be validated. As such, the results from this exploratory analysis will 
not be included in the clinical study report. 
8.5.4 
Immunogenicity (Cohort A, C and E only) 
Detection of anti-iscalimab (Cohort A) or anti-MAS825 (Cohort C) or anti-
ianalumab (Cohort E) antibodies 
The immunogenicity of multiple s.c. doses of iscalimab (Cohort A) as well as MAS825 
(Cohort C) and anti-ianalumab (Cohort E) will be assessed via the quasi-quantitative analysis 
of anti-iscalimab antibodies in plasma for Cohort A or anti-MAS825 and anti-ianalumab 
antibodies in serum for Cohort C and E. 
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Blood samples collected for immunogenicity testing will be obtained from all subjects and 
analysis will be performed for active- and placebo-treated subjects (to assess the rate of 
pre-existing anti-drug antibodies - ADAs) of the corresponding Cohorts A, C and E. The details 
of sample processing, handling, storage, shipment and analytical method will be described in a 
separate laboratory manual. 
In case of suspected allergic hypersensitivity, the participant should return to the site and a 
sample to assess immunogenicity and an unscheduled PK sample will be collected. In case of 
positive ADA, back-up of previous PK samples could be used to better characterize the onset 
of ADA response. 
The detailed methods and analysis will be described in the Bioanalytical Data Report. 
8.5.5 
Target engagement - Soluble CD40 in plasma (Cohort A only) 
In Cohort A (iscalimab), blood samples will be collected for soluble CD40 concentrations in 
plasma (before and during treatment and follow-up) in order to assess the rate, extent and 
duration of target engagement in WB. 
Blood samples will be obtained from all subjects to protect blinding, but analysis may be 
performed only for subjects receiving active treatment. 
Blood samples will be collected at the timepoints defined in the Assessment schedule 
(Table 8-2). 
The SOM provides operational details including subject numbering, blood log with sample 
numbers. Further details on sample collection, processing and shipment will be provided in the 
Central Lab Manual. The detailed methods and analysis will be described in the Bioanalytical 
Data Report. 
8.5.6 
Target engagement - IL-ȕ, IL-18, and IL-18BP in serum (Cohort C 
only)  
Serum samples for the exploratory measurement of total IL-ȕ,/-18 and IL-18BP will be 
collected from all subjects at all dose levels as described in the Assessment schedule 
(Table 8-4). The number of blood draws and total blood volume collected will not exceed those 
stated in the protocol. Total IL-ȕ,/-18 and IL-18BP will be measured using validated assays. 
The anticipated lower limit of quantification (LLOQ) is 
pg/mL for IL-ȕ ca. 
pg/mL for 
IL-18 (total IL18) and ca.  ng/mL for IL-18BP. A detailed description of the will be included 
in the bioanalytical data report. 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
Subjects may voluntarily discontinue the study for any reason at any time. The investigator 
must discontinue study treatment for a given subject, if, on balance, he/she believes that 
continuation would be detrimental to the subject’s well-being. 
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9.1.1 
Discontinuation of study treatment 
Study treatment must be discontinued under the following circumstances: 
• Subject withdraws consent 
• Pregnancy 
• Following emergency unblinding 
• The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation 
• Emergence of the following adverse events related to study drug:  
• Grade 3 or higher allergic or hypersensitivity reaction (CTCAE, version 5.0 or higher) 
• Acute infection, grade 3 or higher (CTCAE, version 5.0 or higher) in particular 
infections that resist short term antibiotic therapy  
• Neutropenia grade 3 or higher (CTCAE, version 5.0 or higher) 
• If a liver or renal event occurs, follow guidelines outlined in Appendix 1 and Appendix 2 
regarding discontinuation of study treatment. 
• Clinical worsening of hidradenitis suppurativa as per investigator judgement 
• Any other protocol deviation that results in a significant risk to the subject’s safety 
For Cohort A (iscalimab) (in addition to the above): 
• Severe injection-related reactions. Immediate interruption of the study drug administration 
is required where possible in such case. 
• Subject received a live vaccine 
• Any acute infections with clinical signs and symptoms such as fever, rash, etc. which at 
the discretion of the investigator jeopardizes the safety or impact negatively on 
risk/benefit of the subject.  
• Confirmed active CMV infection (presence of IgM or PCR) 
• Significant changes in standard coagulation parameters, including prothrombin time (PT) 
and activated partial prothrombin time (aPTT) suggesting an increased risk for 
hypercoagulability or any sign or symptom of a thromboembolic event. 
For Cohort C (MAS825) (in addition to the above): 
• Severe injection-related reactions. Immediate interruption of the study drug administration 
is required where possible in such case. 
• Subject received a live vaccine  
• Any acute infections with clinical signs and symptoms such as fever, rash, etc. which at 
the discretion of the investigator jeopardizes the safety or impact negatively on 
risk/benefit of the subject. 
For Cohort D (remibrutinib) (in addition to the above): 
• Clinically significant spontaneous bleeding events 
• New confirmed diagnosis of malignancy of any organ system (other than localized basal 
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• Platelets <75 x 109L 
• Any acute infections with clinical signs and symptoms such as fever, rash, etc. which at 
the discretion of the investigator jeopardizes the safety or impact negatively on 
risk/benefit of the subject. 
• Subject received a live virus vaccination during the study 
For Cohort E (ianalumab) (in addition to the above): 
• Subject received a live virus vaccinee. 
In addition, in case of emergence of the following adverse events discontinuation must be 
considered jointly by the Investigator and Novartis: 
• Persistent neutropenia ≤ 1,000 / µL that may preclude further administration of a B cell 
depleting agent 
Subjects who discontinue study treatment should NOT be considered withdrawn from the study 
UNLESS they withdraw their consent. Where possible, they should return for the assessments 
as defined in the applicable Assessment schedules (Table 8-2 for Cohort A, Table 8-3 for 
Cohort B, Table 8-4 for Cohort C, Table 8-5 for Cohort D and Table 8-6 and Table 8-7 for 
Cohort E). If they fail to return for these assessments for unknown reasons, every effort 
(e.g. telephone, e-mail, letter) should be made to contact them as specified in Section 9.1.3. 
Cohort E only: Patients who discontinue after having received at least one ianalumab 
administration and who do not complete the visits in the respective treatment period will be 
asked to remain in the study, and continue the assessments as per treatment visit schedule until 
EOT or, if they do not agree they will enter the mandatory Safety Follow up period. 
This contact should preferably be done according to the study visit schedule. If the subject 
cannot or is unwilling to attend any visit(s), the site staff should maintain regular telephone 
contact with the subject, or with a person pre-designated by the subject. This telephone contact 
should preferably be made according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code Section 6.6.3. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:  
Does not want to participate in the study anymore, and 
Does not allow further collection of personal data.  

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In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. 
A final evaluation at the time of the subject’s study withdrawal should be made as detailed in 
the Table 8-2, Table 8-3, Table 8-4, Table 8-5 or Table 8-6 and Table 8-7. 
Novartis will continue to keep, and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred. 
9.1.4 
Study stopping rules 
The study, or any of its individual respective cohorts, will be paused for further enrollment: 
pending full safety data review if one or more of the following criteria are met: 
• Any death or life-threatening event suspected to be related to study treatment 
• Two or more subjects per cohort presenting with the same SAE related to the 
investigational drug. 
• Two or more subjects per cohort presenting with active treatment-suspected severe 
systemic infection or opportunistic infection that requires treatment, e.g., sepsis, urosepsis, 
mycoses, pneumonia 
• Three or more subjects per cohort experience a similar AE which was assessed as severe 
in intensity, and are considered as potentially related to the study treatment as determined 
by the investigator and / or Novartis 
• The Sponsor considers that the number and/or severity of AEs, abnormal safety 
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• Other clinically significant events that in the opinion of the investigator or sponsor 
preclude to continue dosing (especially events that are suspected to be drug related, such 
as severe infections or other non-serious renal events) 
For Cohort A (iscalimab) only:  
• One subject presenting with suspected iscalimab-related thromboembolic event that is at 
least of moderate severity and is unrelated to pre-existing co-morbidities 
For Cohort B (LYS006) only: 
• One serious renal and/or pancreatitis adverse event causally related to LYS006 
For Cohort C (MAS825) only:  
• No additional criteria are necessary for MAS825 
For Cohort D (remibrutinib) only:  
• Two subjects presenting with clinically significant bleeding events, that are considered 
drug related 
For Cohort E (ianalumab) only:  
• More than one injection-related reaction of severe intensity within the first five (5) treated 
subjects or an incidence of >20% thereafter 
In these cases, ad hoc internal experts will carefully evaluate the safety data of the entire study. 
The experts will recommend whether the study can be continued, should be stopped or if other 
safety measures need to be taken. The findings and recommendations of the internal experts 
will be documented and will be made available to the respective Ethics Committees/Review 
Boards. 
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed, and according to local regulations. 
9.1.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. Should this be necessary, Subjects must 
be seen as soon as possible and treated as a prematurely discontinued subject. 
Reasons for early termination:  
• Unexpected, significant, or unacceptable safety risk  
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development  
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. Study completion is defined as when the last subject 

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completes his/her Study Completion visit, and any repeat assessments associated with this visit 
have been documented and followed-up appropriately by the investigator, or in the event of an 
early study termination decision, the date of that decision. 
For Cohort E (ianalumab) only: 
The end-of-study will be performed at Visit 299, and EOS may be initiated within 4 weeks 
following confirmation of B cell count recovery (defined as ≥80 % of baseline or ≥50 cells/μL). 
Subjects who discontinue during the follow up period will be asked to complete the end of study 
(EoS) visit. 
Subjects must be monitored for AEs and SAEs for the durations outlined in Section 10.1. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation. The investigator must provide follow-up medical care for all subjects who are 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care. 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them, unless required by local regulations. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 10.1 for an overview 
of the reporting requirements. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination finding, laboratory test 
finding, or other assessments. 
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information (as far as 
possible) (if the event is serious refer to Section 10.1.2): 

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• the Common Toxicity Criteria (CTC) AE grade: Adverse events will be assessed and 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 or higher 
• the causality: the investigator is obligated to assess the relationship between any treatment 
used in the study (study treatment, AxMP) and each occurrence of each AE. The 
investigator will use clinical judgment to determine the relationship. A reasonable 
possibility of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. Alternative 
causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study intervention administration, will be 
considered and investigated.  
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
If the event is due to lack of efficacy or progression of underlying illness (i.e. progression 
of the study indication) the assessment of causality will usually be ‘Not suspected.’ The 
rationale for this guidance is that the symptoms of a lack of efficacy or progression of 
underlying illness are not caused by the trial drug, they happen in spite of its administration 
and/or both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject 
• its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
• whether it constitutes an SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
• action taken regarding with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
• its outcome 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days or 5 half-lives following the 
last dose of study treatment, or end of study visit, whichever is longer.  
• Cohort A (iscalimab): EOS or 14 weeks (5 half-lives) following the last dose, whichever is 
longer 
• Cohort B (LYS006): EOS or 30 days following the last dose, whichever is longer 

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x Cohort C (MAS825): EOS or 
 weeks 
half-lives) following the last dose, whichever is 
longer. 
x Cohort D (remibrutinib): EOS or 30 days following the last dose, whichever is longer 
x Cohort E (ianalumab): EOS  
In the event of a subject discontinuing study participation early, at minimum, every effort 
(e.g. telephone, e-mail, letter) should be made to contact the subject at the end of the adverse 
event monitoring period listed above, to record any AEs or SAEs. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
x they induce clinical signs or symptoms, 
x they are considered clinically significant, 
x they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be nontypical in Subjects with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Section 16.1 and Section 16.2, respectively. 
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for subjects that fail screening. 
Reporting of AEs related to AxMP(s) 
All AEs related to any authorized auxiliary medicinal product used in this study must be 
reported to Novartis. 
In assessing causality, the investigators will use the points above. 
If a suspicion that medical occurrence could be related to study treatment (and/or interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply as well. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
x is fatal or life-threatening 
x results in persistent or significant disability/incapacity 
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• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention. 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH E2D Guideline 2003).  
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH E2D Guideline 2003). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law).  
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 
understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data. 
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and subject Safety (CMO & PS) as per 
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10.1.3 
SAE reporting 
10.1.3.1 Screen Failures 
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis. 
10.1.3.2 Randomized/ Treated Subjects 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until the end of the adverse event monitoring period listed in 
Section 10.1, must be reported to Novartis safety immediately, without undue delay, but under 
no circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. 
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO& PS) Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to Novartis 
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Reporting of SAEs related to AxMP(s) 
All SAEs related to any auxiliary medicinal product (whether authorized or not) used in this 
study must be reported to Novartis within 24 hours of the site becoming aware of it. 
In assessing causality, the investigators will use the points in Section 10.1.1. 
If a suspicion that the medical occurrence could be related to study treatment (or and interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply as well. 
10.1.4 
Pregnancy reporting 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother. Newborns will be followed up (monitored) up to 12 months post-birth. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported to 
Chief Medical Office and Patient Safety (CMO& PS) department if the treatment error is 
associated with an SAE. 
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety (CMO& 

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PS). As such, instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 10-1 summarizes the reporting requirements. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness. 
For more information on AE and SAE definition and reporting requirements, please see 
Section 10. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Section 16.1 for complete definitions of liver laboratory triggers and liver events. 
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2 Repeat liver chemistry tests (ALT, AST, TBL, 
PT/INR, ALP and G-GT) to confirm elevation. 

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• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results reported on the unplanned local laboratory CRF 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
Refer to the Site Operations Manual for additional details. 
10.2.2 
Renal safety monitoring 
Every renal laboratory trigger or renal event as defined in Section 16.2 should be followed up 
by the investigator or designated personnel at the trial site as summarized in Section 16.2. 
Refer to the Site Operations Manual for additional details. 
10.2.3 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of the clinical trial, safety data, and critical efficacy variables and make recommendations to 
the sponsor whether to continue, modify or terminate the trial. 
Specific details regarding composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 

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11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
After database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site. Certain data may be captured via other source documentation (such as 
safety laboratory data report, imaging) and then transcribed, uploaded or transferred to the CRO 
working on behalf of Novartis or to Novartis. This, and any additional data treated in this 
manner, will be source data verified by the study monitor per the monitoring plan and the 
location of source data (i.e., Source, paper or a local electronic system) will be documented 
prior to study start in the Data Handling Plan. When using an electronic source record as the 
original point of data capture, there is no additional data entry step for the site for data collected 
directly into the application; rather, the electronic source record directly populates the study 
database. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis. 
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely. 
The investigator must certify that the data entered into the eCRF are complete and accurate. 
After database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site. 
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedules (Table 8-1, Table 8-2, Table 8-3, Table 8-4, Table 8-5, Table 8-6 and 
Table 8-7) and can be recorded directly on the CRFs. All other data captured for this study will 
have an external originating source (either written or electronic) with the CRF not being 
considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
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11.2 
Database management and quality control 
Novartis staff and the CRO working on behalf of Novartis review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query Form 
will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back 
to Novartis staff or to the CRO working on behalf of Novartis who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management. 
11.2.1 
 
 
 
 
 
 
 
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11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of subject records, 
the accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis or delegated CRO organization. Additionally, a 
central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs. The investigator must also keep the original informed 
consent form signed by the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
The analysis will be conducted on all subject data at the time the trial ends. Unless otherwise 
specified, placebo data from each cohort will be pooled. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
The main rationale for pooling the placebo data is to reduce the number of subjects exposed to 
placebo. The difference in the inclusion criterion on the baseline lesion count, minimum 
3 inflammatory lesions for the oral compound versus minimum 5, for the injectable, is expected 
to have little impact on the key efficacy endpoints in HS patients (Kimball et al 2012 and 
Kimball et al 2016). In Cohort E, prednisone and prednisolone are classified as intermediate 
half-life corticosteroids with half-lives between 12-36 hours. Administration of a single oral 
dose 50 mg prednisolone at baseline is unlikely to affect the primary-endpoint simplified 
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The final results of each cohort will be described in the relevant Investigators Brochure when 
they become available. For completeness, primary CSR will be submitted to all participating 
Health Authorities. Any relevant safety signal and/or safety findings interfering with the 
benefit/risk profile of the drug in this or other indications will also be reported.  In case 
additional sub-protocols/arms (cohorts) are included, the protocol will be modified to ensure 
data transparency in the trial of these additional arms. 
The two remibrutinib doses will be considered as two different treatment groups and the outputs 
will therefore be reported by the remibrutinib dose. The possibility of pooling the two 
remibrutinib doses will be investigated.   
Baseline values, if not specified otherwise, refer to the values taken on Day 1, prior to the first 
dosing. 
12.1 
Analysis sets 
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
The safety analysis set will include all subjects that received any study drug. 
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data. 
The PD analysis set will include all subjects who received any study drug and had no protocol 
deviations with relevant impact on PD data. 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the safety analysis set. Categorical data will 
be presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term by treatment group. 
12.3 
Treatments 
The safety analysis set will be used for the analyses described in this section. Categorical data 
will be summarized as frequencies and percentages. For continuous data, mean, standard 
deviation, median, minimum, and maximum will be presented. 
The duration of exposure in weeks to placebo, Iscalimab, LYS006, MAS825, remibrutinib and 
ianalumab will be summarized by means of descriptive statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by treatment group. 

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Use of pain medications as rescue medication will be explored across cohorts and treatment 
groups to assess the balances of the usage between treatment groups and cohorts where 
necessary. 
12.4 
Analysis of the primary endpoint(s) 
The primary analysis to compare either iscalimab, LYS006, MAS825, each remibrutinib 
regimen or ianalumab against placebo will use the pooled placebo data from all cohorts. The 
primary objective of this Proof of concept platform study is to compare each compound to the 
pooled placebo and not to compare compounds with each other. 
PD analysis set will be used for the analyses.  
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint of this study is the proportion of subjects who have achieved a clinical 
response, as defined by simplified HiSCR, after 16 weeks of treatment. The simplified HiSCR 
is defined as 
• a reduction of at least 50% in abscess and inflammatory nodule counts and 
• no increase in draining fistula count related to baseline. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary variable will be modeled with the binomial distribution. A neutral non-informative 
Beta (1/3, 1/3) distribution will be used as the prior for the response rate for all treatment groups. 
Based on the priors and the observed primary outcome, posterior distributions for the response 
rate for the investigational treatment and pooled placebo groups will be computed respectively. 
The posterior distribution of the difference of response rates, investigational treatment 
(iscalimab/LYS006/MAS825/each remibrutinib regimen/ianalumab) minus placebo, will be 
obtained by simulations, i.e. sampling from the posterior distributions of the corresponding 
treatment groups. The posterior probabilities for the difference of response rates will be assessed 
according to the following dual criteria as a guide to decision making. Each investigational 
treatment will be assessed separately in comparison to the pooled placebo group. 
The efficacy criteria are predefined as: 
1. Better than placebo with high confidence (at least 90% probability that the simplified 
HiSCR rate at week 16 for an investigational treatment is better than placebo, i.e., Prob 
(delta >= 0) > 90% ), AND 
2. Simplified HiSCR rate 15% above placebo (at least 50% probability that the simplified 
HiSCR rate at week 16 for an investigational treatment is 15 percentage points above that 
of placebo, i.e., Prob (delta >= 0.15) > 50%.), 
where delta is the difference in percentage points for investigational treatment versus placebo 
for simplified HiSCR rate. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Intercurrent events (IE) that may affect the assessment of the simplified HiSCR are 
discontinuations from study treatment before week 16.  For the purpose of primary endpoint 

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analysis, a composite strategy will be used to take account of such discontinuations whereby 
subjects who discontinue study treatment before 16 weeks will be considered as follows:  
• Subjects who do not complete the 16 week treatment due to lack of efficacy or adverse 
events due to worsening of disease, will be considered as non-responders and treated like 
completers.  
• For subjects who discontinue for other reasons prior to 16 weeks of treatment, the 
following method will be used:  
• If among these subjects, those that discontinue before 12 weeks of treatment 
constitute <= 10% of the PD analysis set population, then such patients will be 
considered as non-responders and those who have had at least 12 weeks of treatment 
will have their simplified HiSCR taken to be their response after 16 weeks of 
treatment. The primary analysis will be pursued as described in Section 12.4.2 with 
the imputed responses as described above.  
• However, if such non-completers (< 12 weeks of treatment) constitute > 10% of the 
PD analysis set, multiple imputation methods will be used to impute missing abscess, 
inflammatory nodule and draining fistula counts while accounting for baseline 
covariates such as baseline disease characteristics and/or other demographic factors 
believed to affect HS. More details on the imputation model will be specified in the 
Statistical Analysis Plan. 
The primary response, simplified HiSCR, will be derived for each of the imputed 
dataset, which will be merged with data on subjects with IE for whom non-response is 
imputed in a composite strategy. Primary analysis will then be run on each imputed 
dataset, resulting in posterior distribution of the estimand and corresponding averages. 
Comparison of the primary response estimates based on data with and without MI will 
allow assessing the level of effect of treatment withdrawals. 
• Any encounters of surgical incisions and excisions affecting the lesion counts will be 
handled in the following ways: 
• Excised lesions will be considered to be permanently present and included in the 
overall lesion counts and lesion counts by type at all the time points following the 
excision. 
• The lesions that experienced any incisions will be analyzed as the type observed at 
any given time or as not present (if not present) at any given time. 
12.4.4 
Sensitivity and Supportive analyses 
12.4.4.1 Sensitivity analyses 
The planned Bayesian analysis uses a non-informative prior for the response rate in each 
treatment group. Should additional data on placebo response rates for other trials become 
available, sensitivity analyses may be performed using alternative prior response rate 
distributions derived from these trials. 
An additional sensitivity analysis will be conducted for the primary endpoint where the lesions 
that experienced any incisions will be included with Last Observation Carried Forward (LOCF), 

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with the type of lesion prior to the incision being used for the type of lesion at any time point 
after the incision, in order to assess the impact of surgical incisions on efficacy. 
12.4.4.2 Supportive analyses 
Supportive Bayesian analysis will be performed where the placebo subjects will not be pooled. 
Each investigational treatment will be compared to its respective placebo. 
Supportive Bayesian analysis will be performed on placebo subjects to assess differences in the 
response rate across multiple cohorts. This is to address the assumption of nearly equal response 
among placebo arms of different cohorts, which may vary due to the route of administration 
(oral vs. iv) or differences in their eligibility criteria. 
Supportive logistic regression analysis will be performed to investigate cohort-specific 
influence of baseline disease characteristics and other demographic factors believed to affect 
HS (such as weight and smoking status) on the treatment effect. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Not applicable. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of LYS006 and remibrutinib or 3 months after the 
last actual treatment of iscalimab, MAS825 and ianalumab. 
12.5.2.1 Adverse events 
All information obtained on adverse events will be displayed by treatment group and subject. 
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication) will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
Separate summaries may be provided for study medication related adverse events, death, 
serious adverse events, other significant adverse events leading to discontinuation if the number 
of events warrants such further detail. 

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The number (and proportion) of subjects with adverse events of infections (all cohorts) and 
renal events (for LYS006) will be summarized by treatment. 
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
12.5.2.2 Vital signs 
All vital signs data will be displayed graphically showing data over time. 
12.5.2.3 12-lead ECG 
All ECG data will be displayed graphically showing data over time. 
12.5.2.4 Clinical laboratory evaluations 
All laboratory data may be listed by treatment group, subject, and time and if normal ranges are 
available abnormalities will be flagged. Graphical displays of data over time will be provided. 
Shift tables using the low/normal/high classification will be used to compare pre-treatment to 
the worst on-treatment value. 
12.5.2.5 Immunogenicity 
Please refer to Section 12.6.4. 
12.6 
Analysis of exploratory endpoints 
12.6.1 
Exploratory efficacy endpoints 
The PD analysis set will be used for analysis of exploratory efficacy objectives. The relevant 
data mainly include: 
x Proportion of subjects meeting the simplified HiSCR over time (as defined in 
Section 8.3.2) 
x Proportion of subjects meeting the simplified HiSCR75, original HiSCR50, HiSCR75, and 
HiSCR90 over time (as defined in Section 8.3.2) if applicable 
x Proportion of 
 responders over time, 
 responder defined as an 
 
score of clear, minimal, or mild with at least a 2-grade improvement relative to baseline 
x 
 score over time 
x Different types of HS inflammatory lesion counts over time 
x New or flared existing boils 
x 
 score over time 
x 
 score over time 
x NRS pain score over time 
x 
 score over time 
x 
 over time 
x 
 over time 
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x Proportion of subjects who experience at least one flare over 16 weeks of treatment. Flare 
is defined as an at least 25% increase in total abscess and inflammatory nodule counts 
(AN counts) with a minimum increase of 2 AN relative to baseline. 
x Proportion of subjects achieving NRS30 
 
156LVGHILQHGDVDWOHDVWUHGXFWLRQDQGDWOHDVWXQLW
reduction from baseline in Skin Pain NRS scale 
x Proportion of patients achieving 50%, 75%, 90% and 100% reduction from baseline in 
sum of abscesses and nodules 
x Change in anatomical HS regions involved over time 
x 
 (for Cohorts D and E only) 
x 
(for Cohorts D and E only) 
In general the variables will be presented graphically and/or summarized via descriptive 
statistics. For continuous/binary endpoints over time, mixed models for repeated measures 
(MMRM) may be used to estimate the values for each treatment at each time point and perform 
group comparisons over 16 weeks of treatment. Model-based estimates may be used for the 
visualizations. Data collected after a subject has discontinued treatment will not be used in these 
summaries and analyses. 
12.6.2 
Exploratory safety 
For subjects in Cohort B, the proportion of subjects with 
 and other exploratory 
markers in 
 (such as, but not limited to, 
) will be 
summarised by treatment group. Safety analysis set will be used for this analysis. 
12.6.3 
Pharmacokinetics 
PK analysis set will be used for analyses in this section. 
12.6.3.1 Cohort A (iscalimab) 
Iscalimab plasma concentrations will be listed by subject, and visit/sampling time point and 
displayed graphically. Descriptive summary statistics will be provided by visit/sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics, and will be treated as missing in geometric mean calculation. 
Pharmacokinetic parameters for iscalimab (Ctrough's; observed analyte concentration at the end 
of a dosing interval) will be listed by subject. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. 
12.6.3.2 Cohort B (LYS006) 
LYS006 concentrations in plasma, blood and 
 over time will be listed, summarized and 
displayed graphically. Where steady state concentrations profiles are recorded, the PK 
parameters (max,ss, Cmax,ss. AUCtau,ss) derived from this will be summarized. 
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12.6.3.3 Cohort C (MAS825) 
MAS825 serum concentrations will be listed by subject, and visit/sampling time point and 
displayed graphically. Descriptive summary statistics will be provided by visit/sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics, and will be treated as missing in geometric mean calculation. 
Pharmacokinetic parameters for MAS825 (Ctroughs; observed analyte concentration at the end 
of a dosing interval) will be listed by subject. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. 
12.6.3.4 Cohort D (Remibrutinib) 
Remibrutinib whole blood concentrations will be listed by subject, and visit/sampling time point 
and displayed graphically. Descriptive summary statistics will be provided by visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as 
zero. Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics, and will be treated as missing in geometric mean calculation. 
Pharmacokinetic parameters for remibrutinib (Ctroughs; observed analyte concentration at the 
end of a dosing interval and apparent Cmax at 
and 
hrs) will be listed by subject. 
Descriptive summary statistics will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum and maximum. 
12.6.3.5 Cohort E (Ianalumab) 
Ianalumab serum concentrations will be listed by subject, and visit/sampling time point and 
displayed graphically. Descriptive summary statistics will be provided by visit/sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics, and will be treated as missing in geometric mean calculation. 
Pharmacokinetic parameter for ianalumab (Ctroughs; observed analyte concentration at the end 
of a dosing interval) will be listed by subject. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. 
12.6.4 
Pharmacodynamics 
PD analysis set will be used for the analyses. 
12.6.4.1 Cohort A (iscalimab) 
Soluble CD40 in plasma will be presented with descriptive summary statistics by visit/sampling 
timepoint. Summary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum and maximum. 
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12.6.4.2 Cohort B (LYS006) 
LTB4 levels in ex vivo stimulated and non-stimulated whole blood and in non-stimulated 
plasma over time will be summarized and displayed graphically. 
12.6.4.3 Cohort C (MAS825) 
Target engagement biomarker (IL-18, IL-1ß, IL-18BP) in serum will be presented with 
descriptive summary statistics by visit/sampling timepoint. Summary statistics will include 
mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. 
12.6.4.4 Cohort D (Remibrutinib) 
BTK occupancy in stimulated whole blood will be presented with descriptive summary 
statistics by visit/sampling timepoint. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. 
12.6.4.5 Cohort E (Ianalumab) 
 in serum will 
be presented with descriptive summary statistics by visit/sampling timepoint. Summary 
statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum and maximum. 
12.6.5 
Exposure-response relationship 
Graphical methods will be used to investigate the relationships between concentrations of the 
investigational treatments and HS lesion counts, for each investigational drug separately. 
12.6.6 
Immunogenicity (Cohort A, C and E) 
Immunogenicity results may be listed by subject and visit/time (no descriptive statistics) in the 
CSR or a separate standalone document. The proportion/incidence of ADA-positive subjects 
will be summarized. An integrated PK/PD/Immunogenicity approach, focusing on the clinical 
and functional consequences of ADAs will be applied to allow an appropriate clinical 
management of subjects developing an ADA response to iscalimab, MAS825 and ianalumab. 
An immune response to iscalimab, MAS825 and ianaluamb may be correlated with a loss of 
efficacy, a loss of exposure (PK), a loss of target engagement and/or the appearance of immune 
related adverse events. 
12.6.7 
Exploratory biomarkers 
Exploratory biomarker data may be reported in the CSR or a separate standalone document. 
The exploratory biomarkers include PD biomarkers in blood described in Section 12.6.4 and: 
x Disease-related markers such as 
 
 
x 
 
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x Cohort B: Levels of soluble biomarkers related to state of inflammation, cell infiltrates 
and activation, such as, but not limited to
 
 
measured from skin tape strip. 
x Protein levels of exploratory 
 
 may be assessed if warranted by observation of clinical signs of 
 
 formation. 
x 
 
 
 
 
 
 
x For subjects in Cohort B, LYS006 soluble biomarkers in 
 to explore 
LQIODPPDWLRQPDUNHUVHJ/7%DQG032DQGQHXWURSKLOFKHPRNLQHVHJ*52Į,/-8) 
x For subjects in Cohort C, soluble circulating target engagement biomarkers (e.g. ILȕ, 
total/free IL-18, IL18-BP and downstream pathway biomarkers e.g. CXCL9, IP-
10/CXCL10, IL-6 and markers of immune activation such as sIL2R) 
x For subjects in Cohort D, BTK occupancy in stimulated whole blood. Additional 
assessments may include the analysis of certain
 and occurrence of 
 
 over time for a subset of patients 
x For subjects in Cohort E, B cell subsets and 
 
 
These variables may be displayed graphically over time for raw values and/or percentage 
change from baseline. Graphical methods and inferential models may be used to investigate 
whether some selected biomarkers (details to be specified in statistical analysis plan) associated 
with efficacy measures such as HS lesion counts or clinical response. PD analysis set will be 
used for these analyses. Additionally, hypothesis-free analysis methods may be applied to data 
from biomarker profiling in relation to disease severity, disease-endotypes and clinical efficacy. 
12.6.8 
Other optional exploratory endpoints 
PD analysis set will be used for this analysis. 
12.6.8.1 
 
Exploratory 
 
 
 
 
 
 
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12.7 
Interim analyses 
Interim analyses for assessing efficacy and safety may be conducted during the study. 
These will be conducted when approximately half the planned subjects have completed the 
respective treatment period of the concerned cohort (16 weeks of treatment). Such early IAs, if 
conducted, are to ensure no safety issues with investigational drug treatment and also gain 
preliminary understanding of efficacy throughout a panel of efficacy endpoints.  
If one cohort were to stop at an early IA (early signs of efficacy would not lead to the 
interruption of that cohort), all ongoing subjects in all treatment arms in this cohort would be 
discontinued and not be replaced. In this case for the final analysis of binary response rates, 
subjects who were discontinued only due to the stopping of a cohort will be excluded from the 
analysis. 
Different cohorts may complete enrolment at different times and so interim analyses are also 
planned when all subjects in a cohort have completed the respective treatment period of the 
concerned cohort (16 weeks of treatment). These end-of-cohort interim analyses are intended 
to help with the planning of later steps in the development program of each treatment. 
Additional interim analyses may be conducted to support decision making, concerning the 
current clinical study, the sponsor’s clinical development projects in general, or in case of any 
safety concerns. 
In general the analyses will follow the methods described above. For the assessment of binary 
response rate efficacy data, only data from subjects who have either completed the treatment 
period or who have discontinued treatment will be included. For subjects who were still ongoing 
in the treatment period at the time of the IA, will not be included in the efficacy analysis.  
For interim analyses, conducted after approximately half the planned subjects in a cohort have 
reached 16 weeks of treatment, all available data from all cohorts at the time of the analysis will 
be used, i.e. including placebo data from other cohorts. These results will not be communicated 
with individuals directly involved in treating the study’s subjects or assessing clinical data. 
For interim analyses conducted after the completion of one cohort, only the data relative to that 
specific cohort will be communicated externally. However, for the purpose of internal decision 
making, all available data from all cohorts at the time of the analysis will be used. For example, 
for an end-of-cohort analysis of Cohort B, all data including valid placebo data from Cohort A, 
C and D will be used for the purpose of internal decision making. The results of these analyses 
will not be communicated with individuals directly involved in treating the study’s subjects or 
assessing clinical data. 
Unblinded interim analysis results will be reviewed by the clinical team, following the blinding 
requirement in Section 6.4.  
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Approximately 240 subjects are to be recruited, with approximately 40-45 in each of Cohort A 
and B, approximately 
in Cohort C, approximately 70 in Cohort D (approximately 30 subjects 
will receive remibrutinib 
 mg 
., approximately 30 subjects will receive remibrutinib 
mg 
and approximately 10 subjects corresponding placebo), and approximately 40 in 
Cohort E. Within the analysis set of the primary endpoint, if more than 10% treatment 
withdrawals/discontinuations are observed before completion of 12 weeks of treatment, the 
discontinued subjects may be replaced to ensure enough data are available to effectively assess 
the treatment effect. Subjects will be randomized in a 2:1 ratio to the investigational treatment 
or placebo within Cohorts A and B, 3:1 ratio for Cohorts C and E, and 3:3:1 ratio for Cohort D.
Based on 30 subjects for a given investigational treatment and 60 for placebo (pooled), it is 
estimated that this study will have approximately 80.5% probability of meeting the success 
criteria (as outlined in Section 12.4.2), if the true difference between an investigational 
treatment and placebo in the simplified HiSCR rate is 25% (25 percentage points). 
Conversely there is a low (7.6%) probability of meeting the success criteria when there is no 
difference between the investigational treatment and placebo. The outcome of the operating 
characteristics is presented in Figure 12-1. These results come from simulations of the trial 
outcomes and assume a placebo response rate of 42% (estimated from a previous study 
CCJM112X2202). For a range of placebo response rates (20% to 60%), the design of 30 versus 
60 is able to provide a consistent power around 80.5%, i.e. 80.5% chance to meet the dual 
efficacy criteria with a true effect of 25%.
Figure 12-1 
Operating characteristics for simplified HiSCR at interim and final 
analysis
For the iscalimab and LYS006 cohort:
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For the MAS825 cohort: 
 
For the remibrutinib cohort: 
 

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For the ianalumab cohort: 
 
Note: placebo sHiSCR assumed in this figure is 42%, based on the internal study CCJM112X2202. 
12.8.2 
Secondary endpoint(s) 
Not applicable. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 

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For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last subject Last Visit to be a reviewer and signatory for the clinical study report. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last subject last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 

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14.1 
Protocol Amendments 
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 10 (Safety Monitoring) must be followed and the Study Lead 
informed. 

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15 
References 
References are available upon request 
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Giamarellos-Bourboulis EJ, Argyropoulou M, Kanni T, et al (2020) Clinical efficacy of 
complement C5a inhibition by IFX-1 in hidradenitis suppurativa: an open-label single-arm 
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Gottlieb A, Natsis NE, Kerdel F, et al (2020) A Phase II Open-Label Study of Bermekimab in 
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Gudjonsson JE, Tsoi LC, Ma F, et al (2020) Contribution of plasma cells and B cells to 
hidradenitis suppurativa pathogenesis. JCI Insight; 5(19):e139930. 
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16 
Appendices 
16.1 
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-1 
Liver Event and Laboratory Trigger Definitions 
  
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
• 
3 x ULN < ALT / AST ≥ 5 x ULN 
1.5 x ULN < TBL ≥ 2 x ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
  
• 
ALP > 2 × ULN (in the absence of known bone 
pathology) 
  
• 
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome) 
  
• 
ALT or AST > 3 × ULN and INR > 1.5 
  
• 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP 
to > 2 × ULN) 
  
• 
Any clinical event of jaundice (or equivalent term) 
  
• 
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia 
  
• 
Any adverse event potentially indicative of a liver 
toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 

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Table 16-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
• 
Must be reported as an 
SAE even before all other 
causes of liver injury have 
been excluded.  
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 1.5 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 
48 hours 
• 
If elevation persists, 
continue follow-up 
monitoring 
• 
If elevation persists for 
more than 2 weeks, 
discontinue the study drug 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 

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Criteria 
Actions required 
Follow-up monitoring 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (subject is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the subject 
Investigator discretion 
Monitor LFT within 1 to 
4 weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
• 
Repeat LFT within 
48 hours 
• 
If elevation persists, 
establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
Investigator discretion 
Monitor LFT within 1 to 
4 weeks or at next visit 

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Criteria 
Actions required 
Follow-up monitoring 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Repeat LFT within 
48 hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (subject is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the subject 
Investigator discretion 
Monitor LFT within 1 to 
4 weeks or at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the subject 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
concomitant medication, 
medical history, laboratory 
assessments) in the 
appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 

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16.2 
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-3 
Specific Renal Alert Criteria and Actions 
Serum Event                                                                        Actions 
eGFR decrease 25-49% compared to baseline 
 
 
 
 
 
 
 
eGFR decrease > 50% compared to baseline  
• 
Consider causes and possible 
interventions Repeat test after >24 
hours but < 5 days after assessment of 
the first abnormal lab values. Assess 
patient for signs and symptoms of illness 
and acute kidney injury 
 
• 
Consider causes and possible 
interventions 
• 
Repeat test within 48 hours after receipt 
of abnormal lab values. Assess patient 
for signs and symptoms of illness and 
acute kidney injury 
• 
Consider study treatment interruption 
unless other causes are identified and 
corrected 
• 
Consider referral to nephrologist for 
diagnosis and management  
• 
Consider subject hospitalization/ 
specialized treatment  
Urine Event                                                                          Actions                                                       
New onset dipstick proteinuria ≥3+, 
OR 
Protein-creatinine ratio (PCR)>1g/g or >100 
mg/mmol 
 
 
 
 
New dipstick hematuria >1+ not due to trauma  
• 
Repeat test after >24 hours but < 5 days 
after assessment of the first abnormal 
lab values. Ideally confirm presence of 
true proteinuria by quantification: PCR 
on first morning void 
• 
Consider causes and possible 
interventions 
• 
Assess serum albumin and total serum 
protein  
• 
Consider drug interruption or 
discontinuation unless other causes are 
identified and corrected  
• 
Consider referral to a nephrologist 
 
• 
Repeat test after >24 hours but < 5 days 
after assessment of the first abnormal 
lab values. 
• 
Assess serum creatinine  
• 
Exclude other causes (infection, trauma, 
menstruation, bleeding from urinary 
tract/bladder, bleeding disorder)  

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Follow-up for all renal events:  
 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor subject regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio, 1g/g creatinine or 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.