Clinical trial NCT04541589
Conditions: Sjogren's Syndrome
Keywords: Sjogren's Syndrome autoimmune ESSDAI ESSPRI anti-CD40 CFZ533 iscalimab TWINSS Extension
Sponsor: Novartis Pharmaceuticals
Start date: 2021-01-05; Completion date: 2024-08-19
Enrollment: 206 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and tolerability of iscalimab at two dose levels in patients with Sjögren's Syndrome, who participated in the TWINSS core study, CCFZ533B2201 (NCT03905525). Additionally, this Extension study will further explore the pharmacokinetics (PK) and efficacy of iscalimab at two dose level.

Detailed description:
This study was a continuation of the TWINSS core study CCFZ533B2201 (NCT03905525) that offered continuation of treatment for participants who completed the core study and were deemed by the Investigator to clinically benefit from continued iscalimab therapy based upon response to therapy at the end of the treatment period of the core study. The extension study was a 48-week treatment study, with a safety follow-up period of 12 weeks, to provide additional safety and tolerability information for iscalimab.At Week 60 of the TWINSS core study, eligible participants had the option to enroll in the extension study.

Participants were classified as treatment responders or non-responder based on their European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) and EULAR Sjögren's syndrome patient reported index (ESSPRI) scores from predefined time points in the core study. In the extension study, participants were reassigned to either iscalimab 600 mg or 300 mg subcutaneously via prefilled syringes (PFS) based on their responder status and the iscalimab doses that they received in the core study

All participants enrolled in the extension study received a weekly loading regimen at the start of the treatment period for the initial 3 weeks, followed by a subcutaneous maintenance regimen (600 or 300 mg subcutaneously every 2 weeks). Injections were performed at site or at home by site staff or participant/caregiver.

Study blinding for the extension study was maintained until final database lock of the core study, upon which the participants and Investigators were unblinded, making it an open-label study through Week 120 (end of study visit).

Arms: arm 1: Participants received 600 mg (2 injections of 300 mg/2 mL) of iscalimab subcutaneously weekly for the initial 3 weeks as loading doses, followed by a bi-weekly maintenance regimen at 600 mg (2 injections of 300 mg/2 mL). arm 2: Participants received one dose of 600 mg (2 injections of 300 mg/2 mL) of iscalimab subcutaneously on the first day of the extension study; then 300 mg weekly (1 injection of 300 mg/2 mL of iscalimab and 1 injection of 2 mL of placebo) for the next 2 weeks as loading doses. This was followed by a bi-weekly maintenance regimen of 300 mg (1 injection of 300 mg/2 mL of iscalimab and 1 injection of 2 mL of placebo). After the final database lock of the core study, participants underwent unblinding, leading to the discontinuation of placebo injections.
Interventions: intervention 1: Iscalimab intervention 2: Placebo
Intervention descriptions: intervention 1: Iscalimab 600 mg or 300 mg was administered subcutaneously weekly for the first 3 weeks. Subsequently, iscalimab was administered subcutaneously bi-weekly (every other week or Q2W). intervention 2: Placebo (1 injection of 2 ml) administered to participants in the iscalimab 300 mg arm to maintain blinding until the final database lock of the core study

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
CFZ533 
Clinical Trial Protocol CCFZ533B2201E1 / NCT04541589
A TWINSS extension trial to evaluate the safety and 
tolerability of CFZ533 (iscalimab) at two dose levels 
administered subcutaneously in patients with Sjögren’s 
Syndrome 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-001942-20 
Version number: 
v01 (Clean) 
Clinical Trial Phase: 
IIb 
Release date: 
17-Feb-2021
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 1 (17-Feb-2021) ................................................................................................... 13 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Purpose .................................................................................................................. 17 
2 
Objectives and endpoints ................................................................................................... 18 
2.1 
Primary estimands ................................................................................................. 19 
2.2 
Secondary estimands ............................................................................................. 19 
3 
Study design ...................................................................................................................... 19 
4 
Rationale ............................................................................................................................ 21 
4.1 
Rationale for study design ..................................................................................... 21 
4.1.1 
Rationale for choice of background therapy ......................................... 22 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 22 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 23 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 24 
4.5 
Risks and benefits .................................................................................................. 24 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 26 
5 
Study Population ............................................................................................................... 26 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 28 
6.1 
Study treatment ...................................................................................................... 28 
6.1.1 
Investigational and control drugs .......................................................... 28 
6.1.2 
Additional study treatments .................................................................. 29 
6.1.3 
Treatment arms/group ........................................................................... 29 
6.1.4 
Treatment duration ................................................................................ 31 
6.2 
Other treatment(s) .................................................................................................. 31 
6.2.1 
Concomitant therapy ............................................................................. 32 
6.2.2 
Prohibited medication ........................................................................... 32 


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6.2.3 
Rescue medication ................................................................................ 33 
6.3 
Participant numbering, treatment assignment, randomization .............................. 34 
6.3.1 
Participant numbering ........................................................................... 34 
6.3.2 
Treatment assignment, randomization .................................................. 34 
6.4 
Treatment blinding ................................................................................................ 35 
6.5 
Dose escalation and dose modification.................................................................. 36 
6.5.1 
Dose modifications ................................................................................ 36 
6.5.2 
Dose interruptions ................................................................................. 36 
6.5.3 
Follow-up for toxicities ......................................................................... 37 
6.6 
Additional treatment guidance ............................................................................... 37 
6.6.1 
Treatment compliance ........................................................................... 37 
6.6.2 
Emergency breaking of assigned treatment code .................................. 37 
6.7 
Preparation and dispensation ................................................................................. 38 
6.7.1 
Handling of study treatment and additional treatment .......................... 38 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 40 
7 
Informed consent procedures ............................................................................................ 41 
8 
Visit schedule and assessments ......................................................................................... 43 
8.1 
Screening ............................................................................................................... 49 
8.1.1 
Information to be collected on screening failures ................................. 49 
8.2 
Participant demographics/other baseline characteristics ....................................... 49 
 
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8.4 
Safety ..................................................................................................................... 50 
8.4.1 
Laboratory evaluations .......................................................................... 51 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 52 
8.4.3 
Pregnancy and assessments of fertility ................................................. 53 
8.4.4 
Other safety evaluations ........................................................................ 53 
8.4.5 
Appropriateness of safety measurements .............................................. 54 
8.5 
Additional assessments .......................................................................................... 54 
 
 54 
8.5.2 
Pharmacokinetics .................................................................................. 56 


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8.5.3 
Immunogenicity .................................................................................... 56 
 
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9 
Study discontinuation and completion .............................................................................. 58 
9.1 
Discontinuation and completion ............................................................................ 58 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 58 
9.1.2 
Withdrawal of informed consent ........................................................... 59 
9.1.3 
Lost to follow-up ................................................................................... 60 
9.1.4 
Early study termination by the sponsor ................................................. 60 
9.2 
Study completion and post-study treatment .......................................................... 60 
10 Safety monitoring and reporting ........................................................................................ 60 
10.1 
Definition of adverse events and reporting requirements ...................................... 60 
10.1.1 
Adverse events ...................................................................................... 60 
10.1.2 
Serious adverse events .......................................................................... 62 
10.1.3 
SAE reporting........................................................................................ 63 
10.1.4 
Pregnancy reporting .............................................................................. 64 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 64 
10.2 
Additional Safety Monitoring ................................................................................ 65 
10.2.1 
Liver safety monitoring ......................................................................... 65 
10.2.2 
Renal safety monitoring ........................................................................ 66 
10.2.3 
Data Monitoring Committee ................................................................. 66 
11 Data Collection and Database management ...................................................................... 66 
11.1 
Data collection ....................................................................................................... 66 
11.2 
Database management and quality control ............................................................ 67 
11.3 
Site monitoring ...................................................................................................... 67 
12 Data analysis and statistical methods ................................................................................ 68 
12.1 
Analysis sets .......................................................................................................... 68 
12.2 
Participant demographics and other baseline characteristics ................................. 69 
12.3 
Treatments ............................................................................................................. 69 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 69 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 69 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 70 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 70 
12.4.4 
Handling of missing values not related to intercurrent event ............... 71 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 71 


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12.4.6 
Supplementary analysis ......................................................................... 71 
12.4.7 
Supportive analyses ............................................................................... 71 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 71 
12.5.1 
Pharmacokinetics .................................................................................. 71 
12.5.2 
PK/PD relationships .............................................................................. 71 
12.5.3 
Immunogenicity .................................................................................... 71 
 
 72 
12.7 
Interim analyses ..................................................................................................... 72 
12.8 
Sample size calculation.......................................................................................... 72 
13 Ethical considerations and administrative procedures ...................................................... 72 
13.1 
Regulatory and ethical compliance ........................................................................ 72 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 72 
13.3 
Publication of study protocol and results............................................................... 72 
13.4 
Quality Control and Quality Assurance ................................................................. 73 
14 Protocol adherence ............................................................................................................ 73 
14.1 
Protocol amendments............................................................................................. 73 
15 References ......................................................................................................................... 74 
16 Appendices ........................................................................................................................ 76 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 76 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 78 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 82 
16.4 
Appendix 4: Hepatitis B serology results and interpretation ................................. 83 
16.5 
Appendix 5: Blood Logs ........................................................................................ 84 
 
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16.10 Appendix 10: Satisfaction with self-injection using a prefilled syringe 
questionnaire .......................................................................................................... 97 
16.11 Appendix 11: Study design of core study CCFZ533B2201 .................................. 98 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 18 
Table 4-1 
Potential risks associated with CFZ53 .................................................. 24 
Table 6-1 
Investigational and control drug ............................................................ 29 
Table 6-2 
Prohibited medication ........................................................................... 32 


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Table 6-3 
Blinding and unblinding plan ................................................................ 35 
Table 8-1 
Assessment Schedule ............................................................................ 44 
Table 8-2 
Assessment and Specifications ............................................................. 51 
Table 8-3 
Laboratory Evaluations ......................................................................... 52 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 65 
Table 16-1 
Clinically notable laboratory values and vital signs ............................. 76 
Table 16-2 
Liver event and laboratory trigger definitions ...................................... 78 
Table 16-3 
Follow up requirements for liver events and laboratory triggers .......... 78 
Table 16-4 
Specific Renal Alert Criteria and Actions and Event Follow-up .......... 82 
Table 16-5 
(A) - Blood Logs ................................................................................... 84 
Table 16-6 
(B) - Blood Logs ................................................................................... 86 
 
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Table 16-15 
Satisfaction with self-injection using a prefilled syringe 
questionnaire ......................................................................................... 97 
List of figures 
Figure 3-1 
TWINSS extension study (CCFZ533B2201E1) design ........................ 21 
Figure 4-1 
Iscalimab doses and regimen ................................................................ 22 
Figure 6-1 
IRT Algorithm for treatment reassignment ........................................... 31 
 


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List of abbreviations 
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
 
 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
 
 
CFR 
Code of Federal Regulation 
ClinRO 
Clinician Reported Outcomes 
CMO&PS  
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus ( Human- Cytomegalovirus) 
CNS 
Central nervous system 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria  
Ctrough 
Trough concentration 
CV 
coefficient of variation 
DMARD 
Disease modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EOS 
End of study 
 
  
eSource 
Electronic Source 
ESR 
Erythrocyte sedimentation rate 
ESSDAI 
EULAR Sjögren's syndrome disease activity index 
ESSPRI 
EULAR Sjögren's syndrome patient reported index 
EULAR 
European League Against Rheumatism 
 
 


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FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
HBc 
HB core antigen 
HBs 
HB surface antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
hCG 
Human chorionic gonadotropin 
HDL 
High density lipoprotein 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
 
 
IEC 
Independent Ethics Committee 
IFU 
Instructions for use 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LDH 
lactate dehydrogenase 
LDL 
Low density lipoprotein 
LFT 
Liver function test  
LLOQ 
lower limit of quantification 
LN 
Lupus nephritis 
LVV 
Large vessel vasculitis 
mAb 
Monoclonal antibody 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MMF 
Mycophenolate Mofetil 
NHP 
Non-human primates 
NSAID 
Nonsteroidal anti-inflammatory drugs 
OL 
Open-label 


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PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PFS 
Prefilled syringe 
 
 
 
 
PK 
Pharmacokinetic(s) 
PNS 
Peripheral nervous system 
PoC 
Proof of Concept 
PRO 
Patient Reported Outcomes 
pSS 
primary Sjögren's syndrome  
PT 
prothrombin time 
PTLD 
Post-transplantation proliferative disorder  
PTT 
Partial thromboplastin time 
Q2W 
every 2 weeks, bi-weekly 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RA 
Rheumatoid arthritis 
 
 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SjS 
Sjögren's Syndrome  
SLE 
Systemic lupus erythematosus 
SoC 
Standard-of-care 
SOP 
Standard operating procedures 
SSA 
Sjögren's syndrome-related antigen A 
 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TD 
Study Treatment Discontinuation 
TDAR 
T cell-dependent antibody response  
TEAE 
Treatment emergent adverse events 
TFQ 
Trial feedback questionnaire 
TMDD 
Target mediated drug disposition 
ULN 
upper limit of normal 
VAS 
Visual analog scale 
WBC 
white blood cell(s) 
WHO 
World Health Organization  


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WOCBP 
Women of child-bearing potential 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg 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 participant entry into the study at which informed consent must 
be obtained  
Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Randomization 
number 
A unique identifier assigned to each randomized participant 


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Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
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 or intervention 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 participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendment 1 (17-Feb-2021) 
Amendment rationale  
The main purpose of this protocol amendment is to include an additional assessment time point 
as part of the Interactive Response Technology (IRT) algorithm criteria for participant rollover 
from the TWINSS core study (CCFZ533B2201) to extension study. ESSDAI and ESSPRI 
scores at Week 0 may be used for the IRT algorithm in the absence of a score at Week 4 of the 
core study. This change will allow participants who have missed their ESSDAI (Cohort 1 and 
Cohort 2) and/or ESSPRI (Cohort 2) assessments at Week 4 to be considered for inclusion in 
the extension study if these assessments were completed at Week 0 (baseline) of the core study.  
Specific guidance concerning public health emergency situations as declared by local or 
regional authorities (i.e., pandemic, epidemic or natural disaster) has been included in 
Section 4.6, as well as mitigation procedures to ensure participant safety and trial integrity in 
the relevant sections. At the time of this amendment, Novartis has performed a study-specific 
medical and safety risk assessment and concluded that based on the current data, the benefit/risk 
of iscalimab due to COVID-19 pandemic remains unchanged in the target population. 
Additionally, this protocol amendment includes the correction of typographical and formatting 
errors and minor editorial changes for increased clarity of the text. Consequently, a small 
number of changes were implemented throughout the protocol. 
Changes to the protocol 
The following sections have been updated in the amended protocol: 
• Section 3 and Section 6.1.3 updated to include the use of ESSDAI (Cohort 1 and Cohort 
2) and ESSPRI (Cohort 2) scores at Week 0 for the IRT algorithm if a score is missing 
at Week 4 of the core study.  
• Section 4.1 text updated to clarify rationale for study design. 
• Section 4.6  added for Public Health Emergency mitigation procedures. Section 6.7, 
Section 8, Section 8.3, Section 8.4 and Section 8.4.3 have been updated accordingly. 
• Section 5.2 exclusion criterion #6 added to exclude a participant rolling over from the 
core study to the extension study in the case of a missing ESSDAI (Cohort 1 and Cohort 
2) or ESSPRI (Cohort 2) score in the core study at Weeks 0 and 4 or Weeks 40 and 48.    
• Figure 6-1 IRT Algorithm for treatment reassignment updated to include the use of 
ESSDAI (Cohort 1 and Cohort 2) and ESSPRI (Cohort 2) scores at Week 0 if a score is 
missing at Week 4 of the core study.  
• Section 6.3.2 updated to clarify the process for transfer of ESSDAI and ESSPRI data 
from the core study to the extension study IRT database. 
• Section 6.4 deletion of text to clarify that blood samples for PK, immunogenicity and 
.  
• Section 6.5.2 and Section 8 updated to clarify the treatment period and follow-up period 
of the extension study.  


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• Section 6.7.2 updated with following text for more clarity: “Prior to self-administration 
at home, participants should contact the investigator/site staff in the case they are 
experiencing any AE/SAEs or have any concerns or there have been changes to the 
ongoing concomitant medications.”   
• Section 7 updated to include information on the digital injection care management 
device.   
• Section 8.3 Instructions were added to use paper PRO as a back-up solution in case of 
case of device(s) failure.   
• Table 8-3 Laboratory evaluations (Section 8.4.1) updated to remove FSH listed under 
additional assessments as fertility will not be assessed in the extension study.  
• Section 8.5.1.2 text added to clarify that the PFS Questionnaire feedback is anonymous 
and individual participant level responses will not be reviewed by Investigators. 
• Section 10.2.2, Table 16-1 and Table 16-4 updated to reflect the correct standard units 
for potassium and protein-creatinine ratio parameters.  
• Section 16.5 Appendix 5: Blood Logs updated to align the blood volumes as per central 
laboratory requirements.  
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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Protocol summary 
Protocol number 
CCFZ533B2201E1 
Full Title 
A TWINSS extension trial to evaluate the safety and tolerability of CFZ533 
(iscalimab) at two dose levels administered subcutaneously in patients 
with Sjögren’s Syndrome 
Brief title 
Study of safety and tolerability of CFZ533 in patients with Sjögren’s 
Syndrome 
Sponsor and Clinical 
Phase 
Novartis 
Phase IIb 
Investigation type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this 1-year extension study is to provide additional safety 
and tolerability information of the two doses of CFZ533 (iscalimab 600 mg 
and 300 mg) administered via prefilled syringes (PFS).  
Primary Objective(s)  The primary objective of this study is to evaluate the safety and tolerability 
of iscalimab at two dose levels (600 mg and 300 mg) in patients with 
Sjögren’s Syndrome, who participated in the TWINSS core study, 
CCFZ533B2201. 
Secondary 
Objectives 
Objective 1: To assess the pharmacokinetics (PK trough levels) and dose-
exposure relationship of iscalimab 
Objective 2: To assess immunogenicity of iscalimab 
Study design 
Study CCFZ533B2201E1 is a multicenter extension study. Study blinding 
for the extension study will be maintained until final database lock of the 
core study, CCFZ533B2201, upon which the participants and Investigators 
will be unblinded, making it an open-label study through Week 120 (end of 
study visit). 
Study population 
The study population will consist of approximately 160 male and female 
participants (≥18 years old at the time of consent) who completed the core 
study (CCFZ533B2201) and who meet the inclusion/exclusion criteria. 
Key Inclusion 
criteria 
• 
Participants must have participated in the TWINSS core study, 
CCFZ533B2201, and must have completed the entire treatment period 
up to Week 48 and the follow-up period up to Week 60  
• 
In the judgement of the Investigator, participants must be expected to 
clinically benefit from continued iscalimab therapy 
Key Exclusion 
criteria 
• 
Sjögren’s Syndrome overlap syndromes where another autoimmune 
rheumatic disease constitutes the principle illness, specifically:  
• 
Moderate-to-severe active systemic lupus erythematosus (SLE) with 
anti-dsDNA positivity and renal involvement, or other organ 
involvement that impedes on ability to score ESSDAI domains 
• 
Active rheumatoid arthritis (RA) that impedes on the ability to score the 
ESSDAI articular domain 
• 
Systemic sclerosis 
• 
Any other concurrent connective tissue disease (e.g., lupus nephritis 
(LN), large vessel vasculitis (LVV), Sharp syndrome (mixed connective 
tissue disease) that is active and requires immunosuppressive 


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treatment outside the scope of this trial and would impede on Sjögren's 
Syndrome organ domain assessments 
• 
Use of other investigational drugs other than iscalimab during the core 
study 
• 
Active uncontrolled viral, bacterial or other infections requiring systemic 
treatment at the time of enrollment, or history of recurrent clinically 
significant infection or of bacterial infections with encapsulated 
organisms 
• 
Missing ESSDAI (Cohort 1 and Cohort 2) or ESSPRI (Cohort 2) scores 
in the core study at Weeks 0 and 4 or Weeks 40 and 48 
Study treatment 
CFZ533 (iscalimab) will be administered as two 2 mL bi-weekly 
subcutaneous (Q2W s.c.) injections in prefilled syringes (PFS). 
Participants will be re-assigned to one of the following two treatment arms: 
• 
Arm 1 - Iscalimab 600 mg s.c. Q2W 
• 
Arm 2 - Iscalimab 300 mg s.c. Q2W 
Pharmacodynamic 
assessments  
 
Pharmacokinetic 
assessments  
Trough iscalimab plasma concentrations 
Key safety 
assessments 
Adverse event monitoring, physical examinations, vital signs, monitoring of 
laboratory markers in blood and urine, monitoring of 
. 
Other assessments 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
Data analysis 
Descriptive statistics will be provided for this study. 
Summary statistics for continuous variables will include N, mean, standard 
deviation (SD), minimum, lower quartile, median, upper quartile, and 
maximum. Summary statistics for discrete variables will be presented in the 
number and percent of patients in each category. 
Key words 
Sjögren’s Syndrome, autoimmune disease, ESSDAI, ESSPRI, monoclonal 
antibody, anti-CD40, CFZ533, iscalimab, prefilled syringe (PFS), 
subcutaneous injection, TWINSS extension 


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1 
Introduction 
1.1 
Background 
Sjögren's Syndrome (SjS) is a chronic autoimmune disease of unknown etiology, characterized 
by lymphoid infiltration and progressive destruction of exocrine glands. Although primarily 
organ-specific for the lacrimal and salivary glands, the inflammatory process can target any 
organ (Asmussen et al 1996). Thus, the clinical features range from dryness, pain and fatigue 
affecting nearly all patients, to severe, extra-glandular and systemic involvement in a more 
limited subset. The increased B-cell activity underlying SjS also results in an increased risk for 
malignant transformation, with lymphoma development occurring in up to 5% of Sjögren's 
Syndrome (SjS) patients (Ramos-Casals et al 2005, Theander et al 2011). Sjögren's Syndrome 
(SjS) is second only to rheumatoid arthritis (RA) in prevalence as a systemic autoimmune 
disease, with an estimated prevalence of 0.2%-0.5%. The disease affects mainly women with a 
female/male ratio of 9:1 and can occur at any age (Qin et al 2015). 
Current standard of care (SoC) treatment for SjS patients is limited to symptomatic care for the 
mucosal signs and symptoms (dryness). Steroids and conventional disease-modifying 
antirheumatic drugs (DMARDs), although used in selected patients, have not been proven 
efficacious, and no pharmacologic intervention is effective against the severe, disabling fatigue. 
Hence, there are no approved treatments available for active, systemic disease. 
CFZ533 (iscalimab) is a fully human Fc-silenced, non-depleting, Immunoglobulin G1 (IgG1) 
anti-CD40 monoclonal antibody (mAb) that blocks the CD154-induced activation of CD40 
pathway signaling, thereby preventing CD40 pathway signaling and activation of all CD40+ 
cell types (B-cells, activated parenchymal cells, antigen presenting cells). The relevance of the 
CD40/CD154 pathway for autoimmunity and inflammation in multiple cell types and functions 
is well established (Karnell et al 2019). In the context of SjS, the most important molecular and 
cellular action of iscalimab is expected to be inhibition of T cell-dependent antibody response 
(TDAR) and disruption of germinal center formation in secondary lymphoid tissues in the 
affected salivary glands. 
The therapeutic hypothesis was successfully tested in a first proof-of-concept (PoC) study of 
iscalimab in patients with primary Sjögren's Syndrome (pSS). Briefly, in this randomized 
controlled trial, the primary endpoint of European Sjögren’s Syndrome Disease Activity Index 
(ESSDAI) improvement was met, along with improvements in patient reported outcomes 
(PRO) including fatigue (Fisher et al 2017); please see current Iscalimab Investigator's 
Brochure (IB) for details. The overall risk/benefit profile was favorable, warranting continued 
development in this indication. 
Limited safety data are currently available for iscalimab in any indication that is under 
investigation. This extension study (CCFZ533B2201E1) will allow us to demonstrate the 
additional safety and tolerability of two doses (600 mg and 300 mg) of treatment with iscalimab 
in patients with Sjögren's Syndrome (SjS). 
1.2 
Purpose 
Study CCFZ533B2201 (TWINSS) is a double-blinded Phase IIb study enrolling two distinct 
populations of patients with SjS and is defined as the "core study". Study CCFZ533B2201E1 


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is designed as a 1-year extension to the core study. The extension study will be open only to 
eligible participants from the TWINSS core study who, in the opinion of the Investigator, may 
potentially derive clinical benefit from continued administration of CFZ533 (iscalimab). The 
primary purpose of this 1-year extension study is to provide additional safety and tolerability 
information of the two doses of iscalimab (iscalimab 600 mg and 300 mg) administered via 
prefilled syringes (PFS). Additionally, this extension study will further explore the 
pharmacokinetics (PK) and efficacy of iscalimab 600 mg and 300 mg doses. Key additional 
safety data will be used to better understand the overall safety profile of iscalimab at two dose 
levels and potentially inform study design elements of subsequent clinical studies (i.e. Phase 
III). 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the safety and tolerability of 
iscalimab at two dose levels (600 mg and 
300 mg) in patients with SjS, who 
participated in the TWINSS core study, 
CCFZ533B2201 
• 
Incidence of Treatment-emergent adverse 
events (TEAEs)/ serious adverse events 
(SAEs) 
Routine hematology and clinical chemistry 
laboratory test results at analysis visits up to 
end of study 
Vital signs at analysis visits up to end of 
study 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the pharmacokinetics (PK trough 
levels) and dose-exposure relationship of 
iscalimab 
• 
Free iscalimab concentration in plasma 
during the treatment (Ctrough) and follow-up 
(up to end of study) periods  
• 
To assess immunogenicity of iscalimab 
• 
Incidence of anti-iscalimab antibodies in 
plasma at analysis visits up to end of study 


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2.1 
Primary estimands 
Not applicable.  
2.2 
Secondary estimands 
Not applicable. 
3 
Study design 
TWINSS Core Study (CCFZ533B2201) Design 
TWINSS is a basket trial consisting of two distinct study parts termed Cohort 1 and Cohort 2. 
Cohort 1 is a randomized, double-blind, placebo-controlled, parallel group, dose-range finding 
study, planned to enroll approximately 160 participants. Cohort 2 is a randomized, double-
blinded, placebo-controlled proof-of-concept study, planned to enroll approximately 100 
participants. 
During a 6-week screening period, all participants fulfilling the American College of 
Rheumatology/European League Against Rheumatism (ACR/EULAR) 2016 classification 
criteria will be assessed for all 12 ESSDAI domains and will be randomized to Cohort 1 (Arms 
A, B, C and D) or Cohort 2 (Arms E and F) accordingly (refer to CCFZ533B2201 core study 
protocol for further details). The study design for the TWINSS core study is provided in 
Section 16.11. 
TWINSS Extension Study (CCFZ533B2201E1) Design 
Study CCFZ533B2201E1 is a continuation of the core study and is planned as a multicenter 
trial. This study will offer continuation of treatment for participants who have completed the 
core study and are deemed by the Investigator to clinically benefit from continued iscalimab 
therapy. 
Enrollment will be determined by the number of participants completing the core study. It is 
estimated that approximately 160 participants from both Cohort 1 and Cohort 2 of the core study 


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may choose to enter the extension study. Study blinding for the extension study will be 
maintained until final database lock of the core study, upon which the participants and 
Investigators will be unblinded, making it an open-label study through Week 120 (end of study 
visit). All visit numbers (in weeks) used in the extension study are relative to the baseline visit 
of the core study. The baseline for the extension study (Week 60E1) will be carried out on the 
same day as the Week 60 visit of the core study. For more details refer to Table 8-1 
The extension study is a 48-week treatment study, with a safety follow-up period of 12 weeks 
(Figure 3-1). Participants who complete 48 weeks of treatment and the mandatory 12 weeks of 
follow-up in the core study are eligible to participate in the extension study. The 12 weeks of 
follow-up in the core study is considered mandatory to obtain PK data. The study will help to 
evaluate the sustainability of response (ESSDAI) after a year of treatment in the core study. 
Upon completion of treatment Period 2 (Week 48) of the core study, Investigators will use their 
clinical judgment to decide if it is beneficial for participants to continue with the extension 
study. All participants will be considered for participation in the extension study. A new 
Informed Consent must be signed before proceeding into the extension study. The participant 
should provide their informed consent prior to the start of the Week 60 assessments of the core 
study. 
The treatment will be offered in PFS in the extension study. This is a change from the core 
study, which used s.c. injections prepared from vials. During the treatment period, 25 treatment 
administration visits are planned, including a weekly loading regimen (Week 60E1, Week 61, 
Week 62) at the start of the treatment period. 
All participants enrolled in the extension study will receive a weekly loading regimen (Week 
60E1, Week 61, Week 62) at the start of the treatment period followed by a s.c. maintenance 
regimen (600 or 300 mg s.c. every 2 weeks (Q2W)). One administration equals two s.c. 
injections. Refer to Section 4.2 for more details on dosages of the weekly loading regimen in 
both arms. 
To maintain extension study blinding until final database lock of the core study, an Interactive 
Response Technology (IRT) algorithm will be used to re-assign participants to either iscalimab 
600 mg (Arm 1) or 300 mg (Arm 2) s.c. Q2W in the extension study using ESSDAI (Cohort 1 
and Cohort 2) and ESSPRI (Cohort 2) scores from predefined time points (Week 4 (or Week 0 
if a score is missing at Week 4) and Week 48 (or Week 40 if a score is missing at Week 48)) in 
the TWINSS core study (refer to Section 6.1.3 for further details). 
Participants will be instructed in detail how to self-administer the s.c. injection using the PFS 
formulation. Each injection will be administered into an appropriate injection site of the body 
(thighs, arms, or abdomen). For the first four visits of the study (through Week 64), all injections 
will be performed at the study site. If a participant had good safety and tolerability, with no 
indication of hypersensitivity or other acute reactions from the previous doses, starting from 
Week 66, the participant is allowed to self-administer the study treatment at home according to 
the assessment schedule (Table 8-1). The participant may continue to present at 2 week intervals 
to the study site for injection administrations, based on the participant's preference and the 
Investigator's judgment. Site staff will administer the injection to participants who are not able 
or unwilling to self-administer the PFS injection. The treatment period is from Week 60E1 to 
Week 108. 


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Figure 3-1 
TWINSS extension study (CCFZ533B2201E1) design 
 
 
4 
Rationale 
4.1 
Rationale for study design 
This 1-year extension study will provide additional safety data for two doses of iscalimab (600 
mg and 300 mg). This study will also provide continued administration of iscalimab for 
participants that as per Investigator may potentially derive clinical benefit after completing the 
core study. The extension study will provide additional key safety data for the two doses 
of iscalimab to better understand the overall safety of iscalimab and potentially inform study 
design elements of subsequent clinical studies (i.e., Phase III). The study will allow for the 
assessment of continued evaluation of efficacy and tolerability. Furthermore, digital data 
collected as part of the extension study will build on existing digital data for further validation. 
A follow-up period of 12 weeks (14 weeks after the last dose) is required to reach sub-
pharmacological exposures after completion of dosing and was estimated taking into 
consideration the non-linear pharmacokinetics (target-mediated disposition) of iscalimab - see 
Section 4.2 below for detailed PK considerations. 
The study is blinded until the final database lock of the core study to protect the integrity of the 
data in the ongoing core study. Participants can exit the study upon their own wish or based on 
advice of the Investigator at any time. 


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4.1.1 
Rationale for choice of background therapy 
Local remedies for symptom relief and systemic background medication as per local practice is 
allowed, as long as participants are on stable dose (Section 6.2.1) and in accordance with the 
inclusion/exclusion criteria. 
4.2 
Rationale for dose/regimen and duration of treatment 
CFZ533 (iscalimab) 600 mg or 300 mg will be administered s.c., weekly for the first 3 doses 
(Weeks 60E1, 61 and 62); then, from Week 64, iscalimab will be administered s.c. bi-weekly 
(every other week or Q2W). This is illustrated in Figure 4-1 for Arm 1 (iscalimab 600 mg 
maintenance regimen) and Arm 2 (iscalimab 300 mg maintenance regimen). 
• For participants assigned to the iscalimab 600 mg maintenance regimen (Arm 1), the 
loading doses are 600 mg on Week 60E1, 61 and 62, followed by a bi-weekly 
maintenance regimen at 600 mg. 
• For participants assigned to the iscalimab 300 mg maintenance regimen (Arm 2), the 
loading doses are 600 mg on Week 60E1, and 300 mg on Week 61 and Week 62, followed 
by a bi-weekly maintenance regimen at 300 mg. 
Figure 4-1 
Iscalimab doses and regimen 
 
Rationale for the loading doses 
Iscalimab is subject to CD40-mediated elimination (or target-mediated drug disposition 
(TMDD)), and the level of expression of CD40 receptors in target tissues has the potential to 
affect exposure to iscalimab, and ultimately target engagement. High CD40 expression may be 
associated with high elimination rate of iscalimab and loss of CD40-CD154 (CD40 ligand) 
pathway blockade if CD40 receptors are not fully saturated. 
The proposed loading regimen is aiming to rapidly achieve the CD40 receptor saturation and 
minimal CD40-mediated elimination, in conditions where CD40 expression might be enhanced 
and additionally also to rapidly establish close to steady-state conditions for iscalimab 
concentration in plasma. 


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The 3 weekly loading doses of iscalimab in SjS patients are guided by PK data collected in the 
proof-of-concept (PoC) Study CCFZ533X2203 in pSS. Based on these results the loading and 
further maintenance regimen will rapidly provide and sustain the systemic exposures above the 
threshold of 40 μg/mL for a broad population. This threshold was associated with complete 
suppression of germinal center development in cortical B cell areas of lymph nodes and T cell 
dependent antibody response in non-human primates (NHP). 
As demonstrated in the PoC Study CCFZ533X2203 in pSS, a single s.c. dose of 600 mg 
iscalimab at Day 1 will deliver plasma concentrations generally above 40 μg/mL after 1 week. 
Subsequent weekly doses on Week 61 and 62 in Arms 1 and 2 are expected (i) to maintain 
CFZ533 plasma levels above 40 μg/mL, and (ii) to deliver iscalimab trough levels that are close 
to expected steady state conditions. 
Further supportive arguments on the selected loading dosing regimen are provided in the 
Rationale for dose/regimen and duration of treatment of the TWINSS core study protocol (refer 
to Section 4 of the core study protocol). 
Rationale for maintenance regimen 
The maintenance regimen of 600 mg s.c. Q2W is expected to provide a median steady state 
trough plasma level at about 144 μg/mL (90% of the population within 282 - 46 μg/mL), in the 
upper range of trough levels observed in the PoC Study CCFZ533X2203-Cohort 2 (i.v. 
regimen; these concentrations were associated with clinical efficacy and suppression of a 
biologically relevant biomarker CXCL13 - a marker of germinal center activity). 
The maintenance regimen of 300 mg s.c. Q2W is expected to deliver a median steady state 
trough plasma level at about 54 μg/mL (90% of the population within 125 - 0.1 μg/mL), with a 
reasonable chance to show efficacy in SjS. 
The between subject variability in exposure within the two treatment arms (to a lesser extent in 
the 600 mg treatment arm) is likely to depend on the biology of CD40 in target tissues 
(expression level, turnover) and its potential modulation during the treatment period.  
Rationale for the duration of the safety follow-up period (target engagement after the last 
dose) 
Based on predicted median CFZ533 plasma concentration-time profile at 600 mg s.c. Q2W 
regimen, at about 14 weeks after the last dose, iscalimab plasma concentrations are expected to 
drop below 20 μg/mL with no expected pharmacodynamic activity in target tissues (e.g., 
germinal centers; data from non-human primates - please see current IB). 
A 12-week follow-up period (14 weeks after the last dose) has been selected for the study and 
is justified to monitor for any related serious adverse events (SAE). 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
There is no placebo or active control group in this study given the purpose and main objectives 
are to extend treatment of participants who completed the core study. The use of two different 
doses of iscalimab (iscalimab 600 mg and 300 mg) will allow evaluation of both doses in terms 
of safety, tolerability and sustainability of clinical benefits. Placebo injection will be provided 


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to maintain blinding until the final database lock of the core study to protect the integrity of the 
data in the ongoing core study. For more details refer to Section 6.1.1. 
4.4 
Purpose and timing of interim analyses/design adaptations 
There is no interim analysis planned for the study. The final analysis of the study will be 
performed at the end of the study. The end of the study is defined when all re-assigned 
participants have completed Week 120 or discontinued earlier. The extension study may be 
amended if deemed necessary based on the results of the TWINSS core study Week 24 primary 
analysis. 
4.5 
Risks and benefits 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
(refer to Section 5) and study procedures, as well as close clinical monitoring. 
Risks: 
The potential safety concerns in humans and the investigator guidance related to administration 
of CFZ533 are based on the data from the available clinical trials with CFZ533, preclinical and 
toxicological data, as well as experience with other compounds of the same class. 
In the indication of SjS there are no identified risks beyond those described in detail in Section 
7 of the current edition of the CFZ533 IB. Important Potential Risks for CFZ533 are 
summarized in Table 4-1 below: 
Table 4-1 
Potential risks associated with CFZ53 
Risk 1 Infections 
Participants treated with CFZ533 may be at an increased risk of infection. CD40 ligation is linked to 
the functional activity of antigen presentation, as well as T-cell priming, B-cell differentiation, 
antibody production and immune memory. Administration of CFZ533 is expected to result in general 
immunosuppression with a decreased capacity to mount a response to novel immunogens, 
including those of bacterial, viral, fungal and parasitic origin when full receptor occupancy has been 
achieved. 
Although the ability to mount a primary immune response will be affected by CFZ533, the memory 
B-cell repertoire should remain intact and protective. In addition, participants will have adequate 
preformed antibody to maintain protective humoral response for extended periods of time (months). 
The participants will be monitored during the study for any signs and symptoms of infections 
including serology tests for cytomegalovirus (CMV; human-cytomegalovirus) infection. 
Risk 2 Malignancy including Lymphoproliferative disorder 
With immunosuppression there is a risk of developing lymphoproliferative disorders. Of note, 
lymphomas are also known to occur more frequently in participants with pSS as compared to the 
age- and sex-matched control population. No signs of lymphoproliferative disorders have been 
observed in NHP studies, or in clinical trials in healthy volunteers or participants where CFZ533 was 
evaluated. 
Hematology will be regularly monitored for changes consistent with a lymphoproliferative disorder. A 
physical examination will be performed to check for unusual lymphadenopathy in the absence of 
infection. 
Risk 3 Thrombophilia/ Thrombosis 


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There is a hypothetical risk for thromboembolic complications when targeting this co-stimulatory 
pathway. This risk is based on clinical results from previous compounds (e.g. BG9588, IDEC-131) 
which have targeted CD154 (CD40 ligand) and resulted in a fatal hyper-coagulation phenotype. 
Although the risk is theoretical, hematologic and coagulation parameters will be monitored in the 
current study. Furthermore, participants with conditions such as antiphospholipid syndrome, who 
are at a higher risk for thromboembolism, will be excluded unless they are receiving antithrombotic 
prophylaxis. CFZ533 binds to CD40 receptor and is Fc-silent mAb hence does not appear to carry 
the same risk of thrombosis. Both preclinical and clinical data from an extensive Phase 2 clinical 
program across healthy subjects and participants across different indications have not indicated a 
risk of thrombosis with CFZ533. 
Risk 4 Immunogenicity 
As with any monoclonal antibody, there is a hypothetical risk of developing anti-CFZ533 antibodies. 
However, it is likely that CFZ533 doses will achieve complete receptor occupancy during the 
treatment period. In these conditions, it is expected that CFZ533 will retain its capacity to block 
immune responses, including those directed against the drug itself, neutralizing or not. 
Samples will be collected during study to assess immunogenicity. Immunogenicity will be monitored 
during clinical development and the consequences of an immune response to CFZ533 could be 
correlated with, a loss of exposure (PK), a loss of peripheral CD40 receptor occupancy (PD), and/or 
the appearance of immune related adverse events including injection site reactions. 
Risk 5 Vaccination Failure 
Vaccination of participants during treatment with CFZ533 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. Administration of live attenuated vaccines should be avoided while receiving 
CFZ533 treatment and for at least 14 weeks thereafter. 
One fatal event (potential CMV infection) was reported in the CCFZ533X2202 clinical trial in 
Lupus nephritis, suspected to be related to the study medication by the Investigator. 
The event was confounded by CMV infection present before first administration of the study 
medication, low lymphocyte count at baseline and concomitant immunosuppressive 
medications like MMF and prednisolone. The ultimate cause of death remains unclear; 
however, the events leading to fatal outcome could have been associated with the CMV 
infection and/or with a bacterial superinfection, and a role of study drug cannot be excluded. 
Currently, the causal effect of CFZ533 remains unclear, however, active viral infections do 
remain a potential risk. Specific detection measures have been implemented to monitor the risk 
of CMV infection across the clinical development program for CFZ533. 
The infections including CMV are considered as an important potential risk for CFZ533 and 
will continue to be closely monitored and mitigated in the current study. 
Lastly, women of childbearing potential (WOCBP) must be informed that taking the study 
treatment may involve unknown risks to the fetus if pregnancy were to occur during the study. 
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 participant will not reliably comply, 
they should not be entered or continue in the study. 
For further information on the above specific risks and other potential adverse effects of the 
compound please refer to Section 7 of the current edition of the CFZ533 IB. 


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Benefits: 
The study design allows that all participants are treated with standard treatment for SjS, 
including systemic treatments such as hydroxychloroquine or immunosuppressive medicines 
where indicated, as long as the dose is kept stable (Section 6.2.1) and the potential risks and 
benefits from these medicines are known. Based on the preliminary safety and efficacy data 
from the exploratory PoC study of iscalimab in pSS, it is possible that a number of participants 
in one or both iscalimab dose arms experience clinically important benefit from iscalimab 
treatment in the current study. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
The study population will consist of male and female participants ≥ 18 years, with SjS defined 
according to the American College of Rheumatology/European League Against Rheumatism 
(ACR/EULAR) 2016 classification criteria (Shiboski et al 2017) who have completed the entire 
treatment period up to Week 48 and the mandatory 12 weeks follow-up period up to Week 60 
of the TWINSS core study. The study population has previously been described in detail in the 
core study protocol (refer to Section 5 of the core study protocol). Enrollment will be 
determined by the number of participants completing the core study. It is estimated that 
approximately 160 participants may choose to enter the extension study from the core study.  
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Participants must have participated in the TWINSS core study, CCFZ533B2201, and must 
have completed the entire treatment period up to Week 48 and the follow-up period up to 
Week 60  
2. Signed informed consent must be obtained prior to participation in the extension study 
(i.e. before commencement of the Week 60 assessments of the core study) 
3. In the judgement of the Investigator, participants must be expected to clinically benefit 
from continued iscalimab therapy 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Sjögren’s Syndrome overlap syndromes where another autoimmune rheumatic disease 
constitutes the principle illness, specifically: 


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• Moderate-to-severe active systemic lupus erythematosus (SLE) with anti-dsDNA 
positivity and renal involvement, or other organ involvement that impedes on ability 
to score ESSDAI domains 
• Active rheumatoid arthritis (RA) that impedes on the ability to score the ESSDAI 
articular domain 
• Systemic sclerosis 
• Any other concurrent connective tissue disease (e.g., lupus nephritis (LN), large 
vessel vasculitis (LVV), Sharp syndrome (mixed connective tissue disease) that is 
active and requires immunosuppressive treatment outside the scope of this trial and 
would impede on Sjögren's Syndrome organ domain assessments 
2. Use of other investigational drugs other than iscalimab during the core study 
3. Active uncontrolled viral, bacterial or other infections requiring systemic treatment at the 
time of enrollment, or history of recurrent clinically significant infection or of bacterial 
infections with encapsulated organisms 
4. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
Chorionic Gonadotropin (hCG) laboratory test 
5. Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and for 14 weeks after stopping of investigational drug 
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization (at least 6 months prior to screening and confirmed as successful). 
For female patients in the study, the vasectomized male partner should be the sole 
partner for that patient. In case the vasectomized male partner is not the sole partner 
of the female patient, highly effective method of contraception must be applied 
(double barrier contraception is not sufficient) 
• Use of oral, (estrogen and progesterone), 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 stable on the same pill 
for a minimum of 3 months before taking investigational drug 
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), total hysterectomy or tubal ligation at least 


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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 she is considered 
not of childbearing potential. 
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the Informed Consent Form (ICF). 
6. Missing ESSDAI (Cohort 1 and Cohort 2) or ESSPRI (Cohort 2) scores in the core study 
at Weeks 0 and 4 or Weeks 40 and 48. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
The following drugs will be used in this study and will be administered in accordance with this 
protocol and where applicable, current local labeling. 
• CFZ533 (iscalimab) 300 mg provided in 2.0 mL PFS for s.c. injection  
• Placebo provided in 2.0 mL PFS for s.c. injection required for blinding 
• CFZ533 (iscalimab) 300 mg provided in 2.0 mL PFS for s.c. administration (open-label 
(OL) supplies) 
Before enrollment in this extension study, all participants electing to continue will sign an 
Informed Consent form. At extension study entry, participants/caregiver will be provided with 
detailed instructions for self-administration of the s.c. injection (Instructions for Use (IFU)) 
using the PFS formulation. In cases where the participant is not comfortable or confident that 
he/she can successfully self-administer the full dose of PFS in a home setting, a caregiver can 
be trained to administer the treatment to the participant. 
Each injection will be administered by the participant/caregiver into an appropriate injection 
site of the body. Site staff will administer the injection to participants who are not able or 
unwilling to self-administer the PFS injection. For the first four visits at Weeks 60E1, 61, 62 
and 64, injections will be performed at site. Starting from Week 66 participants will have the 
choice of self-administration or injection by caregiver (once trained) at home or continuing with 
administration at site, based on personal preference and the Investigator's clinical judgment. 
The study is blinded until the final database lock of the core study to protect the integrity of the 
data in the ongoing core study. Once study unblinding occurs after the final database lock of 
the core study, the participants will continue to receive the same dose of iscalimab (either 600 
mg or 300 mg) and for those assigned to the 300 mg regimen, they will no longer receive the 
placebo PFS. 
Note: PFS do not need to be prepared at the site. PFS will be packaged both as open-label and 
double-blind supplies. When the final database lock for the TWINSS core study is achieved, 
the extension study will become an OL study and the PFS will be provided in an OL manner 
with no further requirements for placebo PFS injections. 


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Novartis Global Clinical Supply (GCS) would provide the following IMPs in the trial. No other 
medication would be supplied by GCS. 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
CFZ533 300 
mg/2 mL 
Solution for 
injection 
Subcutaneous 
Use 
Blinded; PFS 
Novartis Pharma 
AG 
Placebo/2 mL 
Solution for 
injection 
Subcutaneous 
Use 
Blinded; PFS 
Novartis Pharma 
AG 
CFZ533 300 
mg/2 mL (OL) 
Solution for 
injection 
Subcutaneous 
Use 
Open-label; PFS 
Novartis Pharma 
AG 
Instructions for administration of CFZ533 (iscalimab) and matching placebo are described in a 
separate manual. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
6.1.3 
Treatment arms/group 
No re-randomization is planned for the extension study. The treatment re-assignment for the 
extension study occurs at visit Week 60E1 which is the last visit of the core study (Week 60). 
Upon completion of the core study, Investigators will use their clinical judgment including 
responder definitions provided below to decide if it is beneficial for participants to continue 
with the extension study based upon response to therapy at the end of the treatment period of 
the core study. 
Participants will be re-assigned to one of the following two treatment arms: 
• Arm 1 - Iscalimab 600 mg s.c. Q2W 
• Arm 2 - Iscalimab 300 mg s.c. Q2W 
At Week 60 of the TWINSS core study, all eligible participants from the core study can opt to 
be enrolled in the extension study via IRT. The Week 60E1 visit will be performed on the same 
day once the Week 60 visit of the core study is completed by the participant. The Investigator 
or his/her delegate will contact the IRT after confirming that the participant fulfills all the 
extension study inclusion/exclusion criteria. An IRT algorithm will be programmed to assign 
the participant to blinded treatment in the extension study using ESSDAI (Cohort 1 and Cohort 
2) and ESSPRI (Cohort 2) assessment scores from predefined time points in the TWINSS core 
study. 
• For participants rolling over from Cohort 1 in the TWINSS core study, the change in 
ESSDAI score between Week 4 and Week 48 will be used to determine if the participant 
responded to treatment in the core study. If an ESSDAI score is missing at Week 4 and/or 
Week 48, then Week 0 or Week 40 scores should be respectively used for the algorithm. A 
decrease of 3 points or more from Week 4 (or Week 0 if the ESSDAI score is missing at 
Week 4) will classify the participant as a treatment responder in Cohort 1. 


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• For participants rolling over from Cohort 2 in the TWINSS core study, a change in both 
ESSDAI and ESSPRI scores between Week 4 and Week 48 will be used to determine if 
the participant responded to treatment in the core study. If an ESSDAI or ESSPRI score is 
missing at Week 4 and/or Week 48, then Week 0 or Week 40 scores should be 
respectively used for the algorithm. A decrease of 1 point or more in both the ESSDAI and 
ESSPRI scores from Week 4 (or Week 0 if the ESSDAI or ESSPRI score is missing at 
Week 4) will classify the participant as a treatment responder in Cohort 2.   
Week 4 is being used as a baseline assessment to assess change over time, solely for the 
purposes of re-assigning patients to 300 mg or 600 mg, in a non-randomized manner, in this 
extension trial and was selected to minimize any potential placebo effect and regression to the 
mean observed at study treatment initiation in clinical trials. 
Taking the treatment received during Treatment Period 2 of the TWINSS core study, and the 
responder status as the reference, the IRT algorithm will re-assign a dose level for extension 
study treatment. The maintenance treatment assigned for the extension study will be the same 
dose as in the core study or a higher dose level (Figure 6-1). 
• Participants receiving iscalimab 600 mg s.c. Q2W or 300 mg s.c. Q2W in the core study 
and who meet the definition of a response will continue with the same dose in the 
extension study. 
• Participants receiving iscalimab 600 mg s.c. Q2W in the core study and who do not meet 
the definition of a response will continue in the extension study with the same dose. 
• Participants receiving iscalimab 150 mg s.c. Q2W in the core study and who meet the 
definition of a response will be re-assigned to 300 mg s.c. Q2W in the extension study. 
• Participants receiving iscalimab 300 mg s.c. Q2W or 150 mg s.c. Q2W in the core study 
and who do not meet the definition of a response will be re-assigned to 600 mg s.c. Q2W 
in the extension study. 
 
 
 
 
 
 
 
 


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Figure 6-1 
IRT Algorithm for treatment reassignment 
 
 
6.1.4 
Treatment duration 
The planned duration of study treatment is 48 weeks. Participants may be discontinued from 
treatment earlier (see Section 9.1.1). 
6.2 
Other treatment(s) 
Participants experiencing disease signs and symptoms may receive short-term symptomatic 
care with over-the-counter, anti-inflammatory/analgesic agents such as nonsteroidal anti-
inflammatory drugs (NSAID) and paracetamol. Participants whose SjS disease signs and 
symptoms are not adequately controlled by symptomatic care, and/or who suffer from more 
severe SjS disease manifestations not suitable for such treatment, may receive rescue therapy 
with corticosteroids, if determined by the Investigator to be medically necessary (Section 6.2.3). 
There is currently no consensus on the definition of flare in SjS. With reference to the recently 
completed JOQUER trial in pSS (Gottenberg et al 2014) that reported 12 flares among 120 
patients during 12 months, it is conceivable that < 10% of all patients in the current iscalimab 
trial will experience a deterioration (or ‘flare’) that warrants treatment escalation. Treatment 
escalation would, for example, be increasing the steroid dose, or introducing de novo an 
immunosuppressant agent like azathioprine. Participants who require escape treatment (other 
than allowed rescue medications – see Section 6.2.3) must be discontinued from study 
medication, enter the safety follow-up period and follow the local standards for treatment of 
SjS worsening. In the absence of consensus guidelines for treatment of systemic manifestations 
in SjS, it is recommended to consult the SLE treatment guidelines as far as they pertain to the 
respective organ involvement observed in the trial (for example renal, nervous system or skin 
vasculitis). 


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Any medication used to treat Adverse Events (AE) must be recorded on the Case Report Form 
(CRF). 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact the Novartis medical monitor before re-
assigning treatment for a participant or allowing a new medication to be started. If the 
participant is already enrolled, contact Novartis to determine if the participant should continue 
participation in the study. 
Concomitant treatment may include standard of care for dry eye and dry mouth symptoms, such 
as the use of artificial tears and artificial saliva/salivary stimulants (e.g., cevimeline, 
pilocarpine) at the discretion of the treating physician. Amount and frequency of use should be 
recorded at each visit. 
Short term use of oral analgesics (NSAIDs, paracetamol) is permitted. Azathioprine (up to 150 
mg/day), methotrexate (≤ 25 mg/week) and hydroxychloroquine (≤ 400 mg/day) are allowed as 
stable background medication defined as continued treatment ≥ 3 months without dose 
adjustments. Steroids (prednisone or equivalent ≤ 10 mg/day) are allowed during the extension 
study and tapering is permitted at intervals not exceeding prednisone 2.5 mg/2 weeks.  
Pre-emptive therapy with lamivudine or entecavir is allowed for participants with Hepatitis B 
surface antigen (HBsAg) seroreversion while on study treatment. Similarly, CMV antiviral 
medication used as pre-emptive therapy is allowed for participants with detectable virus by 
PCR. 
Note: Background and concomitant medications will not be provided by Novartis and must be 
supplied by the study center. 
6.2.2 
Prohibited medication 
Use of treatments displayed in the below table is not allowed in study periods as indicated. 
Table 6-2 
Prohibited medication 
Medication 
Prohibited in Study Period 
Action to be taken 
Other experimental therapies 
All 
Study treatment discontinuation 
required, participants should 
remain in the study and follow 
visit schedule 
Other biologics (for treatment 
of autoimmune diseases e.g., 
SjS, SLE, RA) 
All 
Study treatment discontinuation 
required, participants should 
remain in study and follow visit 
schedule 


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Medication 
Prohibited in Study Period 
Action to be taken 
DMARDs or other immune 
suppressive agents or changes 
in an existing DMARD regimen 
(hydroxychloroquine, 
methotrexate, azathioprine) 
Treatment period 
Study treatment discontinuation 
may be required on a case-by-
case basis 
Prednisone >10 mg (or 
equivalent other corticosteroid) 
Treatment period 
Study treatment discontinuation 
may be required on a case-by-
case basis 
Intravenous or oral 
cyclophosphamide; oral 
cyclosporine; oral MMF 
All 
Study treatment discontinuation 
required, participants should 
remain in the study and follow 
visit schedule 
Existing co-medications 
observed to cause in an 
individual patient a major side 
effect of dry mouth/eyes. 
Examples include 
antihistamines, 
antidepressants, 
anticholinergics, sedatives, 
antipsychotic drugs, anti-
Parkinson agents 
A comprehensive guide to 
medications with documented 
effects on salivary gland 
function or symptoms has been 
published by Wolff et al 2017 
(please see the footnote). 
Treatment period 
Study treatment discontinuation 
may be required on a case-by-
case basis 
Live/attenuated vaccine 
During treatment and for at 
least 14 weeks thereafter 
Study treatment discontinuation 
required, participants should 
remain in the study and follow 
visit schedule 
Wolff A, Joshi R, Ekström J, et al (2017) A guide to medications inducing salivary gland dysfunction, 
xerostomia, and subjective sialorrhea: A systemic review sponsored by the World Workshop on Oral 
Medicine VI; Drugs R D.; 17 (1): 1-28. 
6.2.3 
Rescue medication 
There is no established, approved immunosuppressive treatment for SjS. Participants may 
receive NSAIDs, paracetamol, or symptomatic care at the discretion of the treating physician 
as outlined in Section 6.2.1. Each concomitant drug must be individually assessed against all 
exclusion criteria and prohibited medication (Table 6-2). When in doubt the Investigator should 
contact the Novartis medical monitor before treatment reassignment or allowing a new 
medication to be started. If any of the medications listed in Table 6-2 is deemed a necessary 
rescue therapy, the Investigator must follow the actions to be taken outlined in this table. Rescue 
treatment is to be provided by the study center or personal physician. Participants must be 
encouraged to continue the follow-up visits even when discontinued permanently from the 
study treatment. 


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Corticosteroids may be administered to participants for SjS clinical disease flares after 
enrollment into this study as determined necessary by the responsible Investigator. 
 
 
: 
• the incremental daily steroid dose is > 2.5 mg/day prednisone or equivalent, or 
• the increased daily steroid dose is administered > 2 days within a 4-week period. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.) that is 
assigned when the participant is enrolled into core study, CCFZ533B2201, and is retained for 
the participant throughout his/her participation in the trial. This being an extension study, the 
Participant No. will remain the same as that of the core study; new participant numbers will not 
be assigned. 
The Participant No. consists of the Centre Number (Centre No.) assigned by Novartis to the 
investigative site with a sequential participant number suffixed to it, so that each participant's 
participation is numbered uniquely across the entire database. During the extension study, each 
participant will be uniquely identified by a Participant No.. 
6.3.2 
Treatment assignment, randomization 
No re-randomization will be performed in this study. At Week 60 of the core study, all eligible 
and consenting participants from the core study will be enrolled via Interactive Response 
Technology (IRT) and will be re-assigned to one of the treatment arms (refer to Section 6.1.3). 
An IRT algorithm will be programmed to assign the participant to blinded treatment in the 
extension study using ESSDAI (Cohort 1 and Cohort 2) and ESSPRI (Cohort 2) scores from 
predefined time points in the TWINSS core study. ESSDAI and ESSPRI scores at predefined 
time points will be transferred to the extension study IRT database by the electronic clinical 
outcome assessment (eCOA) vendor after the Investigator or his/her delegate has confirmed 
this transfer in the core study (for details, refer to the IRT user guide). The IRT will assign a 
number to the participant, which will be used to link the participant to a treatment arm and will 
specify a unique medication number for the first package of study treatment to be dispensed to 
the participant. 
• For participants rolling over from Cohort 1 in the TWINSS core study, the change in 
ESSDAI score between Week 4 and Week 48 will be used to determine if the participant 
responded to treatment in the core study. If an ESSDAI score is missing at Week 4 and/or 
Week 48, then Week 0 or Week 40 scores should be respectively used for the algorithm. A 
decrease of 3 points or more from Week 4 (or Week 0 if the ESSDAI score is missing at 
Week 4) will classify the participant as a treatment responder in Cohort 1. 
• For participants rolling over from Cohort 2 in the TWINSS core study, a change in both 
ESSDAI and ESSPRI scores between Week 4 and Week 48 will be used to determine if 
the participant responded to treatment in the core study. If an ESSDAI or ESSPRI score is 
missing at Week 4 and/or Week 48, then Week 0 or Week 40 scores should be 


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respectively used for the algorithm. A decrease of 1 point or more in both the ESSDAI and 
ESSPRI scores from Week 4 (or Week 0 if the ESSDAI or ESSPRI score is missing at 
Week 4) will classify the participant as a treatment responder in Cohort 2. 
6.4 
Treatment blinding 
This will be a double-blind treatment until the final database lock of Core study. Participants, 
Investigator, site staff, and persons performing the assessments will remain blinded to the 
identity of the treatment until the final database lock of the core study, using the following 
methods: 
1. Treatment assignment data are kept strictly confidential until the time of unblinding and 
will not be accessible by anyone else involved in the study with the exception of the 
bioanalyst 
2. The identity of the treatments will be concealed by the use of investigational treatments 
that are all identical in packaging, schedule of administration and appearance 
The re-assignment codes associated with participants from whom PK samples are taken will 
only be disclosed to the PK bioanalysts who will keep the PK results confidential until primary 
database lock of the core study (Week 24). Blood samples for PK, immunogenicity and 
 
assessment will be collected for all participants. 
Whenever needed or requested by the clinical team, before the open-label part of the extension 
study, the bioanalyst will share bioanalytical data in a blinded fashion with the 
pharmacokineticist. 
Up to final database lock of core study, unblinding will only occur in the case of subject 
emergencies (see Section 6.6.2). 
After final database lock of core study, the treatment arm for individual participant will be 
unblinded and the study will be conducted open-label. 
Unblinding of the CTT will occur at the time of the primary database lock at Week 24 for each 
cohort of the core study. 
Table 6-3 
Blinding and unblinding plan 
  
Time or Event 
  
Role 
Treatment re-
assignment 
list 
generated 
Treatment 
allocation & 
dosing 
Safety event 
(single 
participant 
unblinded) 
Primary 
database 
lock at Week 
24 of core 
study 
Final 
database 
lock of core 
study 
Participants 
B 
B 
B 
B 
U 
Site staff 
B 
B 
UI 
B 
U 
PK sample 
analyst(s) 
B 
U 
UI 
U 
U 
Global Clinical 
Supply and 
Randomizatio
n Office 
U 
U 
U 
U 
U 


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Time or Event 
  
Role 
Treatment re-
assignment 
list 
generated 
Treatment 
allocation & 
dosing 
Safety event 
(single 
participant 
unblinded) 
Primary 
database 
lock at Week 
24 of core 
study 
Final 
database 
lock of core 
study 
Unblinded 
Pharmacovigil
ance sponsor 
staff 
B 
UI 
UI 
UI 
U 
Data 
Monitoring 
Committee 
(DMC) 
B 
U 
U 
U 
U 
CTT and other 
sponsor 
teams (trial 
team, project 
team, 
management 
& decision 
boards, 
support 
functions) 
B 
B 
B 
U 
U 
Key: 
UI: Allowed to be unblinded on individual participant level 
U: Unblinded 
B: Remains blinded 
6.5 
Dose escalation and dose modification 
Dose escalation is not applicable in this study. 
6.5.1 
Dose modifications 
Dose modifications of the investigational drug are not permitted. 
6.5.2 
Dose interruptions 
For participants who are not able to follow the protocol-specified dosing schedule due to 
unresolved AEs, or for any other reason cannot attend a visit within a time window specified in 
Section 8, dose interruptions may be occasionally permitted. A maximum of 1 dose of study 
treatment may be missed in a 3 month period, as specified below. In case of an AE or for any 
reason (e.g., non-compliance, operational hurdle) resulting in additional interruptions of the 
dosing scheme, consultation and agreement with Novartis will be necessary to decide whether 
the participant can continue or needs to be withdrawn from the treatment. 
Treatment Period 
• No dose interruptions are allowed prior to completion of Week 66 (Day 463): this is a 
critical period to ensure CD40 occupancy in target tissues 


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• From Week 68 (Day 477) to Week 108 (Day 757): 1 dose of study treatment may be 
missed in a 3 month period 
These changes must be recorded on the appropriate eCRF. 
In all cases the original visit schedule should be maintained (no recalculation from the last 
visit). 
6.5.3 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
All participants must be followed up for adverse events and serious adverse events for 14 weeks 
following the last dose of CFZ533. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The site staff will administer the study treatment assigned by IRT to the participants during 
onsite visits. Kit numbers are collected in the IRT and the site staff will record study drug 
administration in the eCRF. The compliance will also be assessed by means of site and patient-
specific drug accountability by Novartis monitors during site monitoring visits using medication 
pack numbers, drug label information and information from IRT. 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant's 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the Investigator and/or study personnel at each visit based on 
information provided by the participant. This information should be captured in the source 
document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log. 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant 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 participant 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 participant, he/she must provide the requested participant identifying 
information and confirm the necessity to break the treatment code for the participant. The 
Investigator will then receive details of the investigational drug treatment for the specified 


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participant and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken. Participants 
unblinded following an intentional emergency code breaking should be discontinued from the 
study. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide: 
• protocol number 
• participant number 
In addition, oral and written information to the participant 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 CFZ533 (iscalimab) and placebo by Novartis, 
in packaging as described under investigational and control drugs section. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant 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 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a participant’s home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the event the Investigator 
has decided that an on-site visit by the participant is no longer appropriate or possible, and that 
it is in the interest of the participant’s health to administer the study treatment even without 
performing an on-site visit. The dispatch of IMP from the site to the participant’s home remains 
under the accountability of the Investigator. Each shipment/provisioning will be for a maximum 
of 3-month’s supply. In this case, regular phone calls or virtual contacts (every 4 weeks or more 
frequently if needed) will occur between the site and the participant for instructional purposes, 
safety monitoring, drug accountability, investigation of any adverse events, ensuring 
participants continue to benefit from treatment and discussion of the participant´s health status 
until the participants can resume visits at the study site. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 


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instructions specified on the labels and in the IB. Clinical supplies are to be dispensed only in 
accordance with the protocol. The Investigator should educate the participant on how to 
properly store the study treatment if the participant is self-administering at home. Technical 
complaints are to be reported to the respective Novartis Country Organization (CO) Quality 
Assurance. 
The investigational drug iscalimab will be provided in PFS of 300 mg/2mL as a solution for s.c. 
administration. The matching placebo will be provided in PFS of 0 mg/2 mL as a solution for 
s.c. administration. Two injections of 2 mL each will be administered to the participant at every 
dosing visit, as follows: 
Loading regimen: 
CFZ533 (iscalimab) 600 mg or 300 mg will be administered s.c., weekly for the first 3 doses 
(Weeks 60E1, 61 and 62); then, from Week 64, iscalimab will be administered s.c. bi-weekly 
(every other week or Q2W) as described below. 
Maintenance regimen: 
• Arm 1 (iscalimab 600 mg): two 2 mL syringes, each containing 300 mg of iscalimab 
• Arm 2 (iscalimab 300 mg): one 2 mL syringe of placebo and one 2 mL syringe 
containing 300 mg of iscalimab 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. 
If local regulations allow, some study participants will be asked to use a Digital Injection Care 
Management device for disposal of used syringes after home use in a Smart Sharps bin rather 
than in a standard biohazard sharps bin. This is an optional pilot project that will be conducted 
at selected countries/sites. The digital box allows to capture the real time date and image of the 
disposal of the syringe. The connected device/box reminds the participant when medication is 
due, tracks when medication is taken and interventions as per the Novartis trial protocols. 
Detailed instructions on use and handling will be described in a separate manual. For the study 
participants using the Digital Injection Care Management device, there are no risks associated 
with the disposal of used syringes after home use in the Smart Sharps bin and/or return of the 
Smart Sharps bin with the used syringes after home use to the study site.  
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the Investigator 
folder at each site. 


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6.7.1.2 
Handling of additional treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Study treatment (iscalimab 600 mg and 300 mg) will be administered s.c. by the participant, 
caregiver or site staff. The PFS will be provided by the site staff to the participant, who will 
self-administer the injections at the specified study time point. Participants will be instructed in 
detail how to self-administer the s.c. injection using the PFS. Site staff will administer the 
injection to those participants who are not able or unwilling to self-administer the PFS injection. 
Detailed instructions on the self-administration of the study treatment will be described in the 
IFU and provided to each participant. It shall be recorded on the corresponding eCRF(s) 
whether the participant self-administered the PFS or whether site staff or caregiver administered 
the PFS and whether it was administered at home or at the site. 
Iscalimab 600 mg s.c. Q2W 
• Iscalimab loading doses will be 600 mg s.c. (2 injections of 300 mg/2 mL) on Week 60E1 
(Day 421),  Week 61 (Day 428) and Week 62 (Day 435) 
• From Week 62 the participant will receive 600 mg s.c. Q2W iscalimab until Week 106 
(last dose) 
Iscalimab 300 mg s.c. Q2W 
• Iscalimab loading doses will be 600 mg s.c. (2 injections of 300 mg/2 mL) on Week 60E1 
(Day 421), 300 mg s.c. (1 injection of 300mg/2 mL and 1 injection of 2 mL of the 
placebo) on Week 61 (Day 428) and 300 mg s.c. Week 62 (Day 435) 
• From Week 62 the participant will receive 300 mg s.c. Q2W iscalimab until Week 106 
(last dose) 
The first study treatment administration will occur at Week 60E1 after the inclusion/exclusion 
criteria have been confirmed, all study scheduled assessments have been performed and the 
scheduled blood samples have been drawn. For the loading doses on Week 60E1 (Day 421), 
Week 61 (Day 428) and Week 62 (Day 435), all injections will be self-administered by the 
participant at the study site under the supervision of a site staff member after the study 
assessments for the visit have been completed. Participants will be required to attend the study 
site for the Week 64 visit and starting at Week 66, the participants will be allowed to self-
administer the study medication at home on an alternating basis through to Week 106 or 
continue to present at the study site for injection administrations, based on the participant's 
preference and the investigator's judgment. 
The trial-related safety and efficacy procedures will be conducted as indicated in Table 8-1. 
While at the site visits, participants will be asked to refer to the IFU and to proceed with self-
injection. At study visits requiring pre-dose blood samples, the participant will self-administer 
study treatment only after the blood samples have been collected. 
For each study visit at the site, all study assessments including completion of Patient Reported 
Outcomes (PROs) should be completed prior to the self-administration of the study treatment. 


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All dosages prescribed and dispensed to the participants and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. Immediately before dispensing 
the package to the participant, site staff will detach the outer part of the label from the packaging 
and affix it to the source document (Drug Label Form) for that participant's unique participant 
number. 
The investigator should promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant's 
safety and the validity of the study. The participant should be instructed to contact the 
Investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Administration  
Single syringes will be packed in individual boxes. The site and participant should refer to the 
IFU for storage and handling instructions. Each injection should be administered into an 
appropriate injection site of the body (thighs, arms, or abdomen). Each new injection should be 
administered at the same site on opposite sides of the body or given on two different body sites. 
If the participant chooses the abdomen, a 2-inch area around the navel should be avoided. 
Investigational drug should not be injected into areas where the skin is tender, bruised, red, or 
hard or where participant has scars or stretch marks. Injection sites should be alternated to 
reduce the risk of reaction. Used safety syringes should be disposed immediately after use in a 
sharps container or according to the regulatory needs to the respective countries. 
Home administration 
Participants (or caregivers) will be allowed to self-administer the PFS at home when they are 
not visiting the site for any other trial-related procedures. Participants will be allowed to self-
administer the PFS at home (starting at Week 66) only if they have exhibited correct use for 
self-administering the PFS at the site during the first 4 visits for treatment during the extension 
study. At such time points, if requested by the participant, a caregiver would be allowed to 
administer the study medication. Optional site visits have been included in the assessment table 
between the visits at which trial-related procedures are not to be conducted at the site. 
Participants will be allowed to self-administer the PFS at home or to visit the site during the 
optional visits to self-administer the PFS under the supervision of the site staff. If the participant 
is not able or not confident to self-administer the PFS, he/she should visit the site at every 
optional site visit (e.g., every 4 weeks) during the treatment period and the site staff will 
administer the PFS. 
Prior to self-administration at home, participants should contact the investigator/site staff in the 
case they are experiencing any AE/SAEs or have any concerns or there have been changes to 
the ongoing concomitant medications. 
7 
Informed consent procedures 
The following informed consents are included in this study:  
1. Main study consent, which also includes a subsection that requires a separate signature for 
the optional consent for digital assessments and optional consent for digital injection care 
management device.  


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2. As applicable, Pregnancy Outcomes Reporting Consent for female subjects who took study 
treatment.  
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
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 participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant during the study as needed. Any new information 
regarding the safety profile of the investigational drug 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 discussed with the participant. 
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. 
 
 
 
 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 


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8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. 
Every efforts should be made to adhere to the weekly dosing schedule (loading doses) and the 
bi-weekly maintenance dosing regimen in both arms in this trial. 
Visits can be performed with the following time windows: 
Treatment Period 
• +/- 1 calendar day: from Week 60E1 (Day 421) to Week 61 (Day 428) 
• +/- 2 calendar days: from Week 62 (Day 435) to Week 66 (Day 463) 
• +/- 5 calendar days: from Week 68 (Day 477) to Week 108 (Day 757) 
Follow-up Period 
+/- 5 calendar days from Week 112 (Day 785) to Week 120 (Day 841) 
Note: All efforts need to be made to maintain the actual duration of 48-week study treatment 
period. Therefore, a study visit subsequent to a visit, which has been delayed or brought forward 
needs to be planned as per original visit schedule. 
Missed or rescheduled visits should not lead to automatic discontinuation. Participants who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the CRF.  
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 


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Table 8-1 
Assessment Schedule 
Period 
Extension-Treatment 
Visit Name 
Wk 
60E11 
Wk 
61 
Wk 
62 
Wk 
64 
Wk 
66 
Wk 
68 
Wk 
70 
Wk 
72 
Wk 
74 
Wk 
76 
Wk 
78 
Wk 
80 
Wk 
82 
Wk 
84 
Wk 
86 
Wk 
88 
Wk 
90 
Wk 
92 
Wk 
94 
Wk 
96 
Days 
421 
428 
435 
449 
463 
477 
491 
505 
519 
533 
547 
561 
575 
589 
603 
617 
631 
645 
659 
673 
Weeks 
60 
61 
62 
64 
66 
68 
70 
72 
74 
76 
78 
80 
82 
84 
86 
88 
90 
92 
94 
96 
Optional site visit2 
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Informed consent 
X3 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Contact IRT 
X4 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Smoking history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior therapy for 
Sjögren's Syndrome 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse Events5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
C6 
  
  
S7 
  
S7 
  
S7 
  
S7 
  
S7 
  
S7 
  
S7 
  
S7 
  
S7 
Vital signs and body 
measurements 
C6 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Electrocardiogram 
(ECG) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis and CMV 
monitoring (local)9 
C6 
  
  
  
  
  
  
S7 
  
  
  
  
  
S7 
  
  
  
  
  
S7 


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Period 
Extension-Treatment 
Visit Name 
Wk 
60E11 
Wk 
61 
Wk 
62 
Wk 
64 
Wk 
66 
Wk 
68 
Wk 
70 
Wk 
72 
Wk 
74 
Wk 
76 
Wk 
78 
Wk 
80 
Wk 
82 
Wk 
84 
Wk 
86 
Wk 
88 
Wk 
90 
Wk 
92 
Wk 
94 
Wk 
96 
Days 
421 
428 
435 
449 
463 
477 
491 
505 
519 
533 
547 
561 
575 
589 
603 
617 
631 
645 
659 
673 
Weeks 
60 
61 
62 
64 
66 
68 
70 
72 
74 
76 
78 
80 
82 
84 
86 
88 
90 
92 
94 
96 
Hematology 
C6 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Clinical Chemistry 
C6 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Coagulation Panel10 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
Immunology 
C6 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
Cryoglobulins11 
C6 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
Pregnancy test12 
C6 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
PK blood collection13 
C6 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
  
Immunogenicity13 
C6 
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
  
Urinalysis dipstick 
C6 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Prefilled syringe 
questionnaire16 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Trial feedback 
questionnaire16 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Period 
Extension-Treatment 
Post-Treatment Follow-Up 
Visit Name 
Wk 98 
Wk 100 
Wk 102 
Wk 104 
Wk 106 
Wk 108/TD19 
Wk 112 
Wk 120/EOS20 
Days 
687 
701 
715 
729 
743 
757 
785 
841 
Weeks 
98 
100 
102 
104 
106 
108 
112 
120 
Optional site visit2 
X 
  
X 
  
X 
  
  
  
Informed consent 
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
  
  
  
  
  
  
  
  
Contact IRT 
  
X 
  
X 
  
  
  
  
Study drug administration 
X 
X 
X 
X 
X21 
  
  
  
Demography 
  
  
  
  
  
  
  
  
Smoking history 
  
  
  
  
  
  
  
  
Medical history/current medical 
conditions 
  
  
  
  
  
  
  
  
Prior therapy for Sjögren's 
Syndrome 
  
  
  
  
  
  
  
  
Adverse Events5 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
  
S7 
  
S7 
  
S7 
S7 
S7 
Vital signs and body measurements 
  
X 
  
X 
  
X 
X 
X 
Electrocardiogram (ECG) 
  
  
  
  
  
X 
  
  
Hepatitis and CMV monitoring 
(local)9 
  
  
  
  
  
S7 
  
S7 
Hematology 
  
X 
  
X 
  
X 
X 
X 
Clinical Chemistry 
  
X 
  
X 
  
X 
X 
X 
Coagulation Panel10 
  
  
  
  
  
X 
  
  
Immunology 
  
X 
  
  
  
X 
X 
X 
Cryoglobulins11 
  
  
  
  
  
X 
  
X 
Pregnancy test12 
  
X 
  
X 
  
X 
X 
X 


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Period 
Extension-Treatment 
Post-Treatment Follow-Up 
Visit Name 
Wk 98 
Wk 100 
Wk 102 
Wk 104 
Wk 106 
Wk 108/TD19 
Wk 112 
Wk 120/EOS20 
Days 
687 
701 
715 
729 
743 
757 
785 
841 
Weeks 
98 
100 
102 
104 
106 
108 
112 
120 
PK blood collection13 
  
  
  
  
  
X 
  
X 
Immunogenicity13 
  
  
  
  
  
X 
  
X 
Urinalysis dipstick 
  
X 
  
X 
  
X 
X 
X 
Prefilled syringe questionnaire16 
  
  
  
  
  
X 
  
  
Trial feedback questionnaire16 
  
  
  
  
  
  
  
X 


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Period 
Extension-Treatment 
Post-Treatment Follow-Up 
Visit Name 
Wk 98 
Wk 100 
Wk 102 
Wk 104 
Wk 106 
Wk 108/TD19 
Wk 112 
Wk 120/EOS20 
Days 
687 
701 
715 
729 
743 
757 
785 
841 
Weeks 
98 
100 
102 
104 
106 
108 
112 
120 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Corresponds to the Week 60 visit of the core study. Assessments carried out as part of Week 60 as per core study protocol should be used for Week 60E1 of the 
extension study.  
2 Optional site visits - Week 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106. Participants who are unable to self-administer the PFS injections at home will visit the site and 
site staff will supervise self-administration or administer the PFS injection for them. Other participants who can self-administer the PFS injection can do so at home at 
these optional visits. 
3 Informed consent should be obtained before commencement of the Week 60 assessments of the core study.  
4 Contact IRT for new treatment reassignment. 
5 AEs/SAEs occurring after the participant has signed the informed consent must be captured on the appropriate eCRF page. 
6 C - These assessments shall be conducted as part of the core study CCFZ533B2201 and will not be repeated in this extension study 
7 S - Assessment to be recorded in the source documentation only 
8 
. 
9 Local lab testing of CMV IgG, IgM and DNA (by PCR) must be performed every 3 months until end of study. Hepatitis B monitoring applicable to HBsAg (-) patients 
who were HBcAb (+) and HBV DNA (-) at screening during the core study. Local lab testing of HBsAg and HBV DNA must be performed every 3 months until end of 
study. 
10 While on treatment, coagulation monitoring applies only to participants who have antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin antibodies) and/or 
who are on pre-existing antithrombotic therapy/prophylaxis, as reflected in the exclusion criteria of the TWINSS core study protocol. 
11 Analysis of cryoglobulins will be done only for participants who were positive at screening in the TWINSS core study. 
12 Urine pregnancy tests will be performed throughout the study 
13 Blood sample is collected pre-dose. 
14 
  
15 
. 
16 Optional 
17 
. 
18 
. 
19 In case of premature discontinuation, participants will enter the follow-up after completing assessments for this visit. 
20 Mandatory to all participants, including those who have discontinued the study prematurely.  
21 Week 106 is the last dose administration visit in the Treatment Period.  


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8.1 
Screening 
Not applicable for this extension study. 
8.1.1 
Information to be collected on screening failures 
Not applicable for this extension study. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Participant demographic and baseline characteristic data to be collected on all participants 
include: age, sex, race, ethnicity, smoking history, relevant medical history/current medical 
condition present before signing informed consent where possible, diagnoses instead of 
symptoms will be recorded. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF if, in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 


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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
For details on AE collection and reporting, refer to Section 10. 
Table 8-2 
Assessment and Specifications 
Assessment 
Specification 
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/or pelvic exams may be performed. 
A short physical exam will include the examination of general appearance 
and vital signs (blood pressure and pulse). A short physical exam will be at all 
visits where ESSDAI assessments are not required. 
The Investigator should ask the participant for and pay attention to presence 
of signs and symptoms of infection. 
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 recorded on the appropriate CRF 
that captures medical history. Significant findings made after signing informed 
consent which meet the definition of an Adverse Event must be recorded as 
an adverse event. 
Vital signs 
If possible, vital sign assessments should be performed by the same study 
site staff member using the same validated device throughout the study. Vital 
signs include blood pressure (BP) and pulse measurements. After the 
participant has been sitting for five minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be 
measured three times using an automated validated device, with an 
appropriately sized cuff. 
Clinically notable vital signs are defined in Section 16.1. 
Body 
measurements 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) 
in indoor clothing, but without shoes) will be measured as specified in Table 
8-1. 
Body mass index (BMI) will be calculated using the following formula: BMI = 
Body weight (kg) / [Height (m)]2 
8.4.1 
Laboratory evaluations 
Clinically notable laboratory findings are defined in Section 16.1. 
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 AE 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. 


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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 participant to continue in the study. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. All listed below laboratory evaluations will be 
performed by a central laboratory with exception of erythrocyte sedimentation rate (ESR), 
urinalysis, urine pregnancy test, cryoglobulins and hepatitis monitoring (HBsAg and HBV-
DNA) applicable to HBsAg-negative, anti-HBc positive participants continuing from the 
TWINSS core study and CMV monitoring. 
Table 8-3 
Laboratory Evaluations 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Bands, Other), Erythrocyte sedimentation rate (ESR - local testing) 
Chemistry 
Albumin, Alkaline phosphatase, Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST), Gamma-glutamyl- transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Direct Bilirubin, Indirect Bilirubin, 
Total Bilirubin, Total Cholesterol, Low Density Lipoprotein (LDL), High 
Density Lipoprotein (HDL), Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (non-fasting), C-reactive 
protein (CRP). Estimated creatinine clearance will be calculated using MDRD 
formula. 
Urinalysis (locally) 
Macroscopic Panel: (Dipstick) 
pH, Glucose, Protein, Blood, Bilirubin, Urobilinogen, Ketones, Urine nitrite, 
Leukocytes, Specific Gravity. 
If the dipstick result is positive for protein, nitrite, leucocytes and/ or blood, the 
sample will be analyzed locally for culture and for microscopic analysis of 
white blood cells, red blood cells and casts. 
Coagulation 
Prothrombin time (PT), Partial Thromboplastin Time (PTT), International 
normalized ratio (INR) 
Immunology 
 Complement (C3, C4) 
CMV, Hepatitis 
monitoring (locally, 
as applicable) 
HBsAg, HBV-DNA, CMV serology (CMV IgG, IgM) and CMV DNA by PCR 
Additional tests 
Cryoglobulins (local testing), PK, PD (
) and immunogenicity 
(anti-CFZ533 anti-bodies) blood samplings, 
 
Pregnancy Test 
Urine pregnancy test (please see Section 8.4.3) 
8.4.2 
Electrocardiogram (ECG) 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The preferred sequence of cardiovascular data collection during study 
visits is ECG collection first, followed by vital signs, and blood sampling, and then all other 
assessments. The Fridericia QT correction formula (QTcF) should be used for clinical 
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Single 12 lead ECGs are collected. The original ECGs on non-heat-sensitive paper and a 
certified copy on non-heat sensitive paper, appropriately signed, must be collected and archived 
at the study site. Each ECG tracing must be labeled with study number, participant number, 
date and time, and filed in the study site source documents. Any identifier details must be 
redacted (e.g., participant initials, date of birth). Results must be entered into the eCRF. 
For any ECGs with participant safety concerns (e.g., severe arrhythmia, conduction abnormality 
of QTcF > 500 ms), two additional ECGs must be performed to confirm the safety finding. If 
the participant is hemodynamically compromised, the investigator or a medically qualified 
person must initiate appropriate safety procedures without delay (for example cardioversion). 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have local urine pregnancy tests 
monthly, as indicated in Table 8-1. Additional pregnancy testing might be performed if 
requested by local requirements. A positive urine test requires immediate interruption of study 
drug and needs to be confirmed with a serum β-hCG test (serum pregnancy test). If positive, 
the participant must be discontinued from the study treatment. Highly effective method of birth 
control must be used for women of childbearing potential (see exclusion criteria definitions, 
Section 5.2). In consideration of the patient population and overall iscalimab risk benefit 
profile, women of child-bearing potential must utilize highly effective contraception methods 
to avoid becoming pregnant while receiving iscalimab and for 14 weeks after the last dose or 
until data from the reproductive toxicity studies suggest otherwise. Women who are nursing 
may not participate in this trial. The washout period of 14 weeks after the last dose is justified 
based on predicted PK profiles at 10 mg/kg, where iscalimab is predicted to be fully cleared 
from plasma and tissues, with no residual pharmacodynamic activity. 
If participants cannot visit the site to have pregnancy tests, urine pregnancy test kits may be 
used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first, and only if the test result is negative are they to proceed with administration of the study 
treatment. A communication process should be established with the participant so that the site 
is informed and can verify the pregnancy test results (e.g., following country-specific 
measures). 
8.4.4 
Other safety evaluations 
Malignancies 
For participants on study treatment and in follow-up, any type of malignancies (including skin 
neoplasms, leukemia, post-transplantation proliferative disorder (PTLD)) should be reported as 
an SAE and recorded on the appropriate eCRFs. An SAE report should be completed for 
malignancies occurring until the last visit (for participants in follow-up) or for 14 weeks after 
the last dose of study treatment taken (for participants in the treatment period or who completed 
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Infections 
Infections should be recorded with start and end date, type of infection, and medications used 
on the appropriate eCRFs. If medications are used to treat the infection, the name of the 
medication must be entered on the appropriate eCRF. If the participant is hospitalized an SAE 
report must be completed and reported. 
8.4.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
 
• 
 
• 
 
• 
 
 
 
 
 
 
 
 
 
 
 


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Trial Feedback 
This trial will include an option for participants to complete an anonymized questionnaire, ‘Trial 
Feedback Questionnaire’ (TFQ) for participants to provide feedback on their experience in a 
Novartis clinical trial. The TFQ is a validated web-based questionnaire. The TFQ has been 
tested and validated by research conducted by Adelphi, PatientsLikeMe and HRM using 
established PRO methodology and is based on feedback from 400 adult participants across 
different therapeutic areas. 
The optional questionnaire will be completed at the site at Week 120, end of the study period. 
TFQ questions relate to both protocol-specified and site-specific components, including study 
burden and interaction with site staff. Feedback is anonymous. Individual participant level 
responses will not be reviewed by Investigators. Responses will be used by Novartis to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the participant's disease, symptoms, treatment effect or adverse 
events and therefore the TFQ data is not trial data. 
The TFQ data will be stored in the eCOA vendor provider database, separate from the clinical 
trial database. 
Satisfaction with self-injection using a prefilled syringe questionnaire (PFS 
Questionnaire) 
This trial will include an option for participants self-administering CFZ533 (iscalimab) or 
placebo with PFS outside of clinic to complete a study-specific questionnaire to evaluate their 
experience and satisfaction with using the PFS (Section 16.10). Feedback is anonymous. 
Individual participant level responses will not be reviewed by Investigators. 
The questionnaire consists of five questions and measures the confidence, ease of use, 
convenience, satisfaction and the participant's willingness to self-inject. Each question has five 
answers from “1 = not easy/not confident/not convenient/not satisfied/definitely not” to “5 = 


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very easy/very confident/very convenient/very satisfied/yes definitely”. The scores will be 
reported per question and no overall score will be calculated. Higher scores mean higher 
satisfaction, better experience. The questionnaire will be available in each language for each 
country participating in this study following a validated translation process. 
The optional questionnaire will be completed at the site at Week 108, end of the treatment 
period. 
Site and participants will receive clear instructions on the completion of the questionnaire. Site 
must allow participants to complete the questionnaire on their own without any assistance from 
the site staff. 
The PFS data will be stored in the eCOA vendor database, separate from the clinical trial 
database. 
8.5.2 
Pharmacokinetics 
Free CFZ533 (iscalimab) plasma concentrations will be measured in all participants. 
PK samples will be collected at the visits defined in the assessment schedule. All blood samples 
will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. 
Details of sample processing, handling, storage and shipment will be described in a separate 
laboratory manual. 
All samples will be given a unique sample number and a dose reference identification number 
as listed in the Section 16.5. The actual sample collection date and time will be entered on the 
appropriate eCRF. 
Free CFZ533 (iscalimab) plasma concentrations will be determined using a validated target-
based sandwich assay. The data and details of the analytical methods will be provided in a 
standalone Bioanalytical Data Report. 
Concentrations below the lower limit of quantification (LLOQ) will be reported as “zero” and 
missing data will be labeled as such in the Bioanalytical Data Report. 
For each PK sample, the actual recorded sampling time will be captured, and the elapsed time 
since the first and since the last dose will be calculated. 
8.5.3 
Immunogenicity 
The presence of anti-CFZ533 (iscalimab) antibodies will be determined in all participants, using 
a validated assay.  
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein. Details of sample processing, handling, storage and shipment will be 
described in a separate laboratory manual. 
All samples will be given a unique sample number as listed in the Section 16.5. The data and 
details of the analytical methods will be provided in a standalone Bioanalytical Data Report. 


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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
• Following emergency unblinding of the treatment arm 
• Emergence of the following adverse events:  
• Persistent neutropenia Common Terminology Criteria (CTC) grade 3 or higher 
• SAEs or severe AEs of infection 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the follow-up assessments indicated in the Assessment Schedule. If they fail to 
return for these assessments for unknown reasons, every effort (e.g., telephone, e-mail, letter) 


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should be made to contact the participant/pre-designated contact as specified in the lost to 
follow-up section. This contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done 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 participant’s discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section (Section 6.6.2). 
9.1.1.1 
Replacement policy 
Participants who are prematurely withdrawn or discontinued from the study will not be 
replaced. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, and 
• Does not want any further visits or assessments, and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
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 participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 


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9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the time point of his/her last study visit has 
passed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible and treated as a prematurely withdrawn 
subject. 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 or sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
(all visits until Week 120 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. The final analysis of the study will be performed 
at the end of the study (EOS). The EOS is defined when all re-assigned participants have 
completed Week 120 or discontinued earlier. All available data in the extension study will be 
included in the analysis and will be reported in a final CSR. 
The investigator must provide follow-up medical care for all participants who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include another treatment outside of the study as deemed appropriate by the investigator. 
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 (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. 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 
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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 product are also considered an 
adverse event irrespective if a clinical event has occurred. 
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 findings, laboratory test 
findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must 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 non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Section 16.1. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. its relationship to the study treatment (Yes/ No) 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment  
All adverse events must be treated appropriately. Action taken with the study medication 
must be recorded. It may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome 
• not recovered/not resolved; 
• recovered/resolved; 


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• recovering/resolving, 
• recovered/resolved with sequelae; 
• condition deteriorated 
• fatal, or unknown. 
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 14 weeks following the last dose of 
study treatment. 
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). 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 medicinal product 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 has then 
to be discussed with the subject.  
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
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: 
• fatal 
• life-threatening 
Life-threatening in the context of an 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 the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
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• 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 signing the informed consent (e.g., 
liver allograft biopsy, hospitalization for rejection treatment, revision of an incisional 
hernia, etc..) 
• social reasons and respite care in the absence of any deterioration in the subject’s general 
condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
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. Such events should be 
considered as “medically significant.” 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 the ICH- 
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 14 weeks following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
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 safety 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 
within 24 hours of the investigator receiving the follow-up information. 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. 


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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 Medial Office & 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. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information. 
10.1.4 
Pregnancy reporting 
Pregnancies 
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 should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). 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 pregnancy must be reported. Information will be collected at three 
time points after the estimated date of delivery and for a period of 12 months. 
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, 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. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF 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. 


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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (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 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
There has been no safety signal for liver toxicity with iscalimab to date in all healthy volunteers 
and patients exposed, and from a mechanism of action standpoint there is no known effect on 
the liver (refer to the current Investigator's Brochure). Standard liver function tests (LFT) will 
be obtained at regular intervals. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE): 
• 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 16.2 for complete definitions of liver laboratory triggers and liver events. 
Every liver laboratory trigger or liver event as defined in Section 16.2 should be followed up 
by the investigator or designated personnel at the trial site as summarized below. Detailed 
information is outlined in Section 16.2. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are associated 
with this event must be reported on the Liver CRF pages. 
• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 


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• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver event 
overview CRF pages. 
10.2.2 
Renal safety monitoring 
The available data does not suggest a risk of renal injury with iscalimab. Standard renal function 
tests will be obtained at regular intervals. 
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
1. Serum event  
• confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status 
2. Urine event  
• New dipstick proteinuria ≥3+ OR Protein-creatinine ratio ≥150 mg/g or ≥15 mg/mmol 
• New dipstick hematuria ≥3+ on urine dipstick. Every renal laboratory trigger or renal 
event as defined in Section 16.3 should be followed-up by the investigator or 
designated personnel at the trial site as summarized. 
10.2.3 
Data Monitoring Committee 
No separate data monitoring committee (DMC) will be formed for the extension study. The 
DMC of the core study may review the safety data of this trial at less frequent intervals (i.e., 
planned every 6 months) until final database lock of the core study. Specific details regarding 
the DMC process will be available in the core study DMC charter. 
Additional meetings may be scheduled if discussion of any issue is required. 
11 
Data Collection and Database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1) and can be recorded directly on the eCRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the eCRF 
not being considered as source. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR (Code of Federal Regulation) Part 11 requirements, 
Investigator site staff will not be given access to the Electronic Data Capture (EDC) system 
until they have been trained. Automatic validation programs check for data discrepancies in the 


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eCRFs. The EDC system allows modification and/or verification of the entered data by the 
investigator staff. 
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (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. 
Re-assignment codes and data about all study treatment(s) dispensed to the participant 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 data will be sent 
electronically to Novartis at specific timelines. 
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. 
Once all the necessary 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 made available for data 
analysis. Any changes to the database after that time can only be made after written agreement 
by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., 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 monitoring 
will be performed according to relevant sections of the monitoring plan. Blinded monitors will 
visit the site to check the completeness and appropriate storage of investigator site files, subject 
records, the accuracy of data capture / data entry, the adherence to the protocol, to the study 


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procedures and to Good Clinical Practice. The monitor is also responsible to report any 
deviation from the protocol or defined procedures and to follow the progress of enrollment. 
Monitors are responsible 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 monitors during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/CRA (Clinical Research Associate) organization. 
Additionally, a central analytics organization may analyze data and identify risks and 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 eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent forms signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents in paper or 
electronic format 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 eCRFs 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 after all participants have finished the extension study. Any data 
analysis carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 
Summary statistics for continuous variables will include N, mean, standard deviation (SD), 
minimum, lower quartile, median, upper quartile, and maximum. Summary statistics for 
discrete variables will be presented in the number and percent of patients in each category. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants to whom study treatment for the 
extension study has been assigned by the re-assignment algorithm. For analysis on FAS, 
participants will be analyzed according to the treatment group to which they have been assigned. 
Only data in the extension study will be included in the analysis. 
The Safety Set (SAF) includes all participants who received at least one dose of study treatment 
during the extension study. Participants will be analyzed according to the study treatment 
received, where treatment received is defined as the assigned treatment if the participant took 
at least one dose of that treatment or the first treatment received if the assigned treatment was 
never received. Only data in the extension study will be included in the analysis. 


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12.2 
Participant demographics and other baseline characteristics 
Analyses will be based on the FAS. 
Demographics and baseline characteristics: 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables from core study for each treatment group. The number and percentage of participants 
in each category will be presented for categorical variables for each treatment group and all 
participants. 
Medical history: 
Disease-specific medical history and any condition entered as medical history or current 
medical conditions at core baseline will be coded using the MedDRA dictionary. They will be 
summarized by system organ class and preferred term of the MedDRA dictionary. 
12.3 
Treatments 
Analyses of treatment will be based on the SAF. 
Study treatment: 
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of participants with exposure of at least certain thresholds (e.g., any exposure, ≥2 
weeks ≥4 weeks ≥6 weeks ≥8 weeks etc.) will be displayed. 
Prior and concomitant medication: 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered. 
Prior and concomitant medications will be summarized in separate tables. Medications will be 
presented in alphabetical order, by Anatomical Therapeutic Classification (ATC) codes and 
grouped by anatomical main group. Tables will show the overall number and percentage of 
participants receiving at least one treatment of a particular ATC code and at least one treatment 
in a particular anatomical main group. 
The number and percentage of participants receiving systemic therapies for pSS as prior and 
concomitant background medication will be presented separately by preferred term. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
The analysis for the primary endpoint will be performed on SAF. 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
All safety data, including laboratory measurements, vital signs, and AEs are considered primary 
endpoints. 


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12.4.2 
Statistical model, hypothesis, and method of analysis 
Only descriptive statistics will be provided, no inferential statistics will be conducted. 
Adverse events: 
Treatment emergent adverse events (TEAEs) will be summarized. Only primary paths within 
MedDRA will be considered for AE reporting. The definition for “treatment emergent” is as 
follows: 
• Events started on or after the first dose of study treatment or events present prior to the 
first dose of study treatment but increased in severity based on preferred term; 
• AEs observed four weeks after last study-drug administration will not be considered as 
treatment-emergent 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of participants having any AE, having an AE in each primary system organ class and having 
each individual AE (preferred term). Summaries will also be presented for AEs by severity and 
for study treatment related AEs. If a participant reported more than one AE with the same 
preferred term, the AE with the greatest severity will be presented. If a participant reported 
more than one AE within the same primary system organ class, the participant will be counted 
only once with the greatest severity at the system organ class level, where applicable. 
SAEs will also be summarized. 
Separate summaries will be provided for deaths, SAEs, and other significant AEs leading to 
discontinuation. 
All AEs including non-treatment emergent AEs will be listed. 
Laboratory data: 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). Descriptive summary statistics for the change from baseline 
to each study visit will be presented. These descriptive summaries will be presented by 
laboratory test and treatment group. Change from baseline will only be summarized for 
participants with both baseline and post-baseline values. For each parameter, the maximum 
change from baseline will be analyzed analogously. Number and percentage of participants with 
notable abnormalities will be summarized. 
Vital signs: 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for 
participants with both baseline and post-baseline values. Number and percentage of participants 
with notable abnormalities will also be summarized. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
All the data will be included in the analysis, regardless of intercurrent events that have occurred. 


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12.4.4 
Handling of missing values not related to intercurrent event 
Not applicable. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
Not applicable. 
12.4.6 
Supplementary analysis 
Not applicable. 
12.4.7 
Supportive analyses 
Not applicable. 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Pharmacokinetics 
Trough free iscalimab plasma concentrations will be listed by treatment arm, subject, and 
visit/sampling time point.  
Descriptive summary statistics will be provided by iscalimab dose level and analysis visits, 
including the frequency (n, %) of concentrations below the LLOQ. Summary statistics will 
include mean (arithmetic and geometric), SD, coefficient of variation (CV) (arithmetic and 
geometric), median, minimum and maximum. 
Concentrations below LLOQ will be treated as zero in summary statistics. 
The following PK parameters will be determined: trough concentration (Ctrough), steady state 
(ss), and will be directly derived from the bioanalytical data (summary statistic tables; no non-
compartmental analysis will be performed). 
For each iscalimab concentration (or sample), an elapsed time since first (and last) dose of 
iscalimab will be calculated based on a Dose Reference ID (provided in the Blood Log). The 
time window for deriving the elapsed time will be defined in the SAP. 
Graphical presentation of the data will be provided. 
12.5.2 
PK/PD relationships 
Data from this study may be used with pharmacokinetics/pharmacodynamics (PK/PD) models 
developed based on the core study CCFZ533B2201. This will be reported separately, if 
applicable. 
12.5.3 
Immunogenicity 
All the results for immunogenicity data (anti-iscalimab antibodies) will be listed by visit/time. 
If appropriate, summary statistics and shift tables will also be presented. 


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12.7 
Interim analyses 
Not applicable. 
12.8 
Sample size calculation 
It is estimated that approximately 160 participants enrolled in the core study will complete the 
core study and be eligible for entry into the extension study. 
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 CFR 21), 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, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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 
monitor, 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. 
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 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.). 


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For details on the publication policy including authorship criteria, please refer to the 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 System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
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. 
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 participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
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. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety 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 participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Asmussen K, Andersen V, Bendixen G, et al (1996) A new model for classification of disease 
manifestations in primary Sjögren's syndrome: evaluation in a retrospective long-term study. J 
Intern Med; 239:475-82. 
 
Fisher B, Zeher M, Ng W-F, et al (2017) The Novel Anti-CD40 Monoclonal Antibody 
CFZ533 Shows Beneficial Effects in Patients with Primary Sjögren’s Syndrome: A Phase IIa 
Double- Blind, Placebo-Controlled Randomized Trial [abstract]. Arthritis Rheumatol; 69 
(suppl 10). 
Gottenberg JE, Ravaud P, Puéchal X, et al (2014) Effects of hydroxychloroquine on 
symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical 
trial. JAMA; 312(3):249-58. 
Karnell JL, Rieder SA, Ettinger R, et al (2019) Targeting the CD40-CD40L pathway in 
autoimmune diseases: Humoral immunity and beyond. Adv. Drug Deliv. Rev. p. 92-103. 
 
Qin B, Wang J, Yang Z, et al (2015) Epidemiology of primary Sjögren's syndrome: a 
systematic review and meta-analysis. Ann Rheum Dis; 74:1983-9. 
Ramos-Casals M, Tzioufas AG, Font J (2005) Primary Sjögren's syndrome: new clinical and 
therapeutic concepts. Ann Rheum Dis; 64:347-54. 
 
 
 
 
Shiboski CH, Shiboski SC, Seror R, et al (2017) 2016 American College of 
Rheumatology/European League Against Rheumatism Classification Criteria for Primary 
Sjögren's Syndrome: A Consensus and Data-Driven Methodology Involving Three 
International Patient Cohorts. Arthritis Rheumatol; 69(1):35-45. 
Stack RJ, Southworth S, Fisher BA, et al (2017) A qualitative exploration of physical, mental 
and ocular fatigue in patients with primary Sjögren's Syndrome. PLoS ONE; 
12(10):e0187272. 
Theander E, Vasaitis L, Baecklund E, et al (2011) Lymphoid organisation in labial salivary 
gland biopsies is a possible predictor for the development of malignant lymphoma in primary 
Sjögren's syndrome. Ann Rheum Dis; 70:1363-8. 


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Wolff A, Joshi RK, Ekström J, et al (2017) A Guide to Medications Inducing Salivary Gland 
Dysfunction, Xerostomia, and Subjective Sialorrhea: A Systematic Review Sponsored by the 
World Workshop on Oral Medicine VI. Drugs R D; 17:1-28. 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Table 16-1 
Clinically notable laboratory values and vital signs 
Laboratory variable 
Liver function and related 
variables 
Standard units 
SI units 
SGOT (AST) 
≥ 3 × ULN 
≥ 3 × ULN 
SGPT (ALT) 
≥ 3 × ULN 
≥ 3 × ULN 
Bilirubin 
≥ 3 × ULN 
≥ 3 × ULN 
Alkaline phosphatase 
≥ 5 × ULN 
≥ 5 × ULN 
GGT 
≥ 5 × ULN 
≥ 5 × ULN 
Renal function, metabolic and 
electrolyte variables 
  
  
Urea 
≥ 5 × ULN 
≥ 5 × ULN 
Creatinine 
≥ 3 mg/dL 
≥ 265 μmol/L 
Uric acid 
M ≥ 12 mg/dL 
M ≥ 714 μmol/L 
  
F ≥ 9 mg/dL 
F ≥535 μmol/L 
Glucose 
< 45 mg/dL 
< 2.5 mmol/L 
  
> 250 mg/dL 
> 13.9 mmol/L 
Cholesterol 
≥ 350 mg/dL 
≥ 9.1 mmol/L 
Triglycerides 
≥ 750 mg/dL 
≥ 8.5 mmol/L 
CK (MB) 
None 
None 
Potassium 
≤ 3.0 mEq/L 
≤ 3 mmol/L 
  
≥6.0 mEq/L 
≥6 mmol/L 
Calcium 
≤ 6 mg/dL 
≤ 1.5 mmol/L 
  
≥ 13 mg/dL 
≥ 3.2 mmol/L 
Magnesium 
< 1.0 mg/dL 
< 0.4 mmol/L 
  
> 3.6 mg/dL 
> 1.5 mmol/L 
Amylase 
≥ 2 x ULN 
≥ 2 x ULN 
Lipase 
≥ 2 x ULN 
≥ 2 x ULN 
Hematology variables 
  
  
Hemoglobin 
< 7 g/dL 
< 4.39 mmol/L 
Platelets (thrombocytes) 
< 50 k/mm3 
< 50 × 109/L 
  
≥ 700 k/mm3 
≥ 700 × 109/L 
Leukocytes (WBCs) 
≤ 2.0 k/mm3 
≤ 2.0 × 109/L 
  
≥ 16 k/mm3 
≥ 16 × 109/L 
Hematology variables: 
Differential 
  
  


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Laboratory variable 
Liver function and related 
variables 
Standard units 
SI units 
Granulocytes (poly, 
neutrophils)  
≤ 1,000/mm3 
≤ 1 x 109/L 
Eosinophils 
≥ 12%  
≥ 12% 
Lymphocytes 
≤ 1,000/mm3 
≤ 1 × 109/L 
Vital sign variables 
Notable criteria 
Systolic BP (mm/Hg) 
Either an increase of ≥ 30 that results in ≥ 180 or > 200 (mm/Hg) 
OR a decrease of ≥30 that results in ≤ 90 or < 75 (mm/Hg) 
Diastolic BP (mm/Hg) 
Either an increase of ≥ 20 that results in ≥ 105 or > 115(mm/Hg) 
OR a decrease of ≥20 that results in ≤ 50 or < 40 (mm/Hg) 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-2 
Liver event and laboratory trigger definitions 
LIVER LABORATORY TRIGGERS 
LIVER EVENTS 
Definition/ threshold 
• 
3 x ULN < ALT / AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x ULN 
• 
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 
Table 16-3 
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., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT 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., 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc  (frequency at 
investigator discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
conmeds, med hx, lab) in 
the appropriate CRF 
> 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. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT 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 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
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., 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 


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Criteria 
Actions required 
Follow-up monitoring 
conmeds, med hx, lab) in 
the appropriate CRF 
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., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT 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. 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 


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*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. 
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.Based on investigator’s 
discretion investigation(s) for contributing factors for the liver event can include: 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. 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up  
Table 16-4 
Specific Renal Alert Criteria and Actions and Event Follow-up 
Serum Event 
Serum creatinine increase 25 – 49% 
compared to baseline 
Confirm 25% increase after 24-48h Follow up within 
2-5 days 
Acute Kidney Injury: Serum creatinine 
increase ≥ 50% compared to baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption 
Consider patient hospitalization /specialized treatment 
Urine Event 
New dipstick proteinuria ≥3+ 
OR 
Protein-creatinine ratio ≥150 mg/g or ≥15 
mg/mmol  
Consider causes and possible interventions 
• Assess serum albumin & serum total protein 
• Repeat assessment to confirm 
• Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New dipstick hematuria ≥3+ on urine 
dipstick 
Repeat assessment to confirm 
• Distinguish hemoglobinuria from hematuria 
• Urine sediment microscopy 
• Assess sCr 
• Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation 
• Consider bleeding disorder 
For all renal events: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, 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. 


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16.4 
Appendix 4: Hepatitis B serology results and interpretation 
Not Applicable 


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16.5 
Appendix 5: Blood Logs 
Table 16-5 
(A) - Blood Logs 
Period 
Visit 
Name 
Days 
Weeks 
Hemato
logy 
Clinical 
Chemis
try 
Coagul
ation 
Panel2 
Immun
ology 
Cryogl
obulins
3 
PK blood collection4 
Total 
(mL) 
  
  
  
  
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Sample 
Numbe
r 
Dose 
referen
ce ID 
  
Extensi
on-
Treatm
ent 
Wk 
60E15 
421 
60 
- 
- 
1.8 
- 
- 
- 
- 
- 
9.3 
  
Wk 61 
428 
61 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 62 
435 
62 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 64 
449 
64 
2 
2.5 
- 
- 
- 
- 
- 
- 
4.5 
Wk 66 
463 
66 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 68 
477 
68 
2 
2.5 
- 
6 
- 
- 
- 
- 
10.5 
Wk 70 
491 
70 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 72 
505 
72 
2 
2.5 
1.8 
- 
2 
- 
- 
- 
8.3 
Wk 74 
519 
74 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 76 
533 
76 
2 
2.5 
- 
6 
- 
3 
101 
1 
13.5 
Wk 78 
547 
78 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 80 
561 
80 
2 
2.5 
- 
- 
- 
- 
- 
- 
4.5 
Wk 82 
575 
82 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 84 
589 
84 
2 
2.5 
1.8 
6 
2 
- 
- 
- 
21.8 
Wk 86 
603 
86 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 88 
617 
88 
2 
2.5 
- 
- 
- 
- 
- 
- 
4.5 


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Period 
Visit 
Name 
Days 
Weeks 
Hemato
logy 
Clinical 
Chemis
try 
Coagul
ation 
Panel2 
Immun
ology 
Cryogl
obulins
3 
PK blood collection4 
Total 
(mL) 
  
  
  
  
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Size 
(mL) 
Sample 
Numbe
r 
Dose 
referen
ce ID 
  
Wk 90 
631 
90 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 92 
645 
92 
2 
2.5 
- 
6 
- 
3 
102 
2 
13.5 
Wk 94 
659 
94 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 96 
673 
96 
2 
2.5 
1.8 
- 
2 
- 
- 
- 
8.3 
Wk 98 
687 
98 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 100 
701 
100 
2 
2.5 
- 
6 
- 
- 
- 
- 
10.5 
Wk 102 
715 
102 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 104 
729 
104 
2 
2.5 
- 
- 
- 
- 
- 
- 
4.5 
Wk 106 
743 
106 
- 
- 
- 
- 
- 
- 
- 
- 
0 
Wk 108/ 
TD6 
757 
108 
2 
2.5 
1.8 
6 
2 
3 
103 
3 
24.8 
Post-
Treatm
ent 
Follow-
Up 
Wk 112 
785 
112 
2 
2.5 
- 
6 
- 
- 
- 
- 
10.5 
  
Wk 120/ 
EOS7 
841 
120 
2 
2.5 
- 
6 
2 
3 
104 
3 
15.5 
  
Total 164.5 mL 
  
1 
. 2 While on treatment, coagulation monitoring applies only to participants who have antiphospholipid 
antibodies (lupus anticoagulant, anti-cardiolipin antibodies) and/or who are on pre-existing antithrombotic therapy/prophylaxis, as reflected in the exclusion 
criteria of the TWINSS core study protocol. 3 Analysis of cryoglobulins will be done only for participants who were positive at screening in the TWINSS core 
study. 4 Blood sample is collected pre-dose. 5 Corresponds to the Week 60 visit of the core study. Assessments carried out as part of Week 60 as per core 
study protocol can be used for Week 60E1 of the extension study. 6 In case of premature discontinuation, participants will enter the follow up after 
completing assessments for this visit. 7 Mandatory to all subjects, including those who have discontinued the study prematurely. 


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Table 16-6 
(B) - Blood Logs 
Period 
Visit Name 
Days 
Weeks 
Immunogenicity1 
Total (mL) 
  
  
  
Size (mL) 
Sample ID 
  
Extension-
Treatment 
Wk 60E12 
421 
60 
- 
- 
0 
Wk 61 
428 
61 
- 
- 
0 
Wk 62 
435 
62 
- 
- 
0 
Wk 64 
449 
64 
- 
- 
0 
Wk 66 
463 
66 
- 
- 
0 
Wk 68 
477 
68 
- 
- 
0 
Wk 70 
491 
70 
- 
- 
0 
Wk 72 
505 
72 
- 
- 
0 
Wk 74 
519 
74 
- 
- 
0 
Wk 76 
533 
76 
4 
201 
6 
Wk 78 
547 
78 
- 
- 
0 
Wk 80 
561 
80 
- 
- 
0 
Wk 82 
575 
82 
- 
- 
0 
Wk 84 
589 
84 
- 
- 
0 
Wk 86 
603 
86 
- 
- 
0 
Wk 88 
617 
88 
- 
- 
0 
Wk 90 
631 
90 
- 
- 
0 
Wk 92 
645 
92 
4 
202 
6 
Wk 94 
659 
94 
- 
- 
0 
Wk 96 
673 
96 
- 
- 
0 
Wk 98 
687 
98 
- 
- 
0 
Wk 100 
701 
100 
- 
- 
0 
Wk 102 
715 
102 
- 
- 
0 


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Period 
Visit Name 
Days 
Weeks 
Immunogenicity1 
Total (mL) 
  
  
  
Size (mL) 
Sample ID 
  
Wk 104 
729 
104 
- 
- 
0 
Wk 106 
743 
106 
- 
- 
0 
Wk 108/TD3 
757 
108 
4 
203 
6 
Post-
Treatment 
Follow-Up 
Wk 112 
785 
112 
- 
- 
0 
Wk 120/EOS4 
841 
120 
4 
204 
6 
  
 Total 24.0 mL 
1 Blood sample is collected pre-dose. 2 Corresponds to the Week 60 visit of the core study. Assessments carried out as part of Week 60 as per core 
study protocol can be used for Week 60E1 of the extension study. 3 In case of premature discontinuation, participants will enter the follow up after 
completing assessments for this visit. 
4 Mandatory to all subjects, including those who have discontinued the study prematurely. 


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16.10 
Appendix 10: Satisfaction with self-injection using a prefilled 
syringe questionnaire 
Table 16-15 
Satisfaction with self-injection using a prefilled syringe questionnaire 
 


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16.11 
Appendix 11: Study design of core study CCFZ533B2201 
 
The core study will consist of a 6-week screening, 2 treatment periods of 24 weeks each, and a 
follow-up period of 12 weeks. In Periods 1 and 2, 13 treatment administration visits are planned, 
including weekly loading regimen (2 visits) at the start of each treatment period. One 
administration equals two s.c. injections. 
Primary analysis will occur at Week 24 including all participants but the analysis for Cohort 1 
and analysis for Cohort 2 may occur at different time points depending on patient recruitment 
and preparation timelines. While maintaining the blinding at Week 24, participants in the 
placebo arms D and F will be automatically switched to iscalimab (Arms D1 and F1, 
respectively) for treatment Period 2. All other participants (Arms A, B, C and E) will continue 
with their randomized iscalimab treatment from Period 1 into Period 2 (additional 24 weeks). 
The purpose of this second treatment period is to collect longer-term efficacy and safety data in 
a controlled, double-blinded fashion, while minimizing the number of participants who will 
continue to receive only placebo. 

SAP_001.pdf: 




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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
Analysis sets ...................................................................................................................... 15 
2.2 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.2.1 
Patient disposition ................................................................................. 16 
2.2.2 
Demographics and baseline characteristics ........................................... 16 
2.2.3 
Medical history ...................................................................................... 17 
2.3 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.3.1 
Study treatment / compliance ................................................................ 17 
2.3.2 
Prior, concomitant and post therapies ................................................... 17 
2.4 
Safety analyses ....................................................................................................... 18 
Adverse events (AEs) ............................................................................................ 18 
2.4.1 
Disclosure reporting .............................................................................. 19 
Adverse events of special interest / grouping of AEs ............................................ 19 
2.4.2 
Deaths .................................................................................................... 19 
2.4.3 
Laboratory data ..................................................................................... 19 
2.4.4 
Other safety data ................................................................................... 21 
2.5 
Pharmacokinetic and immunogenicity endpoints .................................................. 21 
 
 22 
 
 22 
 23 
 23 
 
 24 
2.7 
Interim analysis ...................................................................................................... 24 
3 
Change to protocol specified analyses .............................................................................. 24 
4 
Appendix ........................................................................................................................... 25 
4.1 
Imputation rules ..................................................................................................... 25 
4.1.1 
Study drug ............................................................................................. 25 
4.1.2 
AE date imputation ............................................................................... 25 


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4.1.3 
Concomitant medication date imputation ............................................. 25 
 
 25 
 
 25 
4.2 
AEs coding/grading ............................................................................................... 25 
Laboratory parameters derivations .................................................................................... 26 
4.3 
Statistical models ................................................................................................... 26 
4.3.1 
Analysis of binary (and categorical) data .............................................. 26 
5 
Reference ........................................................................................................................... 27 


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List of abbreviations 
ADA 
Anti-drug antibody 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
Antinuclear antibody 
AST 
aspartate aminotransferase 
ATC 
Anatomical therapeutic classification 
BMI 
Body Mass Index 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical study report 
CTCAE 
Common Terminlolgy Criteria for Adverse Events 
C-trough 
Trough concentration 
CV 
coefficient of variation 
DMARD 
Disease modifying antirheumatic drugs 
ECG 
Electrocardiogram 
EoP3 
End of study period 3 
EoS 
End of study 
 
 
ESSDAI 
EULAR Sjögren’s syndrome disease activity index 
ESSPRI 
EULAR Sjögren's syndrome patient reported index 
EULAR 
European League Against Rheumatism 
 
 
FAS 
Full analysis set 
 
 
 
 
 
 
IRT 
Interactive Response Technology 
LLN 
lower limit of normal 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
 
 
PD 
Pharmacodynamic(s) 
PFS 
Pre-filled syringe 
 
 
 
 
SAE 
serious adverse event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
 
 
SD 
standard deviation 
SjS 
Sjögren's Syndrome 


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SMQ 
Standardized MedDRA Query 
SSA 
Sjögren’s-syndrome-related antigen A 
TBL 
Total Bilirubin 
TEAE 
Treatment emergent adverse events 
ULN 
upper limit of normal 
VAS 
Visual analog scale 
 


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1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in section 12 of the study protocol. 
 
This document covers the statistical and analytical plans for the analysis of all data collected up 
to the end of the study.  
1.1 
Study design 
Study CCFZ533B2201E1 (TWINSS extension) is a continuation of the core study 
CCFZ533B2201 and is planned as a multicenter trial. This study will offer continuation of 
treatment for participants who have completed the core study and are deemed by the 
Investigator to clinically benefit from continued iscalimab therapy. The primary purpose of this 
1-year extension study is to provide additional safety and tolerability information of the two 
doses of iscalimab (iscalimab 600 mg and 300 mg) administered via prefilled syringes (PFS). 
A total of 206 participants from both Cohort 1 and Cohort 2 of the core study were enrolled. 
Study blinding for the extension study will be maintained until final database lock of the core 
study, upon which the participants and Investigators will be unblinded, making it an open-label 
study through Week 120 (end of study visit). All visit numbers (in weeks) used in the extension 
study are relative to the baseline visit of the core study CCFZ533B2201. The baseline visit for 
the extension study (Week 60E1) will be carried out on the same day as the Week 60 visit of 
the core study.  
The extension study is a 48-week treatment study, with a safety follow-up period of 12 weeks 
(Figure 1-1). Participants who complete 48 weeks of treatment and the mandatory 12 weeks of 
follow-up in the core study CCFZ533B2201 are eligible to participate in the extension study. 
The 12 weeks of follow-up in the core study is considered mandatory to obtain PK data. The 
extension study will help to evaluate the sustainability of response (ESSDAI) after a year of 
treatment in the core study. 
Upon completion of treatment Period 2 (Week 48) of the core study, Investigators will use their 
clinical judgment to decide if it is beneficial for participants to continue with the extension study 
based upon response to therapy at the end of the treatment period. All participants will be 
considered for participation in the extension study. A new Informed Consent must be signed 
before proceeding into the extension study. The participant should provide their informed 
consent prior to the start of the Week 60 assessments of the core study. 
The treatment will be administered via pre-filled syringe (PFS) in the extension study. This is 
a change from the core study, which used s.c. injections prepared from vials. During the 
treatment period, 25 treatment administration visits are planned, including a weekly loading 
regimen. All participants enrolled in the extension study will receive a weekly loading regimen 
(Week 60E1, Week 61, Week 62) at the start of the treatment period followed by a s.c. 
maintenance regimen (600 or 300 mg s.c. every 2 weeks (Q2W)). One administration equals 
two s.c. injections. 
To maintain extension study blinding until final database lock of the core study, an Interactive 
Response Technology (IRT) algorithm will be used to re-assign participants to either iscalimab 


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600 mg (Arm 1) or 300 mg (Arm 2) s.c. Q2W in the extension study using ESSDAI (Cohort 1 
of core study) or ESSDAI and ESSPRI (Cohort 2 of core study) scores at predefined time points 
(Weeks 4 (or Week 0 in case of a missed visit) and 48 (or Week 40 in the case of a missed visit)) 
in the TWINSS core study. 
Participants will be instructed in detail how to self-administer the s.c. injection using the PFS 
formulation. Each injection will be administered into an appropriate injection site of the body 
(thighs, arms, or abdomen). For the first four visits of the study (through Week 64), all injections 
will be performed at the study site. If a participant had good safety and tolerability, with no 
indication of hypersensitivity or other acute reactions from the previous doses, starting from 
Week 66, the participant is allowed to self-administer the study treatment at home according to 
the assessment schedule. The participant may continue to present at 2 week intervals to the 
study site for injection administrations, based on the participant's preference and the 
Investigator's judgment. Site staff will administer the injection to participants who are not able 
or unwilling to self-administer the PFS injection. The treatment period is from Week 60E1 to 
Week 108. 
Figure 1-1 
Study design 
 
 
 
 
 


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1.2 
Study objectives and endpoints 
The objectives and related endpoints planned in the Clinical Study Report (CSR) are listed in 
Table 1-1. 
 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the safety and tolerability of 
iscalimab at two dose levels (600 mg and 
300 mg) in patients with SjS, who 
participated in the TWINSS core study, 
CCFZ533B2201 
• 
Incidence of Treatment-emergent adverse 
events (TEAEs)/ serious adverse events 
(SAEs) 
Routine hematology and clinical chemistry 
laboratory test results at analysis visits up 
to end of study 
Vital signs at analysis visits up to end of 
study 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the pharmacokinetics (PK trough 
levels) and dose-exposure relationship of 
iscalimab 
• 
Free iscalimab concentration in plasma 
during the treatment (Ctrough) and follow-
up (up to end of study) periods  
• 
To assess immunogenicity of iscalimab 
• 
Incidence of anti-iscalimab antibodies in 
plasma at analysis visits up to end of study 


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2 
Statistical methods 
2.1 
Data analysis general information 
Novartis will perform the analyses for this study. Statistical software SAS version 9.4 or later 
will be used.   
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies. 
If not otherwise specified, two-sided confidence intervals will be displayed. Unless otherwise 
stated, the level of significance will be set to 5% (two-sided). 
All safety listings will be presented by treatment sequence from extension study.  
All efficacy/PRO listing will be presented by core study cohort and extension treatment group  
Only descriptive statistics will be provided, no inferential statistics will be conducted. 
2.1.1 
General definitions  
2.1.1.1 
Study treatment 
CFZ533 (iscalimab) 600 mg or 300 mg will be administered s.c., weekly for the first 3 doses 
(Weeks 60E1, 61 and 62); then, from Week 64, iscalimab will be administered s.c. bi-weekly 
(every other week or Q2W). This is illustrated in Figure 2-1 for Arm 1 (iscalimab 600 mg 
maintenance regimen) and Arm 2 (iscalimab 300 mg maintenance regimen). 
• For participants assigned to the iscalimab 600 mg maintenance regimen (Arm 1), the 
loading doses are 600 mg on Week 60E1, 61 and 62, followed by a bi-weekly 
maintenance regimen at 600 mg. 
• For participants assigned to the iscalimab 300 mg maintenance regimen (Arm 2), the 
loading doses are 600 mg on Week 60E1, and 300 mg on Week 61 and Week 62, followed 
by a bi-weekly maintenance regimen at 300 mg. 








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Group 4:  Hematology, Clinical Chemistry, Urinalysis Dipstick pregnancy, Physical Examinations, SSSD  
  
 
Group 7: ECG 
Group 8: Cryoglobulins, Hepatitis and CMV monitoring 
 
 
Group 11: Immunology    
 
 
The visit window will not be used for the listings. 
2.1.1.7 
Multiple assessments within visit windows 
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window (See Table 
2-2). 
Table 2-2 
Rules for selecting values for analysis within a given visit window 
Timing of 
measurement 
Type of data 
Rule 
Baseline 
All data 
The last non-missing measurement made prior to or on the date of 
administration of the first dose of study treatment in the extension 
study (the reference start date / Day 1). If a patient did not receive 
any dose of study treatment then the IFC date in the extension 
study will be used. Only date part is considered if just one 
assessment on Day 1. 
If there are multiple assessments on Day 1, following rules will 
apply: 
(a) If assessment time exists,  
- 
select the last available measurement prior to 
reference start date/time considering time; 
- 
if no measurement prior to reference start date/time 
considering time, select the earliest measurement 
post reference start date/time considering time . 
(b) 
If assessment time does not exist, select the available 
measurement from the lowest CRF visit number. 
 


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Timing of 
measurement 
Type of data 
Rule 
Post-baseline safety 
Summary visit 
information (e.g. 
lab, Vital signs, 
etc.) 
For quantitative variables: 
• 
The measurement closest to the target will be used. In the 
event two measurements are taken equally apart (e.g. 1 
before target date and 1 after) the first one will be used.  
• 
Cases where the same parameter is recorded more than 
once on the same date will be handled as follows: 
o 
If time of completion exists the earliest measurement 
will be used; 
o 
If time does not exist the measurement from the 
lowest CRF visit number will be used. 
For qualitative variables:  the worst record is selected. It is noted 
that in the analyses performed, worst case is always well defined 
(e.g., for urine protein values “+” and “++”, the worst case is 
defined as “++”). 
In the case qualitative variables are based on quantitative 
variables, e.g. 
 response, the visit will be assigned to the 
quantitative variable, and this visit will be used for the derived 
qualitative variable. 
Post-baseline safety  
Notable 
abnormalities (e.g. 
lab) 
The most extreme measurement in the window will be used.  Note 
this means a patient can have a notably high and notably low 
measurement within a window.  
Analysis sets 
Full Analysis Set (FAS): The FAS comprises all participants to whom study treatment for the 
extension study has been assigned by the re-assignment algorithm. For analysis on FAS, 
participants will be analyzed according to the treatment group to which they have been assigned. 
Only data in the extension study will be included in the analysis. 
Summaries of extension data in FAS will be based on the core study cohort assignment and re-
assigned treatment groups.  
• Cohort 1 - CFZ533 600 mg 
• Cohort 1- CFZ533 300 mg 
• Cohort 2 - CFZ533 600 mg 
• Cohort 2 - CFZ533 300 mg 
 
Safety Set (SAF): The Safety Set includes all subjects who received at least one dose of study 
treatment. Subjects will be analyzed according to the actual treatment received. The safety set 
will be used in the analysis of all safety variables. 
The actual treatment received in a period is defined as the treatment dose level (including 
loading dose) that a subject was most frequently exposed to during the period. The frequency 
will be calculated using data collected on the Dose Administration Record (DAR). In case a 
subject is exposed to more than one dose level for the same number of times during a period, 
the actual treatment is the earliest one administered to the subject in that period.   


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Summaries of extension data in SAF will be based on the re-assigned treatment groups.  
• CFZ533 600 mg 
• CFZ533 300 mg 
 
The PK Set (PKS) includes all subjects who received at least one dose of iscalimab treatment 
and have quantifiable PK measurements of iscalimab. Analysis of plasma PK, 
 
will be based on PKS and by the iscalimab treatment dose level a subject is most frequently 
exposed to, including the loading dose, during the study. Only data in the extension study will 
be included in the analysis. 
Summaries of extension data in PKS will be based on the re-assigned treatment groups. 
• CFZ533 600 mg 
• CFZ533 300 mg 
 
The IM Set (IMS) includes all subjects who received at least one dose of iscalimab treatment 
and have quantifiable immunogenicity measurements of iscalimab. Analysis of 
immunogenicity data will be based on PKS and by the iscalimab treatment dose level a subject 
is most frequently exposed to, including the loading dose, during the study. Only data in the 
extension study will be included in the analysis. 
Summaries of extension data in IMS will be based on the re-assigned treatment groups. 
• CFZ533 600 mg 
• CFZ533 300 mg 
2.2 
Patient disposition, demographics and other baseline 
characteristics 
Analyses will be based on the FAS. 
2.2.1 
Patient disposition 
The number and percentage of subjects in the FAS who completed study periods and who 
discontinued the study prematurely (including the reason for discontinuation) after Week 60E1 
will be presented for each treatment group and all subjects. 
For each protocol deviation, the number and percentage of subjects for whom the deviation 
applies will be tabulated. 
2.2.2 
Demographics and baseline characteristics 
Demographic and other baseline data, including disease characteristics, will be summarized 
by treatment groups for FAS. 
• Gender, age, race, ethnicity, weight, height, BMI (Body Mass Index), disease duration 
and smoking status. 
• 
 




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summarized by treatment group for the safety set unless otherwise specified. Concomitant 
treatments will be displayed for the treatment period. 
Medications will be presented by ATC code and preferred term. ATC codes will be displayed 
in alphabetical order, and grouped by anatomical main group (the 1st level of the ATC codes). 
Tables will also show the overall number and percentage of subjects receiving at least one drug 
of a particular ATC code and at least one drug in a particular anatomical main group. 
Prior medications are defined as drugs taken and stopped prior to the first dose of study 
treatment in core study. Any medication given at least once between the day of first dose of 
study treatment during extension period, and the last dose during extension period will be a 
concomitant medication, including those which were started pre-week 60 and continued into 
the extension treatment period. Any medication given at least once between the day of first dose 
of study treatment, and the last dose during core study period, which is stopped before end of 
extension study will be a concomitant medication only for core study. 
2.4 
Safety analyses 
All safety endpoints (i.e., adverse events, laboratory data, and vital signs in extension study will 
be summarized by treatment for all subjects of the safety set. 
Adverse events (AEs) 
All adverse events in extension study are summarized based on treatment emergent only. The 
definition for “treatment emergent” is as below: 
TEAE includes all events up to the last dose date plus 14 weeks (98 days) or the end of the 
entire study period (including the safety follow-up period), whichever occurred earlier.  A 
listing of all adverse events during the study will be produced, with those defined as TEAE for 
the study treatment period with “treatment emergent” flag displayed. 
The number and percentage of patients with treatment emergent adverse event (TEAE) will be 
summarized for the following:  
• by treatment, primary system organ class and preferred term 
• by treatment, primary system organ class, preferred term and maximum severity 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Summaries will also be provided for study treatment related adverse events, serious adverse 
events, treatment related serious adverse events, deaths, and adverse events leading to 
permanent discontinuation of study-drug.  
If a particular AE ‘severity’ is missing, this variable will be listed as missing and treated as 
missing in summaries. If a subject reported more than one adverse event with the same preferred 
term, the adverse event with the greatest severity will be presented. If a subject reported more 
than one adverse event within the same primary system organ class, the subject will be counted 
only once with the greatest severity at the system organ class level, where applicable. 


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The most common adverse events reported (≥ 5% in any group for each preferred term in the 
table by PT or ≥ 5 % in any group for each SMQ table) will be presented in descending 
frequency according to its incidence in all subjects starting from the most common event.  
2.4.1 
Disclosure reporting 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent AEs: non-SAEs with an incidence greater than 5%, and deaths and SAEs including 
events suspected to be related to study treatment, will be provided by treatment, SOC and PT 
on the Safety Set. 
If, for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment/ non-SAE has to be checked in a block e.g. among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
These tables will be provided at the final analysis after all participants have completed the study.  
 
Adverse events of special interest / grouping of AEs 
Adverse events of special interest for the treatment will also be summarized. AEs of special 
interest for CFZ533 treatment include the following, specified as compound-level risk factors 
defined in the Case Retrieval Strategy (eCRS). The search criteria in the latest eCRS 
corresponding the MedDRA version at the database lock will be used and reported in the CSR. 
2.4.2 
Deaths 
Separate summary and listing will be provided for deaths. 
2.4.3 
Laboratory data 
Only data from the central labs will be used for analysis in this section unless otherwise 
specified. 
The summary of laboratory evaluations in extension study will be presented for two groups of 
laboratory tests (hematology and serum chemistry).  
Descriptive summary statistics for the change from baseline to each study visit in extension 
study will be presented by laboratory test 
 and treatment group.  Change 


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from baseline will only be summarized for subjects with both baseline and post baseline values 
and will be calculated as: 
change from baseline = post baseline value – extension baseline value 
For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. These laboratory 
values will be displayed in listings using the standard unit with the reported sign (“<” or “>”).” 
  
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-3: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), and others. 
 The number and percentage of patients with clinically notable laboratory results after baseline 
(Week 60E1) will also be presented by laboratory test groups and parameters listed in section 
4.2. These summaries will be split into hematology and chemistry. Central and local lab results 
will be displayed in separate tables for clinically notable laboratory results 
Table 2-3 
CTCAE grades for laboratory parameters to be analyzed 
 
CTCAE v5.00 Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased (Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L  
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Platelet count 
decreased 
<LLN – 75.0 
x10e9 /L 
<75.0 - 50.0 
x10e9 /L 
<50.0 – 25.0 
x10e9 /L 
<25.0 x 10e9 /L 
White blood cell decreased 
<LLN - 3.0 x 
10e9 /L 
<3.0 - 2.0 x 
10e9 /L 
<2.0 - 1.0 x 
10e9 /L 
 
<1.0 x 10e9 /L 
Neutrophil count decreased 
<LLN - 1.5 x 
10e9 /L 
<1.5 - 1.0 x 
10e9 /L 
<1.0 - 0.5 x 
10e9 /L 
<0.5 x 10e9 /L 
Lymphocyte count decreased 
<LLN - 0.8 x 
10e9/L 
<0.8 - 0.5 x 
10e9 /L 
<0.5 - 0.2 x 
10e9 /L 
<0.2 x 10e9 /L 
Creatinine increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
TBL increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 10.0 x 
ULN 
>10.0 x ULN 
ALT increased 
>ULN - 3.0 x 
ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
AST increased 
>ULN - 3.0 x 
ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
ALP increased 
>ULN - 2.5 x 
ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
GGT increased 
>ULN - 2.5 x 
ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
INR increased 
>1.2 - 1.5 x 
>1.5 - 2.5  
>2.5  
- 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase analyzed.  
 


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2.4.4 
Other safety data 
2.4.4.1 
ECG 
A listing of all newly occurring or worsening abnormalities (based on the treatment period/study 
period) will be provided, as well as a by-subject listing of all quantitative ECG parameters. 
Notable abnormal QTc will be defined as: 
QTc > 500 msec 
QTc > 480 msec 
QTc > 450 msec 
QTc changes from baseline > 30 msec 
QTc changes from baseline > 60 msec 
PR > 250 msec 
2.4.4.2 
Vital signs 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed by vital sign and treatment group. 
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as: 
change from baseline = post-baseline value – extension baseline value 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-5 below. A listing 
of subjects with newly occurring notably abnormal vital signs will be provided. 
Table 2-5     Criteria for notable vital sign abnormalities 
Vital sign (unit) 
Notable abnormalities 
Systolic blood pressure (mmHg) 
 Either an increase of ≥ 30 that results in ≥ 180 or > 200 
(mm/Hg) OR a decrease of ≥30 that results in ≤ 90 or < 75 
(mm/Hg) 
 
Diastolic blood pressure (mmHg) 
 Either an increase of ≥ 20 that results in ≥ 105 or > 
115(mm/Hg) OR a decrease of ≥20 that results in ≤ 50 or < 
40 (mm/Hg) 
 
Pulse (bpm) 
> 100 bpm or <40 bpm 
2.5 
Pharmacokinetic and immunogenicity endpoints   
PK data will be analyzed in PK set by iscalimab treatment. To preserve blinding of treatment 
assignment, the PK data will be accessible to blinded personnel in the CTT only after unblinding 
for the primary analysis. 
Trough free plasma concentration (C-trough in microg/mL) of iscalimab will be directly 
derived from the bioanalytical data and loaded into clinical database.  










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Laboratory parameters derivations 
Clinically notable laboratory values 
Biochemistry 
1. ALT (SGPT): ≥3xULN 
2. AST (SGOT): ≥3xULN 
3. Elevation of AST and/ or ALT (>3xULN) accompanied by elevated bilirubin 
(>1.5xULN, >2xULN) 
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to >2x ULN 
5. Gamma-Glutamyltransferase (GGT): >3x ULN 
6. Creatinine (serum): ≥3x ULN 
7. Creatinine clearance (CrCl) (Cockroft-Gault formula): ≥25% decrease from baseline 
8. 
 
Hematology 
1. Hemoglobin: ≥20 g/L decrease from baseline or <100 g/L 
2. Platelet count (per CTCAE v5.0) 
a. CTC Grade 1: <Lower Limit of Normal (LLN) – 75 x 109/L 
b. CTC Grade 2: <75 – 50 x 109/L 
c. CTC Grade 3: <50 – 25 x 109/L 
d. CTC Grade 4: <25x 109/L 
3. White blood cell count (per CTCAE v5.0)  
a. CTC Grade 1: <LLN – 3 x 109/L 
b. CTC Grade 2: <3 – 2 x 109/L 
c. CTC Grade 3: <2 – 1 x 109/L 
d. CTC Grade 4: <1 x 109/L 
4. Absolute neutrophils (per CTCAE v5.0) 
a. CTC Grade 1: <LLN – 1.5 x 109/L 
b. CTC Grade 2: <1.5 – 1 x 109/L 
c. CTC Grade 3: <1 – 0.5 x 109/L 
d. CTC Grade 4: <0.5 x 10E9/L 
5. Absolute lymphocytes: <LLN 
6. Absolute eosinophils: ≥2.5x, ≥3x ULN 
4.3 
Statistical models 
4.3.1 
Analysis of binary (and categorical) data 
4.3.1.1 
Summary statistics 
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies. If applicable, confidence intervals will be derived as 
well based on the score method including continuity correction [Newcombe (1998)]: 


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With z as (1-alpha/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), 
n as total number of subjects (i.e. number of subjects in the denominator), and pas estimated 
crude incidence (number of subjects with event / n) it is 
 
Then the lower limit is for 
 
(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is for 
 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
For response variables the placebo adjusted response rates (risk difference) including 95% 
confidence interval will be derived by visit. 
5 
Reference 
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872. 
 
p
q
−
=1
(
),
0
for
0
,0
=
=
>
p
L
p
(
),
1
for
1
,1
=
=
<
p
U
p