A Placebo-controlled, Patient and Investigator Blinded, Randomized Parallel Cohort Study to Assess Pharmacodynamics, Pharmacokinetics, Safety, Tolerability and Preliminary Clinical Efficacy of VAY736 and CFZ533 in Patients With Systemic Lupus Erythematosus (SLE)
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus (SLE)
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
VAY736(ianalumab)
CFZ533 (iscalimab)
Clinical Trial Protocol CVAY736X22081&7
A placebo-controlled, patient and investigator blinded, 
randomized parallel cohort study to assess 
pharmacodynamics, pharmacokinetics, safety, tolerability 
and preliminary clinical efficacy of VAY736and CFZ533in 
patients with systemic lupus erythematosus (SLE)
Document type:
Amended Protocol Version
EUDRACT number:
2018-001508-12
Version number:
v04 (Clean)
Clinical Trial Phase:
II
Release date:
25-Feb-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis

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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol amendment, providing the 
operational details for study procedures.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................24
1
Introduction .......................................................................................................................29
1.1
Background............................................................................................................29
1.1.1
Systemic lupus erythematosus ..............................................................29
1.1.2
VAY736 (ianalumab; anti-BAFF-R mAb) ...........................................30
1.1.3
CFZ533 (iscalimab; anti-CD40 mAb) ..................................................31
1.2
Purpose ..................................................................................................................32
2
Objectives and endpoints...................................................................................................33
3
Study design ......................................................................................................................35
4
Rationale............................................................................................................................37
4.1
Rationale for study design .....................................................................................37
4.1.1
Rationale for choice of SoC therapy.....................................................38
4.2
Rationale for dose/regimen and duration of treatment ..........................................39
4.2.1
Study treatment duration.......................................................................39
4.2.2
VAY736 dosing ....................................................................................39
4.2.3
CFZ533 dosing......................................................................................40
4.3
Rationale for choice of control drugs (comparator/placebo).................................44
4.4
Purpose and timing of interim analyses/design adaptations..................................44
4.5
Risks and benefits..................................................................................................44
4.5.1
VAY736: specific risks.........................................................................47
4.5.2
CFZ533 specific risks ...........................................................................49
4.5.3
Benefits of VAY736 and CFZ533 ........................................................50
4.5.4
Blood sample volume............................................................................50
4.6
Rationale for Public Health Emergency mitigation procedures ............................51
5
Population..........................................................................................................................51
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5.1
Inclusion criteria ....................................................................................................51
5.2
Exclusion criteria...................................................................................................52
6
Treatment...........................................................................................................................55
6.1
Study treatment......................................................................................................55
6.1.1
Investigational and control drugs..........................................................55
6.1.2
Additional study treatments ..................................................................56
6.1.3
Treatment arms/group ...........................................................................56
6.2
Other treatment(s)..................................................................................................56
6.2.1
Concomitant therapy.............................................................................56
6.2.2
Permitted concomitant therapy requiring action (guided CS 
tapering) ................................................................................................57
6.2.3
Prohibited medication ...........................................................................58
6.2.4
Rescue medication ................................................................................59
6.3
Subject numbering, treatment assignment, randomization....................................59
6.3.1
Subject numbering ................................................................................59
6.3.2
Treatment assignment, randomization ..................................................59
6.4
Treatment blinding.................................................................................................60
6.5
Dose modification..................................................................................................61
6.6
Additional treatment guidance...............................................................................62
6.6.1
Treatment compliance...........................................................................62
6.6.2
Recommended treatment of adverse events..........................................62
6.6.3
Emergency breaking of assigned treatment code..................................62
6.7
Preparation and dispensation.................................................................................63
7
Informed consent procedures ............................................................................................63
8
Visit schedule and assessments .........................................................................................64
8.1
Screening ...............................................................................................................72
8.1.1
Re-Screening.........................................................................................72
8.1.2
Eligibility screening ..............................................................................72
8.2
Subject demographics/other baseline characteristics.............................................72
8.3
Efficacy/ Pharmacodynamics ................................................................................73
8.3.1
Pharmacodynamics ...............................................................................73
8.3.2
Clinical efficacy ....................................................................................73
8.3.3
Patient reported outcomes (PRO)..........................................................75
8.4
Safety/ Tolerability................................................................................................76
8.4.1
Laboratory evaluations..........................................................................77
8.4.2
Electrocardiogram (ECG) .....................................................................78

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8.4.3
Pregnancy and assessments of fertility .................................................79
8.4.4
Other safety evaluations........................................................................79
8.5
Additional assessments..........................................................................................82
8.5.1
Pharmacokinetics ..................................................................................82
8.5.2
Immunogenicity ....................................................................................83
9
Study discontinuation and completion ..............................................................................86
9.1
Discontinuation......................................................................................................86
9.1.1
Discontinuation of study treatment .......................................................86
9.1.2
Replacement policy...............................................................................87
9.1.3
Withdrawal of informed consent...........................................................87
9.1.4
Lost to follow-up...................................................................................88
9.1.5
Study/ Cohort stopping rules.................................................................88
9.1.6
Early study termination by the sponsor.................................................89
9.2
Study completion and post-study treatment ..........................................................89
10 Safety monitoring and reporting........................................................................................90
10.1
Definition of adverse events and reporting requirements......................................90
10.1.1
Adverse events ......................................................................................90
10.1.2
Serious adverse events ..........................................................................91
10.1.3
SAE reporting........................................................................................92
10.1.4
Pregnancy reporting ..............................................................................93
10.1.5
Reporting of study treatment errors including misuse/abuse................94
10.2
Additional Safety Monitoring................................................................................94
11 Data Collection and Database management......................................................................94
11.1
Data collection.......................................................................................................94
11.2
Database management and quality control............................................................95
11.3
Site monitoring ......................................................................................................95
12 Data analysis and statistical methods ................................................................................96
12.1
Analysis sets ..........................................................................................................96
12.2
Subject demographics and other baseline characteristics......................................96
12.3
Treatments .............................................................................................................97
12.4
Analysis of the primary endpoint(s) ......................................................................97
12.4.1
Definition of primary endpoint(s).........................................................97
12.4.2
Statistical model, hypothesis, and method of analysis..........................98
12.4.3
Supportive analyses...............................................................................98
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12.5
Analysis of secondary endpoints ...........................................................................99
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................99
12.5.2
Safety endpoints....................................................................................99
12.5.3
Pharmacokinetics ................................................................................101
12.5.4
PK/PD relationships............................................................................101
12.6
Analysis of exploratory endpoints.......................................................................101
12.6.1
Clinical Outcome Assessment.............................................................102
12.7
Interim analyses...................................................................................................104
12.8
Sample size calculation........................................................................................105
12.8.1
Primary endpoint(s).............................................................................105
12.8.2
Secondary endpoint(s).........................................................................106
13 Ethical considerations and administrative procedures ....................................................106
13.1
Regulatory and ethical compliance......................................................................106
13.2
Responsibilities of the investigator and IRB/IEC................................................106
13.3
Publication of study protocol and results.............................................................107
13.4
Quality Control and Quality Assurance...............................................................107
14 Protocol adherence ..........................................................................................................107
14.1
Protocol Amendments .........................................................................................108
15 References .......................................................................................................................109
16 Appendices ......................................................................................................................113
16.1
1997 Update of the 1982 ACR Revised Criteria for Classification of Systemic 
Lupus Erythematosus...........................................................................................113
16.2
The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-
2K).......................................................................................................................115
16.3
British Isles Lupus Activity Group (BILAG) score ............................................116
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List of tables
Table 2-1
Objectives and related endpoints ..........................................................33
Table 6-1
Investigational and control drug............................................................55
Table 6-2
Allowed concomitant medications........................................................57
Table 6-3
Prohibited medication ...........................................................................58
Table 6-4
Blinding and unblinding plan (up to Study Week 29) ..........................61
Table 8-1
Assessment Schedule, Cohort 1 & 2 – Treatment period .....................65
Table 8-2
Assessment Schedule, Cohort 1 & 2 - Follow up period......................69
Table 8-3
Hepatitis screening................................................................................80
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................94
Table 16-1
ACR Revised Criteria for Classification of SLE ................................113
List of figures
Figure 3-1
Study design..........................................................................................35
Figure 12-1
Operating characteristics at interim analysis 1 and 2..........................106
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List of abbreviations
ADA
anti-drug antibodies
AE
adverse event
ALP
alkaline phosphatase
ADCC
antibody-dependent cytotoxicity
ANA
anti-nuclear antibodies
APC
antigen presenting cell 
aPTT
activated partial thromboplastin time
BAFF
B cell activating factor
BAFF-R
B cell activating factor receptor
BILAG
British Isles Lupus Assessment Group
BUN
blood urea nitrogen
BW
body weight
CD
cluster of differentiation
CD
cognitive dysfunction
CDC
complement-dependent cytotoxicity
CFR
U.S. Code of Federal Regulations
CK
creatinine kinase
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CMO&PS
Chief Medical Office & Patient Safety
CMV
cytomegalovirus
CRF
Case Report/Record Form (paper or electronic)
CRO
contract research organization
CS
corticosteroids
CTC
Common Toxicity Criteria
CV
coefficient of variation
d
day
DC
dendritic cell
DMARDs
disease modifying anti-rheumatic drugs
DNA
Deoxyribonucleic Acid
DSUR
Development Safety Update Report
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ENA
extractable nuclear antigens
ELISA
enzyme-linked immunosorbent assay
EoS
End of Study
EOT
End of Treatment
eSAE
Electronic Serious Adverse Event
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
eSource
Electronic Source

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ESSPRI
EULAR Sjogren's Syndrome Patient Reported Index
FcRn
neonatal Fc receptor
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue Scale
FDA
Food and Drug Administration
FIH
first-in-human
GC
germinal center
GCP
Good Clinical Practice
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HepBc Ab
hepatitis B core antibody
HIV
human immunodeficiency virus
IA
interim analysis
IB
Investigator’s Brochure
i.v.
intravenous
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
Ig
immunoglobulin
INR
International Normalized Ratio
IRB
institutional review board
IRT
interactive response technology
LDH
lactate dehydrogenase
LLDAS
Lupus Low Disease Activity State
LLOQ
lower limit of quantification
LLN
lower limit of normal
LON
late onset neutropenia
MedDRA
Medical Dictionary for Regulatory Activities
MFI
Multi-dimensional Fatigue Index
mg
milligram(s)
mL
milliliter(s)
MTB
Mycobacterium tuberculosis
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PGA
Patient's Global Assessment
PhGA
Physicians’ Global Assessment
PK
pharmacokinetic(s)
PoC
Proof of concept
PRO
Patient reported outcome
pSS
Primary Sjögren’s syndrome

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PT
prothrombin time
RA
rheumatoid arthritis
RBC
red blood cell(s)
RDC
Remote Data Capture
s.c.
subcutaneous
SAE
serious adverse event
SD
standard deviation
SF-36
36-Item Short Form Health Survey
SLE
systemic lupus erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SoC
standard of care 
SOM
Site Operations Manual
SRI
SLE Responder Index
SUSAR
suspected unexpected serious adverse reactions
TB
tuberculosis
TBL
total bilirubin
TD
Study Treatment Discontinuation
TfH
T follicular helper cells
ULN
upper limit of normal
ULQ
upper limit of quantification
UPCR
urine protein creatinine ratio
US
ultrasound
VAS
visual analog scale
WBC
white blood cell(s)
WHO
World Health Organization
WoC
withdrawal of consent

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 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 subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up) which applies 
across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Part
A single component of a study that contains different objectives or populations 
within that single study. Common parts within a study are: a single dose part 
and a multiple dose part, or a part in patients with established disease and in 
those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject’s medications or other 
intervention)
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource

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Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow further collection 
personal data.

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Protocol summary
Protocol number
CVAY736X2208
Full Title
A placebo-controlled, patient and investigator blinded, randomized parallel 
cohort study to assess pharmacodynamics, pharmacokinetics, safety, 
tolerability and preliminary clinical efficacy of VAY736 and CFZ533 in 
patients with systemic lupus erythematosus (SLE)
Brief title
Study the efficacy and safety of VAY736 and CFZ533 in SLE patients
Sponsor
Clinical Phase
Novartis
Phase IIa
Investigation type
Biologics
Study type
Interventional
Purpose and 
rationale
This study is designed to evaluate the safety, tolerability, pharmacokinetics 
and therapeutic efficacy of treatment with either VAY736 or CFZ533 in 
patients with SLE to enable further development of these compounds as 
treatment in this disease population
Primary Objective(s) 
The primary objective of this study is to determine the effect of VAY736 and 
of CFZ533 versus their respective placebo on disease activity in SLE 
patients using the SRI-4 index
Secondary 
Objectives

To assess safety and tolerability of VAY736 and of CFZ533 in patients 
with SLE by recording all adverse events

To determine the change from baseline in the Physicians’ Global 
Assessment (PhGA) at Week 29 in VAY736-, CFZ533- or their 
respective placebo-treated arms by using a visual analogue scale 
(VAS)

To determine the change from baseline in the Patient's Global 
Assessment (PGA) at Week 29 in VAY736, CFZ533 or their respective 
placebo-treated arms by using a patient VAS

To determine the pharmacokinetics (PK) of multiple doses of VAY736 
(s.c.) and CFZ533 (i.v.) in SLE patients by analyzing PK concentrations 
in blood

To assess the effect of VAY736 and of CFZ533 versus their respective 
placebo to prevent disease flares in SLE patient’s using BILAG (British 
Isles Lupus Assessment Group)-2004 score 

To evaluate the immunogenicity of multiple doses of VAY736 (s.c.) or 
CFZ533 (i.v.) in SLE patients by analyzing anti-drug antibodies in blood

To evaluate the pharmacodynamics (PD; rate, extent and duration of 
target engagement) of multiple doses of CFZ533 in SLE patients by 
analyzing total soluble CD40 in plasma
Study design
This is an exploratory, randomized, patient- and investigator-blind, placebo-
controlled, parallel-group study to assess the safety, tolerability, 
pharmacokinetics, immunogenicity, pharmacodynamics and preliminary 
clinical efficacy of multiple doses of VAY736 or of CFZ533 in patients with 
active SLE
Population
Approximately 120 male and female patients 18 to 75 years of age with 
active SLE disease will be randomized

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Key Inclusion 
criteria
Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification 
criteria for SLE at screening
Patient diagnosed with SLE for at least 6 months prior to screening
Elevated serum titers at screening of ANA (≥1:80) in a pattern consistent 
with an SLE diagnosis, including at a minimum anti-double stranded DNA 
(anti-ds DNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear 
ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm)
Currently receiving corticosteroids and/or anti-malarial and/or thalidomide 
treatment and/or another DMARD according to the following:

Where corticosteroids are the single standard-of-care medication: an
oral dose of ≤30 mg/d for a minimum of 8 weeks prior to randomization
and at a stable dose for ≥2 weeks prior to randomization

Where oral corticosteroids are not as a single standard-of-care
medication: a stable oral dose of ≤30 mg/d of prednisone or equivalent
for a minimum of 8 weeks prior to randomization and at a stable dose
for ≥2 weeks prior to randomization

An anti-malarial and/or thalidomide treatment and/or one of the
following DMARDs: methotrexate or an imidazole derivative (e.g.,
azathioprine, mizoribine) or mycophenolic acid derivatives (e.g.,
mycophenolate mofetil) for a minimum of 12 weeks prior to screening
and at a stable dose for ≥8 weeks prior to randomization.
Combination of other DMARDs is not permitted
SLEDAI-2K score of ≥6 at screening
BILAG-2004 score at screening of

at least one “A” in either the mucocutaneous domain or in the
musculoskeletal domain,
OR

one “B” in either the mucocutaneous or musculoskeletal  domain AND
at least one “A” or “B” in a second domain
Weigh at least 40 kg at screening

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Key Exclusion 
criteria
Cohort 2 (CFZ533/Placebo) only: Patients who are at significant risk for 
thromboembolic events based on the following:

History of either thrombosis or 3 or more spontaneous abortions

Presence of lupus anticoagulant or significantly prolonged activated 
partial thromboplastin time (aPTT) consistent with co-existent anti-
phospholipid syndrome and without concurrent prophylactic treatment 
with aspirin or anticoagulants as per local standard of care
All Cohorts:
History of receiving prior to screening:

Within 12 weeks: i.v. high dose corticosteroids, calcineurin inhibitors or 
other oral DMARD except as listed in inclusion criterion 6

Within 24 weeks: cyclophosphamide, or biologics such as intravenous 
Ig, plasmapheresis, anti-TNF-α mAb, CTLA4-Fc Ig (abatacept) or 
BAFF targeting agents (e.g., belimumab)

Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, 
anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks
prior to screening and B-cell count <50 cells/μL at the time of screening
Presence of severe lupus kidney disease as defined by proteinuria above   
6 g / day or equivalent using spot urine protein to creatinine ratio, or serum 
creatinine greater than 2.5 mg/dL(221.05 µmol/L), or requiring immune 
suppressive induction or maintenance treatment exceeding protocol-
defined limits 
Active viral, bacterial or other infections at the time of screening or 
enrollment, or history of recurrent, clinically significant infection or of 
recurrent bacterial infections with encapsulated organisms
CMV IgM positive in the absence of positive CMV IgG, or quantifiable CMV 
DNA by PCR (patients with detectable but NOT quantifiable DNA test result 
may be eligible for the study)
Receipt of live/attenuated vaccine within a 2-month period before first 
dosing
Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). A positive 
HBV surface antigen (HBsAg) test excludes a subject. HBsAg negative 
patients who are hepatitis B core antibody (HepBc Ab) positive are also 
excluded, except if both of the 2 following criteria are met: i) HBV DNA is 
negative, ii) hepatitis B monitoring is implemented (HBsAg and HBV DNA 
tested on a monthly basis). In addition, the following conditions must be 
fulfilled:

For Cohort 1 (VAY736/Placebo): prophylactic anti-viral treatment 
(e.g., lamivudine or entecavir) must be initiated at latest by Day 1 
(start of study drug) and continued until at least 12 months after 
last treatment with VAY736. If Hepatitis B prophylaxis antiviral 
treatment is not recommended as per local guidelines for patients 
who are HepBc Ab positive and HBV DNA negative, ONLY HBsAg 
and HepBc Ab negative patients must be enrolled in the study.

For Cohort 2 (CFZ533/Placebo): anti-viral treatment (e.g., 
lamivudine or entecavir) must be initiated immediately in case of 
sero-conversion of either HBsAg or HBV DNA and continued until 
at least 6 months after last treatment with CFZ533.

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Any evidence of hepatitis B reactivation during monitoring (detectable 
serum levels of HBV DNA and/or HepBsAg seropositivity) require 
discontinuation of study medication.
Subjects with a positive HCV antibody test should have HCV RNA levels 
measured. Subjects with positive (detectable) HCV RNA should be 
excluded.
Pregnant or nursing (lactating) women
Study treatment
Efficacy 
assessments

SRI-4 (SLE responder index)

Physician Global Assessment Visual Analogue Scale (PhGA-VAS)

Patient Global Assessment (VAS)

Flare Rate by BILAG-2004 score

Lupus Low Disease Activity State (LLDAS)
Pharmacodynamic 
assessments 

Total soluble CD40 in Cohort 2
Pharmacokinetic 
assessments 

PK concentrations of VAY736 in Cohort 1

PK concentrations of CFZ533 in Cohort 2
Key safety 
assessments

Adverse event monitoring

Physical examinations

Monitoring of laboratory markers in blood and urine

Hepatitis B monitoring

CMV monitoring

ECG evaluation

Vital signs
Other assessments 
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Data analysis
The primary endpoint will be analyzed using a Bayesian logistic regression 
model. The model will include treatment group, ENA status, baseline 
SLEDAI-2K (<10, ≥10) as fixed effects. Weakly informative priors will be 
used to obtain the posterior estimates. The primary analysis will be 
performed for each cohort separately.
Bayesian posterior probabilities will be used to assess the following criteria 
as a guide for decision making (Fisch et al 2015).
Efficacy criteria (for primary endpoint):
Week 29 responder rate in active group better than that in placebo group 
with high confidence (90%), i.e., Prob (θ_active - θ _ placebo >0) >90%, 
AND
Average magnitude of effect on Week 29 responder rate >15% over placebo, 
i.e., Prob (θ_active - θ _ placebo >15%) >50%.
Where θ is the Week 29 responder rate, i.e., the proportion of responders 
per definition.
Futility criteria 
Week 29 responder rate in active group worse than that in placebo with 
confidence higher than 60%, i.e., Prob (θ_active - θ _ placebo <0) >60%.
The posterior estimates of the treatment effect of VAY736 and CFZ533 
compared to their matching placebos (along with the 90% credible intervals) 
at Week 29 will be provided. The results will be reported in terms of 
difference in probability of responders.
Descriptive statistics will be provided for the safety data (e.g., AEs, vital 
signs, ECGs, lab evaluations etc.).
Key words
Anti-CD40, anti-BAFF-receptor, B-cell depletion, systemic lupus 
erythematosus, SLE, VAY736, ianalumab, CFZ533, iscalimab,
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1
Introduction
1.1
Background
1.1.1
Systemic lupus erythematosus
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of unknown etiology 
characterized by an inflammatory process that can target any organ. Most patients suffer from 
constitutional signs such as fever and weight loss. Other common manifestations include oral 
ulcers, skin rash, joint pain and neurocognitive impairment ranging from disabling fatigue to 
psychosis. Hematological complications can include anemia, leukopenia and thrombocytopenia, 
and anti-nuclear antibodies occur in the vast majority of patients. Renal involvement will occur 
at one point in the disease course of 40% of SLE patients; leading, in many, cases to renal 
failure. The disease can also affect the lungs, gastrointestinal tract and heart, and the risk of 
cardiovascular death is 3-10x higher in patients with SLE compared to the general population. 
Patients with SLE also have an increased risk for lymphoma.
The prevalence of SLE varies globally from 20 to 70 per 100,000. Approximately 90% of lupus 
patients are women, with a typical disease onset during the childbearing years. Lupus also 
occurs more often among certain populations such as African, Asian and Hispanic ethnic groups 
compared to frequency of the disease among Caucasians.
The pathobiology of SLE is complex and thought to begin with loss of tolerance by the immune 
system to nucleic acid self-antigens, possibly triggered by viral infection or other means of 
tissue damage. Subsequent immune amplification follows with generation of type 1 interferons 
activating anti-viral responses. Production of BAFF leads to B cell activation and expression of 
the co-stimulatory molecule CD40, which together with its ligand CD154 on activated T cells, 
drives B cell proliferation and maturation into autoantibody-producing plasmablasts and plasma 
cells. These autoantibodies form immune complexes that cause deposits in tissues throughout 
the body and cause end-organ injury. The activated T cells and macrophages can generate 
additional damaging inflammation. It is by this disease process that SLE patients can experience 
varied and diverse clinical manifestations.
Treatment of SLE depends on the severity and organ system involved. The anti-malarial agent 
hydroxychloroquine has been used since the 1960s for controlling milder disease manifestations. 
However, high dose steroids are required for treating more severe disease, and cytotoxic agents 
are used for steroid sparing and to treat severe disease involving the CNS and kidneys. 
Although these treatments have improved the overall SLE 10-year survival from 63% in the 
1950s to 95% in the 1980s, there have been no further major improvements since. Approved 
targeted therapy for SLE is limited to the anti-soluble BAFF monoclonal antibody (mAb)
belimumab, with clinical benefits primarily in patients with milder disease. Inconsistent clinical 
responses have been achieved in SLE patients with the B cell depleting agent rituximab, 
attributed in part to interference of B cell targeting by BAFF:BAFF-R signaling, leading to SLE 
trials evaluating combination therapy with rituximab induction followed by maintenance 
belimumab (Kraaij et al 2018; CALIBRATE, NCT02260934).
 
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1.1.2
VAY736 (ianalumab; anti-BAFF-R mAb)
VAY736 is a human IgG1/κ mAb designed to specifically bind to B cell activating factor 
receptor (BAFF-R) that is predominantly expressed on B cells, thereby preventing the binding 
of B cell activating factor (BAFF). BAFF:BAFF-R mediated signaling is critically involved in 
the maturation of transitional B cells, for survival and activation of mature B cells, and for 
isotype class switching in response to T cell-dependent antigens. The anti-BAFF-R mAb 
VAY736 was designed to eliminate BAFF-R+ B cells by a dual mechanism in vivo: (i) by 
antibody-dependent cytotoxicity (ADCC) and (ii) the induction of B cell apoptosis by 
preventing BAFF:BAFF-R interaction and blocking the prominent BAFF-induced survival 
pathway in B cells. Expression of BAFF-R is limited to immature and mature B cells up to the 
lymphoblast stage, and thus earlier stage pro- and pre-B cells are not directly affected by 
VAY736
This unique, dual mode-of-action supports the therapeutic hypothesis of increased efficacy of 
VAY736 over single targeting of B cell functions by either CD20 depletion (e.g., rituximab) or 
soluble BAFF blockade (e.g., belimumab).
As of 07-Dec-2021, an estimated total of 480 patients have been exposed to VAY736 at various 
doses in 11 clinical studies, including four phase 1 studies CVAY736X2101 (n=55), 
CVAY736A2101 (n=43) both in patients with rheumatoid arthritis (RA), CVAY736Y2101 
(n=3) and CVAY736Y2102 (n=37), both in chronic lymphocytic leukemia (CLL). In addition, 
there have been five phase 2a studies that include primary Sjögren’s syndrome (pSS; 
CVAY736X2201, n=23), multiple sclerosis (MS; CVAY736X2202, n=8), pemphigus vulgaris 
(PV; CVAY736X2203, n=12), idiopathic pulmonary fibrosis (IPF; CVAY736X2207, n=14)
and systemic lupus erythematosus (SLE; CVAY736X2208, n=50). One ongoing phase 2b in 
pSS (CVAY736A2201, n= 188, enrollment completed) and one phase 2b/3 study in 
autoimmune hepatitis (AIH; CVAY736B2201, n=47). Out of the 480 subjects treated with 
VAY736 across these clinical trials up until the above cut-off date, data from 289 patients have 
been analyzed and included in the IB (dated 14-May-2021), including the FIH study 
CVAY736X2201 in RA, VAY736Y2101 in CLL and the phase 2a studies in PV, MS, CLL and 
pSS; the other trials remain ongoing.
Clinically, acute infusion reactions (CTCAE 4.03 grade 1-2) as a consequence of rapid, ADCC-
depletion of circulating B cells and unrelated to dosage were observed in the phase 1 studies in 
the absence of any pre-medication, resolving with administration of paracetamol. There have
been no significant differences observed between VAY736- and placebo-treated patients, with 
the exception of dose-related increases in the occurrence of local injection-related site reactions.
There were no notable differences in infection, although increases were observed in the 
incidence of upper respiratory tract infections in patients receiving VAY736. In the 
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CVAY736A2201 study (Bowman et al 2022), common infections reported included respiratory 
tract infections, urinary tract infections, oral herpes and conjunctivitis. In contrast to other high 
dose B-cell depleting agents, VAY736 so far has not shown increased occurrence of severe 
infections or cases of rare infections (please refer to the IB). Overall, VAY736 is considered as 
having an acceptable risk/benefit profile and therefore considered adequate for development in 
SLE.
Efficacy: The 12-week efficacy results in pSS clinical outcomes observed in the proof-of-
concept study CVAY736X2201 with single infusions of two different i.v. doses of VAY736 
(3 mg/kg and 10 mg/kg) in 27 patients suggest early and clinically meaningful improvements 
in signs and symptoms compared to placebo (Dörner et al 2019). These were measured using
patient reported outcomes (PROs) including EULAR Sjogren's Syndrome Patient Reported 
Index (ESSPRI), 36-Item Short Form Health Survey (SF-36) physical component score, 
Multi-dimensional Fatigue Index (MFI), and global assessments of disease activity by 
physicians (PhGA) and patients (PGA). Moreover, numerical improvements were seen in the 
EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), a disease activity score that 
measures 12 domains across multiple organ and body systems. Full tissue-level PD effects 
provided by sustained receptor occupancy with multiple VAY736 dosing have yet to be 
evaluated. The shared clinical characteristics and pathobiology elements between pSS and SLE 
suggest potential for efficacy of VAY736 in SLE. 
1.1.3
CFZ533 (iscalimab; anti-CD40 mAb)
CFZ533 is a non-agonistic, fully human, Fc-silent, antagonistic IgG1 anti-CD40 mAb that binds 
to the CD154 binding site on CD40 and prevents the binding of CD154 to CD40. Since it is Fc-
silent, CFZ533 binding is able to block the CD40/CD154 costimulatory pathway and inhibit 
cellular proliferation and other effector functions but does not cause ADCC or complement-
dependent cytotoxicity (CDC).
CD40 is a transmembrane glycoprotein constitutively expressed on B cells and antigen 
presenting cells (APCs) such as monocytes, macrophages, and dendritic cells (DCs). CD40 is 
also expressed on platelets and, under certain conditions, can be expressed on eosinophils, and 
inflamed parenchymal cells. Binding of the ligand for CD40, CD154 (also known as CD40 
ligand or CD40L), results in cellular activation and provides an important signal for DC 
maturation as well as monocyte survival and cytokine secretion. In addition, CD40 pathway 
stimulation is required for many B cell effector functions including germinal center (GC) 
formation, memory B cell development, immunoglobulin (Ig) isotype switching, antibody 
production and affinity maturation.
CFZ533 inhibits CD154-induced activation in vitro and T cell-dependent antibody formation 
and germinal center formation in vivo. CFZ533 was able to prolong non-human primate renal 
allograft survival alone or in combination with sub-therapeutic doses of cyclosporine. 
In addition, CFZ533 was able to completely suppress primary and secondary antibody 
responses to immunization with a T cell-dependent antigen.
 
 
 
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CFZ533 is expected to be devoid of the thromboembolic risk characteristic of the Fc-active 
anti-CD154 antibodies such as BG9588, as CFZ533 does not target activated platelets
expressing CD154. The hypothesis that BG9588 induced thromboembolism via targeting 
CD154 on activated platelets has been supported by recent data with CDP7657 (dapirolizumab 
pegol) showing no platelet activation (Chamberlain et al 2017;
Tocoian et al 2015). 
As of 15 Nov 2021, 88 healthy volunteers and 1106 patients have been enrolled into the clinical 
development program that includes one phase 1 study in rheumatoid arthritis (CCFZ533X2101, 
n=20) and 11 phase 2a/2b studies, including renal transplant (CCFZ533X2201, n=59), primary 
Sjögren’s syndrome (CCFZ533X2203, n=69), myasthenia gravis (CCFZ533X2204, n=44), 
Graves` disease (CCFZ533X2205, n=15), hidradenitis suppurativa (CCFZ533H12201BC, 
n=45), kidney transplant (CCFZ533A2201, n=406), liver transplant (CCFZ533A2202, n=113), 
Sjögren’s 
syndrome 
(CCFZ533B2201, 
n=240), 
systemic 
lupus 
erythematosus 
(CVAY736X2208, n=41) and lupus nephritis (CCFZ533X2202, n=43) and type 1 diabetes 
mellitus (CCFZ533X2207, n=11). In total from these aforementioned studies, approximately 
888 subjects received CFZ533. In these patients, CFZ533 was generally well tolerated and 
specifically not associated with an increased risk of infection or neutropenia, nor was there 
evidence for an increased risk of drug-related thromboembolic events in dosed subjects.
Based on preliminary data, multiple i.v. doses of 10 mg/kg CFZ533 were safe and improved 
the signs and symptoms of pSS as measured by relevant clinical endpoints, including the 
ESSDAI. With the similarities in B cell and T cell involvement in pSS and in SLE, such as 
circulating autoantibodies and CD40 pathway-related abnormalities, this clinical efficacy in 
pSS by CFZ533 may further strengthen the rationale for targeting CD40 in patients with SLE.
In summary, experience with VAY736 and with CFZ533 suggest that their respective 
mechanisms-of-action represent safe and efficacious therapeutic approaches for the treatment 
of SLE for which no approved disease modifying therapy exists and where the unmet medical 
need is high.
1.2
Purpose
This study is designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic 
efficacy of treatment with either VAY736 or CFZ533 in patients with SLE to enable further 
development of these compounds as treatment in this disease population.
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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 determine the effect of VAY736 and of 
CFZ533 versus their respective placebo on 
disease activity in SLE patients at Week 29
compared to baseline

SRI-4 response status at Week 29 with 
reduced steroid dose maintained between 
Weeks 17 and 29
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess safety and tolerability of 
VAY736 and of CFZ533 in patients with 
SLE

Adverse events and other safety data such as 
vital signs, ECG and laboratory results
recorded during study 

To determine the change from baseline in 
the Physicians’ Global Assessment
(PhGA) at Week 29 in VAY736-, CFZ533-
or their respective placebo-treated arms

Changes between baseline and Week 29 in 
the PhGA visual analog scale (VAS) 
assessing patient’s overall disease activity

To determine the change from baseline in 
the Patient's Global Assessment (PGA) at 
Week 29 in VAY736, CFZ533 or their 
respective placebo-treated arms

Changes between baseline and Week 29 in 
the patients’ VAS assessing their global 
disease activity

To determine the pharmacokinetics (PK) of 
multiple doses of VAY736 (s.c.) and 
CFZ533 (i.v.) in SLE patients

PK Cohort 1 (VAY736): free VAY736 serum 
concentration (Cmax,ss, Ctrough,ss)

PK Cohort 2 (CFZ533): free CFZ533 
concentration in plasma (Cmax,ss, 
Ctrough,ss)

To assess the effect of VAY736 and of 
CFZ533 versus their respective placebo to 
prevent disease flares in SLE patients

Flare rate and time to first flare, with flare 
defined as one new ‘A’ score or two or more 
‘B’ score using BILAG -2004

To evaluate the immunogenicity of multiple 
doses of VAY736 (s.c.) or CFZ533 (i.v.) in 
SLE patients

Anti-VAY736 (Cohort 1) or anti-CFZ533 
(Cohort 2) antibodies and incidence of ADA-
positive patients

To evaluate the pharmacodynamics (PD; 
rate, extent and duration of target 
engagement) of multiple doses of CFZ533 
in SLE patients

PD Cohort 2 (CFZ533): total soluble CD40 in 
plasma

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Objective(s)
Endpoint(s)
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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3
Study design
This is a randomized, patient- and investigator-blind, placebo-controlled, parallel-group, 
non-confirmatory study to assess the safety, tolerability, pharmacokinetics, immunogenicity, 
pharmacodynamics and preliminary clinical efficacy of multiple doses of VAY736 or of 
CFZ533 in patients with active SLE (see Figure 3-1).
Figure 3-1
Study design
Key study design features are as follows:

Patient randomization into one of two treatment cohorts (VAY736 or CFZ533) and to 
either active or placebo

Seven-month, placebo-controlled, blinded treatment

Guided corticosteroid taper from Study Week 5 to Study Week 17

A 5-month, open label treatment followed by a final outcomes assessment

Four-month follow up for safety/PK/PD, with additional follow up for VAY736-treated 
patients until B cell recovery criteria are met
Screening and randomization
The study will randomize approximately 120 patients to test two active treatments against their 
matching placebo in parallel cohorts. After a 28-day screening period, eligible patients will be 
enrolled and stratified according to serum extractable nuclear antigens (ENA) status (positive 
or negative) and baseline SLEDAI-2K score (<10, ≥10). At the baseline visit, patients who are 
eligible for both cohorts will be randomly assigned to one of the four treatment arms. 
Patients who are eligible for only one cohort will be randomly assigned to either of the two 
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treatment arms in that cohort. Randomization across the cohorts will be implemented via central 
randomization aiming for randomization ratio of 1:1:1:1. 
Blinded treatment phase
Within the treatment cohort, blinded treatment with the investigational drug (VAY736 or 
CFZ533) or placebo will be administered on top of patients’ stable standard of care therapy for 
SLE. Visits to assess safety and/or efficacy are scheduled at 4-week intervals. An additional 
safety visit is scheduled at Week 3 (within the placebo-controlled period) and Week 31 (within 
the open label period) where patients in Cohort 2 (CFZ533) will receive an additional treatment 
dose (see Section 4.2.2).
At the baseline visit Day 1, following patient eligibility confirmation and completion of all 
assessments, first dose of study drug/placebo will be administered. The last treatment in the 
blinded treatment period will be given at the Week 25 visit. The readout for the blinded 
treatment period will be performed at Week 29. Study drug will be administered every 4 weeks. 
Unless otherwise stated, all assessments must be completed BEFORE the next dose of study 
drug is administered.
Guided corticosteroid (CS) reduction

Patients entering the study on a stable CS regimen are required to undergo a guided CS 
taper from baseline levels starting at Week 5 in order to achieve by Week 17:

a daily CS dose of ≤5 mg/day prednisone or equivalent,

or a CS dose that is less than the baseline dose, whichever is the lower dose.

In addition, the patient should remain at the lowered CS dose achieved at Week 17 
through to Week 29.

Patients entering the study without background CS therapy should remain free of any 
CS regimen or increase in SoC DMARDs through to Week 29.

Patients exceeding the rescue therapy allowances may continue in trial but will be 
labeled a non-responder for primary endpoint. 

During the open label phase, further reductions in patients’ SoC CS and DMARDs may
be made on an individual basis as deemed appropriate by the investigator. For details 
on the guided CS tapering please refer to Section 6.2.2
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Open-label treatment phase
At the end of the Week 29 visit, after all assessments have been performed, the first -open label
treatment will be administered. Patients in Cohort 1 will receive VAY736 and patients in Cohort 
2 will receive CFZ533. Study drug will be administered every 4 weeks. The last treatment will 
be given at the Week 49 visit, and the End-of-Treatment (EoT) visit will be performed 4 weeks 
thereafter, at Week 53.
Follow-Up period
After completion of the open-label treatment period, all patients will enter a Follow-Up period 
in order to monitor safety and efficacy up to Week 69. The Week 69 visit is the End of Study 
(EoS) visit for patients in Cohort 2 (CFZ533). Study duration for patients in Cohort 2 will be 
approximately 18 months.
For Cohort 1 (VAY736). Patients who do not achieve B-cell recovery by Week 69 Visit will 
enter into a Secondary Follow-Up period until achieving B cell recovery criteria (B-cell count 
is at ≥50 cells/µl or at least 80% of baseline levels). Safety follow-up visits will be scheduled 
as deemed appropriate until the patient achieves the B cell recovery criteria, followed by an 
EoS 4 weeks later.
Please also refer to the Assessment Schedule.
4
Rationale
4.1
Rationale for study design
This study design is based on published randomized clinical trials in SLE (Furie et al 2017;
Kalunian et al 2017) and the latest EMA 2015 guidelines for evaluation of medicinal products 
intended for the treatment of this patient population. Two different study treatments are tested 
against placebo in the same study setting for better comparability and possibility to stop or adapt 
the individual cohorts independently if needed. In the open-label period, all patients will receive
active treatment. Blinded randomization to active versus placebo in each cohort is employed
during the blinded-treatment phase to provide an unbiased assessment of efficacy in this patient 
population known for a high placebo response rate. 
Patients are selected for a disease activity level sufficient to require systemic therapy. 
Stratification for high disease severity will reduce imbalances of this parameter between the 
different arms. In addition, patients are stratified based on ENA seropositivity, based on 
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evidence that patients tested positive for ENA autoantibodies may have distinct resistance or 
response to B cell depleting therapy (Cambridge et al 2006 and Cambridge et al 2007).
Patients with resolved hepatitis B infection who remain seropositive for the hepatitis B core 
antibody (HepBc Ab) are at increased risk for viral re-activation under immune suppressed 
conditions. Over half the clinical sites participating in this study are located in Asian-Pacific 
countries for which adult prevalence rates for HepBc Ab positivity range from 20% in Japan to 
up to 80% in target populations of Thailand, Taiwan and China mainland. Given that such 
patients with potentially latent hepatitis B infection represent a substantial proportion of the 
world SLE population, it is important in this study to demonstrate effective application of 
current clinical practice guidelines for use of immune suppressive agents in these patients
(EASL 2017, Terrault et al 2018). Therefore, enrolled HepBc Ab+ patients with inactive 
infection (i.e., negative for both hepatitis B surface antigen (HBsAg) and blood viral DNA) will 
require monitoring during study participation. In accordance with the guidelines in reference to 
B cell depleting agents, patients randomized to the VAY736 treatment arm will additionally 
require anti-viral prophylaxis during study participation. Evidence of viral reactivation will 
result in termination of study treatment.
To reduce potential interference in the effects of the study drugs upon the SLE disease 
mechanisms, specific limitations are placed on patients' concomitant use of corticosteroids and 
other immunosuppressive therapies. Patients are excluded who require higher dose 
corticosteroids (>30 mg/day of prednisone or equivalent), cytotoxic or immune suppressive 
induction/maintenance therapies for severe organ dysfunction (e.g., proliferative renal disease, 
CNS lupus).
The impact of study treatment on reducing background corticosteroid dosing will be 
demonstrated by including a guided corticosteroid taper followed by a sustained period at the 
lower dosing level prior to assessment of primary and key secondary outcomes. Enrolled 
patients who require additional corticosteroid dosing beyond the limited rescue therapy (see 
Section 6.2.4, Rescue medication and Table 6-3 Prohibited medicine) through to Week 29 may 
remain in study but are considered non-responder for primary endpoint.
4.1.1
Rationale for choice of SoC therapy
The antimalarial agent hydroxychloroquine has been used since the 1960s for controlling milder 
SLE disease manifestations (reviewed in Kaul et al 2016). More severe disease manifestations 
often require systemic CS therapy and cytotoxic therapies leading to numerous adverse effects 
common with chronic exposure to this drug class. Disease modifying anti-rheumatic drugs
(DMARDs) such as methotrexate or an imidazol derivative (e.g., azathioprine, mizoribine) or 
mycophenolic acid derivatives (e.g., mycophenolate mofetil) are typically added as steroid-sparing 
agents to allow reduction of daily CS dosage. Thalidomide has emerged as second line treatment 
for severe, refractory mucocutaneous disease (Chasset et al 2018). Background therapy with 
CS and DMARDs in this trial will be limited to prevent potential over-immune suppression in 
patients receiving VAY736 or CFZ533. In addition, this study in SLE patients limits the 
severity of active kidney involvement, thus reducing potential for requiring higher 
corticosteroid dosing or addition of other cytotoxic drugs such as cyclophosphamide.

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To reduce the high placebo responder rate typical of SLE trials, patients will be assessed for 
primary outcomes only after a defined period at a lowered CS dose achieved by a guided taper 
(Merrill et al 2017, Thanou and Merrill 2018).
4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Study treatment duration
The 28 weeks of blinded treatment are considered appropriate to show clinical effects of the 
study treatments on the underlying SLE disease mechanism. The 5-month open label period,
starting at Study Week 29, offers patients on placebo the potential benefit of active treatment.
The overall treatment duration of up to 48 weeks will demonstrate effects on disease flare rate 
and sustainability of clinical effects.
4.2.2
VAY736 dosing
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4.2.3
CFZ533 dosing
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4.3
Rationale for choice of control drugs (comparator/placebo)
Placebo use in this blinded trial is justified by providing it as add-on to standard-of-care 
background therapy along with use of rescue glucocorticoid therapy if required. Placebo arms 
respective to the VAY736 and to the CFZ533 cohorts are required due to the different dosing 
requirements for these two experimental treatments that include s.c. versus i.v., pre-medication
and loading regimen; all factors that could affect the known high placebo response rate typically 
seen in SLE trials.
4.4
Purpose and timing of interim analyses/design adaptations
A first interim analysis (IA1) is planned after approximately 50% of randomized patients have 
completed all Week 29 assessments. The efficacy endpoints up to Study Week 29 along with 
relevant safety data will be examined as a preliminary evaluation of therapeutic effects. 
A second IA (IA2) is planned after all enrolled patients have completed their Week 29 
assessments.
An ongoing blinded review of safety data will be conducted at frequent intervals.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study or project, the sponsor's clinical development projects in general or in case 
of any safety concerns.
4.5
Risks and benefits
Initially, patients have a 50% chance of being treated with a potentially efficacious treatment, 
VAY736 or CFZ533, for a chronic disease with possible long-term outcomes that include 
serious disabilities. All patients who received placebo in the blinded treatment phase up to Study 
Week 25 will receive active treatment in the open-label treatment phase starting at Week 29,
respective to their cohort (either VAY736 or CFZ533), for the subsequent 5 months.
All patients are permitted to stay on their stable standard-of-care therapy.
Both VAY736 and CFZ533 are systemic immune-suppressive therapies and thus the study 
population is limited to patients with moderate-to-severe SLE who are most likely to benefit 
from such treatment. However, to avoid over-immune suppression and reduce potential 
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interference with the effects of the study drugs upon SLE disease mechanisms, patients with 
severe disease requiring high corticosteroid dosing (prednisone >30 mg/day or equivalent) or 
immune suppressive induction/maintenance therapies for severe organ dysfunction (e.g., 
proliferative renal disease, CNS lupus) should not be included in this initial trial, and thus
concurrent use of these medications are not permitted.
Allergic reactions. Although no allergic or anaphylactic reactions following i.v. or s.c. 
administration were observed to date in patients receiving either VAY736 or CFZ533, the 
potential to develop an allergic reaction to either compound in a predisposed subject cannot be 
ruled out. Routine monitoring as for other biologic treatments is warranted as described in the 
respective IBs.
Anti-drug antibodies (ADAs) are assessed in all VAY736- or CFZ533-treated subjects across 
all clinical trials involving these compounds. Only limited signs and symptoms of 
immunogenicity have been observed thus far in patients exposed to VAY736 or CFZ533. 
Other potential clinical manifestations of immunogenicity can include local skin reactions at 
the injection site, pyrexia and an influenza-like syndrome.

Of about 435 subjects treated with CFZ533 (up to 15 November 2019), only 2 cases were 
reported: one healthy volunteer and one patient in the Sjögren’s syndrome study 
CCFZ533X2203 have tested positive for immunogenicity with no consequences on PK, 
PD or safety. Nonetheless, administration of monoclonal antibodies, independent of the 
antibody specificity carries the risk of immune reactions such as acute anaphylaxis, serum 
sickness and the generation of anti-drug antibodies (ADAs).
Vaccinations. In immune suppressed patients, live vaccinations may cause serious adverse 
events and success with any form of vaccination may be attenuated. No data exist on the effect 
of VAY736 or CFZ533 on response to vaccinations in general, but vaccinations prior to 
clearance of the mAbs and, in the case of VAY736, during marked B cell depletion, are likely 
to result in failure to produce protective antibody titers. Study subjects should therefore receive 
appropriate vaccinations before entering the study in accordance with current immunization 
guidelines at least 4 weeks prior to study medication administration (>2 months before dosing 
for live/attenuated vaccines).
Infections. Both VAY736 and CFZ533 target one or more elements of the immune system and 
thus effect immune suppression that can increase risks of infection. The Investigator should 
remind the patient of the potential increased risk of infection and instruct them to promptly 
report any symptoms of infections to the Investigator. An increase in mild -to -moderate upper 
respiratory tract infections compared to placebo has been associated with use of VAY736. The 
available data for CFZ533 (cut-off date 15 November 2021) in over 888 treated subjects suggest 
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no overall increased risk of infection in CFZ533-treated subjects compared to placebo or 
standard of care in patients with autoimmune diseases and those with kidney transplant. A Phase 
1 study of CFZ533 did not reveal evidence for T cell or B cell lymphopenia or increased rate or 
severity of infections versus placebo in healthy volunteers. 
In the 
completed (CCFZ533X2201) and ongoing (CCFZ533A2201) study in kidney transplant 
patients, the rate of infections in CFZ533-treated patients was not increased compared to 
patients receiving tacrolimus. However, the risk of infection with VAY736 or with CFZ533 
may increase if either agent is combined with steroids or other strong immune suppressive 
agents. In the current study, concurrent background therapy of patients is restricted to CS 
dosing ≤30 mg prednisone or equivalent and to drugs with low-to-moderate risk for immune 
suppression. Stronger immune suppressive drugs such as cyclophosphamide and cyclosporine 
A are prohibited. In addition, patients with current, active or latent infection susceptible to 
reactivation will be excluded from entry into study CVAY736X2208.
In the CCFZ533X2202 phase 2 study in lupus nephritis, a patient presented with a 
gastrointestinal infection suspected for CMV disease. During hospitalization, the patient 
developed a respiratory infection that progressed to a fatal outcome.
Currently the causal effect of CFZ533 remains unclear, however, active viral infections do 
remain a potential risk. Therefore, CMV screening and monitoring have been implemented to 
mitigate the risk across the clinical development program for CFZ533. 
Overall, the risk-benefit remains unchanged since the latest updated IB and is considered 
favorable to support investigation of CFZ533 patients with autoimmune diseases and in solid 
organ transplant patients.
For the most up-to-date information on infections, please refer to the latest edition of the 
respective IB.
Safety monitoring. Patients enrolled in both VAY736 and CFZ533 treatment cohorts will be 
monitored at all scheduled site visits for safety risks standard for this study population by 
routine assessments, including complete physical examination and general laboratory 
assessments. The risk for patients in this trial will be minimized by compliance with the 
eligibility criteria and study procedures, close clinical monitoring and compliance with criteria 
for treatment interruption outlined in the protocol. The IB’s respective to the two study 
compounds provide specific advice on monitoring for and diagnosing infections. Additional, 
cohort-specific risks and safety monitoring are detailed in the following Section 4.5.1 and 
Section 4.5.2. Women of child-bearing potential must be informed that taking the study 
treatment may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the subject will not 
reliably comply with, they should not be entered or continue in the study.
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4.5.1
VAY736: specific risks
The identified safety risks of BAFF receptor blockade and ADCC with VAY736 are systemic 
injection reactions and upper respiratory tract infections. Potential risks include infections and 
neutropenia related to B cell depletion. Since B cell depletion can persist for several months or 
even years after the last treatment with B cell depleting agents, monitoring requirements are in 
place for patients receiving VAY736 over an extended follow up period.
Injection-related reactions. Consistent with VAY736 mode of action, mild-to-moderate, non-
allergic systemic reactions, including symptoms such as headache, fever/pyrexia, 
shivering/chills,
nausea,
dizziness, rash,
flushing, myalgia, fatigue, tachycardia
and 
hypotension have occurred in VAY736 single and multiple dose administrations. Symptoms 
were most often observed after the first VAY736 dose, but new-onset and recurrent reactions 
after repeated dosing have occasionally been reported. Reactions typically occurred within a 
range of 30 minutes up to 24 hours after initial VAY736 dosing and were manageable by 
treatment with paracetamol, antihistamines and corticosteroids, or in case of i.v. administration 
of the drug, by short-term cessation of the mAb infusion and restarting the infusion at a slower 
rate. In severe cases, the associated signs and symptoms may be indistinguishable from those 
of allergic reactions, although the required treatment is similar for both of these conditions. Pre-
medication with paracetamol alone has been ineffective to prevent these acute injection 
reactions. Orallyor i.v. administered corticosteroids may be used to prevent or treat these 
reactions.
 Symptoms included erythema, swelling, pain, itching/pruritus, rash and tenderness 
For safety monitoring, patients in Cohort 1 are required to stay at the clinic 
until at least 2 hours after first study medication on Day 1 and on the Week 29 visit. Patients 
should remain at the study site under observation during this period. Patients should be 
instructed to promptly report symptoms occurring within 24 hours after study drug 
administration.
Potential side effects of the methylprednisolone pre-medication are short term and may include 
sodium retention-related weight gain and fluid accumulation, hyperglycemia and glucose 
intolerance, hypokalemia and gastrointestinal upset. These symptoms are generally self-limited 
and do not require treatment. Patients with uncontrolled diabetes or hypertension will be 
excluded from the trial.
In the study CVAY736A2201, local injection-related reactions (site reactions) were the 
most commonly reported AEs.  
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around the injection site. Some local injection reactions have been reported with a delayed onset 
and lasted up to several weeks. The majority of local reactions did not require treatment or were 
managed symptomatically as warranted.
Neutropenia. Neutropenia occurring during the B cell recovery period (>16 weeks post 
treatment) has been associated with rituximab-mediated B cell depletion, termed ‘late onset 
neutropenia’ (LON), which remains of unclear etiology, is typically self-resolving and has only 
rarely been associated with infections (Wolach et al 2012; Tesfa et al 2011). Adverse events of 
neutropenia with VAY736 exposure have been reported which have been primarily transient 
CTC Grades 1 (1500/mm3 to LLN) and 2 (1000/mm3 to 1500/mm3) (see IB). As VAY736 is 
expected to similarly induce B cell depletion followed by recovery, SLE patients enrolled in the 
VAY736 cohort will have regular monitoring of neutrophil counts throughout the treatment and 
follow up periods for potential occurrence of both early and late onset of neutropenia.
Hypoimmunoglobulinemia. In patients treated with VAY736, a trend toward reduction in IgM 
levels was observed with VAY736 in pSS patients and in RA patients; a finding consistent with 
reported experiences with other B cell depleting agents targeting CD20 such as rituximab
(Marco et al 2014) and ocrelizumab. In the Ph2b study (CVAY736A2201) in pSS patients. For 
IgG, the proportion of patients below normal reference range at any time was low (2.1% in 
4/188 patients) and there were no serious infections reported in these 4 patients. While this 
study is ongoing, the observations of sustained IgG below normal reference range ≥ 12 weeks 
thus far is low (1.1%, 2/187) (refer to IB). There were no disseminated infections with 
opportunistic pathogens to date in patients treated with VAY736. Patients enrolled into the 
VAY736 cohort will have IgG and IgM levels monitored regularly during the study and follow
up periods.
In humans, transient peripheral B-cell depletion and lymphocytopenia have been reported in 
infants born to mothers exposed to anti-CD20 antibodies during pregnancy. The potential 
duration of B-cell depletion in infants following maternal exposure to VAY736 in utero, and
the impact of B-cell depletion on the safety and effectiveness of vaccines, are both unknown. 
Women of child-bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and then should 
agree that in order to participate in the study, they must adhere to the contraception requirements 
required during the period of study treatment administration and the period after discontinuation 
of study drug as outlined in the protocol’s exclusion criteria. 
Malignancies:  There is no evidence to suggest that VAY736 increases the risk of malignancy 
to date. However, there is a risk of malignancies in immunocompromised patients in general, 
including those patients receiving immunosuppressive therapies and/or those patients who were 
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immunocompromised from prior therapies. Patients with autoimmune disorders are also prone 
to develop specific types of cancer, depending on type of autoimmune disease. Based on the 
description of the individual cases reported from the VAY736 clinical trials and the 
confounding factors present (e.g., underlying disease, prior/concomitant treatment with 
immunosuppressants), a causal association with VAY736 cannot be established at this time.
However, given that patients receiving immunosuppressive therapies are at increased risk of 
malignancies, and based on the safety information from other anti-CD20 mAb and soluble 
BAFF-inhibitor therapies, ‘Malignancy’ is considered as an Important Potential risk for 
VAY736. Based on overall data analysis to date, it does not alter the benefit-risk profile of 
VAY736/ianalumab. In ongoing non-oncology studies, there exists long-term treatment-free 
safety follow-up of patients until B-cell count recovery thresholds are met (up to 2 years post-
treatment). During this time all SAEs, including any malignant neoplasm, are collected to 
provide for further evaluation of this important potential risk of malignancy.
Please refer to Section 7 in the VAY736 IB current edition for additional information on details 
of the above specific risks and other potential adverse effects of the compound.
4.5.2
CFZ533 specific risks
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 immune suppression with a decreased capacity to mount 
a response to novel immunogens, including those of bacterial, viral, fungal and parasitic origin. 
However, although the ability to mount a primary immune response will be affected by CFZ533, 
the memory B cell and plasma cell repertoire should remain intact and protective. In addition, 
subjects will have adequate preformed serum antibody to maintain protective humoral response 
for extended periods of time. Infections in patients treated with CFZ533 in clinical trials 
involving healthy volunteers or patients with RA or other rheumatic diseases are overall mild-
to-moderate in severity.
Thrombosis. Thromboembolic events have been reported in clinical trials with CD154
(CD40 ligand) blocking antibodies, but not with CD40 blocking antibodies. The risk of 
thromboembolic events with CFZ533 is considered minimal.
Investigation in human FcγR transgenic mice revealed the absence of thromboembolic activity 
of a blocking, non-depleting anti-CD40 mAb, whereas anti-CD154 mAb caused 
thrombocytopenia and thrombi formation. In vitro whole blood aggregation assays also 
demonstrated platelet activation liabilities of anti-CD154 but not anti-CD40 mAbs. Clinical
data for CFZ533 available to date do not suggest an increased risk of thromboembolism. 
Furthermore, there have been no reports of thromboembolic complications with other anti-
CD40 antibodies, including dapirolizumab, lucatumumab or ASKP1240 (anti-CD40 antibody 
by Astellas Pharma). Although risk of thromboembolism is theoretical, hematologic and 
coagulation parameters will be monitored in the current study. Furthermore, patients with 
conditions such as anti-phospholipid syndrome who are at a higher risk for thromboembolism
will be excluded from the CFZ533 arm unless they are receiving anti-thrombotic prophylaxis.
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Please refer to Section 7 in the CFZ533 IB current edition for further information, further details 
on the above specific risks and other potential adverse effects of the compound.
4.5.3
Benefits of VAY736 and CFZ533
There is a large, unmet need in SLE for new immunosuppressive treatments with less severe 
adverse effects. The expected benefit profiles in patients with SLE for VAY736 and CFZ533 
are anticipated to provide reductions in disease activity and improved quality of life along with 
reduced toxicities compared to existing treatments. Additionally, these clinical benefits from 
VAY736 and from CFZ533 are expected to reduce dependence on chronic corticosteroid use
and prevent long term organ damage.
4.5.4
Blood sample volume
A total blood volume of approximately 790 mL will be collected over the course of the initial 
13-month screening / treatment phase up to Study Week 53. Approximately 205 mL of 
additional blood will be collected during the 4-month Follow-up period (Study Week 57 to 
Week 69). Thus, for the entire study from Screening until the Week 69 visit, an overall total 
blood volume of approximately 995 mL over 18 months will be collected.
For patients tested positive for HepBc Ab, an additional overall blood volume of approximately 
140 mL will be taken up to V399 (Month 18) for both Cohorts. Monthly hepatitis B monitoring 
will be continued after V399 to V400 (12 months after last treatment) for all patients in Cohort 
1 who tested positive for HepBc Ab. For patients who do not achieve B-cell recovery, testing 
will continue at every visit (8 mL at each visit) until EoS visit Cohort 1.
For patients randomized to the CFZ533 cohort, an additional blood volume of approximately 
115 mL from Baseline until Week 69 will be collected for local CMV monitoring.
Patients in Cohort 1 (VAY736) who do not achieve B-cell recovery criteria at the Week 69 visit 
will continue the study and enter into a secondary Follow-Up period starting after the Week 69 
visit has been completed. At each of the safety follow-up visits in the secondary Follow-Up
period, approximately 15 mL of blood (plus 8 mL if HepB monitoring is required) will be 
collected to monitor safety laboratory and B-cell recovery. At EoS visit for Cohort 1 
approximately 60 mL of blood will be collected. Since each patient in Cohort 1 (VAY736) will 
have an individual follow-up time to achieve B cell recovery criteria, a total blood volume taken 
throughout the study cannot be given. Additional samples may be required for safety monitoring
or repeat measures.
Timings of blood sample collection are outlined in the Assessment Schedule.
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A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and central laboratory manual.
4.6
Rationale for Public Health Emergency mitigation procedures
During a public health emergency as declared by local or regional authorities e.g., 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, which should be then
permitted/approved by local or regional Health Authorities and Ethics Committees as 
appropriate.
5
Population
The patient population will be comprised of adult male and female patients with active SLE. 
The investigator must ensure that all patients being considered for the study meet the following 
eligibility criteria. No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
Patient re-screening will be allowed in the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients 18 to 75 years of age
3. Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification criteria for 
SLE (Hochberg 1997; Tan et al 1982) at screening
4. Patient diagnosed with SLE for at least 6 months prior to screening
5. Elevated serum titers at screening of ANA (≥1:80) of a pattern consistent with an SLE 
diagnosis, including at a minimum either anti-double stranded DNA (anti-ds DNA) or
anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-
Smith (anti-Sm)
6. Currently receiving corticosteroids and/or anti-malarial and/or thalidomide treatment 
and/or another DMARD
:
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7. SLEDAI-2K score of ≥6 (Gladman et al 2002) at screening
8. BILAG-2004 score at screening of:

at least one “A” in either the mucocutaneous domain or in the musculoskeletal 
domain,
OR

one “B” in either the mucocutaneous or musculoskeletal  domain AND at least one 
“A” or “B” in a second domain (Isenberg et al 2005, Isenberg et al 2011, Yee et al 
2006, Yee et al 2010)
9. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study
10. Weigh at least 40 kg at screening
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Cohort 2 (CFZ533/Placebo) only: Patients who are at significant risk for thromboembolic 
events based on the following:

History of either thrombosis or 3 or more spontaneous abortions

Presence of lupus anticoagulant or significantly prolonged activated partial 
thromboplastin time (aPTT) consistent with co-existent anti-phospholipid syndrome
and without concurrent prophylactic treatment with aspirin or anticoagulants as per 
local standard of care
2. History of receiving prior to screening:

Within 12 weeks: high dose corticosteroids (i.e., ≥500 mg Solumedrol or equivalent), 
calcineurin inhibitors, or other oral DMARD except as listed in inclusion criterion 6 

Within 24 weeks: cyclophosphamide or biologics such as intravenous Ig, 
plasmapheresis, anti-TNF-a mAb, CTLA4-Fc Ig (abatacept) or BAFF-targeting 
agents (e.g., belimumab)

Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 
mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening, and a 
B-cell count <50 cells/μL at the time of screening. 
3. Evidence of past exposure to tuberculosis (TB) as assessed by Quantiferon testing at 
screening. Patients with history of latent TB infection may be eligible if they have 
received and completed appropriate anti-TB treatment according to national guidelines
4. Presence of human immunodeficiency virus (HIV) infection at screening
5. Any of the following abnormal laboratory values:

Platelets < 50,000/mm3 (< 50 x 109/L)

Hemoglobin (Hgb) < 8.0 g/dL (< 5 mmol/L)
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
Neutrophil count (< 1,000/mm3) (< 1.0 X 109/L)
6. Have donated blood or experienced a loss of blood > 400 mL within 3 months prior study
entry, or longer if required by local regulations
7. Severe organ dysfunction or life-threatening disease
8. Presence of severe lupus kidney disease as defined by proteinuria above 6 g/day or
equivalent using spot urine protein creatinine ratio, or serum creatinine greater than
2.5 mg/dL (221.05 µmol/L), or requiring immune suppressive induction or maintenance
treatment exceeding protocol defined limits
9. Active viral, bacterial or other infections at the time of screening or enrollment, or history
of recurrent clinically significant infection or of recurrent bacterial infections with
encapsulated organisms.
10. Receipt of live/attenuated vaccine within a 2-month period before first dosing
11. Uncontrolled, co-existing serious disease, e.g., uncontrolled hypertension, heart failure,
type I diabetes, thyroid disease within 3 months prior to first dosing, or significant,
unresolved illness within 2 weeks prior to first dosing
12. History of hypersensitivity to drugs of similar chemical class (e.g., IgG biologics)
13. History of non-compliance with medical regimens or considered potentially unreliable
14. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations.
15. Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). A positive HBV surface
antigen (HBsAg) test excludes a subject. HBsAg negative patients who are HepBc Ab 
positive are also excluded, except if both of the 2 following criteria are met: i) HBV DNA 
is negative, ii) Hepatitis B monitoring is implemented (HBsAg and HBV DNA tested on a 
monthly basis).
Subjects with a positive HCV antibody test should have HCV RNA levels measured. 
Subjects with positive (detectable) HCV RNA should be excluded.
16. History of malignancy of any organ system (other than localized basal cell carcinoma or
squamous cell carcinoma of the skin or in-situ cervical cancer), treated or untreated,
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within the past 5 years, regardless of whether there is evidence of local recurrence or 
metastases.
17. Pregnant or nursing (lactating) women.
18. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective (for Cohort 1
VAY736/Placebo) or effective (for Cohort 2 CFZ533/Placebo) methods of contraception
during dosing and for 6 months (for Cohort 1 VAY736/Placebo) or 14 weeks (for Cohort
2 CFZ533/Placebo) after stopping of investigational drug (or longer if required by
concomitant medications).
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19. Any surgical, medical, psychiatric or additional physical condition that the Investigator
feels may potentially jeopardize the patient in case of participation in this study
20. Subjects who are committed to an institution by way of official or judicial order
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM and the Pharmacy Manual.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and Strength)
Pharmaceutical Dosage Form
Route of 
Administration
Clinical supplies are to be dispensed only in accordance with the specified study procedures. 
A pharmacist or authorized designee is required to prepare the study drug. Instructions for 
storage and handling of study medication vials and preparation of infusion solution are 
described in the Pharmacy Manual (which is provided as a separate document).
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6.1.2
Additional study treatments
6.1.3
Treatment arms/group
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Permitted standard-of-care co-medications include oral CS and/or an anti-malarial agent 
(e.g., hydroxychloroquine) and/or thalidomide and/or one of the listed DMARDs: (see
Inclusion criteria Section 5.1).
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Table 6-2
Allowed concomitant medications
Medication
Condition
Ad hoc use of oral analgesics 
(NSAIDs, acetylsalicyclic acid, 
paracetamol)
All use must be recorded in the concomitant medications / 
significant non-drug therapies
Corticosteroids
If CS is patient’s single, SoC medication, an oral dose ≤30 mg/d
≥8 weeks prior randomization and stable dose for ≥2 weeks prior 
to randomization
If CS is not patient’s single SoC medication, an oral, stable dose 
of ≤30 mg/d for ≥2 weeks prior to randomization
Maintain baseline CS dosing from Study Week 1 to Week 5
Anti-malarials
Anti-malarial drugs (i.e., hydroxychloroquine, chloroquine, 
quinacrine) and/or thalidomide at stable dosing ≥8 weeks prior 
screening and remaining stable throughout blinded treatment 
period. Substitution between anti-malarial drugs is permitted if 
equivalent dosing is maintained.
DMARDS
Methotrexate or an imidazole derivative (e.g., azathioprine, 
mizoribine) or a mycophenolic acid derivative (e.g., 
mycophenolate mofetil) if at stable dosing 
≥8 weeks prior to randomization and remaining stable throughout 
blinded treatment period.
Any DMARDs that will be discontinued by the patient prior to study 
entry will require a minimum wash-out period of 4 weeks
(methotrexate requires 8 weeks) or 5 half-lives, whichever is 
longer, unless noted otherwise in the protocol
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 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis/sponsor to determine if the subject should continue participation in 
the study.
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications / significant non-drug therapies
6.2.2
Permitted concomitant therapy requiring action (guided CS tapering)
Corticosteroids. Patients on stable, maintenance dosing of oral corticosteroids (≤30 mg/day
prednisone or equivalent) prior to randomization should continue this dosing level until Week 5. 
From Week 5 visit onwards, patients will undergo a guided CS dose reduction from baseline 
levels according to the following schedule:

Achieve by Week 17 a prednisone dose or equivalent of ≤5 mg/day or less than CS dose at
Baseline, whichever dose is lower.

Any remaining corticosteroid dosing at Week 17 should subsequently be kept stable up to
the Week 29 visit.
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
Patients who are unable to reach these reduced CS dose level goals by week 17 or
maintain these achieved CS dose levels through to Week 29 will be considered a non-
responder for primary endpoint.

Limited adjustments in CS dosing after Week 17 are provided (see Section 6.2.4 Rescue
medication and Table 6-3 Prohibited medication).

Further adjustments of corticosteroids and of other DMARD co-medications may take
place during the open label period after Week 29 according to PI discretion.
6.2.3
Prohibited medication
Use of the treatments displayed in the below Table 6-3 are not allowed after the start of the 
study.
Table 6-3
Prohibited medication
Medication
Prohibition period
Action taken
Other immune suppressive agents and 
biologics:

Calcineurin inhibitors

Cyclophosphamide, intravenous Ig,
plasmapheresis, anti-TNF-α mAb,
CTLA4-Fc Ig (abatacept) or BAFF
targeting agents (e.g., belimumab)

Any B-cell depleting therapies (e.g.,
anti-CD20 mAb, anti-CD22 mAb,
anti-CD52 mAb), atacicept, (TACI-
Ig)
Throughout treatment period 
through EoS
Withdrawal may be required on a 
case-by-case basis

Total CS >30 mg/d prednisone or
equivalent
Throughout treatment period 
through Week 29
Designated non-responder for 
primary endpoint

Changes in CS dose
Within 2 weeks of Study Visit 
Week 29
Designated non-responder for 
primary endpoint

Other experimental therapies
Throughout treatment period 
through to EoS
Withdrawal may be required on a 
case-by-case basis

Live/ attenuated vaccines
For Cohort 1 (VAY736):
Throughout treatment period
and follow up period until
achieving B cell recovery
For Cohort 2 (CFZ533):
Throughout treatment period
and up to 14 weeks after last
CFZ533 dosing
Study treatment discontinuation; 
patient should remain in study 
and follow visit schedule for 
safety monitoring until achieving 
EoS visit for their respective 
cohorts

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6.2.4
Rescue medication
Corticosteroids may be administered to patients for SLE clinical disease flares after enrollment 
into this study as determined necessary by the responsible PI. However, patients receiving
increased CS dose will be considered non-responders for primary study endpoint if any of 
following criteria was met: 

total daily CS dose is >30 mg/d prednisone or equivalent, or

increased daily CS dose is administered >2 days within a 4-week treatment cycle from
Week 17 to Week 29, or

daily CS dose is increased within 2 weeks of Study Visit Week 29.
Where acute corticosteroid administration occurs for purposes other than the treatment of SLE 
disease activity, such as short-acting hydrocortisone dosed peri-operatively in patients with 
suppressed hypothalamic-pituitary-adrenal axis, patient responder status will be discussed on 
a case-by-case basis.
All Concomitant Medications as well as their dose changes must be recorded in the eCRF.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number will be assigned through the eCRF capture system to a patient at the 
screening visit and remains the unique identifier for the patient throughout the study. For more 
detailed information on subject numbering, please see ‘Subject numbering’ section in the Site 
Operations Manual.
6.3.2
Treatment assignment, randomization
Randomization has to be performed via the IRT system at the Baseline visit at the latest. All 
eligible participants will be randomized to one of the available treatment arms using the IRT
system. The Investigator or his/her delegate will contact the IRT system after confirming that 
the participant satisfies all the inclusion/exclusion criteria. The IRT system will specify a unique 
medication number for the package of investigational drug to the participant. The randomization 
number will not be communicated to the requester.
The randomization scheme for participants will be reviewed and approved by a member of the 
Novartis Randomization Office.
If study participants are only eligible for VAY736 Cohort (i.e., meeting exclusion criterion 1), 
they will be randomized to either active arm or placebo arm of Cohort 1. Otherwise, the 
participants will be randomized to one of four treatment arms of two cohorts. 
Randomization will be stratified by ENA status (positive vs. negative) and SLEDAI-2K <10, 
≥10 status at Baseline, based on screening results, in order to remove any possible confounding 
impact on treatment effects.

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6.4
Treatment blinding
This is a patient and investigator-blinded study. Patients and investigators will remain blinded 
to study treatment throughout the blinded treatment phase of the study, except where indicated 
below.
Patients, investigator staff, persons performing the assessments, and the clinical trial team (CTT)
will remain blind to the identity of the treatment from the time of randomization until end of 
the Week 29 visit applying the following rules:

Randomization data are kept strictly confidential until the time of unblinding,

Unblinding will occur in the case of subject emergencies and at the conclusion of the
study.

Unblinding of the CTT members may occur at the time of the interim analyses.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the blinded 
treatment phase of the study.
Unblinding a single patient at site for safety reasons (necessary for subject management) will 
occur via an emergency system (IRT) in place at the site.
Drug product will be supplied in open label medication packs; therefore an unblinded
pharmacist who is independent of the study team will be required in order to maintain the blind. 
The unblinded pharmacist will receive the appropriate treatment allocation numbers via the IRT
system. Appropriate measures must be taken by the unblinded pharmacist to ensure that the 
treatment assignments are concealed from the rest of the site staff.
Sponsor staff or delegate
The following unblinded sponsor roles are required for this study:
The randomization codes associated with subjects from whom PK samples are taken will be 
disclosed to PK analysts who will keep PK results confidential until data base lock.

Unblinded sample analysts

Unblinded Clinical Trial Associate role to have oversight of randomization in IRT system

Unblinded field monitors
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual subjects. The unblinded monitors will also be able to review 
the randomization list provided to the unblinded pharmacist. 
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The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-4. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g., decision boards) as required for internal decision making on the study or the project at the 
time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-4
Blinding and unblinding plan (up to Study Week 29)
Time or Event
Role
Randomi-
zation list 
generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis 
Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff e.g., pharmacy staff 
UI
UI
UI
UI
Drug Supply and Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff e.g., for study 
treatment re-supply, unblinded monitor(s), 
sample analyst(s), 
UI
UI
UI
UI
Statistician/statistical programmer/ data 
analysts 
B
B
UI
UI
All other sponsor staff not identified above (trial 
team, project team, management & decision 
boards, support functions)
B
B
UI
UI
UI: Allowed to be unblinded on individual subject level
B: Remains blinded  
6.5
Dose modification
Investigational study treatment dose adjustments and/or interruptions are not allowed and must 
be discussed with the sponsor on a case-by-case basis if considered appropriate by the 
investigator.
Study drug dose adjustments are not permitted in this study; in case of an AE or for any reason 
(e.g., non-compliance, operational issue) resulting in a deviation from the required dosing 
CCI
CCI

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scheme, consultation and agreement with Novartis will be necessary to decide whether the 
patient can continue or needs to be withdrawn from the treatment. 
If not avoidable, dosing can be brought forward or delayed by up to 1 week for administrative 
reasons. The subsequent dose should be given according to the original schedule (i.e., do not 
move subsequent dose dates). 
Any change in dosing must be recorded on the Dosage Administration Record eCRF.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Study treatment will be administered at the clinical sites for all patients; therefore, treatment 
compliance is monitored by the clinical staff and recorded in the eCRF.
Serum/plasma concentrations for VAY736 and CFZ533 will be obtained, and pharmacokinetic 
parameters (measures of treatment exposure) will be determined in all patients treated with
VAY736 and CFZ533, as detailed in Section 8.5.1.
6.6.2
Recommended treatment of adverse events
Patients experiencing disease signs and symptoms may receive symptomatic care with over-the-
counter, anti-inflammatory/analgesic agents such as NSAIDs and paracetamol.
For patients with SLE disease signs and symptoms not adequately controlled by symptomatic 
care and/or have more severe SLE disease manifestations not suitable for such treatment may 
receive rescue therapy with corticosteroids if determined by the PI to be medically necessary. 
However, any increases in corticosteroid dosing during the blinded treatment period to treat 
increased SLE disease activity may result in the patient labeled as a non-responder for primary 
endpoint (see Table 6-2 and Table 6-3 for allowed and prohibited concomitant medications, 
respectively).
Any medication used to treat AEs must be recorded on the Concomitant Medications/
Significant non-drug therapies CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT system. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is an appropriate procedure in place to 
allow access to the IRT system at any time in case of emergency. 

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In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given patient. 
In case the study drug will be discontinued, patients should continue the study without receiving 
study treatment in order to monitor their safety, wherever possible.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
Preparation of both study drugs is described in detail in a separate Pharmacy Manual.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the patient by contacting 
the IRT system and obtaining the medication number(s). 
Each study site will be supplied with study drug in packaging as described in Section 6.1.
An unblinded pharmacist at each site will identify the study medication kits to dispense to the 
patient by contacting the IRT system and obtaining the medication number(s), and will prepare 
the study medication accordingly. VAY736, CFZ533 and corresponding placebos will be 
administered to the patient via s.c. injection or i.v. infusion, respectively, at the study site by 
trained and competent site personnel. Please refer to the respective Pharmacy Manuals for 
further details.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)-
approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed model informed 
consent form (ICF) that complies with the ICH GCP guidelines and regulatory requirements 
and is considered appropriate for this study. Any changes to the proposed model consent form 
suggested by the investigator must be agreed by Novartis before submission to the IRB/IEC.
The model ICFs will be adapted locally to comply with local regulations.

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Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the patient before and during the study as needed. Any new information 
regarding the safety profile of the investigational drug 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 patient.
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements.
For patients receiving SoC background therapy, contraception requirements and pregnancy 
warnings must be discussed with the PI, as per local practices.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
8
Visit schedule and assessments
The Assessment schedule lists all assessments and indicates with an “X” at which visits they 
are to be performed. All data obtained from these assessments must be entered into the eCRF
and must be supported in the patient’s source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Patients 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. 
Patients who prematurely discontinue the treatment with study drug for any reason should be 
encouraged to continue their study participation and complete all safety study visits as deemed 
necessary by the investigator, if possible. 
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
e.g., 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 and 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 and until it is safe for the participant to visit the site again.
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Table 8-1
Assessment Schedule, Cohort 1 & 2 – Treatment period
Epoch
Screening
Treatment
EoT
Visit Name
Screen
Base-
line 2
Treatment – blinded period
Treatment – open label period
EoT
Visit Numbers1
1
20
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
299
Days
-28 ±2
-1 to 1
1
15
±2
29
±2
57
±2
85
±2
113
±2
141
±2
169
±3
197
±3
211
±2
225
±3
253
±3
281
±3
309
±3
337
±4
340
±1
365
±5
Weeks
-4
-1 to 1
1
3
5
9
13
17
21
25
29
31
33
37
41
45
49
49
53
Months
-1
-1 to 1
1
1
2
3
4
5
6
7
8
8
9
10
11
12
13
13
14
Informed consent
X
In/Exclusion criteria
X
X
Medical history
X
Demography
X
Vital signs 3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)
X
X
X
X
X
X
X
X
X
Corticosteroid induction 4
X4
X4
SLEDAI-2K
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BILAG-2004
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PhGA - VAS (physician)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGA – VAS (patient)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis & HIV Screen 7
X
CMV Monitoring6,25
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Epoch
Screening
Treatment
EoT
Visit Name
Screen
Base-
line 2
Treatment – blinded period
Treatment – open label period
EoT
Visit Numbers1
1
20
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
299
Days
-28 ±2
-1 to 1
1
15
±2
29
±2
57
±2
85
±2
113
±2
141
±2
169
±3
197
±3
211
±2
225
±3
253
±3
281
±3
309
±3
337
±4
340
±1
365
±5
Weeks
-4
-1 to 1
1
3
5
9
13
17
21
25
29
31
33
37
41
45
49
49
53
Months
-1
-1 to 1
1
1
2
3
4
5
6
7
8
8
9
10
11
12
13
13
14
HepB monitoring7,24
X
X
X
X
X
X
X
X
X
X
X
X
X
Tuberculosis test 7
X
X
Pregnancy test 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel 7
X
X6
X6
X6
X6
Autoantibodies 7
X
X
X
X
X
X
IMI blood sample 7, 16
X
X
X
IMI urine sample 7, 16
X
X
X
Steroid taper 11
X
X
X
X
PK Cohort 1 12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Cohort 2 12
X13
X
X13
X
X13
X
X
X
X13
X
X13
X
X13
X
X13
X
Immunogenicity 12, 14
X
X
X
X
X
X
X
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Epoch
Screening
Treatment
EoT
Visit Name
Screen
Base-
line 2
Treatment – blinded period
Treatment – open label period
EoT
Visit Numbers1
1
20
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
299
Days
-28 ±2
-1 to 1
1
15
±2
29
±2
57
±2
85
±2
113
±2
141
±2
169
±3
197
±3
211
±2
225
±3
253
±3
281
±3
309
±3
337
±4
340
±1
365
±5
Weeks
-4
-1 to 1
1
3
5
9
13
17
21
25
29
31
33
37
41
45
49
49
53
Months
-1
-1 to 1
1
1
2
3
4
5
6
7
8
8
9
10
11
12
13
13
14
IRT
X
X23
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dose administration 21
X22
X6
X
X
X
X
X
X
X22
X6
X
X
X
X
X
Adverse Events
As required
Concomitant Treatment
As required
Comments
As required
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X Assessment to be recorded in the clinical database, EoT – End of Treatment
1 Visit structure given for internal programming purpose only
2 Baseline visit may be combined with Visit 110 at Day 1
3 Body Weight, Height (screening only), Temperature, Blood Pressure, Pulse Rate
4 Only for Cohort 1 (VAY736); i.v. CS to be applied approximately 1 hour before first dose
5 Pregnancy test on Visit 1 (Screening) in serum, all other visits in urine, only females
7 Central Lab
11 Corticosteroids should be tapered down to 5 mg/day or lower
12 Samples are collected pre-dose unless otherwise stated
13 Cohort 2 (CFZ533): take one PK sample at pre-dose and another sample 90 min AFTER THE START of i.v. infusion
14 Cohort 1 (VAY736): serum Cohort 2 (CFZ533): plasma
16 Only selected sites
21 Dosing must be done after all assessments are completed, except for PK blood sampling in Cohort 2 (CFZ533) at visits V110, 130, 150, 190, 210, 230 and 250 where 
    pre and post dose blood sampling is required
22 Post-dose observation time of 2 hours after first dose for Cohort 1 (VAY736), only
23 Randomization assignment at Baseline
24 This test will only be applied as follows: for HepBc Ab positive patients at screening, followed by monthly HBV DNA and HBsAg testing
25 CMV test (CMV serologies IgM and IgG and CMV DNA by PCR) will be performed in the local laboratory at screening for all patients. Starting from visit 110 this testing
will be repeated on a monthly basis only for patients randomized to Cohort 2 (CFZ533).
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Table 8-2
Assessment Schedule, Cohort 1 & 2 - Follow up period
Epoch
Follow Up - Cohort 1&2
Secondary Follow-Up
EoS Disposition
Visit Name
Follow Up
FU 1 Cohort 1/ 
EoS Cohort 2
FU 2 Cohort 1 3
EoS Disposition2
Visit Numbers1
300
310
320
399
400
410
420
430
440
1999
Days
393
±5
421
±5
449
±5
477
±5
645
±10
813
±10
981
±10
1233
±10
1569
±10
-
Weeks
57
61
65
69
93
117
141
177
225
0
Months
15
16
17
18
24
30
36
45
57
0
Vital signs 4
X
X
X
Physical Examination
X
X
X
Electrocardiogram (ECG)
X
X
X
SLEDAI
X
X
X
BILAG-2004
X
X
X
PhGA-VAS (physician)
X
X
X
X
X
X
X
X
X
X
PGA-VAS (patient)
X
X
X
X
X
X
X
X
X
X
HepB monitoring7,15,16
X
X
X
X
X
X
X
X
X
X
CMV monitoring6, 17
X
X
X
X
Tuberculosis test
X
Pregnancy test 5
X
X
X
X
X
X
Hematology 7
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry 7
X
X
X
X
X
X
X
X
X
X
Coagulation Panel 6
X6
X6
Autoantibodies 7
X
X
X
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Epoch
Follow Up - Cohort 1&2
Secondary Follow-Up
EoS Disposition
Visit Name
Follow Up
FU 1 Cohort 1/ 
EoS Cohort 2
FU 2 Cohort 1 3
EoS Disposition2
Visit Numbers1
300
310
320
399
400
410
420
430
440
1999
Days
393
±5
421
±5
449
±5
477
±5
645
±10
813
±10
981
±10
1233
±10
1569
±10
-
Weeks
57
61
65
69
93
117
141
177
225
0
Months
15
16
17
18
24
30
36
45
57
0
PK Cohort 1
X
X
X
X
X
PK Cohort 2
X
X
X
X
Immunogenicity
X
X
X
Adverse Events
As required
Concomitant Treatment
As required
Comments
As required
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X Assessment to be recorded in the clinical database, EoS – End of Study
1 Visit structure given for internal programming purpose only
2 Cohort 1 (VAY736), only: End of study visit will be performed within 4 weeks after the visit where B-cell depletion is no longer persistent. If a patient B-cells recovery is 
confirmed at Week 69, no additional follow-up or EOS visit is needed, and therefore Week 69, FU 1 Cohort 1/ EoS Cohort 2 will be the last visit. 
3 Cohort 1 (VAY736), only: Follow-up visits in Cohort 1 have to be performed until B-cell count is at ≥50 cells/ul or at least 80% of baseline levels. If a patient B-cells 
recovery is confirmed at Week 69 no additional follow-up or EOS visit is needed, and therefore Week 69, FU 1 Cohort 1/ EoS Cohort 2 will be the last visit.
4 Body Weight, Temperature, Blood Pressure, Pulse Rate
5 Pregnancy test on Visit 1 (Screening) in serum, all other visits in urine, only women
7 Central Lab
15 Monthly HepB monitoring will be continued after V399 to V400 for all patients in Cohort 1 who tested positive for HepB core Ab. For patients who do not achieve B-cell 
recovery, testing will continue at every visit until EoS visit Cohort 1.
16 This test will only be applied for HepBc Ab positive patients at screening; followed by monthly HBV DNA and HBsAg testing.
17 CMV test (CMV serologies IgG and IgM and CMV DNA by PCR) will be continued at the local laboratory after V300 to V399 on a monthly basis only for patients 
randomized to Cohort 2 (CFZ533)
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8.1
Screening
8.1.1
Re-Screening
It is permissible to re-screen a patient if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis. In case a new ICF version is 
available, the patient needs to sign the updated ICF. In a situation where information/data from 
procedures that have been previously performed as part of the patients’ routine disease care 
(prior to enrolling in the trial) will need to be used for inclusion this also needs to be agreed 
with the Sponsor on a case-by-case basis.
In the event a patient is being re-screened a new subject-ID will be assigned.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to randomization. If the 
repeat value remains outside of the specified ranges, the patient must be excluded from the 
study.
8.1.2
Eligibility screening
Following registering in the IRT system for screening, patient eligibility will be checked once 
all screening procedures are completed. 
Patients who sign an informed consent but fail to be started on treatment for any reason will be
considered a screen failure. The reason for not being started on treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a serious adverse event during the screening phase (see SAE section
(Section 10.1.2 and Section 10.1.3) for reporting details). If the patient fails to be randomized, 
the IRT system must be notified within 2 days of the screen fail that the patient was not 
randomized.
8.2
Subject demographics/other baseline characteristics
Demographic and baseline characteristic data will be collected on all patients. Patients’ race 
and ethnicity are collected to assess the diversity of the study population as required by Health 
Authorities. Relevant medical history/current medical conditions data will also be collected 
until the time/date of the signature of informed consent. Investigators have the discretion to 
record abnormal test findings on the medical history CRF, if in their judgment, the test 
abnormality occurred prior to the informed consent signature. Additional screening occurs for 
potential, underlying diseases that may compromise safety, including latent or active infections 
(Mycobacterium tuberculosis, viral hepatitis, HIV). Date of the original diagnosis of SLE 
should be recorded.
Serology for autoimmunity is obtained for diagnostic purposes, and both ENA status and the 
screening SLEDAI score will be used as stratification factors.

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8.3
Efficacy/ Pharmacodynamics
8.3.1
Pharmacodynamics
Pharmacodynamic samples will be collected at the time
points defined in the 
Assessment schedule. Follow instructions outlined in the Central Lab Manual regarding sample 
collection, numbering, processing and shipment.
In order to better define the PD profile, the timing of the sample collection may be altered based 
on emergent data. The number of samples/blood draws and total blood volume collected will 
not exceed those stated in the protocol. The results of the sample analyses need to remain 
blinded during the study.
Generally, pharmacodynamic samples will be obtained and evaluated in all subjects, including 
the placebo group. 
Soluble CD40
In Cohort 2 (CFZ533) blood samples will be collected for soluble CD40 concentrations in 
plasma (baseline, during treatment and follow-up) in order to assess the rate, extent and duration 
of target engagement. Blood samples will be obtained from all patients to protect blinding, but 
analysis may be performed only for patients receiving active treatment.
In Cohort 1 (VAY736) blood samples will be collected for soluble CD40 concentration in 
plasma (baseline, end of placebo-controlled period, and end of follow-up period) to explore if 
VAY736 treatment has the ability to modulate the expression of CD40 levels. Blood samples 
will be obtained from all patients to protect blinding, but analysis may be performed only for 
patients receiving active treatment
8.3.2
Clinical efficacy
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8.3.3
Patient reported outcomes (PRO)
The following PROs are not disease specific but applied conventionally to assess SLE and other 
chronic diseases. A detailed training manual relating to the administrative procedures of the 
questionnaires will be provided to the sites.
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8.4
Safety/ Tolerability
Safety assessments are specified below with the Assessment Schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.1.
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 pelvic exams may be 
performed.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be included in the Medical History part of the CRF. 
Significant findings made after first administration of investigational drug which meets
the definition of an Adverse Event must be recorded on the Adverse Event section 
of the eCRF.
Vital signs
Vital signs include body temperature (recorded in °C), blood pressure (BP) and pulse 
measurements. The location of the temperature measurement (e.g., otic, oral) should  
be the same at every visit and will be documented in the Source data. After the 
patient has been sitting for three minutes, with back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured three times using 
a validated device, (e.g., OMRON) with an appropriately sized cuff. The repeat sitting 
measurements will be made at 1- to 2-minute intervals. In case the cuff sizes 
available are not large enough for the patient's arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. If vital signs are 
out-of-range additional readings can be obtained. At least the last reading must be 
within the specified ranges in order for the patient to qualify.
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Assessment
Specification
In case of repeated vital assessments, the CRF should contain all repeat 
measurements.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured.
As per Section 4.6, during a public health emergency as declared by local or regional authorities 
e.g., 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. If participants cannot visit the site for protocol-specified safety lab 
assessments, an alternative lab (local) collection site may be used, as applicable.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of specimens collected that are listed below. 
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in a separate Central Laboratory manual. For timing of the blood 
sampling please refer to the Assessment Schedule.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE e(CRF) pages as appropriate
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
measured.
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin (TBL), bicarbonate/CO2, calcium, cholesterol, 
chloride, creatinine, creatinine kinase (CK), -GT, glucose, LDH, inorganic phosphorus, lipase, 
amylase, magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, blood urea
nitrogen/BUN and uric acid.
If the TBL concentration is increased above 1.5 times the upper limit of normal, direct and 
indirect reacting bilirubin should be differentiated.
Urinalysis
A midstream urine sample will be obtained, in order to avoid contamination with epithelial cells 
and sediments. The sample will be analyzed for specific gravity, creatinine, pH, glucose, protein, 
bilirubin, ketones, nitrite, leucocytes or blood, and microscopic analysis of white blood cells, 
red blood cells, and casts will be performed.

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Coagulation panel
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) will be measured for 
characterization of SLE disease (e.g., anti-phospholipid (aPL) syndrome) and general safety. 
Additional parameters, e.g., INR, may be assessed at the Investigator’s discretion.
Serum immunoglobulins
Serum levels of immunoglobulins (Ig) may be reduced by B cell-targeted interventions and so 
both IgG and IgM levels will be assessed.
8.4.2
Electrocardiogram (ECG)
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Single 12-lead ECGs are collected. The original ECGs, appropriately signed, should be 
collected and archived at the study site.
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Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, be appropriately signed and dated to confirm review and filed in the study site source 
documents. For any ECGs with subject safety concerns, two additional ECGs should be 
performed to confirm the safety finding. Clinically significant ECG findings prior to dosing 
with investigational treatment must be discussed with the Sponsor.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate.
The eCRF will contain:

date and time of ECG

heart rate

PR interval

QT uncorrected

QTcF

QRS duration.
8.4.3
Pregnancy and assessments of fertility
Pregnancy tests are required in all women of child-bearing potential. 
Serum pregnancy tests will be performed at screening. At all other times urine pregnancy tests 
may be used.
If a urine pregnancy test is performed and is found to be positive, this will require 
immediate performing a serum β-hCG test. If positive, the study drug must be discontinued, 
and the Sponsor and Investigator will decide if discontinuation from the trial is required or 
whether study assessments can continue without compromising the patient’s safety.
8.4.4
Other safety evaluations
Quantiferon test
Both VAY736 and CFZ533 suppress the immune system and thus have potential for increasing 
susceptibility 
to 
mycobacterial 
infection. 
To 
identify 
patients 
exposed 
to 
Mycobacterium tuberculosis (MTb), a QuantiFeron test will be performed and read at screening
(or within 6 months prior to randomization). Test may be repeated if test result is not 
unambiguous. A positive QuantiFeron test at screening will exclude the subjects from 
participation in the study.
T-SPOT or other types of ELISPOT assays based on interferon-gamma release may also be 
used for MTb diagnosis as per local practice.
Precautions against TB should be handled according to the best medical practice consistent to 
the local standards in each country with prior consultation with Novartis. Patients requiring 
administration of antibiotics against latent MTb infection should complete their treatment and 
should be considered cured prior to being re-considered for entry into this study (consultation 
with Novartis must occur before allowing the patient to enter the study).
Results will be available as source data and will not be recorded within the eCRF.

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Hepatitis, HIV and CMV 
Hepatitis
The immune suppressive effects of VAY736 and CFZ533 may exacerbate disease in patients 
with active viral hepatitis. All subjects will be screened for HBsAg and for HepBc Ab. 
Table 8-3
Hepatitis screening
HBsAg
HepBc 
Ab
HBV DNA
Eligible
Comment
-
-
-
Yes
-
+
-
Yes
Cohort 1 (VAY736/Placebo): monitoring 
required, prophylactic anti-viral treatment 
Cohort 2 (CFZ533/Placebo): monitoring
only required
-
+
+
No
+
+
+
No
In case of HepBc Ab positivity:

Cohort 1 (VAY736/Placebo): HBsAg negative patients who are HepBc Ab positive 
are also excluded except if all 3 following criteria are met: i) HBV DNA is negative, 
ii) prophylactic anti-viral treatment (e.g., lamivudine or entecavir) initiated latest on 
day 1 and continued until 12 months after last treatment. and iii) hepatitis B monitoring
at study is implemented (HBsAg and HBV DNA) at study visits until EoS. In case of 
sero-conversion (i.e., if either HBsAg or HBV DNA turn positive), second line anti-
viral treatments (e.g., tenofovir) will be initiated.
If Hepatitis B prophylaxis antiviral treatment is not recommended as per local guidelines 
for patients who are HepBc Ab positive and HBV DNA negative, ONLY HBsAG and 
HepBc Ab negative patients must be enrolled in the study

Cohort 2 (CFZ533/Placebo): HBsAg negative patients who are HepBc Ab positive are 
also excluded except if both following criteria are met: 1) HBV DNA is negative and 
2) monthly hepatitis B monitoring is implemented (HBsAg and HBV DNA). In case of 
sero-conversion (i.e., if either HBsAg or HBV DNA turn positive), anti-viral treatment 
(e.g., lamivudine or entecavir) must be initiated immediately, and continued until EoS 
of Cohort 2.
Any evidence of hepatitis B reactivation during monitoring (detectable serum levels of hepatitis 
B viral DNA and/or HBsAg seropositivity) require discontinuation of study medication.
Screening for Hepatitis C will be based on HCV antibodies. Subjects with a positive HCV 
antibody test should have HCV RNA levels measured. Subjects with positive (i.e., detectable) 
HCV RNA should be excluded.
This protocol guidance is the minimum required. If individual countries have additional criteria 
or applicable local guidelines, these must be adhered to.

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HIV
Evaluation for HIV sero-positivity will be performed, and, if positive, confirmed by a second 
technique available at the laboratory site, e.g., by Western blot. 
Appropriate subject counseling will be made available by the Investigator in the event of a 
positive finding. Notification of state and federal authorities as required by law will be the 
responsibility of the Investigator.
Results will be available as source data and will not be recorded within the eCRF.
CMV
Detection during Screening and monitoring
At screening, patients with active viral infections (quantifiable CMV DNA by PCR or positive 
IgM in the absence of a positive IgG) will not be eligible for randomization. However, a patient 
at screening with CMV serologies positive for IgM and negative for IgG with no detectable 
viral DNA may be determined to have a false positive IgM and thus to be study eligible if, upon 
repeat testing ≥4 weeks later, CMV serologies remain unchanged and viral DNA is still 
undetectable.
Patients randomized into the CFZ533 cohort will be monitored for potential CMV reactivation 
or primary infections by measurements at baseline and monthly thereafter for CMV serologies 
(IgG and IgM) and for the presence of viral DNA using PCR.
Management of asymptomatic, confirmed or probable disease

During the study, for patients who develop evidence of asymptomatic, active CMV infection 
based on viral load measurement (quantifiable CMV DNA in copies/mL or IU equivalent), 
it is required that:
-
CMV monitoring is increased to at least weekly intervals of DNA monitoring by serial 
PCR assessments as well as clinical monitoring for early signs of CMV end organ 
disease until resolution
-
consider initiation of pre-emptive anti-CMV therapy when PCR-determined viral load 
is >1,000 copies/mL, in consultation with an infectious disease expert
-
consider reducing or stopping the dose of other immunosuppressive agents
-
consider stopping the study drug
-
if primary CMV infection is suspected, based on confirmed prior negative serology 
CMV IgG, repeat CMV IgG serology after resolution of primary infection and after 
completion of study treatment

During the study, for patients with confirmed or probable CMV disease activity who 
develop clinical symptoms, it is required that:
-
appropriate anti-CMV therapy is initiated
-
the study drug is stopped
-
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For patients with potential infectious symptoms during the trial in the absence of laboratory 
support of CMV etiology, consider age- and country-appropriate infectious exposure risks; 
consider direct isolation of pathogens, virology, and/or serology and initiating appropriate 
targeted anti-viral or anti-bacterial therapies as indicated in consult with an expert.
Guidance to investigators
CMV infections will be recorded as Adverse Events and on the CMV-specific CRF. CMV 
infection is identified by assessments of laboratory and/or clinical signs/symptoms
(Ljungman et al 2017). 

Laboratory-defined CMV (antigenemia-positive, PCR positive).

CMV syndrome (fever for 2 days, neutropenia, leucopenia, viral syndrome)

CMV disease (organ involvement).
Infections
All occurrences of infections must be carefully monitored by the Investigator.
Significant findings meeting the definition of infection must be recorded in the Adverse Event 
eCRF.
IMI samples
Novartis is a member of a consortium of the European Innovative Medicines Initiative (IMI). 
Novartis will contribute blood and urine samples from placebo-treated patients enrolled in this 
SLE study from selected sites to the IMI biobank for additional research within this IMI project.
8.5
Additional assessments
8.5.1
Pharmacokinetics
For Cohort 1 (VAY736) and Cohort 2 (CFZ533), PK blood samples will be collected at the 
time points defined in the Assessment Schedule. Follow instructions outlined in the SOM 
regarding sample collection, numbering, processing and shipment.
PK samples will be obtained from all patients (CFZ533-, VAY736-, and placebo-treated) to 
maintain blinding, but the analysis (free CFZ533 concentration in plasma, free VAY736 in 
serum) will only be conducted for CFZ533- and VAY736-treated patients.
 
 
 
 
 
 
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8.5.2
Immunogenicity 
The immunogenicity of multiple i.v. doses of CFZ533 and of multiple s.c. doses of VAY736 
will be assessed via the quasi-quantitative analysis of anti-CFZ533 antibodies in plasma, and 
anti-VAY736 antibodies in serum, respectively.
Blood samples collected for immunogenicity testing will be obtained from all patients and 
analysis will be performed for CFZ533-, VAY736-, and placebo-treated patients (to assess the 
rate of pre-existing ADAs). The details of sample processing, handling, storage, shipment and 
analytical method will be described in a separate laboratory manual.
The SOM is providing operational details including subject numbering, blood log with sample 
numbers. Further details on sample collection, processing and shipment will be provided in the 
Central Lab Manual. The detailed methods and analysis will be described in the Bioanalytical 
Data Report.
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she believes 
that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision - subjects may choose to discontinue study treatment for any 
reason at any time

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation

Severe injection-related reactions (Cohort 1, VAY736) or infusion-related reactions
(Cohort 2, CFZ533). Immediate interruption of the study drug administration is required 
where possible in such cases

Severe hypersensitivity reaction e.g., anaphylaxis. Immediate interruption of the 
infusion/injection is required in such cases.

Pregnancy (see Section 10.1.4 (Pregnancy reporting))

Patient received a live/ attenuated vaccine

Reactivation of hepatitis B infection (e.g., seroconversion of HBsAg or detection of viral 
DNA); suspected or confirmed active CMV infection (see Section 8.4.4, Hepatitis, HIV 
and CMV screening)

Any situation or protocol deviation that may result in a significant safety risk to the patient

Patient withdraws his/her consent (when patients also must be withdrawn from the study)

Adverse events, abnormal laboratory values or abnormal test results that indicate a safety 
risk to the patient. 

Use of prohibited treatment as outlined in Table 6-3

In addition, in case of emergence of the following adverse events, discontinuation must be 
considered jointly by the investigator and Novartis:

Persistent neutropenia ≤1,000/µl that may preclude further administration of a B cell 
depleting agent (Cohort 1, only: VAY736/Placebo)
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
Cohort 2 (CFZ533/Placebo) only: significant changes in standard coagulation 
parameters, including prothrombin time (PT) and activated partial prothrombin time 
(aPTT) suggesting an increased risk for hypercoagulability or any sign or symptom of 
a thromboembolic event

SAEs or severe AEs of infection that are suspected to be related to study treatment
Discontinuations from study treatment may be considered jointly by the investigator and the 
sponsor on a case-by-case basis if individual treatment doses are missed. The appropriate 
personnel from the site and Novartis will assess whether investigational drug treatment should 
be discontinued for any subject whose treatment code has been broken inadvertently for any 
reason. If discontinuation of study treatment occurs, investigator must determine the primary 
reason for the subject’s premature discontinuation of study treatment and record this 
information on the Dosage Administration eCRF.
Subjects 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 Section 9.1.3, Withdrawal of Informed Consent). 
Patients who discontinue after having received at least one study drug administration should 
continue the study as planned but without receiving further study treatment, if possible. If they 
fail to return to the sites for unknown reasons, every effort (e.g., telephone, e-mail, or letter) 
should be made to contact the subject/pre-designated contact as specified in Section 9.1.4
(Lost to follow-up). This contact should preferably be done according to the study visit schedule. 
Patients receiving at least one dose of study drug with subsequent study treatment stopped 
prematurely and who do not withdraw their consent should stay in the study and continue to 
come to the study visits as per Assessment Schedule for safety monitoring. Premature study 
discontinuation should be discussed with the investigator and the sponsor on a case-by-case basis.
The investigator must also contact the IRT system to report the patient’s discontinuation from 
study treatment.
9.1.2
Replacement policy
Over-recruitment of approximately 10% will be allowed to compensate for early dropouts.
9.1.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
Does not want to participate in the study anymore, and
Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.

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Further attempts to contact the subject are not allowed unless safety findings require 
communication or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. 
A final evaluation at the time of the subject’s study withdrawal should be made as detailed in 
the assessment table.
Novartis will continue to keep, and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
For Japan and US: all biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: all biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.5
Study/ Cohort stopping rules
The relevant study cohort will be put on hold for further enrollment pending further safety data 
analysis if any of the following criteria occur in patients receiving VAY736 or CFZ533:

Any death or life-threatening event suspected to be related to study treatment

Persisting changes from baseline in vital signs, electrocardiograms of potentially life-
threatening severity, or relevant, persistent changes in laboratory parameters which are not 
consistent with existing co-morbidities or the desired experimental compound mechanism-
of-action (e.g., B cell depletion by VAY736), in >1 patient within the first 5 treated 
subjects or an incidence of >20% thereafter

Three (3) or more patients per cohort with a similar adverse event of severe intensity with 
the following exceptions: 

Events of Special Interest, including injection-related (hypersensitivity, cytokine 
release), decreased neutrophil or leukocyte counts not requiring treatment, and 
diagnostic procedures involving elective or non-urgent hospital admission

Disease-Specific Events that are due to the patient's underlying SLE diagnosis

AEs/SAEs clearly unrelated to the experimental compound as determined by the 
investigator or Novartis

Two (2) or more patients per cohort presenting with active treatment-suspected toxicities, 
including: 

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
Severe systemic infection or severe opportunistic infection that requires treatment, 
e.g., sepsis, urosepsis, mycoses, pneumonia

Cohort 1, VAY736 treatment arm only: more than one (1) injection-related reaction of 
severe intensity within the first five (5) treated patients or an incidence of >20% thereafter

Cohort 2, CFZ533 treatment arm only: one (1) patient presenting with suspected 
CFZ533-related thromboembolic event that is at least of moderate severity and is 
unrelated to pre-existing co-morbidities
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment and/or from study.
If discontinuation occurs because the treatment code has been broken, please refer to 
Emergency breaking of treatment code section.
The study may resume following the safety review, if the Investigators and Sponsor agree it is 
safe to proceed.
9.1.6
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 (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final visit) 
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 patient finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
Each patient will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them, unless required by local regulations.

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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 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
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.
Adverse events must be recorded in the Adverse Events CRF 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. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
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 the study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:  

Dose not changed

Dose reduced/increased

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
Drug interrupted/withdrawn  
6. its outcome:
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae; 
e. fatal, or 
f.
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 until the EoS visit.
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 Brochures (IBs).
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. New information might require an update to the informed consent and has then to 
be discussed with the subject. 
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
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 a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines 2004).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

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
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

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 a 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 Guideline 2004).
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 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, but under no circumstances later than within 
24 hours of obtaining knowledge of the events (Note: If more stringent, local regulations 
regarding reporting timelines prevail). Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site.
1. Screen Failures. SAEs occurring after the subject has provided informed consent until the 
time the subject is deemed a Screen Failure must be reported to Novartis.
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 
the subject has discontinued or stopped the study. 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 
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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
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 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.
Any SAEs experienced after the 30-day period after the last study visit should only be reported 
to Novartis Safety department if the investigator suspects a causal relationship to study 
treatment.
10.1.4
Pregnancy reporting
Pregnancies
All childbearing women will have a local serum β-hCG test (serum pregnancy test) performed 
at screening. From baseline onwards monthly local urine pregnancy tests will be performed as 
indicated in the Assessment schedule. A positive urine pregnancy test requires immediate 
interruption of study drug until serum β-hCG is performed and found to be negative. 
Additional pregnancy testing might be performed if requested by local requirements.
If a female trial participant becomes pregnant, the patient must be asked to read and sign 
pregnancy consent form to allow the Study Doctor ask about her pregnancy.
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. The follow-up for pregnant participants should be done 1 month, 
3 months (for a live birth only) and 12 months (for a live birth only) after estimated date of 
delivery.
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 investigational
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported.

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The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments.
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 collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) eCRF 
(Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring 
Not applicable.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.

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The investigator/designee is responsible for assuring that the data (recorded on CRFs) (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 electronic copies of the subject 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 (or designated CRO) 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 
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.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT) system. 
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 unblinded and 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 with the investigators and 
their staff. During the study, Novartis employs several methods of ensuring protocol and GCP 
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compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of subject records, the accuracy of data capture / data entry, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis Clinical Research Associate (CRA) 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 CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.
12
Data analysis and statistical methods
The analyses will be conducted on all subject data at the time when interim analyses occur and 
when the trial ends. The analyses will be performed on Cohort 1 and Cohort 2 separately unless 
otherwise specified. Any data analysis carried out independently by the investigator should be 
submitted to Novartis before publication or presentation.
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects who received any study drug. 
The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The primary PD analysis set will include all subjects who received any study drug having no 
protocol deviations with relevant impact on PD data.
12.2
Subject demographics and other baseline characteristics
Demographic and baseline characteristics (e.g., SLEDAI-2K, BILAG-2004, Physician Global 
Assessment, Patient Global Assessment, 
and 
baseline steroid dose) will be listed by subject and summarized by treatment group. Categorical 
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data will be presented as frequencies and percentages. For continuous data, mean, standard 
deviation, median, minimum and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, and by treatment group. They will also be 
listed by subject and treatment group.
12.3
Treatments
The safety set will be used for the analyses in this section. Categorical data will be summarized 
as frequencies and percentages. For continuous data, mean, standard deviation, median, 
minimum, and maximum will be presented.
The duration of exposure in weeks to study drug will be summarized by treatment group. 
The listing by subject and by treatment group will also be provided. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)
For either investigational drug, the primary analysis will compare active treatment with its 
matching placebo based on the PD analysis set within either cohort independently.
12.4.1
Definition of primary endpoint(s)
The primary endpoint is a composite of SRI-4 response at Week 29 with sustained reduction in 
oral corticosteroid from Week 17 through Week 29. 
SRI-4 response is defined as below: 

having ≥4 points reduction from baseline in SLEDAI-2K score AND

no new BILAG-2004 A and no more than one new BILAG-2004 B domain scores AND

no worsening, i.e., <10mm increase from baseline if scaled 0-100mm or 0.3-point increase
from baseline if scaled 0 to 3 in the Physician’s Global Assessment
Sustained reduction in oral corticosteroid is defined as below: 

≤5 mg/day or ≤baseline dose, whichever is lower, at Week 17
AND

No increase of that dose from Week 17 through Week 29 according to all of the following
conditions.
o
total daily CS dose remains ≤30 mg/d prednisone or equivalent
o
any increased daily CS dose administered is ≤2 days within a 4-week treatment cycle
from Week 17 to Week 29
o
daily CS dose is not increased within 2 weeks of  Week 29 study visit

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When all these criteria are met, the patient is a responder. Patients who receive rescue 
medication (see Section 6.2.4) will be considered as non-responder.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint will be analyzed using a Bayesian logistic regression model. The model 
will include treatment group, ENA status, baseline SLEDAI-2K (<10, ≥10) as fixed effects. 
Weakly informative priors will be used to obtain the posterior estimates. The primary analysis 
will be performed for each cohort separately.
Bayesian posterior probabilities will be used to assess the following criteria as a guide for 
decision making (Fisch et al 2015).
Efficacy criteria (for primary endpoint):

Week 29 responder rate in active group better than that in placebo group with high 
confidence (90%), i.e., Prob (θ_active - θ _ placebo >0) >90%, AND

Average magnitude of effect on Week 29 responder rate >15% over placebo, i.e., Prob 
(θ_active - θ _ placebo >15%) >50%.
Where θ is the Week 29 responder rate, i.e. the proportion of responders per definition.
Futility criteria:

Week 29 responder rate in active group worse than that in placebo with confidence higher 
than 60%, i.e., Prob (θ_active - θ _ placebo <0) >60%.
The posterior estimates of the treatment effect of VAY736 and CFZ533 compared to their 
matching placebos (along with the 90% credible intervals) at Week 29 will be provided. 
The results will be reported in terms of difference in probability of responders.
12.4.3
Supportive analyses
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Further details of these analyses will be specified in the Statistical Analysis Plan (SAP).
12.5
Analysis of secondary endpoints
Data will be listed by treatment group, period (blinded vs. open label), subject and visit/time as 
appropriate. Details of statistical methodologies for secondary endpoints will be described in 
the SAP. Graphical presentation of the data will be performed where applicable.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
The PD analysis set will be used for analyses in this section.
Physician’s global assessment in visual analog scale (VAS)
Physician’s global assessment (PhGA) in VAS will be listed by treatment group, subject, and 
visit. The change from baseline in physician's VAS will be listed by treatment group, subject
and visit, and summarized by treatment group and visit. Summary statistics will include mean,
SD, median, minimum and maximum. A Bayesian MMRM will be applied to this endpoint, as 
a continuous response variable. The model will include treatment group, ENA status, baseline 
SLEDAI-2K (<10, ≥10) and visit as fixed effects and baseline PhGA as continuous covariate. 
Weakly informative priors will be used to obtain the posterior estimates and unstructured 
covariance will be assumed.
Patient’s global assessment in visual analog scale (VAS)
Patient’s global assessment (PGA) in VAS will be analyzed the same way as physician’s global 
assessment (PhGA) in VAS.
Flare
Flare determined by BILAG-2004 as below (Isenberg et al 2005, Isenberg et al 2011):

Severe flare: developing a BILAG-2004 “A” score in any system due to items that are new 
or worse

Moderate flare: having two or more “B” score due to items that are new or worse
The number of flare and the rate of flare will be summarized by treatment group for different 
severities.
The proportion of patients with flare will be summarized by treatment group. The time to first 
flare will be summarized by treatment group, and listed by treatment group and subject. 
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
period and treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 

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summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment until end 
of study (EoS).
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent adverse events 
(events started after the first dose of study medication or events present prior to start of double-
blind treatment but increased in severity based on preferred term) will be summarized in the 
following ways:
1) by treatment group, primary system organ class and preferred term.
2) by treatment group, primary system organ class, preferred term and maximum 
severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
The number (and proportion) of subjects with adverse events of special interest will be 
summarized by treatment group. A subject with multiple adverse events within a primary 
system organ class is only counted once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit and if ranges are available, 
abnormalities will be flagged. Summary statistics (e.g., change from baseline and shift tables) 
will be provided by treatment group and visit.
12-lead ECG
All ECG data will be listed by treatment group, subject and visit, abnormalities will be flagged. 
Summary statistics will be provided by treatment group and visit.
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
subject during the study. ECG data will be read and interpreted (/locally). 
2. Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. In addition, a listing of these subjects will be produced by 
treatment group.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment group
and visit. Shift tables using the low/normal/high/ (low and high) classification will be used to 
compare baseline to the worst on-treatment value.

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Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit/time. Anti-
VAY736 antibody and anti-CFZ533 antibody results will be listed by treatment group, subject 
and visit. The proportion of ADA-positive patients will be listed by treatment group and visit.
12.5.3
Pharmacokinetics
 
 
 
 
 
 
 
Pharmacokinetic parameters for VAY736 and CFZ533 (Cmax,ss - The highest concentration 
observed during a dosing interval at steady-state, and Ctrough,ss - The trough observed analyte 
concentration at the end of a dosing interval) will be listed by treatment group and subject. 
Descriptive summary statistics will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum and maximum.
12.5.4
PK/PD relationships
Relationships between PK and PD variables may be explored by graphical approach and 
descriptive statistics will be provided. Additional statistical analysis such as analysis of variance 
(ANOVA) or regression analysis may be performed, if necessary. Modeling of the PK and PD 
data may be performed as appropriate. During modeling of the PK of the study drug, the broad 
principles outlined in the FDA, Guidance for Industry: Population Pharmacokinetics, will be 
followed. As the PK and PD data from the current study may be pooled with data from previous 
study, the PK/PD analysis will be described and reported separately in a modeling plan and 
modelling report respectively.
12.6
Analysis of exploratory endpoints
 
 
 
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12.6.1
Clinical Outcome Assessment
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12.7
Interim analyses
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
In total 120 patients are to be randomized to 4 treatment arms, aiming at 30 patients per 
treatment arm. The sample size may be re-estimated based on results of interim analysis 1 based 
on observed response rate in placebo arm. 
With 30 patients in either active or the matching placebo arm, there is 84% chance that the 
predefined efficacy criteria (Section 12.4.2) will be met, assuming the true difference in 
proportion of responders is 25% in favor of active arm and placebo responder rate is 17% 
(Furie et al 2017). If the true different from placebo is zero, the chance of meeting efficacy 
criteria is around 10%. The same assumption is made for either VAY736 or CFZ533 cohort.
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12.8.2
Secondary endpoint(s)
Not applicable.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US 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, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
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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 (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management 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 may be 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 subjects 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.

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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 Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject 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 subject 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.
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College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus 
syndromes. Arthritis Rheum; 42:599-608.
Albrecht J, Taylor L, Berlin JA, et al (2005) The CLASI (Cutaneous Lupus Erythematosus 
Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. 
J Invest Dermatol 125:889-94.
Bombardier C, Gladman DD, Urowitz MB, et al (1992) Derivation of the SLEDAI. A disease 
activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis 
Rheum; 35:630-40.
Bowman SJ, Fox R, Dörner T, et al (2022) Safety and efficacy of subcutaneous ianalumab 
(VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-
controlled, phase 2b dose-finding trial. Lancet; 399(10320):161-171
Cambridge G, Leandro MJ, Teodorescu M, et al (2006) B cell depletion therapy in systemic 
lupus erythematosus: Effecct on autoantibody and antimicrobial antibody profiles. Arthritis 
Rheum; 54:3612-22.
Cambridge G, Isenberg DA, Edwards JCW, et al (2007) B cell depletion therapy in systemic 
lupuserythaematosus: relationships among serum B lymphocyte stimulator levels, 
autoantibody profile and clinical response. Ann Rheum Dis; 67:1011-6.
Castrejón I, Tani C, Jolly M, et al (2014) Indices to assess patients with systemic lupus 
erythematosus in clinical trials, long-term observational studies and clinical care. Clin Exp 
Rheumatol; 32 (Suppl. 85):S85-S95.
Cella D, Yount S, Sorensen M, et al (2005) Validation of the Functional Assessment of 
Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients with 
rheumatoid arthritis. J Rheumatol; 32:811-9.
Chamberlain C, Colman PJ, Ranger AM, et al (2017) Repeated administration of 
dapirolizumab pegol in a randomized phase 1 study is well tolerated and accompanied by 
improvements in several composite measures of systemic lupus erythematosus disease activity 
and changes in whole blood transcriptomic profiles. Ann Rheum Dis; 76:1837-44.
Chasset F, Tounsi T, Cesbron E, et al (2018) Efficacy and tolerance profile of thalidomide in 
cutaneous lupus erythematosus: a systemic review and meta-analysis. J Am Acad Dermatol; 
78:342-50.
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Dörner T, Posch MG, Li Y, et al (2019) Treatment of primary Sjögren’s syndrome with 
ianalumab (VAY736) targeting B-cells by BAFF receptor blockade coupled with enhanced, 
antibody-dependent cellular cytotoxicity. Ann Rheum Dis; 78:641-47.
Ehrenstein MR and Wing C (2016) The BAFFling effects of rituximab in lupus: danger 
ahead? Nat Rev Rheumatol; 12:367-72.
European Association for the Study of the Liver (2017) EASL 2017 Clinical Practice 
Guidelines on the management of hepatitis B virus infection. Journal of Hepatology 67 (2): 
370-398
European Medicines Agency guidelines on clinical investigation of medicinal products for the 
treatment of systemic lupus erythematosus and lupus nephritis. 01 September 2015. 
EMA/CHMP51230/2013.
Fisch R, Jones L, Jones J, et al (2015) Bayesian design of proof-of-concept trials. Therapeutic 
Innov Reg Sci; 49:155-62.
Franklyn K, Lau CS, Navarra SV, et al (2016) Definition and validation of a lupus low 
disease activity state. Ann Rheum Dis; 75:1615-21.
Furie R, Khamashta M, Merrill JT, et al (2017) Anifrolumab, an anti-interferon-α receptor 
monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheum; 
69:376-86.
Furie R, Wang L, Illei G, et al (2018) Systemic lupus erythematosus (SLE) Responder Index 
response is associated with global benefit for patients with SLE. Lupus; 27:955-62.
Gladman DD, Ibañez D, Urowitz MB (2002) Systemic Lupus Erythematosus Disease Activity 
Index 2000. J. Rheumatol; 29:288-91.
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in parotid salivary glands of patients with primary Sjögren’s syndrome after B cell depletion 
therapy. Ann Rheum Dis; 71:1881-87.
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the classification of systemic lupus erythematosus. Arthritis Rheum; 40:1725.
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Isenberg DA, Farewell V, D’Cruz D, et al (2011) An assessment of disease flare in patients 
with systemic lupus erythematosus: a comparison of BILAG-2004 and the flare version of 
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rituximab with belimumab in severe systemic lupus erythematosus. J Autoimm; 91:45-54.
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2:16039. doi: 10.1038/nrdp.2016.39.
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Terrault NA, Lok AS, McMahon BJ, et al (2018) Update on prevention, diagnosis, and 
treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology; 67 (4): 
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Rep; 20:34. doi: 10.1007/s11926-018-0745-1.
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pharmacokinetics and immunogenicity of a PEGylated anti-CD40L antibody fragment 
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on a late complication. Curr Opin Hematol; 19:32-38.
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2004 index: a reliable tool for assessment of systemic lupus erythematosus activity. Arthritis 
Rheum; 54:3300-5.
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16
Appendices
16.1
1997 Update of the 1982 ACR Revised Criteria for Classification 
of Systemic Lupus Erythematosus
(Tan et al 1982; Hochberg 1997)
Table 16-1
ACR Revised Criteria for Classification of SLE
Criterion
Definition
Malar rash
Fixed erythema, flat or raised, over the malar eminences, tending to spare 
the nasolabial folds
Discoid rash
Erythematous raised patches with adherent keratoric scaling and follicular 
plugging; atrophic scarring may occur in older lesions
Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation
Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by a 
physician
Arthritis
Non-erosive arthritis involving two or more peripheral joints, characterized 
by tenderness, swelling, or effusion
Serositis
a)
Pleuritis - convincing history for pleuritic pain or rub heard by a 
physician or evidence of pleural effusion 
OR
b)
Pericarditis – documented by ECG or rub or evidence of pericardial 
effusions
Renal disorder
a)
Persistent proteinuria greater than 0.5 grams per day or greater than 
3+ if quantitation not performed 
OR
b)
Cellular casts – may be red cell, hemoglobin, granular, tubular, or 
mixed
Neurologic disorder
a)
Seizures – in the absence of offending drugs or known metabolic 
derangements 
OR
b)
Psychosis – in the absence of offending drugs or known metabolic 
derangements
Hematologic disorder
a)
Hemolytic anemia – with reticulocytosis 
OR
b)
Leukopenia – less than 4,000/mm3 total on two or more occasions
OR
c)
Lymphopenia – less than 1,500/ mm3 on two or more occasions 
OR
d)
Thrombocytopenia – less than 100,000 mm3 in the absence of 
offending drugs

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Criterion
Definition
Immunologic disorder
a)
Anti-DNA: antibody to native DNA in abnormal titer
OR
b)
Anti-Sm: presence of antibody to Sm or nuclear antigen
OR
c)
Positive finding of antiphospholipid antibodies based on (1) abnormal 
serum level of IgG or IgM anti-cardiolipin antibodies; (2) a positive test 
result for lupus anticoagulant using a standard method; or (3) a false 
positive serologic test for syphilis known to be positive for at least 
6 months and confirmed by Treponema pallidum immobilization or 
fluorescent treponemal antibody absorption test
Antinuclear antibody
An abnormal titer of antinuclear antibody by immunofluorescence or an 
equivalent assay at any point in time and in the absence of drugs known to 
be associated with “drug-induced lupus” syndrome
The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a 
person shall be said to have SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during 
any interval of observation  

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16.2
The Systemic Lupus Erythematosus Disease Activity Index 2000 
(SLEDAI-2K)
(Petri et al 2005, Gladman et al 2002)

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16.3
British Isles Lupus Activity Group (BILAG) score
BILAG 2004 Scoring Index

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(Yee et al 2006; Yee et al 2010; Castrejón et al 2014)
Flare determined by BILAG-2004 as below (Isenberg et al 2005; Isenberg et al 2011):

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