Conditions: Primary Sjögren's Syndrome
Keywords: primary Sjögren's syndrome, pharmacodynamics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
This study was designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic efficacy of a single intravenous infusion of VAY7346 monoclonal antibody in pSS patients

Detailed description:
Patients were enrolled in 2 sequential cohorts:

Cohort 1: 6 patients received 3 mg/kg or Placebo (2:1 ratio) Cohort 2: 21 patients received 10 mg/kg, 3 mg/kg or Placebo (6:1:3 ratio)

At week 24 the blind was broken to assess continuation in the trial:

* If a patient received VAY736 and their B cell recovery was demonstrated at Week 24, then patients completed the trial.
* If a patient received VAY736 and their B cell recovery was NOT demonstrated at Week 24, then patients were followed up until B cell recovery was demonstrated
* If a patient received placebo, they were offered the option of receiving open-label VAY736 (10 mg/kg) in a separate treatment arm.

Arms:
arm 1: single dose iv of VAY736 at a dose of 3mg/kg arm 2: single dose iv of VAY736 at a dose of 10mg/kg arm 3: single dose iv of Placebo. At Week 24 patients were offered to receive open label VAY736 10 mg/kg.

Interventions: intervention 1: VAY736 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
VAY736
Clinical Trial Protocol CVAY736X2201
A single dose, double-blind, placebo-controlled, parallel 
study to assess the pharmacodynamics, pharmacokinetics 
and safety and tolerability of VAY736 in patients with
primary Sjögren’s syndrome
Document type:
Amended Protocol Version
EUDRACT number:
2013-000250-22
Version number:
v06 Clean (incorporating Amendment 06)
Study phase:
IIa
Document status:
Final
Release date:
31-Oct-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Personal Data


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Notification of serious adverse events
A serious adverse event (SAE) is any event which is fatal or life-threatening, which requires 
or prolongs hospitalization, which is significantly or permanently disabling or incapacitating, 
which constitutes a congenital anomaly or a birth defect, or which is medically significant, 
may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above.
Any SAE occurring in a subject from consent until 30 days after stopping the trial/study 
drug must be reported either on the paper SAE report form or via the electronic SAE form 
within the clinical data capture system (where available).
For SAEs reported using the paper SAE report form, the investigator will ensure that the 
form is completed and faxed by the investigator to the local Novartis Drug Safety and 
Epidemiology Department within 24 hours of learning of the occurrence of the SAE even if 
the SAE does not appear to be drug-related. The original SAE form, together with the fax 
confirmation sheet, must be kept with the case report forms at the study site.
For SAEs recorded electronically in the Novartis clinical data capture system, information 
should be entered, saved and e-signed within 24 hours of awareness of the SAE. 
These data will automatically be submitted to Novartis Drug Safety and Epidemiology.
More details in Section 7 of this protocol.
Any update to the Novartis DS&E or personnel information required during the course of the 
study will be communicated directly to the relevant Investigator site(s); a specific protocol 
amendment should not be required.
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Table of contents
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms
12
Protocol synopsis...............................................................................................................32
Assessment schedule .........................................................................................................36
1
Introduction .......................................................................................................................41
1 1
Background
41
1.2
Study purpose ........................................................................................................48
2
Study objectives.................................................................................................................49
2.1
Primary objectives .................................................................................................49
2.2
Secondary objectives .............................................................................................49
2.3
Exploratory objectives...........................................................................................49
3
Investigational plan ...........................................................................................................50
3.1
Study design...........................................................................................................50
3.1.1
Dose escalation decision .......................................................................52
3.2
Rationale of study design.......................................................................................53
3.3
Maintenance of subject/study site personnel blinding...........................................54
3.4
Rationale of dose/regimen, duration of treatment .................................................55
3.5
Rationale for choice of comparator .......................................................................56
3.6
Purpose and timing of interim analyses/design adaptations..................................56
3.7
Risks and benefits..................................................................................................56
3.7.1
Potential risks associated with exposure to VAY736 ...........................57
3.7.2
Risk of ultrasound contrast agent..........................................................59
3.7.3
Pre-medication ......................................................................................59
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3.7.4
Risk mitigation strategy ........................................................................60
4
Population..........................................................................................................................60
4.1
Inclusion criteria ....................................................................................................61
4.2
Exclusion criteria...................................................................................................61
5
Treatment...........................................................................................................................64
5.1
Protocol requested treatment .................................................................................64
5.1.1
Investigational treatment.......................................................................64
5.1.2
Additional study treatment....................................................................65
5.2
Treatment arms ......................................................................................................65
5.3
Treatment assignment............................................................................................66
5.4
Treatment blinding.................................................................................................66
5.5
Treating the subject................................................................................................67
5.5.1
Subject numbering ................................................................................67
5.5.2
Dispensing the study treatment .............................................................68
5.5.3
Handling of study treatment..................................................................68
5.5.4
Instructions for prescribing and taking study treatment........................69
5.5.5
Permitted dose adjustments and interruptions of study treatment ........69
5.5.6
Recommended treatment of adverse events..........................................69
5.5.7
Rescue medication ................................................................................70
5.5.8
Concomitant treatment..........................................................................70
5.5.9
Prohibited treatment..............................................................................71
5.5.10
Discontinuation of study treatment and premature subject 
withdrawal.............................................................................................71
5.5.11
Emergency unblinding of treatment assignment...................................74
5.5.12
Study completion and post-study treatment..........................................74
5.5.13
Early study termination.........................................................................74
6
Visit assessments...............................................................................................................75
6.1
Dietary, fluid and other restrictions.......................................................................75
6.2
Subject demographics/other baseline characteristics.............................................76
6.3
Treatment exposure and compliance .....................................................................76
6.4
Efficacy / Pharmacodynamic assessments.............................................................77
6.4.1
ESSDAI.................................................................................................77
6.4.2
ESSPRI..................................................................................................77
6.4.3
SF-36.....................................................................................................77
6.4.4
MFI........................................................................................................77
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6 4 8
Assessment of salivary flow
79
6.5
Safety.....................................................................................................................81
6.5.1
Physical examination ............................................................................81
6.5.2
Vital signs..............................................................................................81
6.5.3
Height and weight .................................................................................81
6.5.4
Laboratory evaluations..........................................................................81
6.5.5
Electrocardiogram (ECG) .....................................................................83
6.5.6
Pregnancy..............................................................................................83
6.5.7
Other safety assessments.......................................................................84
6.6
Pharmacokinetic assessments ................................................................................84
6.6.3
Pharmacokinetic parameters .................................................................85
6.8
Other assessments..................................................................................................86
7
Safety monitoring ..............................................................................................................89
7.1
Adverse events.......................................................................................................89
7.2
Serious adverse event reporting.............................................................................90
7.3
Liver safety monitoring .........................................................................................92
7.4
Pregnancy reporting...............................................................................................92
7.5
Early phase safety monitoring ...............................................................................93
8
Data review and database management.............................................................................93
8.1
Site monitoring ......................................................................................................93
8.2
Data collection.......................................................................................................93
8.3
Database management and quality control............................................................94
8.4
Data Monitoring Committee..................................................................................95
8.5
Adjudication Committee........................................................................................95
9
Data analysis......................................................................................................................95
9.1
Analysis sets ..........................................................................................................95
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9.2
Subject demographics and other baseline characteristics......................................95
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................95
9.4
Analysis of the primary variable............................................................................96
9.4.1
Variable(s).............................................................................................96
9.4.2
Statistical model, hypothesis, and method of analysis..........................96
9.4.3
Handling of missing values/censoring/discontinuations.......................97
9.5
Analysis of secondary and exploratory variables ..................................................97
9.5.1
Efficacy / Pharmacodynamics...............................................................97
9.5.2
Safety.....................................................................................................98
9.5.3
Pharmacokinetics ..................................................................................99
9.5.4
Pharmacokinetic / pharmacodynamic interactions................................99
9.5.7
Other biomarkers.................................................................................100
9.6
Sample size calculation........................................................................................100
9.7
Power for analysis of key secondary variables....................................................101
10 Ethical considerations......................................................................................................102
10.1
Regulatory and ethical compliance......................................................................102
10.2
Informed consent procedures...............................................................................102
10.3
Responsibilities of the investigator and IRB/IEC................................................103
10.4
Publication of study results..................................................................................103
11 Protocol adherence ..........................................................................................................103
11.1
Protocol Amendments .........................................................................................103
12 References .......................................................................................................................104
15 Appendix 3: ESSDAI ......................................................................................................111
16 Appendix 4: ESSPRI.......................................................................................................115
17 Appendix 5: SF-36 ..........................................................................................................119
18 Appendix 6: MFI.............................................................................................................120
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List of tables
Table 1-1
Summary (geometric mean) of PK parameters of VAY736 in RA 
patients following a single i.v. dose of 0.0003 mg/kg to 10.0 mg/kg 
(CVAY736X2101)................................................................................47
Table 5-1
Study drug VAY736 .............................................................................64
Table 5-2
Prohibited treatment..............................................................................71
Table 14-1
Liver Event Definitions.......................................................................108
Table 14-2
Liver Event Follow Up Requirements ................................................109
Table 15-1
The EULAR Sjögren’s syndrome disease activity index (ESSDAI): 
domain and item definitions and weights............................................111
Table 20-1
Blinding levels ....................................................................................122
Figure 3-1
Study design..........................................................................................53
Figure 9-1
Probability of meeting efficacy criteria for N=16:8 
VAY736:placebo.................................................................................101
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List of abbreviations
ADA
Anti Drug Antibody
ADCC
Antibody-dependent cytotoxicity
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
ANA
Anti-nuclear antibody
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
BAFF
B cell activating factor
BAFF-R
BAFF-Receptor
b.i.d.
Twice a day
BM
Biomarker
BMI
Body Mass Index
BUN
Blood urea nitrogen
CD-ROM
Compact disc – read only memory
CFR
Code of Federal Regulation
CK
Creatinine kinase
CLL
Chronic lymphocytic leukemia
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive protein
CO2
Carbon dioxide
CRO
Contract Research Organization
CV
Coefficient of variation
DLT
Dose limiting toxicity
DMARDS
Disease-modifying anti-rheumatic drugs
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay


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EOS
End Of Study
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren’s Syndrome Patient Response Index
EULAR
European League Against Rheumatism
FDA
Food and Drug Administration
FIH
First in human
GCP
Good Clinical Practice
γ-GT
Gamma-glutamyl transferase
h
Hour
HIV
Human immunodeficiency virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
Immunoglobulin
i.v.
intravenous
IVIG
Intravenous Immunoglobulin
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification
LLN
Lower limit of normal
mAb
Monoclonal antibody
MFI
Multidimensional Fatigue Inventory
mg
Milligram(s)
ml
Milliliter(s)
NCA
Non compartmental analysis
NG sequencing
Next generation sequencing
NK
Natural killer cells
NR
Not reported
o.d.
Once a day
OSS
Ocular staining score
PA
Posteroanterior


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PD
Pharmacodynamic(s)
PEE
Punctate epithelial erosions
PK
Pharmacokinetic(s)
p.o.
Oral
PPD
Purified protein derivative
pSS
Primary Sjögren’s Syndrome
RA
Rheumatoid arthritis
RBC
Red blood cell(s)
REB
Research Ethics Board
RF
Rheumatoid factor
SAE
Serious adverse event
SCA
Salivary collection aid
SF-36
Short Form (36) Health Survey
SLE
Systemic lupus erythematosus
s.c.
Subcutaneous
SAD
Single ascending dose
SD
Single dose
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SD
Standard deviation
sm/sl
submandibular/sublingual
TBL
Total bilirubin
TBUT
Tear breakup time
TK
Toxicokinetics
TMDD
Target Mediated Drug Disposition
ULN
Upper limit of normal
ULQ
Upper limit of quantification
VAS
Visual analog scale
WBC
White blood cell(s)


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to time ‘t’ where t is a defined time point after administration 
[mass x time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x time 
/ volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
T1/2
The terminal elimination half-life [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vz
The volume of distribution during the terminal elimination phase following 
intravenous administration [volume]
Vss
The volume of distribution at steady state following intravenous 
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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Control drug
A study drug used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the 
investigational drug.
Enrollment
Point/time of subject entry into the study; the point at which 
informed consent must be obtained (i.e., prior to starting any of 
the procedures described in the protocol).
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 is
synonymous with “investigational new drug” or “investigational 
medicinal product”.
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls.
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination.
Investigational treatment generally does not include other 
treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved 
indication/dosage.
Medication number
A unique identifier on the label of each study drug package in 
studies that dispense study drug using an IRT system.
Subject number
A number assigned to each subject who enrolls in the study. 
When combined with the center number, a unique identifier is 
created for each subject in the study.
Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the 
planned completion of all study drug administration and 
assessments; at this time all study drug administration is 
discontinued and no further assessments are planned.
Randomization number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment.
Stage
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc.


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Study completion
Point/time at which the subject came in for a final evaluation visit 
or when study drug was discontinued whichever is later.
Study drug/treatment
Any drug (or combination of drugs) administered to the subject as 
part of the required study procedures; includes investigational 
drug, active drug run-ins or background therapy.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for 
any reason; may or may not also be the point/time of premature 
subject withdrawal.
Subject
An individual who has consented to participate in this study. The 
term Subject may be used to describe either a healthy volunteer or 
a patient.
Variable
Information used in the data analysis; derived directly or 
indirectly from data collected using specified assessments at 
specified timepoints.


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Protocol synopsis
Protocol number
CVAY736X2201
Title
A single dose, double-blind, placebo-controlled, parallel study to assess the 
pharmacodynamics, pharmacokinetics and safety and tolerability of VAY736 
in patients with primary Sjögren’s syndrome
Brief title
VAY736 in patients with primary Sjögren’s syndrome
Sponsor and Clinical 
Phase
Novartis Pharma AG
Phase IIa
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This study with VAY736 monoclonal antibody is designed to evaluate the 
safety, tolerability, PD and PK, and to explore therapeutic efficacy of a single 
intravenous infusion of VAY736 monoclonal antibody in pSS patients to 
enable further development of the compound for treatment of this disease 
population.
Primary Objectives 
and Key Secondary 
Objective

To compare the effect of a single i.v. dose VAY736 versus placebo on 
the clinical disease activity of primary Sjögren’s syndrome patients as 
measured by the change of a modified EULAR Sjögren’s Syndrome 
Disease Activity Index (ESSDAI) between base line and week 12

To assess the safety and tolerability of a single i.v. dose VAY736 in 
patients with primary Sjögren’s syndrome as measured by adverse 
events (AEs)
Secondary 
Objectives

To evaluate the effect of a single i.v. dose VAY736 versus placebo on 
self-reported outcomes in pSS patients at 12 weeks compared to 
baseline as measured by the EULAR Sjögren’s Syndrome Patient 
Reported Intensity (ESSPRI), the Short Form (36) Health Survey (SF-36) 
and the Multidimensional Fatigue Inventory (MFI) Questionnaire.

To determine the changes in the physician global assessment of the 
patient’s overall disease activity between baseline and week 12 as 
recorded by a visual analog scale (VAS)

To determine the changes in the patients’ global assessment of their 
disease activity between baseline and week 12 as recorded by a VAS

To determine the pharmacokinetics following a single dose i.v. VAY736 in 
pSS patients
Study design
Randomized, double blind, placebo-controlled, non-confirmatory study in 
approximately 26 patients. Patients that received placebo treatment will be 
offered open-label single dose i.v. VAY736 treatment
Population
Seropositive primary Sjögren’s syndrome
Inclusion criteria

Fulfilled revised European US consensus criteria for pSS

ESSDAI value ≥6

Elevated serum titers at screening of ANA (≥ 1:160) and of RF
or

Seropositive at screening for anti-SSA (±anti-SSB) antibodies

Stimulated whole salivary flow rate at screening of > 0 mL/min


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Exclusion criteria

Prior use of any B-cell depleting therapy (e.g., rituximab or other 
anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb)

Prednisone > 10 mg/d or dose change within 2 weeks of the time of 
randomization

Any of the following within 180 days of randomization
Anti-BAFF mAb
CTLA4-Fc Ig (abatacept)
Anti-TNF-α mAb
Intravenous Ig
Plasmapheresis
i.v. or oral cyclophosphamide

Treatment with azathioprine, or prior use within 84 days of randomization; 
patients taking either hydroxychloroquine or methotrexate at a consistent 
dose for ≥3 months prior to randomization are eligible if dose is 
maintained throughout the study

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

History or evidence of tuberculosis

Receipt of live/attenuated vaccine within a 2 month period before 
enrollment

History of primary or secondary immunodeficiency
Investigational and 
reference therapy

VAY736 3 mg/kg and 10 mg/kg administered intravenously.

Control: VAY736 placebo infusions will be prepared by an unblinded 
pharmacist.

Duration of treatment: single i.v. dose administration and a follow up 
study up to 1 month after a patient’s circulating B cells meet criteria for 
recovery.
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Efficacy 
assessments

PD assessment of circulating B cell levels

Modified EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)

EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI)

Short Form (36) Health Survey (SF-36)

Multidimensional Fatigue Inventory (MFI) Questionnaire

Physician’s and Patient’s assessment of global disease activity

High resolution ultrasound of salivary glands (with optional blood flow 

Salivary gland function using salivary flow (unstimulated and stimulated)

Lacrimal gland function using the Ocular staining score (OSS)

Serum evidence of B cell hyperactivity, 
 
Safety assessments

Physical exam

Vital signs

Laboratory evaluations: hematology, clinical chemistry, urinalysis

Electrocardiogram (ECG)

Pregnancy testing

Occurrences of infection

Adverse event

Serious adverse event

Concomitant medications

Flow cytometry safety panels
Other assessments

Pharmacokinetics
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Data analysis
The primary efficacy variable is the ESSDAI recorded at baseline and 
week 6, 12 and 24.
The change from baseline in ESSDAI will be analyzed using a model 
including terms for the patient effect (as a random effect), treatment effect, 
time (as nominal study week), the interaction between time and treatment 
(all as fixed effects) and with the baseline ESSDAI as a covariate. 
This statistical analysis model will include change from baseline data on the 
ESSDAI from all post-baseline time points at which it was recorded 
(i.e., weeks 6, 12 and 24) but the primary comparison is made for week 12.
Estimates of the difference between VAY736 and placebo at each time point 
will be derived from this model and presented together with 95% credible 
intervals. A positive sign of therapeutic effects will be considered to be a 
difference of at least 5 points in the change from baseline between VAY736 
and placebo with a moderate level of evidence (i.e., 50%). Additionally there 
should be a high level of evidence (i.e., 90%) that there is a difference 
between VAY736 and placebo. The estimates of the posteriors probabilities 
of these criteria being met will be provided, assuming standard non-
information prior Normal distributions.
Secondary efficacy variables (ESSPRI, SF-36, MFI) physician global 
assessment of the patient’s overall disease activity, patient’s global 
assessment of their disease activity) will be analyzed following a similar 
approach. Other assessments supporting the exploratory objectives will be 
summarized
Key words
Primary Sjögren’s syndrome, BAFF-R, B cell depletion








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1
Vital signs: Sitting and standing blood pressure and heart rate measurement required (standing
only at screening and baseline); body height (at screening only), body weight, temperature.
During study drug administration blood pressure and heart rate should be obtained every 
30 minutes.
2
ESSDAI: 
EULAR Sjögren’s Syndrome Disease Activity Index (Section 6.4.1).
3
ESSPRI: 
EULAR Sjögren’s Syndrome Patient Response Index (Section 6.4.2),
SF-36: Short Form (36) Health Survey (Section 6.4.3),
MFI:
Multidimensional Fatigue Inventory (Section 6.4.4).
6
At Screening and Baseline perform a thorough physical examination. At the subsequent visits 
assess relevant organ systems.
7
Pregnancy test: Perform on all females: At screening perform a serum pregnancy test; at 
Baseline and the EOS visit a urine pregnancy test is sufficient.
8
10 B cell hyperactivity: 
 
13 Administration: VAY736 infusion over 2 hours following premedication with paracetamol 
(500 mg 1 hour pre-dose and 5 hours [±30 min.] post dose and 1000 mg 11 hours [±1 hour] 
post dose). H1 receptor blockers may be administered in the event paracetamol pre-medication 
does not prevent infusion reactions sufficiently. The decision may be made on a case-by-case 
basis or as a general recommendation if the paracetamol pre-medication is deemed not 
effective during conduct of the study.
14 To be taken at the end of infusion.
15 Long term follow-up: only in patients with persisting B cell depletion defined as either of the 
following listed below:
a) lower limit of normal (50 cells/µL) or, b) 20% from baseline levels. If B cell recovery criteria 
are not met by week 24 (Day 168) the affected patient should be followed-up. The visits should 
take place at week 32, 40, 52, week 76 and week 100 [±2 weeks] and thereafter every
48 weeks (week 148, 196 and so forth [±2 weeks]) until the patient no longer meets any of the 
criteria used to define persisting B cell depletion.
16 End of Study: Visit 777 will be performed within 4 weeks from the visit B cell depletion is no 
longer persistent (Visit 13 or during long term follow-up).
17 Baseline assessments should be completed between Days -7 and -1.
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19 All adverse events will be reported from the time the subject has provided informed consent to
visit 16 (week 52). Starting from visit 17 until end of study, only AE related to VAY736 as 
assessed by the investigator and AE related to infection, potential malignant events and 
neutropenia will be recorded. Serious adverse events will be reported from the time the subject 
has provided informed consent until 30 days after the last study visit. Any SAEs experienced 
after the 30-day period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment.
20 PPD / QuantiFeron test: At screening or within 6 months prior to randomization.
21 Only in patients who do not meet end of study criteria at week 24.
** optional overnight stay at Day -1.
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1
Introduction
1.1
Background
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease of unknown etiology 
characterized by lymphoid infiltration and progressive destruction of exocrine glands 
(Youinou and Pers 2012). Although primarily organ-specific for the lacrimal and salivary 
glands, the inflammatory process can target any organ. Thus, the clinical features range from 
dryness, pain and fatigue affecting nearly all patients, to severe, extra-glandular and systemic 
involvement in a more limited subset. The increased B cell activity underlying pSS also 
results in an increased risk for malignant transformation, with lymphoma development 
occurring in 5% of Sjögren’s syndrome patients.
Sjögren’s syndrome is second only to rheumatoid arthritis (RA) in prevalence as a systemic 
autoimmune disease. The disease affects mainly women with a female/male ratio of 9:1 and can 
occur at any age. Treatment for pSS patients is limited to symptomatic care for the mucosal signs 
and symptoms. Steroids and typical DMARDs are ineffective, and no pharmacologic intervention 
is effective against the severe, disabling fatigue. Recently, efficacy of B cell depletion therapy 
using the anti-CD20 monoclonal antibody (mAb) rituximab has been shown for both glandular 
and extra-glandular manifestations of pSS as well as for lymphoma management.
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. 
 
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1.1.1.3
Human safety and tolerability data
As of 15-Jun-2013, human clinical experience with VAY736 is primarily limited to RA 
patients (n = 41, 31 treated) of mild-to-moderate disease severity in an ongoing phase I 
study CVAY736X2101 designed to assess the safety, tolerability, pharmacokinetics 
and pharmacodynamics in single-
and multiple-ascending doses of the compound. 
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1.2
Study purpose
This study with VAY736 monoclonal antibody is designed to evaluate the safety, tolerability, 
pharmacokinetics and therapeutic efficacy of a single intravenous infusion of VAY7346 
monoclonal antibody in pSS patients to enable further development of the compound for 
treatment of this disease population.
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2
Study objectives
2.1
Primary objectives

To compare the effect of a single i.v. dose VAY736 versus placebo on the clinical 
disease activity of primary Sjögren’s syndrome patients as measured by the change of 
a modified EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) between base 
line and week 12

To assess the safety and tolerability of a single i.v. dose VAY736 in patients with 
primary Sjögren’s syndrome as measured by adverse events (AEs)
2.2
Secondary objectives

To evaluate the effect of a single i.v. dose VAY736 versus placebo on self-reported 
outcomes in pSS patients at 12 weeks compared to baseline as measured by the 
EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI), the Short Form (36) 
Health Survey (SF-36) and the Multidimensional Fatigue Inventory (MFI)
Questionnaire.

To determine the changes in the physician global assessment of the patient’s overall 
disease activity between baseline and week 12 as recorded by a visual analog scale 
(VAS)

To determine the changes in the patients global assessment of their disease activity 
between baseline and week 12 as recorded by a VAS

To determine the pharmacokinetics following a single dose i.v. VAY736 in pSS 
patients
2.3
Exploratory objectives

High resolution ultrasound of salivary glands as measured by the following 
parameters:

Salivary gland thickness and staging

Parotid salivary gland blood flow with contrast agent (optional)
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
Salivary gland function using the salivary flow (unstimulated and stimulated)

Lacrimal gland function using the Ocular Staining Score

Serum evidence of B cell hyperactivity,
 

To measure the effect of a single i.v. dose VAY736 on leukocyte subsets,
 
3
Investigational plan
3.1
Study design
This is a double-blind, randomized, placebo-controlled, parallel-group, non-confirmatory 
study to assess the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics 
and clinical efficacy of VAY736 administered intravenously as a single dose in pSS patients.
The patients will be enrolled in 2 sequential cohorts:

3 mg/kg cohort (Cohort 1): 6 patients randomized to receive a single dose of VAY736 
at a starting dose of 3.0 mg/kg or placebo at a 2:1 ratio; approximately 4 patients in 
this cohort will receive a 3.0 mg/kg dose of VAY736 and approximately 2 patients will 
receive placebo.

10 mg/kg cohort (Cohort 2): 20 patients randomized to receive a single dose of 
VAY736 at a dose of 10.0 mg/kg or 3.0 mg/kg or placebo at a 6:1:3 ratio, respectively.
Around 12 patients will receive 10 mg/kg of VAY736 in this cohort and around 6 will
receive placebo. Approximately 2 patients will receive 3.0 mg/kg in this cohort to 
maintain a level of blinding regarding the dose received.
Between Cohort 1 and Cohort 2 recruitment will be paused and a safety review will be 
conducted by the VAY736 project team and the principle investigators (see Section 3.1.1).
t  This study will enroll 
around 26 patients with primary Sjögren’s syndrome. At least 24 subjects are expected to 
complete the study.
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Subjects that are prematurely withdrawn from the study for reasons other than safety will be 
replaced on a case by case basis. Data from the withdrawn patients will still be used in the 
primary analysis as much as possible but the sponsor will use replacement patients to obtain 
complete data on at least 24 patients.
For each patient, there will be a maximum 28-day screening period. Subjects who meet the 
eligibility criteria at screening will undergo baseline evaluations (between Days -7 to -1).
Patients may stay overnight at the study site on Day -1 if required for scheduled early morning 
study-related activities on Day 1, but this is not mandatory. All baseline safety evaluation 
results must be available prior to dosing and meet eligibility criteria. 
Enrolled patients will be randomized at a 2:1 ratio to receive treatment with either VAY736
3 mg/kg or placebo in the first cohort. In the second cohort, they will be randomized to 
receive VAY736 10 mg/kg, 3 mg/kg or placebo at a 6:1:3 ratio. Dosing of the patients in the 
first cohort and the first 5 patients enrolled in the second cohort will be staggered at a 
minimum interval of 20 hours. On Day 1, following premedication with paracetamol (and H1 
receptor blocker, if necessary), a single dose of VAY736 or placebo will be administered, 
followed by PK, pharmacodynamics (PD) and safety assessments for up to 24 hours. Patients 
are required to stay overnight at the study site on Day 1 and will be discharged on Day 2 after 
completion of all safety assessments and collection of the 24 h blood samples provided there 
are no safety concerns.
Patients will return to the study center for safety and PK checks at Day 7, Day 14, week 3, 
week 6, week 9 and week 12. Subsequent outpatient visits will occur at 4 week intervals 
thereafter until week 24.
At Week 24 the blind will be broken to confirm treatment allocation. Investigators will follow 
the guidance below:

If a patient received VAY736 and their B cell recovery) is demonstrated at Week 24
(refer to Section 6.4.6 for B cell recovery definition), then patients should return for 
their End of Study visit approximately 4 weeks later.

Those patients who do not meet the criteria for B cell recovery at Week 24, will return 
to the site every 8 weeks until Week 40, then at week 52, every 24 weeks until 2 years 
post dose (week 100) and afterwards every 48 weeks, until B cell recovery is 
demonstrated (refer to Section 6.4.6 for B cell recovery definition) and the End of 
Study visit may be scheduled.

If a patient received placebo, they will be offered the option of receiving open-label 
VAY736 (10 mg/kg) in a separate treatment arm.

Patients that consent to open-label VAY736 treatment will restart the study at 
Day 1 (within 4 weeks [+ 2 week window] of Week 24 visit)

Patients that do not consent to receive open-label VAY736 treatment will return to 
the site for End of Study visit as per Assessment schedule.
Patients will not be informed of their treatment allocation until after all of the assessments 
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Once B cell recovery threshold criteria are met the patient will undergo the end of study visit 
within 4 weeks. End of study visit will include study completion evaluations followed by 
discharge from the study.
Safety assessments at study visits will include vital signs, physical examinations, ECGs, 
standard clinical laboratory evaluations (hematology, blood chemistry,
urinalysis, 
pregnancy test), 
 adverse events and serious adverse 
events monitoring. In particular, subjects will be monitored closely during the first 2 hours 
after starting infusion of VAY736 for signs or symptoms of adverse events, including 
development of an infusion reaction. Treatment of infusion reactions is described under 
Section 5.5.6.
In addition, serum anti-VAY736 antibody levels 
 (Section 6.7) will be 
measured.
For this study of VAY736 in Sjögren’s syndrome patients, 4 different flow cytometry-based 
panels (Section 6.8.2.1) will be conducted on whole blood to monitor responses of circulating 
leukocytes to VAY736 exposure and will include a Leukocyte Immunophenotyping Panel,  
 
Additional planned biomarkers of PD effects by VAY736 will include 
 
 
functional evaluations of 
lacrimal and salivary glands, measures of B cell hyperactivity and tissue imaging of salivary 
glands (non-invasive and invasive).
3.1.1
Dose escalation decision
Progression from the 3 mg/kg dose cohort to the 10 mg/kg cohort will require a minimum 
post-treatment safety observation period of 14 days for all individuals in the prior cohort. 
This 14-day safety period allows sufficient time for maximum PD effects from VAY736 to 
develop. The sponsor and the principal investigator will review 14-day safety data a minimum 
of 14 days after the last subject of this first patient group has received his or her dose of 
VAY736 at 3 mg/kg to ensure that escalation to the 10 mg/kg dose is appropriate and 
acceptable. Data available at safety review will be: AEs, SAEs, out-of-range clinical 
laboratory values, all hematology parameters and flow cytometry safety panels.
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Figure 3-1
Study design
An interim analysis is planned after all patients have completed the week 12 visit in order to assess the 
effect of VAY736 on the primary endpoint.
3.2
Rationale of study design
This study will be conducted in patients with active pSS for which no existing treatment has 
been proven effective against the underlying disease. Current evidence supports a key role for 
B cells in pSS pathogenesis and implicates BAFF:BAFF-R signaling as a contributing factor. 
In addition, B cell targeted therapy with rituximab (anti-CD20 mAb) has demonstrated 
evidence in pSS patients supporting therapeutic efficacy while maintaining a favorable safety 
profile in clinical studies to date.
A randomized, placebo-controlled, double-blind approach is used to eliminate potential bias 
in reporting safety and clinical efficacy data in this first, exploratory study in pSS patients. 
Patients will be randomized to VAY736 or placebo in an overall 18:8 ratio in order to 
VAY736  (3 
mg/kg) or
placebo (2:1)
VAY736  (3 
mg/kg or 10 
mg/kg) or
placebo (6:1:3)
Cohort 1
Cohort 2
Safety
Review
N=6
N=2
N=4
N=2
N=12
Clinical 
assessment
Clinical 
assessment
Clinical 
assessment
VAY736 3 mg/kg
placebo
VAY736 10 mg/kg
VAY736 3 mg/kg
placebo
Week 6
Week 24
Week 12
Safety follow up or open-label VAY736
U
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minimize exposure to placebo and to gather more data on VAY736  
 
Based on published results with a single cycle of rituximab, significant clinical responses in 
pSS patients can be detected as early as 5 weeks, with maximum effect shown at 12 weeks 
(Meijer et al 2010). A follow up evaluation at 24 weeks will provide information on the 
duration of clinical response to VAY736 treatment. Heterogeneity in duration of B cell 
depletion is expected within a given patient treatment group from experience reported with 
rituximab 
. Therefore, after completion 
of the 24 weeks evaluation, patients not meeting criteria for B cell recovery will continue 
under periodic monitoring until such criteria are reached.
3.3
Maintenance of subject/study site personnel blinding
Only the study site pharmacists and the bioanalyst will be unblinded throughout the duration 
of the study. The bioanalyst will not provide individual PK values until an IA or the end of the 
study.
The study will be blinded to patients, investigator site staff and the clinical trial team at the 
time of randomization. Unblinding of patients’ treatment allocation, as they reach the end of 
double-blind treatment period (Week 24), is planned. 
 In order to reduce patient discomfort and help 
reduce the risk of unblinding that might arise if an infusion reaction occurs, all patients will 
receive treatment with paracetamol (and histamine H1 receptor blocker, if necessary) prior to 
infusion with VAY736.
Because of the expected cell depleting effects of VAY736 affecting the patients’ leukocyte 
counts and differentials, an independent safety physician as well as a medical monitor at 
Novartis will be designated to monitor these safety parameters, for all patients, during the 
study and to warrant adequate measures in case of safety concerns.
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3.4
Rationale of dose/regimen, duration of treatment
These dosing considerations are considered important because B cells residing in ectopic 
lymphoid tissues of pSS patients have been shown particularly resistant to depletion by 
rituximab, possibly due to the apoptosis resistant effects of high BAFF tissue levels associated 
with this disease process (Pers et al 2007; Quartuccio et al 2008; Hamza et al 2012). 
In addition, baseline serum levels of BAFF correlate inversely with duration of B cell 
depletion, with potential links to therapeutic efficacy of this approach (Varin et al 2010). 
Finally, the circulating B cell compartment is not representative of the tissue compartment
where pathologic B cells are likely to reside, 
 
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3.5
Rationale for choice of comparator
In the current study, the placebo to VAY736 will be used as comparator to provide objective 
evidence of potential AEs and other safety data, as well as clinical efficacy and PD data 
generated from patients exposed to the experimental therapy during the initial 24-week trial. 
Since there is no established, clinically effective disease modifying treatment for patients with 
pSS, potential treatment with placebo is justified.
Furthermore, after unblinding, patients initially randomized to placebo will be offered 
optional treatment with a single administration of VAY736. The purpose of this optional open 
label administration of VAY736 is to allow all patients who participate in this study to have 
an equitable opportunity to eventually receive study drug.
3.6
Purpose and timing of interim analyses/design adaptations
An interim analysis is planned after all patients have completed the week 12 visit in order to 
assess the effect of VAY736 on the primary endpoints. For these subjects the efficacy 
endpoints up to week 12 (along with relevant safety data) will be examined as a preliminary 
evaluation of therapeutic effects.
In addition, an interim safety review will be performed between Cohort 1 and Cohort 2; 
details are given in Section 3.1.1.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns.
Additional information is presented in Section 9.8.
3.7
Risks and benefits
To date, no evidence-based, systemic therapy has been available for pSS patients. 
Corticosteroids and traditional disease modifying anti-rheumatic drugs have shown only 
modest effects, if any, on disease course. B cells have an established role in pSS pathogenesis, 
and potential benefits have been reported using the B cell depleting therapy rituximab in small 
numbers of pSS patients, with improvements observed in both glandular and extraglandular 
features (Meijer et al 2010; Meiners et al 2012). Thus, therapies targeting B cells show 
promise in the treatment of pSS, although larger, confirmatory clinical studies remain to be done.
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VAY736 is a B cell-depleting biologic of novel mechanism of action that has undergone 
limited phase I testing in RA patients, 
 
 This current study in pSS patients is designed to explore the 
clinical efficacy of VAY736 along with the safety, tolerability, PK and PD. VAY736 has 
never been used in patients with pSS and so no statement can be made of its efficacy in 
treating this disease.
By targeting the BAFF receptor, VAY736 incorporates dual mechanisms of action, 
including depletion of mature and immature B cells along with concurrent blockade of the 
maturation/survival pathway; biological effects that may be more efficacious for targeting the 
highly BAFF-driven, auto-reactive B cells underlying pSS pathogenesis. 
 
3.7.1
Potential risks associated with exposure to VAY736
B cell depletion and blockade of BAFF signaling have been shown to be well-tolerated by 
patients with autoimmune diseases, including pSS patients, when therapeutically targeted 
independently. Experience with concurrent application of these mechanisms of action in 
humans has been limited to the phase I SAD trial of VAY736 in patients with active RA 
disease despite methotrexate treatment.
3.7.1.1
Cytokine release
 
 When large numbers of B cells are rapidly 
eliminated by ADCC, there is the potential for concurrent release of inflammatory cytokines. 
Infusion reactions have been experienced by over a third of RA patients exposed to rituximab 
despite receiving corticosteroid pre-medication (Fleischmann 2009), with a similar safety 
profile reported in rituximab-treated pSS patients (Seror et al 2007; Dass et al 2008); 
(Meijer et al 2010). 
 
 
 
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3.7.1.2
Serum sickness
Primary Sjögren’s syndrome patients treated with rituximab have also shown an increased 
incidence of serum sickness, with reported rates from
6-27% (Pijpe et al 2005;
Seror et al 2007; Dass et al 2008; Meijer et al 2010). Although the etiology of this reported 
increased susceptibility of pSS patients to serum sickness with rituximab remains unknown, 
the condition in humans is typically described as a type III, immune complex hypersensitivity 
reaction to proteins such as antibodies derived from animals. Although VAY736 is a fully 
human IgG monoclonal antibody, its potential for inducing serum sickness in pSS patients 
remains currently unknown.
3.7.1.3
Late onset neutropenia
More recently, late onset neutropenia (LON) is an increasingly recognized late adverse event of 
rituximab therapy, described primarily in oncology patients
(Tesfa and Palmblad 2011;
Wolach et al 2012). The few available reports of late onset neutropenia in the treatment of 
autoimmune diseases, suggest that the incidence is comparable to that in the hematologic 
population (3-27%). LON has been reported to appear from 7-48 weeks following rituximab 
administration and to coincide with the time of B cell recovery. Cases typically self -resolve 
rapidly without the need for colony-stimulating factors and without significant morbidity or 
mortality. The specific cause of late onset neutropenia remains unknown and rechallenge with 
rituximab has not led to recurrent neutropenia in previously affected patients.
One of 3 CLL patients receiving VAY736 in CVAY736Y2101 progressed from a base line 
grade 3 neutropenia to a non-study drug-related grade 4 neutropenia after four weekly doses 
of VAY736 0.002 mg/kg.
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3.7.1.4
Potential immune suppression effects
Infection
In general, the risk of immune suppression is related to 
the intensity and duration of the immunosuppressive regimen administered. The expected 
extent and duration of circulating B cell depletion in patients exposed to VAY736 in this 
single dose, exploratory study is expected to be limited in comparison to patients receivin g 
multiple cycles of rituximab.
Vaccinations
In immune suppressed patients, live vaccinations may cause serious adverse events and 
vaccination success may be attenuated. No data exists on the effect of VAY736 on response to 
vaccinations in general.
3.7.1.5
Administration of a monoclonal antibody
General risks associated with mAb administration in humans include the possibility of a 
hypersensitivity reaction characterized by acute or delayed allergic reaction, anaphylaxis, 
urticaria, rash, dyspnea, hypotension, fever, chills and immunogenicity. A serious infusion 
reaction that results in anaphylaxis is a rare event in monoclonal antibody therapy. VAY736 is 
a fully human mAb of the IgG1 class, and thus expected to be less immunogenic in humans 
than chimeric or humanized antibodies.
3.7.2
Risk of ultrasound contrast agent
The blood flow measurement and elastography of the parotid salivary glands by 
high-resolution ultrasound is optional
 
 The contrast agent SonoVue 
(sulphur hexafluoride microbubble, Bracco Imaging, Italy) is available only in EU.
The contrast agent will be given intravenously to patients for ultrasound assessments. 
SonoVue has a current marketing authorization from EMA. SonoVue is associated only with 
uncommon adverse effects. Adverse events associated with immune system disorders are not 
known in pre-marketing data. 
 
3.7.3
Pre-medication
Adverse effects from paracetamol at the dose to be administered is not expected.
Adverse effects from H1 receptor blockers (e.g., Fenistil™) at the dose to be administered are 
mild and include drowsiness and occasionally gastrointestinal disturbances, dryness of the 
mouth, vertigo excitation and headaches.
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3.7.4
Risk mitigation strategy
This study is being initiated at hospital-based study sites with ready access to intensive care 
facilities for rapid assessment and treatment in the event of a VAY736-induced severe 
infusion reaction. The period during and immediately after (e.g., 2hr) the initial exposure to a 
biologic is the most critical for most infusion reactions (including hypersensitivity, cytokine 
release, anaphylaxis). To improve the safety margin in this study, we will administer VAY736 
over a 1-2 hour period. During this time, the patient will be monitored closely by a physician 
with vital signs taken every 30 minutes. This would allow preventive measures to be taken if 
signs and symptoms indicate a reaction to the VAY736 infusion. In addition, all patients will 
receive pre-medication with paracetamol (and an H1 receptor blocker, if necessary) to 
diminish the signs and symptoms of infusion reactions. The subject will remain in the study 
center overnight post-infusion for observation and measurement of safety parameters. 
Additional precautionary safety measures will include staggering dosing of enrolled 
patients in the first cohort and the first 5 enrolled patients in the second cohort by a minimum 
of 20 hours.
The Sponsor and Principal Investigators will review cumulative, blinded safety data 
continuously and at scheduled quarterly meetings. Of note, the clinical safety plan for this 
study includes close monitoring by the investigator for signs of infection and of hematologic 
parameters that include neutrophil counts, and neutrophil parameters are included in the study 
entry criteria and stopping rules. The stopping criteria and guidelines (Section 5.5.10), 
in addition to the clinical opinion of the investigator, will be used in this phase IIa study for 
evaluating safety data. Although the stopping criteria will not incorporate an absolute 
requirement for causality, the potential relationship between an adverse event and VAY736 
will be evaluated carefully on a case by case basis.
4
Population
Patients with active primary Sjögren’s syndrome will be recruited. A total of around 
26 subjects will be enrolled to participate in the study and to be randomized. At least 
24 subjects are expected to complete the study.
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria at screening and baseline. No additional criteria should be applied 
by the investigator in order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening 
and study baseline. A relevant record (e.g., checklist) of the eligibility criteria must be stored 
with the source documentation at the study sites.
Deviation from any entry criterion excludes a subject from enrollment into the study.
Patients re-screening will be allowed in the study in the event of a delay in treatment, e.g. , in 
the event a wash-out period of more than 28 days needs to be taken into consideration.
Patients, who were previously ineligible due to the autoantibody inclusion criterion that has 
subsequently been amended, may be re-screened to determine eligibility according to the 
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Patients that proceed to the open-label treatment arm of VAY736 will not be re-assessed for
inclusion/exclusion criteria, other than clinical safety laboratory assessments, if clinically 
indicated.
4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria at the 
time of screening and baseline evaluations unless otherwise noted:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female subjects age 18 to 75 years of age included
3. Fulfilled revised European US consensus criteria for pSS (Vitali et al 2002); if key 
inclusion criteria are missing from medical history, information will be obtained at 
screening and may be used as a baseline value if required. 
4. ESSDAI value ≥ 6.
5. Elevated serum titers at screening of ANA (≥ 1:160) and of RF
OR
Seropositive at screening for anti-SSA (± anti-SSB) antibodies
6. Stimulated whole salivary flow rate at screening of > 0 mL/min
7. Subjects must weigh at least 50 kg and no more than 150 kg to participate in the study, 
and must have a body mass index (BMI) within the range of 18 - 35 kg/m2
8. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study:
2. Use of other investigational drugs at the time of randomization, or within 28 days or 
5 half-lives of time of randomization, whichever is longer; or longer if required by 
local regulations.
3. Prior use of any B-cell depleting therapy (e.g., rituximab or other anti-CD20 mAb, 
anti-CD22 mAb, anti-CD52 mAb)
4. Current use of prednisone > 10 mg/d or dose change within 2 weeks of the time of 
randomization
5. Prior treatment with any of the following within 180 days of randomization
Anti-BAFF mAb
CTLA4-Fc Ig (abatacept)
Anti-TNF-α mAb
Intravenous Ig
Plasmapheresis
i.v. or oral cyclophosphamide
6. Treatment with azathioprine, or prior use within 84 days of randomization; patients 
taking either hydroxychloroquine or methotrexate at a consistent dose for ≥3 months 
prior to randomization are eligible if dose is maintained throughout the study 
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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
11. Receipt of live/attenuated vaccine within a 2 month period before enrollment
13. History of primary or secondary immunodeficiency, including a positive HIV 
(ELISA and Western blot) test result
17. History of hypersensitivity to drugs of similar chemical classes (e.g., IgG1 biologics)
or to any of the constituents of the study drug (sucrose, L-Arginine hydrochloride, 
L-histidine, polysorbate 80, hydrochloric acid)
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5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The investigational drug, VAY736 vials will be packed by Novartis and supplied to the 
Investigator as open labeled bulk medication. The dosage form of the supplied drug is 150 mg 
lyophilisate in vial and needs to be reconstituted with water for injection (USP or equivalent) 
and diluted in 5% dextrose infusion bag (USP or equivalent), both may be provided by the 
investigator’s site. Please refer to Table 5-1 for VAY736 formulation information.
The placebo control selected for this study is the 5% dextrose solution in the infusion bag
Bulk medication labels will be in the local language, will comply with the legal requirements of 
each country, and will include storage conditions for the drug but no information about the subject.
Clinical supplies are to be dispensed only in accordance with the specified study procedures.
An unblinded pharmacist or authorized designee is required to prepare the study drug. 
Instructions for storage and handling of VAY736 vials, and preparation of VAY736 and 
placebo infusions are described in the VAY736 Pharmacy Manual (or Dose Preparation 
Manual), provided as a separate document.
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5.1.2
Additional study treatment
5.1.2.1
Pre-medication
To attenuate severity of infusion reactions, all patients in both study arms should receiv e the 
following pre-medication regimen, provided by the study center, prior to the start of the 
infusion (VAY736 or placebo):

500 mg paracetamol p.o. 1 hour pre-dose and 5 hours [±30 min.] post-dose and 
1000 mg 11 hours [±1 hour] post-dose.

H1 receptor blockers (e.g., Fenistil™[dimetinden] intravenously, dosed according to 
local prescribing standards) may be administered in the event paracetamol pre-medication 
does not prevent infusion reactions sufficiently. The decision may be made on a case-by-
case basis or as a general recommendation if the paracetamol pre-medication is deemed 
not effective during conduct of the study.
5.1.2.2
Ultrasound i.v. contrast agent
To enhance echogenicity of the vasculature during high resolution, Doppler sonographic 
imaging of the parotid glands, contrast agent SonoVue (sulphur hexafluoride microbubble, 
Bracco Imaging, Italy) will be given to patients as an i.v. contrast agent for ultrasound 
assessments. This will permit quantitative measurement of parotid gland function 
 
 SonoVue has a current marketing 
authorization from EMA for other indications. The ultrasound blood flow measurement is 
optional and will not be performed at study centers in countries where SonoVue is not 
available.
5.2
Treatment arms
In the first cohort, subjects will be randomized in a 2:1 ratio to one of the following 2 treatment arms, 
defined as:

VAY736 active: single i.v. dose of 3 mg/kg VAY736 from infusion bag containing the 
active compound

VAY736 placebo: single i.v. dose from infusion bag lacking active compound
In the second cohort, subjects will be randomized at a 6:1:3 ratio to one of the following 3 treatment 
arms, defined as:

VAY736 active: single i.v. dose of 10 mg/kg VAY736 from infusion bag containing the 
active compound

VAY736 active: single i.v. dose of 3 mg/kg VAY736 from infusion bag containing the 
active compound

VAY736 placebo: single i.v. dose from infusion bag lacking active compound
Open label
Patients entering the open label cohort will be assigned to receive:

VAY736 active: single i.v. dose of 10 mg/kg VAY736 
 
 
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5.3
Treatment assignment
Randomization numbers will be assigned in ascending, sequential order to eligible subjects 
(see Section 5.5.1 for details). The investigator will enter the randomization number on the CRF.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio. The randomization scheme for subjects 
will be reviewed and approved by a member of the Novartis IIS Randomization Group.
Randomization numbers will be assigned in ascending, sequential order to eligible subjects 
(see Section 5.5.1 for details). The investigator will enter the randomization number on the CRF.
Randomization Procedure for central management of randomization numbers:
When an eligible patient at a participating study site is ready to be randomized into the study, 
the steps below will be followed:
1. The site designee will complete a Randomization Request form and fax or email to the 
Novartis designee.
2. On receiving, the Novartis designee will write the next available randomization number 
within the randomization list for the corresponding part of the study on the form and fax 
or email back.
3. On receiving the allocated randomization number, the unblinded pharmacist or authorized 
designee will use the information on the completed form to ensure that the patient receives 
the correct study medication, according to the provided randomization list.
4. After inclusion of each new patient, the site designee will countersign the Randomization 
Request form, and fax or email it back to the Novartis designee to document the correct 
assignment of the patient’s randomization number and the date the patient received their 
first dose of study medication.
5.4
Treatment blinding
This is a double blind study for the duration of the treatment period (Weeks 0-24), following 
which, treatment will be unblinded on an individual patient level to determine their progress 
in the study (follow-up, open-label VAY736 or End of Study Visit). Subjects, investigator 
staff, persons performing the assessments, and data analysts will remain blind to the identity 
of study treatments according to the specifications provided in Appendix 8. Randomization 
data are kept strictly confidential until the time of unblinding for the respective person(s). 
Further information regarding blinding (and unblinding) is presented in Appendix 8.
The PK bioanalyst will be unblinded during the clinical study, but will not provide individual 
PK data until an IA or prior to data-base lock, to maintain the study blind.
In order to help reduce the risk of unblinding that might arise if an infusion reaction occurs, 
all patients will receive treatment with paracetamol (and a histamine H1 receptor blocker, 
if necessary) prior to infusion with VAY736.


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Because the expected cell depleting effects of VAY736 will affect the patients’ leukocyte 
counts and differentials, the hematology laboratory evaluation results will be concealed from 
the Investigators and patients in order to maintain the study blind (a separate stud y safety
physician will review these results).
The necessary safety review may lead to the Novartis study team being inadvertently 
unblinded, however this information will not be communicated to the investigator.
An unblinded pharmacist at the investigator site will prepare the study treatment for infusion 
from the bulk open-labeled supplies. The diluent (dextrose 5% in water solution) serves as 
placebo and will not contain VAY736.
Further unblinding will only occur in the case of subject emergencies (see Section 5.5.11), at 
the time of an interim analysis and at the conclusion of the study.
5.5
Treating the subject
5.5.1
Subject numbering
Screening number 
Each subject screened is assigned a unique screening number. The screening number is a 
combination of the center number that is provided by Novartis and a three digit number 
starting with 001 for each subject which is assigned by the Investigator. Therefore, if the 
center number is 1 (any leading 0’s in the center number are dropped) the screening numbers 
will be assigned such as 1001, 1002, 1003 in ascending order. If the center number is 
2 (or 0002), the screening numbers will be 2001, 2002, 2003 in an ascending order.
Randomization number
If the subject is deemed eligible for the study and will commence dosing, a randomization 
number will be assigned. Once assigned to a subject, a randomization number will not be reused.
The randomization number becomes the definitive subject number as soon as a subject 
receives the respective study treatment.
There should be a source document maintained at the site which links the screening number to 
the randomization number (once assigned). This source document should be provided to all 
appropriate parties (i.e., Central Laboratory, ECG Laboratory) as soon as this is available.
Randomization numbers will be generated for at least 26 subjects to allow for 24 subjects to 
complete the study. Subjects will be assigned randomization numbers, 5101-5106 in the first 
cohort and randomization numbers 5201-5222 in the second cohort. Replacement lists will be 
generated to replace early dropouts. Replacement subjects will be assigned randomization 
numbers 6101-6106 in the first cohort and 6201-6222 in the second cohort.
Placebo patients entering the open-label part cohort will be issued with a new randomization 
number. These patients will be assigned randomization numbers, 9101-9222. If a patient joins 
the open-label VAY736 part, the new randomization number assigned will correspond to the 
original randomization number (e.g. patients 5102 and 5211 would be assigned 9102 and 
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5.5.2
Dispensing the study treatment
The dosage form of the supplied drug is lyphilizate in vial and needs to be reconstituted with 
water for injection (USP or equivalent) and diluted in 5% dextrose infusion bag (USP or 
equivalent), both provided by the investigator’s site. Please refer to Table 5-1 for VAY736 
formulation information. The placebo control selected for this study is the 5% dextrose 
solution in the infusion bag without addition of VAY736.
For preparation of the study medication, a copy of the randomization schedule will be sent to 
the unblinded pharmacist / technician at the Investigator’s site or to the dispensing contractor.
Clinical supplies are to be dispensed only in accordance with the specified study procedures. 
Appropriate documentation of the subject specific dispensing process must be maintained.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received at the study site by a designated person, handled 
and stored safely and properly, and kept in a secured location to which only the Investigator 
and designated staff have access. Upon receipt, the study drugs should be stored according to 
the instructions specified on the labels.
Storage conditions must be adequately monitored and appropriate temperature/humidity logs 
maintained as Source data.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Drug accountability will be noted by the Monitor duri ng 
site visits and/or at the completion of the trial.
All drug supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, 
or any partly used or unused drug supply.
At the conclusion of the study, and, if allowed during the course of the study, the Investigator 
will provide a copy of the drug accountability ledger to the Monitor.
Only after receiving a written authorization by Novartis, the Investigator/designee will send 
all the unused and partly used drug supplies as well as the empty containers to the address 
provided at the time of authorization for destruction or have the unused and partly used drug 
supplies as well as the empty containers destroyed by the site’s pharmacist, providing a drug 
destruction certificate.
For more information on storage, handling and preparation of VAY736 vials and placebo 
infusions please refer to the Pharmacy Manual.
5.5.3.2
Handling of other study treatment
The following non-investigational treatment has to be monitored specifically:

Use of pre-medication (paracetamol and the H1 receptor blocker (Fenistil™[dimetinden], 
if applicable). For more information see Section 5.1.2.1.

SonoVue according to local standard
Details are described in the monitoring plan.


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5.5.4
Instructions for prescribing and taking study treatment
VAY736 will be administered as an i.v. infusion over approximately 2 hours by the study 
center personnel following the instructions and using the material as described and specified 
in the VAY736 Pharmacy Manual. Any update to the Pharmacy Manual describing the 
preparation of additional doses will be provided as needed directly to the study center 
personnel.
A physician shall be available, e.g., by pager, DECT etc. at all other times throughout the study.
All dosages prescribed and dispensed to the subject and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
5.5.5
Permitted dose adjustments and interruptions of study treatment
If patients are unable to tolerate the protocol-specified dosing scheme, dose adjustments 
and/or interruptions are permitted. The following guidelines should be followed:
In case of suspected infusion reaction, the infusion can be stopped for 15 minutes and the 
patient observed to determine the severity of the reaction. Depending on the assessment of the 
patient, symptomatic treatment can be administered and the infusion can be restarted at a 
reduced rate if necessary.
In case of notable adverse events and/or safety concerns, the following changes to the planned 
dose of the next subject may be considered:

Administration of a dose below the dose of 3 mg/kg or 10 mg/kg, respectively, after 
consultation between the sponsor and the principle investigator.
These changes must be recorded on the Dosage Administration Record CRF.
5.5.6
Recommended treatment of adverse events
The following guidelines are provided using the National Cancer Institute Common Toxicity 
Criteria for allergic reaction, anaphylaxis and cytokine release [NCI-CTCAE/v4.03, 
Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html].
In the case of a suspected infusion reaction, the infusion can be stopped for 15 minutes and 
the patient observed to determine the severity of the reaction. Depending on the assessment of 
the patient, medication can be administered and the infusion can be restarted at a reduced rate 
if necessary.
Additional guidance on severity grading and treatment includes the following:

Mild National Cancer Institute (NCI) grade 1 infusion reactions do not require treatment.

In case of moderate NCI grade 2 infusion reactions requiring symptomatic treatment, the 
patient can be treated with anti-histamines, NSAIDs, paracetamol, intravenous fluids as 
determined by the investigator and the infusion can be stopped for 15 minutes and then 
restarted at a reduced rate.

In case of more severe NCI grade 3 or 4 reactions, the infusion should be stopped and 
corticosteroids according to local guidelines administered intravenously.

Other available medications at the bedside should include paracetamol, adrenaline, 
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Infusion reactions of severity NCI grade ≥ 2 despite pre-medication with paracetamol and an 
H1 receptor blocker may require modification of the pre-treatment regimen. Medication to 
prevent or treat the signs and symptoms of infusion-related reactions will be provided by the 
study site.
Plasmapheresis may be helpful in situations in which decreasing the systemic concentration of 
VAY736 may be of clinical benefit, based on capacity of plasmapheresis to remove IgG 
antibody, such as the IgG monoclonal antibody VAY736, from intra- and extra-vascular 
compartments.
In the case of severe neutropenia requiring treatment, filgrastim (granulocyte colony - stimulating 
factor analog; G-CSF) may be used to stimulate the proliferation and differentiation of 
granulocytes.
In the case of clinically relevant hypogammaglobulinemia, an intervention may be required 
such as replacement by Intravenous Immunoglobulin (IVIG).
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
5.5.7
Rescue medication
There is no established, approved immunosuppressive treatment for pSS. Patients may receive 
NSAIDs, paracetamol, or symptomatic care at the discretion of the treating physician as 
outlined in Section 5.5.8. Rescue medicine is to be provided by the study center or personal 
physician.
5.5.8
Concomitant treatment
Use of artificial tears and artificial saliva/salivary stimulants (e.g., cevimeline, pilocarpine) by 
the patient during participation in the protocol is permitted at the discretion of the treating 
physician. Amount and frequency of use should be recorded at each visit. Both treatment 
modalities are not permitted within 48 hours prior to, or during assessment of clinical disease 
outcome measurements. Artificial tears and artificial saliva are to be provided by the study 
center or personal physician.
The investigator should instruct the subject to notify the study site about any new medications 
he/she takes after the start of the study drug.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.


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5.5.9
Prohibited treatment
Use of the treatments displayed in the table below are NOT allowed after the start of study 
drug until week 24.
Table 5-2
Prohibited treatment
Medication
Action to be taken
Other experimental therapies
Withdrawal may be required on a case-by-case basis
Other biologics
Withdrawal may be required on a case-by-case basis
DMARDs or
other immune suppressive agents or 
changes in an existing DMARD regimen  
(hydroxychloroquine or methotrexate)
Withdrawal may be required on a case-by-case basis
Regular, required treatment affecting 
exocrine gland function (including beta 
blockers, antihistamines, pseudoephedrine, 
selective antidepressants, anticholinergics, 
sedatives, antipsychotic drugs, anti-
Parkinson agents, diuretics)
Intermittent use may be allowed provided 
none of these drugs are taken within 5 half-
lives of the drug in question before 
assessment at the major timepoints
Withdrawal may be required on a case-by-case basis
Patients who choose, subsequent to VAY736, therapy with another B-cell depleting agent
(e.g., rituximab or other anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) at any point 
during the study will be withdrawn from the safety follow up and will be requested to 
complete their EOS visit within 4 weeks.
5.5.10
Discontinuation of study treatment and premature subject withdrawal
Study “Stopping rules”
 
 However, infusion reactions (hypersensitivity, 
cytokine release, anaphylaxis) can occur with administration of biologics, in particular those 
which are lymphocyte-depleting by ADCC. Increased susceptibility to infection is also a 
potential risk with therapies targeting elements of the immune response. Thus, for patients on 
active treatment, the following guidance and stopping rules are provided.
Dose limiting toxicities (DLTs) will be assessed according to the standardized toxicity 
grading scale, the NCI Common Toxicity Criteria for Adverse Events [NCI-CTCAE/v4.03, 
Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html]. Although the stopping criteria will 
not incorporate an absolute requirement for causality, the potential relationship between an 
adverse event and VAY736 will be evaluated carefully on a case-by-case basis.
 
 
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Overall study:
The study will be put on hold pending further safety data analysis, if any of the following 
criteria occur in patients receiving VAY736:

Any death

Decrease in neutrophil count:
a.
If any subject requires G-CSF or GM-CSF treatment for neutropenia, or
b. If two or more subjects manifest a persistent neutrophil count <500 cells/uL, or
c.
If four or more subjects manifest a persistent neutrophil count <1000 cells/uL

More than 1 infusion reaction of grade 3 severity of the NCI-CTCAE/v4.03 Criteria 
within the first 5 treated subjects or an incidence of >20% thereafter

Any grade 3 toxicity of the NCI-CTCAE/v4.03 Criteria with the following exceptions:

Events of Special Interest, including infusion-related (hypersensitivity, cytokine 
release, anaphylaxis), 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 patients underlying pSS diagnosis

AEs/SAEs clearly unrelated to the experimental compound as determined by the 
investigator or Novartis.

Persisting NCI-CTCAE/v4.03 Criteria grade 3 or grade 4 changes from baseline in vital 
signs, electrocardiograms, or relevant, persistent changes in laboratory parameters, which 
are not consistent with existing co-morbidities or the desired mechanism of action of 
VAY736 (e.g., B cell depletion), in >1 patient within the first 5 treated subjects or an 
incidence of >20% thereafter

Any NCI-CTCAE/v4.03 grade 4 event.
In addition, all blinded safety data, including events of special interest and disease specific 
events, will be evaluated by the Sponsor and PI continuously and at scheduled meetings. 
The study may be put on hold pending further data analysis, and the decision to adjust the 
dose or modify the pre-medication considered despite having not met the above listed criteria
if the following additional criteria occur:

The principal investigator or the Sponsor considers that the number and/or severity of AEs 
justify discontinuation of the study.

Other clinically significant changes or effects in the opinion of the Investigator or Sponsor 
that are deemed unsafe to continue dosing.
This study can also be terminated at any time for any reason by Novartis. Should this be 
necessary, the Investigator will be informed of the procedures to be followed to assure that 
adequate consideration is given to the protection of the patients’ interests. The Investigator 
will be responsible for informing the IEC/IRBs of the early termination of the trial.


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Individual subject withdrawal
Due to the single dose nature of this study, no individual treatment stopping rules are provided.
Subjects may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
If a subject withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a subject’s withdrawal from the study and record this 
information on the CRF.
Patients that become pregnant during the study should be followed up as per the 
Assessment schedule. The investigator may determine whether any assessments should not be 
performed if they are considered to not be clinically appropriate, in conjunction with the 
patients treating physician/obstetrician.
Patients who choose, subsequent to VAY736, therapy with another B-cell depleting agent
(e.g., rituximab or other anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) at any point 
during the study will be withdrawn from the safety follow up and will be requested to 
complete their EOS visit within 4 weeks.
If evidence of a clinically relevant acute infection is present before administration of an 
infusion of VAY736, the patient should not receive the infusion. Patient can be considered for 
later administration of VAY736 if infection is completely resolved within the screening 
period or upon re-screening.
Patients who withdraw before week 12 or between week 12 and week 24, should return for 
the long-term follow up period at week 12 or at week 24, respectively where they will have 
visits according to the following schedule until their B cell count is within the recovery 
threshold criteria:

Every 4 weeks until the week 24 visit

Every 8 weeks until the week 40 visit

Every 12 weeks until the week 52 visit

Every 24 weeks until the week 100 visit

Every 48 weeks thereafter
Once B cell recovery threshold criteria are met, the patients will undergo the End of Study 
visit within 4 weeks. The End of Study visit will include study completion evaluations 
followed by discharge from the study.
Patients who discontinue during the safety follow up period will be asked to complete the end 
of study visit.
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the investigator 
should show “due diligence” by documenting in the source documents steps taken to contact 
the subject, e.g., dates of telephone calls, registered letters, etc.


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5.5.11
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, study drug discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
investigator site(s) and a complete set will be available at Novartis. All code break cards must 
be retained until the end of the study and returned to Novartis. They must be stored in a secure 
place but be accessible in case of emergency. The investigator will receive a blinded code 
break card for each subject, with the details of drug treatment covered by a removable, 
scratch-off cover. In an emergency, the scratch-off cover can be removed to determine the 
treatment. The scratch-off covers are not to be removed for any reason other than an 
emergency. When the investigator removes the scratch-off cover he/she must note the date, 
time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code should not be recorded on the CRF.
The investigator must also immediately inform the Novartis local monitor that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IVRS/IWRS/code break cards in case of emergency. If appropriate, the investigator will 
inform the subject how to contact his/her backup in cases of emergency when he/she is 
unavailable.
An assessment will be done by the appropriate site personnel and the sponsor after an 
emergency unblinding to assess whether or not the patient should be withdrawn from the study.
5.5.12
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. The study will complete when the last subject 
completes their Study Completion visit, and any repeat assessments associated with this visit 
have been documented and followed-up appropriately by the Investigator.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
After study participation, the patients will continue to be treated by his/her general
practitioner according to the local standard clinical management related to the underlying
disease.
5.5.13
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.


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6
Visit assessments
The full Assessment schedule is presented at the end of the synoptic section, above.
Subjects should be seen for all visits on the designated day, or as close to it as possible. 
For study visit Day 7, a visit window of ± 1 day is acceptable, and for study visits Day 14 
and Day 21, a visit window of ± 2 days is acceptable. For study visits Day 42, Day 63, Day 84, 
Day 112, Day 140 and Day 168, a visit window of ± 4 days is acceptable. For the follow-up 
visits, a time window of ± 2 weeks is accepted. For ultrasound assessments, a window of ± 7 
days will be acceptable. The End of Study visit will be done within 6 weeks after the previous 
visit.
Subjects who discontinue study treatment before completing the study, and those who 
prematurely withdraw from 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. 
For safety reasons, patients should continue to be evaluated for safety/PK/PD parameters 
according to protocol, up to the study completion visit.
Deviations for the following PK assessment times are acceptable based on logistical and 
operational considerations:
PK assessments post VAY736 infusion of ± 15 minutes up to the first 24 hrs, ± 1 hour up to 
day 7, and ± 2 days thereafter. However, the 1-2h post-dose PK sample may deviate more that 
the allowed 15 min. as it must by definition be taken at the end of the infusion period.
Every effort will be made to take the pharmacokinetic sample at the protocol specified time. 
Other assessments, e.g., ECG, vital signs etc. will be taken after the pharmacokinetic sample.
When the following assessments are scheduled to be performed at the same time-point, the 
order of priority will be as follows:
1) PK specimen; 2) Blood sample for flow cytometry panels; 3) Hematology specimen;
4) BAFF blood specimen; 5) other BM specimens; 6) Chemistry specimen; and 7) other 
remaining laboratory and clinical assessments.
Should it become necessary to repeat an evaluation (e.g., ECGs, laboratory tests, vital signs, 
etc.), the results of the repeat evaluation should be captured. The additional assessment will be 
entered in the ‘Unscheduled Visit’ (e)CRF page provided in the (e)CRF.
6.1
Dietary, fluid and other restrictions
Subjects should maintain their usual diet and life habits during the entire study while not domiciled.
Intake of medications known to cause dry mouth / eyes as a major side effect should be 
interrupted five half-lives prior to efficacy assessments at baseline and on Day 42 (week 6), 
Day 84 (week 12), Day 168 (week 24) and at the end of study.


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6.2
Subject demographics/other baseline characteristics
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, the diagnosis and not symptoms will be recorded.
The date of original diagnosis of primary Sjögren’s syndrome has to be recorded.
Hepatitis screen, HIV screen
All subjects will be screened for Hepatitis B surface antigen (HBsAg). Screening for 
Hepatitis C will be based on HCV antibodies.
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a 
second technique available at the laboratory site, e.g., 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 (e)CRF.
Alcohol test, Drug screen
Subjects will be tested for substances of abuse (e.g., alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates).
Results will be available as source data and will not be recorded within the (e)CRF.
6.3
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with VAY736, as detailed in Section 6.6.
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6.4
Efficacy / Pharmacodynamic assessments
In addition to assessments for safety, PK and PD, exploratory clinical efficacy measurements 
will include components of the ESSDAI and of the ESSPRI and other patient-based 
assessments, along with imaging, histopathology and functional assessments of the exocrine 
glands. Soluble markers of B cell activation and flow cytometry analysis of B cell subsets will 
also be performed.
6.4.1
ESSDAI
The ESSDAI (Appendix 3) is an established disease outcome measure for Sjögren’s syndrome 
that will be applied to the study patients at baseline and again at weeks 6, 12 and 24.
The instrument contains 12 organ-specific domains contributing to disease activity. For each 
domain, features of disease activity are scored in 3 or 4 levels according to their severity. 
These scores are then summed across the 12 domains in a weighted manner to provide the 
total score.
6.4.2
ESSPRI
The ESSPRI (Appendix 4) is an established disease outcome measure for Sjögren’s syndrome 
that will be applied to the study patients at baseline and again at weeks 6, 12, 24 and EOS for 
patients who do not meet end of study criteria at week 24.
6.4.3
SF-36
The Short Form (36) Health Survey (SF-36) is a survey evaluating individual patients’ health 
status which also monitors and compares patients’ disease burden.
The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, 
general health perceptions, physical role functioning, emotional role functioning, social role 
functioning, mental health), which are the weighted sums of the questions in their section.
It will be applied to the study patients at baseline and again at weeks 6, 12, 24 and EOS for 
patients who do not meet end of study criteria at week 24.
6.4.4
MFI
The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed 
to measure fatigue covering the following dimensions: General Fatigue, Physical Fatigue, 
Mental Fatigue, Reduced Motivation and Reduced Activity. It will be applied to the study 
patients at baseline and again at weeks 6, 12, 24 and EOS for patients who do not meet end of 
study criteria at week 24.
6.4.5
Global assessments (VAS) of disease activity
6.4.5.1
Physician’s global assessment
The physician’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question “Considering 
all the ways the disease affects your patient, draw a line on the scale for how well his or her 


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condition is today”. The investigator will then measure the distance in mm from the left edge 
of the scale and the value will be entered on the eCRF.
6.4.5.2
Patient’s global assessment
The patient’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question on how well 
the patient is doing with the disease considering all aspects affected by the disease. 
The investigator will then measure the distance in mm from the left edge of the scale and the 
value will be entered on the eCRF.
6.4.6
Selective depletion of B cells
Depletion of B cells will be evaluated by measuring absolute counts of CD19+ B cells by flow 
cytometry. Additional detail of this depletion will be obtained using a more detailed B cell 
subset panel. The selectivity of B cell depletion will be demonstrated by measuring absolute 
counts of other leukocyte subsets.
Patients need to achieve B cell recovery to complete the study.
When patients reached week 24, the following definition of B cell recovery was applied to 
determine whether a long-term safety follow up would be required: B cells [CD19+] returning 
to within 20% of baseline or ≥80 cells µL).
Following Amendment 05 to the protocol, the cut-off used as a criterion to define B-cell 
recovery during long term follow-up (starting week 32) was decreased to within 20% of 
baseline or ≥50 cells/µL based on published experience with ocrelizumab for which 95% 
(n=237) of RA patients had a CD19+ B cell count ≥40 cells/µL at all available pre-treatment 
visits (Genovese et al 2008). 
6.4.6.1
Pharmacodynamic sample collection and processing
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. For each scheduled visit, one 2.6 mL blood sample will be 
collected in Na-heparin Monovette tubes by aspiration.
From the 2.6 ml blood 4 different assays will be performed:

Immunophenotyping panel: absolute counts of leukocyte subsets (safety markers, 
Section 6.5.4.2) including CD19+ B cells (PD marker)

Lymphocyte activation panel: activation of lymphocytes (Section 6.5.4.2)

B cell subset panel (Section 6.8.2.1)

Additional flow cytometry panels may also be performed.
Optional
specimen
(approximately 2.6 mL): Chemokine receptor expression panel.
Sample collection and processing will follow the local requirements.
For the Immunophenotyping, Lymphocyte activation, B cell subset and additional flow 
cytometry panels 2.6 ml blood need to be distributed on 4 tubes. Antibody mixes and lysis 
buffer needs to be added to the tubes and tubes should be frozen at -80°C as described in 
detail in a separate lab manual provided by BMD, Novartis.


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For detailed description of blood sampling schema, please refer to the Blood Log in Appendix 1.
Detailed information on sample collection, handling and shipment will be provided in a 
separate laboratory manual.
6.4.7
Ultrasound assessments
All patients will undergo assessment by high resolution ultrasound (5 – 14 MHz transducer 
frequency) according to the schedule. The ultrasound protocol will include B-mode 
assessment of both left and right parotid and submandibular glands to determine gland 
thickness (mm) and Sjögren’s ultrasound disease staging (De Vita et al 1992).
At study centers located in countries where SonoVue is available, subject may also be 
assessed for salivary gland (parotid gland only) blood flow and regional blood volume on both 
left and right parotid gland, each after receiving contrast agent. A total of 2 maximum,
approximately 2.4-ml contrast bolus injections of SonoVue (sulphur hexafluoride bubbles; 
Bracco, Milan, Italy) contrast agent into a peripheral vein (e.g., a cubital vein). Regions of 
interest will be placed on the parotid gland and estimates of contrast agent influx and area 
under the curve (AUC) will be calculated.
Each ultrasound assessment visit will last for approximately 30 minutes.
Detailed information will be provided in a separate Ultrasound manual.
6.4.8
Assessment of salivary flow
Both the amount and composition of saliva has been shown to reflect the damage caused by 
the disease process of Sjögren’s syndrome (Pijpe et al 2006). Unstimulated and stimulated 
whole and/or glandular salivary fluid is obtained from patients at screening to evaluate 
eligibility (stimulated only) and at each clinical disease assessment time point (baseline and 
weeks 6, 12 and 24). Patients are instructed not to eat, drink or smoke for 90 minutes before 
assessment of salivary flow. All assessments are performed at a fixed time of the day to 
minimize fluctuations related to the circadian rhythm of salivary flow and composition.
Unstimulated and stimulated salivary secretions are collected over 5 minutes.
The following saliva collection methods may be utilized following the manufacturers’ 
instructions:

Passive drool collected using a Saliva Collection Aids (SCA) constructed of 
polypropylene (e.g., Salimetrics Part no. 5016.02)

Oral cotton swabs (e.g., Salimetrics Oral Swabs or Salivettes)

Cotton swabs containing citric acid solution (2% st/vol)
Additional material may be used following appropriate procedures. For more details refer to 
the laboratory manual.
Saliva collected under unstimulated conditions may also be used for the assessment of saliva 
composition.
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The start time and end time of saliva collection will be recorded to calculate the salivary flow rate.
The same method of saliva collection and salivary flow rate determination should be used for 
an individual patient at each assessment time point and for each purpose, respectively.
6.4.9
Ocular Staining Score
Corneal fluorescein staining pattern (step 1 of the OSS scoring system)
Each cornea is examined at the slit lamp using the cobalt blue filter. Grading of the 
fluorescein pattern is initiated between 4 and 8 minutes after instillation of fluorescein. 
Punctate epithelial erosions (PEEs) that stain with fluorescein are counted and scored 
(Whitcher et al 2010; see Appendix 7 for grading of the scored PEEs). An additional point is 
added if: (1) PEE occurred in the central 4-mm diameter portion of the cornea; (2) one or 
more filaments is seen anywhere on the cornea; or (3) one or more patches of confluent 
staining, including linear stains, are found anywhere on the cornea. The total fluorescein score 
for the cornea (the PEE grade plus any extra points for modifiers) is noted in the central square 
of the SICCA ocular staining score form. The maximum possible score for each cornea is 6.
Conjunctival lissamine green staining pattern (step 2 of the OSS scoring
system)
After the external examination, 1 drop of 1% lissamine green dye is applied to the inferior 
conjunctival fornix of both eyes. Alternatively, lissamine green stripes can be used and placed 
in the inferior conjunctival fornix of both eyes. The same method of administering lissamine
green should be used for an individual patient at each assessment time point. The conjunctivae 
are examined with the slit lamp at x10 magnification, using a neutral density filter over the 
light source to avoid blanching of the conjunctiva. It is important to examine and grade the 
eyes immediately after instilling lissamine green dye because the intensity and extent of the 
ocular staining diminishes rapidly after the first 2 minutes. It is also important for the patient 
to blink several times to keep dye from pooling in the conjunctival folds which c an mimic 
conjunctival staining. If adequate dye is not instilled initially, a second drop can be given and 
the examination performed immediately thereafter. The number of dots is counted (see Appendix 7
for grading of the scored dots; nasal and temporal bulbar conjunctivae graded separately). 
Because of the difficulty of counting individual dots in a moving eye at the slit lamp, any area 
of confluent staining of 4 mm2 or more is considered to be more than 100 dots. Nasal and 
temporal areas of the conjunctiva are graded separately with a maximum score of 3 for each 
area or a total maximum score of 6 for each eye (nasal plus temporal).
Calculation of total OSS 
The total OSS for each eye is the summation of the fluorescein score for the cornea and the 
lissamine green scores for the nasal and temporal bulbar conjunctiva. The maximum possible 
score for each eye is 12.


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6.5
Safety
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and/or pelvic exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded in the CRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History CRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event 
must be appropriately recorded on the Adverse Event CRF.
6.5.2
Vital signs
Vital signs include blood pressure (BP), pulse measurements, and body temperature. After the 
subject has been sitting for 3 minutes, with back supported and both feet placed on the floor, 
systolic and diastolic blood pressure will be measured using an automated validated device, 
with an appropriately sized cuff. In case the cuff sizes available are not large enough for the 
subject’s arm circumference, a sphygmomanometer with an appropriately sized cuff may be used.
6.5.3
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.
6.5.4
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening and/or at baseline, the assessment may be 
repeated once prior to randomization. If the repeat value remains outside of protocol-specified 
ranges, the subject is excluded from the study.
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the laboratory at screening and/or baseline, a decision regarding whether 
the result is of clinical significance or not shall be made by the Investigator and shall be based, 
in part, upon the nature and degree of the observed abnormality. The assessment may be 
repeated once prior to randomization.
In all cases, the Investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the subject to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.


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6.5.4.1
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.
6.5.4.2
Leukocyte subsets and lymphocyte activation
Two flow cytometry-based panels will be conducted on whole blood for monitoring the 
response of circulating leukocytes to VAY736 exposure as well as the activation status of 
lymphocytes:
Blood for these safety flow cytometry panels will be collected together with the blood for the 
PD (B cells depletion) assessment in the same tube (Section 6.8.2.1).
Detailed description on splitting the blood for the three assays as well as further information 
on sample processing (assay procedure) is given in a separate lab manual provided by BMD, 
Novartis.
6.5.4.3
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, chloride, 
creatinine, CK, CRP, -GT, glucose, LDH, inorganic phosphorus, lipase, amylase, magnesium, 
potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUN and uric acid.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
6.5.4.4
Urinalysis
A midstream urine sample (approximately 30 ml) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments.
A semi-quantitative “dipstick” evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and blood.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
6.5.4.5
Special clinical laboratory evaluations
Serum markers of B cell hyperactivity can be present in pSS and may be affected by depletion 
of B cells. 
 
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6.5.5
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed in lying position. Interpretation of the tracing must 
be made by a qualified physician and documented on the ECG / in the ECG section of the 
eCRF. Each ECG tracing should be labeled with the

study number

patient initials

patient number

date
and kept in the source documents at the study site. Clinically significant abnormalities should 
be recorded on the relevant medical history/Current medical conditions CRF page prior to 
informed consent signature and on the Adverse Events page thereafter. Clinically significant 
findings must be discussed with the sponsor.
The CRF will contain:

date and time of ECG

heart rate

PR interval

QTcF interval calculated by ECG machine

QRS duration
The overall interpretation will be collected with a Yes/No statement to confirm if any 
clinically significant abnormalities are present which need to be specified further.
Original ECG tracings, appropriately signed, will be archived at study site.
6.5.6
Pregnancy
Pregnancy tests are required of all female subjects regardless of reported reproductive / 
menopausal status.
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. If positive, 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.
When performed at screening and at baseline, the result of this test must be received before 
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6.5.7
Other safety assessments
6.5.7.1
PPD skin test or QuantiFeron test
A purified protein derivative (PPD) skin test will be performed and read at screening or within 
6 months prior to randomization in order to evaluate an eventual infection with tuberculosis 
(TB). The test dose is bioequivalent to 5 tuberculin units (or as according to local standard 
practice) of standard PPD injected intradermally into usually the volar surface of the forearm. 
The site is cleansed and the PPD extract is then injected into the most superficial dermal layer 
of the skin. If given correctly, the injection should raise a small wheal of about 5 mm, which 
resolves within 10-15 minutes.
Because the reaction (induration) will take 48-72 hours to develop, the subject must return to 
the investigators’ site within that time for a proper evaluation of the test site. This will 
determine whether the subjects have had a significant reaction to the PPD test. A reaction is 
measured in millimeters of induration (hard swelling) at the site. A PPD skin induration 
≥5 mm is interpreted as positive result.
Precautions against tuberculosis 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 tuberculosis should complete 
their treatment and should be considered cured prior to being re-considered for entry into this 
study (consultation with Novartis must occur before allowing the patient to enter the study).
Based on the study site’s normal practice, QuantiFeron test may replace PPD skin test at 
screening. A positive QuantiFeron test at screening will exclude the subjects from the 
participation in the study.
Results will be available as source data and will not be recorded within the (e)CRF.
6.5.7.2
Infections
All occurrences of infections must be carefully monitored by the investigator. Significant findings, 
which meet the definition of infection, must be recorded in the Adverse Event (e)CRF.
6.6
Pharmacokinetic assessments
See Sample log tables Section 13-Appendix 1.
6.6.1
PK Blood collection and processing
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. 3.0 mL of blood will be collected into plain barrier 
(Serum Separator) tubes (no anti-coagulant) to obtain approximately 1.3 mL serum.
Blood samples will be allowed to clot over a minimum of 30 minutes at room temperature 
prior to harvesting of the serum and then centrifuged for 15 minutes at approximately 1500 g 
at room temperature (or sufficient time and force to achieve a clear serum layer above the red 
cell clot). The serum samples will be placed on dry ice, split into 2 aliquots, transferred into 
labeled freezer-proof clear polypropylene screw-cap tubes and then stored (within 1 hour of 
serum collection) at or below -70°C pending shipment. All samples will be given a unique 


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sample number and a collection number (as listed in the blood log Appendix 1). 
Further details on labeling of the PK samples and shipment instructions will be provided in a 
separate laboratory manual. The exact clock time of dosing, as well as actual sample 
collection date and exact time will be entered on the PK blood collection summary page of the 
eCRFs. Sampling problems will be noted in the Notes field of the eCRFs.
6.6.3
Pharmacokinetic parameters
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters of VAY736 will be determined using the actual 
recorded sampling times and non-compartmental method(s) with WinNonlin Phoenix 
(Version 6.2 or higher): Cmax, Tmax, AUClast, AUCinf, T1/2, Vz and CL from the plasma 
concentration-time data.
Concentrations below the LLOQ will be treated as zero for PK parameter calculations. 
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the 
terminal plasma elimination phase for the determination of T1/2 will include at least 3 data 
points after Cmax. If the adjusted R2 value of the regression analysis of the terminal phase 
will be less than 0.75, no values will be reported for T1/2, AUCinf, Vz and CL.
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Refer to the Assessment schedule table, for the time schedule for pharmacogenetic blood 
sampling.
6.8.2
Other biomarkers
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7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 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. Pre-existing medical conditions/diseases (i.e., Medical 
History[ies]) are considered AEs if they worsen after providing written informed consent. 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, or are considered clinically significant, or they require therapy.
The occurrence of adverse events should 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, laboratory test, or 
other assessments.
All adverse events will be reported from the time the subject has provided informed consent 
to visit 16 (week 52). Starting from visit 17 until end of study, only AE related to VAY736 as 
assessed by the investigator and AE related to infection, potential malignant events and 
neutropenia will be recorded (only valid for AE, not for SAE).
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. the CTC-AE grade

If CTC-AE grading does not exist for an adverse event, use 1=mild; 2=moderate, 
3=severe; and 4=life threatening. CTC-AE grade 5 (death) is not used, but is collected 
in other CRFs (e.g., Study Completion, Death/Survival).
2. its relationship to study treatment
3. its duration (e.g., start and end date)
4. whether it constitutes a serious adverse event (SAE)
5. action taken regarding study treatment
6. whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)
7. its outcome
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An SAE is defined as any AE which meets any one of the following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent form

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: no action taken (i.e.,
further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given. The action taken to treat the 
adverse event should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the informed consent 
and should be discussed with the subject during the study as needed.
7.2
Serious adverse event reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the subject has stopped study participation 
(defined as time of last dose of study drug taken or last visit whichever is the later) must be 
reported to Novartis within 24 hours of learning of its occurrence.


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Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow-up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the OC/RDC system (where available). The Investigator must assess the 
relationship to each specific component of the study treatment (if the study treatment consists 
of several components).
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department and also a copy to the Novartis Translational Medical Expert and Clinical Trial 
Leader (according to page 2). The telephone and fax numbers of the contact persons in the 
local Drug Safety and Epidemiology department, specific to the site, are listed on page 2 of 
this protocol and/or in the investigator folder provided to each site. The original copy of the 
SAE Report Form and the fax confirmation sheet must be kept with the case report form 
documentation at the study site. Follow-up information should be provided using a new paper 
SAE Report Form stating that this is a follow-up to a previously reported SAE.
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first. Study site personnel must also inform the Novartis Translational Medical Expert 
and Clinical Trial Leader (according to page 2).
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the investigational treatment a Drug Safety and Epidemiology 
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 investigational 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 Directive 2001/20/EC or as per national regulatory requirements in 
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7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Liver events are divided into two categories:

Liver events of special interest (AESI) which consist of liver function test (LFT) 
elevations

Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and/ or pre-specified adverse events.
Please refer to Appendix 2 for complete definitions of liver events.
Any liver event which meets the criteria for a “medically significant” event should follow the 
standard procedures for SAE reporting as described in Section 7.2.
Every liver event as defined in Appendix 2-Table 14-1 should be followed up by the 
investigator or designated personal at the trial site, as summarized below and detailed in 
Appendix 2-Table 14-2.

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF.
7.4
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of 
the possible relationship of the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.


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7.5
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor 
of any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.
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 CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
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.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 


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transfer of the data to Novartis or the CRO working on behalf of Novartis. The Investigator 
must certify that the data entered into the Electronic Case Report Forms are complete and 
accurate. After database lock, the investigator will receive a CD-ROM or paper copies of the 
subject data for archiving at the investigational site.
All data captured for this study will have an external originating source (either written or 
electronic), the CRF is not considered as source.
8.3
Database management and quality control
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Novartis staff or CRO working on behalf of Novartis will review the data entered into the 
eCRFs by investigational staff for completeness and accuracy and instruct the site personnel 
to make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be sent (e.g., fax, e-mail) to the site. Site personnel will complete and sign the copy, 
then send it (with original signature) back to Novartis staff who will make the correction to 
the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples 
 
will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Randomization codes and data about all study drug dispensed to the subject and all dosage 
changes will be tracked. The database managed by a vendor will be sent electronically to 
Novartis (or a designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head.
Each occurrence of a code break will be reported to the clinical team and monitor. 
The possibility to break the code will remain available until study shut down or upon request 
of Novartis.
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8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
Not required.
9
Data analysis
9.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The full analysis set will include all subjects that received any study drug.
The safety analysis set will include all subjects that received any study drug.
The primary PK analysis set will include all subjects with available PK data. The secondary 
PK analysis set will include all subjects with available PK data and no protocol deviations 
with relevant impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data.
9.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration and concomitant therapies will be listed by treatment 
group and subject.
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9.4
Analysis of the primary variable
The primary aim of this study is to evaluate the effect of a single i.v. dose VAY736 on 
the clinical disease activity of primary Sjögren’s syndrome patients as measured by the 
ESSDAI at week 12 compared to baseline. The statistical analysis model will include data on 
the ESSDAI from all timepoints at which it was recorded (baseline, weeks 6, 12 and 24) but 
the primary comparison is made for week 12.
Summaries of safety and tolerability data to support the second primary objective will be 
provided as detailed in Section 9.5.2.
9.4.1
Variable(s)
The primary efficacy variable is the ESSDAI recorded at baseline and week 12.
9.4.2
Statistical model, hypothesis, and method of analysis
It is assumed that the ESSDAI will follow an approximate normal distribution. If, on blinded 
review of the data, this assumption appears to not be met, alternative statistical methods may 
be applied. These will be described full in the Reporting and Analysis Plan (RAP).
A positive sign of therapeutic effects will be considered to be a difference of at least 5 points 
in the change from baseline between VAY736 and placebo with a moderate level of 
evidence. Additionally there should be a high level of evidence that is a difference between 
VAY736 and placebo. The two active doses will be pooled for the primary efficacy analysis
(unless there is evidence of inferiority of the 3 mg/kg dose to the 10 mg/kg dose). 
These criteria will be evaluated by calculating Bayesian posterior probabilities as follows:
Pr (θVAY736,12w-θplacebo,12w > 0 | data) > 90% and
Pr (θVAY736,12w-θplacebo,12w > 5 | data) > 50%
where θ means change from baseline in ESSDAI at 12 weeks.
It is assumed that Yijt, the observed change from baseline in ESSDAI for subject i receiving 
treatment j (VAY736 or placebo) at time t, follows a normal distribution N(θ jt, 2), 
It is further assumed that θjt follows a standard non-informative prior Normal distribution, 
p(θjt, σ2) = 1/σ2.
The statistical model will include terms for the patient effect (as a random effect), treatment 
effect, post-baseline time (as nominal study week), the interaction between time and treatment 
(all as fixed effects) and with the baseline ESSDAI as a covariate.
Estimates of the difference between VAY736 and placebo at each timepoint will be derived 
from this model and presented together with 95% credible intervals.
The estimates of the posteriors probabilities of the efficacy criteria being met will be provided.
For the interim analysis planned when all patients have completed the week 12 visit, the same 
statistical methods will be applied and the results compared to the specified efficacy decision 
criteria.


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9.4.3
Handling of missing values/censoring/discontinuations
Patients with missing ESSDAI at baseline will not be included in the analysis. Patients with 
missing data at one or more timepoints post baseline will be included in the analysis. 
The planned mixed effects model assumes that missing values are missing at random. 
The reasonableness of this assumption will be checked during the blinded review of the data 
and if necessary further methods may be applied.
9.4.3.1
Supportive analyses
The primary analysis uses a standard mixed model repeated measures approach where 
timepoints are considered as factors. This was chosen since the time course of ESSDAI 
changes following a single dose of VAY736 or placebo is not known. Supportive analyses 
will attempt to model the time effect to better describe changes over time.
Potential differences in efficacy between the 3 mg/kg dose and the 10 mg/kg dose of VAY736 
may be explored.
9.5
Analysis of secondary and exploratory variables
9.5.1
Efficacy / Pharmacodynamics
Secondary efficacy variables supporting the exploratory objectives are:

EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI) change from baseline.

Change in physician global assessment of the patient’s overall disease activity between 
baseline and week 12 as recorded by a visual analog scale (VAS)

Change in the patient’s global assessment of their disease activity between baseline and 
week 12 as recorded by a VAS

Change from baseline for each domain of the Short Form (36) Health Survey (SF-36).

Change from baseline for each dimension of the Multidimensional Fatigue Inventory (MFI) 
Questionnaire.
The secondary efficacy variables will be analyzed following the same approach used for the 
primary efficacy variable.

Salivary flow rates

Ocular Staining Score

Serum levels of B cell activation markers, 
 
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
Leukocyte subsets and lymphocyte activation markers 
Further definition of these exploratory variables and the statistical analysis methods will be 
described in the RAP.
9.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data, including pregnancy tests, will be listed by treatment, subject, and 
visit/time and if normal ranges are available abnormalities will be flagged. Summary statistics 
will be provided by treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
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9.5.3
Pharmacokinetics
VAY736 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as 
zero. Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic 
and geometric), median, minimum and maximum. Concentrations below LLOQ will be 
treated as zero in summary statistics. A geometric mean will not be reported if the dataset 
includes zero values.
Pharmacokinetic parameters will be calculated as described in Section 6.6.3 and will be listed 
by treatment and subject. Descriptive summary statistics will include mean (arithmetic and 
geometric), SD, and CV (arithmetic and geometric), median, minimum and maximum. 
An exception to this is Tmax where median, minimum and maximum will be presented.
Modeling of the PK data may be performed as appropriate. During modeling of the 
pharmacokinetics of the study drug, the broad principles outlined in the FDA Guidance for 
Industry: Population Pharmacokinetics will be followed. Subjects with missing PK parameters 
(e.g., Cmax, AUClast, AUCinf) in some but not all periods will be included in a mixed model 
analysis assuming missing at random.
9.5.4
Pharmacokinetic / pharmacodynamic interactions
PK/PD modeling will be used to explore the relationship between extent and duration of 
B cell depletion and the pharmacokinetic profile of VAY736.
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9.5.7
Other biomarkers
All biomarker data will be listed by treatment, subject, and visit/time. Summary statistics will 
be provided by treatment and visit/time.
In the summary tables, the frequency (n, %) of values below the LLOQ and above the ULOQ, 
respectively, will be included.
In case of censored values (values below the LLOQ and/or values above the ULOQ), the 
summary statistics (arithmetic mean, standard deviation, geometric mean and CV% of 
geometric mean) will be calculated as the maximum likelihood estimates using a parametric 
model for data that can be right censored and left censored assuming the data being normally 
or log-normally distributed.
9.6
Sample size calculation
The sponsor is targeting to enroll around 26 patients in this study (with replacement strategy) 
and expects at least 24 patients to complete the assessments. With 24 patients in the analysis 
of the primary efficacy variable (assuming 16 in the VAY736 group and 8 in the placebo 
group), the study would have around 1% chance of having a false-positive result, i.e., of 
meeting both the efficacy criteria when the true difference between VAY736 and placebo is 
zero. Additionally the chances of meeting both the efficacy criteria remain below 20% for true 
differences between VAY736 and placebo of less than 2 points.
The study would have approximately 80% chance of meeting both the efficacy criteria, when 
the true difference between VAY736 and placebo is 7 points.
These calculations assume that the primary efficacy variable, ESSDAI, follows a normal 
distribution with a standard deviation of 5. This estimate of the standard deviation is based on 
a study of rituximab in patients with primary Sjögren’s syndrome (Meiners et al 2012) in 
which the observed standard deviation at baseline ranged from 5 at baseline to 3-7 after study.


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The figure below (Figure 9-1) shows the chances of meeting the efficacy criteria (shown as 
“Go” in the figure), or of meeting one of the two criteria (shown as “indeterminate”) or of not 
meeting the efficacy criteria (shown as “Stop”) for different true differences between 
VAY736 and placebo.
Figure 9-1
Probability of meeting efficacy criteria for N=16:8 VAY736:placebo
9.7
Power for analysis of key secondary variables
Not applicable.
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10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. Informed consent must 
be obtained before conducting any study-specific procedures (i.e., all of the procedures 
described in the protocol). The process of obtaining informed consent should be documented 
in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study drug 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 requirement for the duration 
of the study. If there is any question that the subject will not reliably comply, they should not 
be entered in the study.
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
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10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. 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 Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs, 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.
10.4
Publication of study results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorized deviations are permitted. 
If the 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/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
11.1
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/REB. 
Only amendments that are required for subject safety may be implemented prior to 
IRB/IEC/REB approval. 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 Health Authorities 
(where required) and the IRB/IEC/REB at the study site should be informed within 
10 working days or less, if required by local regulation.


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12
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Marco H, Smith RM, Jones RB, et al (2014) The effect of rituximab therapy on 
immunoglobulin levels in patients with multisystem autoimmune disease. BMC 
Musculoskeletal Disorders; 15:178.
Meijer JM, Meiners PM, Vissink A, et al (2010) Effectiveness of rituximab treatment in 
primary Sjögren’s syndrome. Arthritis Rheum; 62:960-968.
Meiners PM, Arends S, Brouwer E, et al (2012) Responsiveness of disease activity indices 
ESSPRI and ESSDAI in patients with primary Sjögren’s syndrome treated with rituximab. 
Ann Rheum Dis; 71:1297-1302.
Mikuls TR, O’Dell JR, Stoner JA, et al (2004) Association of rheumatoid arthritis treatment 
response and disease duration with declines in serum levels of IgM rheumatoid factor and 
anti-cyclic citrullinated peptide antibody. Arthritis Rheum; 50:3776-3782.
Pers JO, Devauchelle V, Daridon C, et al (2007) BAFF-modulated repopulation of B 
lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren’s 
syndrome. Arthritis Rheum; 56:1464-1477.
Pijpe J,van Imhoff GW, Spijkervet FKL, et al (2005) Rituximab treatment in patients with
primary Sjögren’s syndrome: an open-label phase II study. Arthritis Rheum; 52:2740-2750.


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Pijpe J, Kalk WWI, Bootsma H, et al (2006) Progression of salivary gland dysfunction in 
patients with Sjögren’s syndrome. Ann Rheum Dis; 66:107-112.
Quartuccio L, Fabris M, Moretti M, et al (2008) Resistance to rituximab therapy and local 
BAFF overexpression in Sjögren’s syndrome-related myoepithelial sialadenitis and low-grade 
parotid B-cell lymphoma. Open Rheumatol J; 2:38-43.
Seror R, Sordet C, Guillevin L, et al (2007) Tolerance and efficacy of rituximab and changes 
in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s 
syndrome. Ann Rheum Dis; 66:351-357.
Seror R, Ravaud P, Bowman S, et al (2011) EULAR Sjögren's syndrome disease activity 
index: development of a consensus systemic disease activity index for primary Sjögren's
syndrome. Erratum in: Ann Rheum Dis; 70:880.
Shiboski SC, Shiboski CH, et al (2012) American College of Rheumatology classification 
criteria for Sjögren’s syndrome: A data-driven, expert consensus approach in the Sjögren’s 
International Collaborative Clinical Alliance Cohort. Arthritis Care Res; 64:475-487
Tesfa D, Palmblad J (2011) Late-onset neutropenia following rituximab therapy: incidence, 
clinical features and possible mechanisms. Expert Rev Hematol; 4:619-625.
Varin MM, Le Pottier L, Youinou P, et al (2010) B-cell tolerance breakdown in Sjögren’s 
syndrome: Focus on BAFF. Autoimmunity Rev; 9:604-608.
Vitali C, Bombardieri S, Jonsson R, et al (2002) Classification criteria for Sjögren’s syndrome: 
a revised version of the European criteria proposed by the American-European Consensus 
Group. Ann Rheum Dis; 61:554-558.
Wolach O, Shpilberg O, Lahav M (2012) Neutropenia after rituximab treatment: new insights 
on a late complication. Curr Opin Hematol; 19:32-38.
Whitcher JP, Shiboski CH, Shiboski SC, et al (2010) A simplified quantitative method for 
assessing keratoconjunctivitis sicca from the Sjögren’s syndrome international registry. Am J 
Ophthalmol; 149:405-415.
Youinou P, Pers JO (2012) Latest update on the primary Sjögren’s syndrome. Presse Med; 41 
(9 pt 2):e437-439.


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Appendix 3:
ESSDAI
Table 15-1
The EULAR Sjögren’s syndrome disease activity index (ESSDAI): domain and item definitions and weights
Domain [weight]
Activity level
Description
Constitutional [3]
Exclusion of fever of 
infectious origin and 
voluntary weight loss
No = 0 
Low = 1
Moderate = 2
Absence of the following symptoms 
Mild or intermittent fever (37.5–38.5°C)/night sweats and/or involuntary weight loss of 5-10% of body 
weight 
Severe fever (>38.5°C)/night sweats and/or involuntary weight loss of >10% of body weight
Lymphadenopathy [4]
Exclusion of infection
No = 0 
Low = 1
Moderate = 2
High = 3
Absence of the following features
Lymphadenopathy ≥1 cm in any nodal region or ≥2 cm in inguinal region
Lymphadenopathy ≥2 cm in any nodal region or ≥3 cm in inguinal region, and/or splenomegaly 
(clinically palpable or assessed by imaging) 
Current malignant B-cell proliferative disorder
Glandular [2]
Exclusion of stone or 
infection
No = 0
Low =1 
Moderate = 2
Absence of glandular swelling
Small glandular swelling with enlarged parotid (≤3 cm), or limited submandibular or lachrymal swelling
Major glandular swelling with enlarged parotid (>3 cm), or important submandibular or lachrymal 
swelling
Articular [2]
Exclusion of osteoarthritis
No = 0 
Low = 1 
Moderate = 2
High = 3
Absence of currently active articular involvement
Arthralgias in hands, wrists, ankles and feet accompanied by morning stiffness (>30 min)
1–5 (of 28 total count) synovitis
≥6 (of 28 total count) synovitis
Cutaneous [3]
Rate as ‘no activity’ stable 
long-lasting features related 
to damage
No = 0
Low = 1
Moderate = 2
High = 3
Absence of currently active cutaneous involvement
Erythema multiforma
Limited cutaneous vasculitis, including urticarial vasculitis, or purpura limited to feet and ankle, or 
subacute lutaneous lupus
Diffuse cutaneous vasculitis, including urticarial vasculitis, or diffuse purpura, or ulcers related to 
vasculitis


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Domain [weight]
Activity level
Description
Pulmonary* [5]
Rate as ‘no activity’ stable 
long-lasting features related 
to damage, or respiratory 
involvement not related to 
the disease (tobacco use, 
etc)
No = 0
Low = 1
Moderate = 2
High = 3
Absence of currently active pulmonary involvement
Persistent cough or bronchial involvement with no radiographic abnormalities on radiography
Or radiological or HRCT evidence of interstitial lung disease with no breathlessness and normal lung 
function test
Moderately active pulmonary involvement, such as interstitial lung disease shown by HRCT with 
shortness of breath on exercise (NYHA II) or abnormal lung function tests restricted to 
70%>DLCO≥40% or 80%>FVC≥60%
Highly active pulmonary involvement, such as interstitial lung disease shown by HRCT with shortness 
of breath at rest (NHYA III, IV) or with abnormal lung function tests DLCO<40% or FVC<60%
Renal [5]
Rate as ‘no activity’ stable 
long-lasting features related 
to damage and renal 
involvement not related to 
the disease.
If biopsy has been 
performed, please rate 
activity based on 
histological features first
No = 0
Low = 1
Moderate = 2
High = 3
Absence of currently active renal involvement with proteinuria <0.5 g/day, no haematuria, no 
leucocyturia, no acidosis, or long-lasting stable proteinuria due to damage
Evidence of mild active renal involvement, limited to tubular acidosis without renal failure or 
glomerular involvement with proteinuria (between 0.5 and 1 g/day) and without haematuria or renal 
failure (GFR ≥60 ml/min)
Moderately active renal involvement, such as tubular acidosis with renal failure (GFR <60 ml/min) or 
glomerular involvement with proteinuria between 1 and 1.5 g/day and without haematuria or renal 
failure (GFR ≥60 ml/min) or histological evidence of extra-membranous glomerulonephritis or 
important interstitial lymphoid infiltrate
Highly active renal involvement, such as glomerular involvement with proteinuria >1.5 g/day or 
haematuria or renal failure (GFR <60 ml/min), or histological evidence of proliferative 
glomerulonephritis or cryoglobulinaemia-related renal involvement
Muscular* [6]
Exclusion of weakness due 
to corticosteroids
No = 0
Low = 1
Moderate = 2
High = 3
Absence of currently active muscular involvement
Mild active myositis shown by abnormal EMG or biopsy with no weakness and creatine kinase 
(N<CK≤2N)
Moderately active myositis confirmed by abnormal EMG or biopsy with weakness (maximal deficit of 
4/5), or elevated creatine kinase (2N<CK≤4N)
Highly active myositis shown by abnormal EMG or biopsy with weakness (defi cit ≤3/5) or elevated 
creatine kinase (>4N)


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Domain [weight]
Activity level
Description
PNS* [5]
Rate as ‘no activity’ stable 
long-lasting features related 
to damage or PNS 
involvement not related to 
the disease
No = 0
Low = 1
Moderate = 2
High = 3
Absence of currently active PNS involvement
Mild active peripheral nervous system involvement, such as pure sensory axonal polyneuropathy 
shown by NCS or trigeminal (V) neuralgia
Moderately active peripheral nervous system involvement shown by NCS, such as axonal 
sensorimotor neuropathy with maximal motor deficit of 4/5, pure sensory neuropathy with presence of 
cryoglobulinamic vasculitis, ganglionopathy with symptoms restricted to mild/moderate ataxia, 
inflammatory demyelinating polyneuropathy (CIDP) with mild functional impairment (maximal motor 
deficit of 4/5 or mild ataxia)
Or cranial nerve involvement of peripheral origin (except trigeminal (V) neuralgia)
Highly active PNS involvement shown by NCS, such as axonal sensorimotor neuropathy with motor 
deficit ≤3/5, peripheral nerve involvement due to vasculitis (mononeuritis multiplex, etc), severe ataxia 
due to ganglionopathy, inflammatory demyelinating polyneuropathy (CIDP) with severe functional 
impairment: motor deficit ≤3/5 or severe ataxia
CNS* [5]
Rate as ‘no activity’ stable 
long-lasting features related 
to damage or CNS 
involvement not related to 
the disease
No = 0
High = 3
Absence of currently active CNS involvement
Highly active CNS features, such as cerebral vasculitis with cerebrovascular accident or transient 
ischaemic attack, seizures, transverse myelitis, lymphocytic meningitis, multiple sclerosis-like 
syndrome with motor deficit
Haematological [2]
For anaemia, neutropenia, 
and thrombopenia, only 
autoimmune cytopenia 
must be considered 
Exclusion of vitamin or iron 
deficiency, drug-induced 
cytopenia
No = 0
Low = 1
Moderate = 2
High = 3
Absence of auto-immune cytopenia
Cytopenia of auto-immune origin with neutropenia (1000<neutrophils<1500/mm3), and/or anaemia 
(10<haemoglobin<12 g/dl), and/or thrombocytopenia (100000<platelets<150000/mm3) 
Or lymphopenia (500<lymphocytes<1000/mm3)
Cytopenia of auto-immune origin with neutropenia (500≤neutrophils≤1000/mm3), and/or anaemia 
(8≤haemoglobin≤10 g/dl), and/or thrombocytopenia (50000≤platelets≤100000/mm3) 
Or lymphopenia (≤500/mm3)
Cytopenia of auto-immune origin with neutropenia (neutrophils <500/mm3), and/or or anaemia 
(haemoglobin <8 g/dl) and/or thrombocytopenia (platelets <50000/mm3)


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Domain [weight]
Activity level
Description
Biological [1]
No = 0
Low = 1
Moderate = 2
Absence of any of the following biological features
Clonal component and/or hypocomplementaemia (low C4 or C3 or CH50) and/or 
hypergammaglobulinaemia or high IgG level between 16 and 20 g/l
Presence of cryoglobulinaemia and/or hypergammaglobulinaemia or high IgG level >20 g/l, and/or 
recent onset hypogammaglobulinaemia or recent decrease of IgG level (<5 g/l)
CIDP, chronic inflammatory demyelinating polyneuropathy; CK, creatine kinase; CNS, central nervous system; DLCO, diffusing CO capacity; EMG, 
electromyogram; EULAR, European League Against Rheumatism; FVC, forced vital capacity; GFR, glomerular filtration rate; Hb, haemoglobin; HRCT, 
high-resolution computed tomography; IgG, immunoglobulin G; NCS, nerve conduction studies; NHYA, New York Heart Association classification; Plt, 
platelet; PNS, peripheral nervous system.
*Clinical investigator subjective scoring based on availability of concurrent clinical data.




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5. How severe has your ocular (eye) dryness been during the last 2 weeks?
No dryness
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Maximal imaginable 
dryness
6. How severe has your oral (mouth) dryness been during the last 2 weeks?
No dryness
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Maximal imaginable 
dryness
7. How severe has your skin dryness been during the last 2 weeks?
No dryness
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Maximal imaginable 
dryness
8. How severe has your nasal dryness been during the last 2 weeks?
No dryness
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Maximal imaginable 
dryness
9. How severe has your tracheal (breathing tubes) dryness been during the last 2 weeks?
No dryness
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Maximal imaginable 
dryness
10. How severe has your vaginal dryness been during the last 2 weeks?
No dryness
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Maximal imaginable 
dryness
If not relevant tick this box
Preliminary Explanation:
You have just evaluated the severity of your symptoms. However, in your everyday life some may be 
more important to you than others. You are now going to evaluate their importance, try to reflect this 
distinction in your answers.


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11. Among the following symptoms, please identify the one you consider the most in need for 
improvement (tick only one box)
Dryness
Fatigue
Pain
Mental Fatigue
12. Among the following symptoms, please rank them by priority order: - from 1: the most in 
need of improvement to 4: the least in need of improvement.
Dryness
Fatigue
Pain
Mental Fatigue
/___/
/___/
/___/
/___/
13. Among the following dryness symptoms, please identify the one you consider the most in 
need for improvement (tick only one box)
Ocular 
Oral 
Skin 
Nasal 
Tracheal 
Vaginal 
14. Among the following dryness symptoms, please rank them by priority order: - from 1: the 
most in need of improvement to 6: the least in need of improvement.
Ocular
Oral
Skin
Nasal
Tracheal
Vaginal
/___/
/___/
/___/
/___/
/___/
/___/
15. How important is it to you to get rid of your dryness?
Not important at all
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Extremely 
important
16. How important is it to you to get rid of your fatigue?
Not important at all
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Extremely 
important


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17. How important is it to you to get rid of your pain?
Not important at all
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Extremely 
important
18. How important is it to you to get rid of your mental fatigue?
Not important at all
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Extremely 
important
19. Considering now your symptoms related to your Sjögren’s syndrome (e.g., dryness, your 
fatigue, pain and your mental fatigue), as well as their consequences on your professional 
or personal life, how severe was your Sjogren’s syndrome during the last 2 weeks?
Inactive
disease
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Very active 
disease
20. How long has it taken you to complete this questionnaire?
_________________minutes
21. How easy or difficult have you found it to complete this questionnaire?
Very
easy
  
  
  
  
  
  
  
  
  
  
  0       1       2       3      4     5       6       7       8       9     10
Very difficult
Comments


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Appendix 5:
SF-36
Will be provided separately.


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Appendix 6:
MFI
Will be provided separately.


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SAP_001.pdf: 
Clinical Development
VAY736
CVAY736X2201
A single dose, double-blind, placebo-controlled, parallel
study to assess the pharmacodynamics, pharmacokinetics
and safety and tolerability of VAY736 in patients with 
primary Sjögren’s syndrome
TSc RAP Module 3: Detailed Statistical Methodology
Document type:
TSc RAP Module 3: Detailed Statistical Methodology
Document status:
Final Version 2
Release date:
11-Jan-2017
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................2
1
Introduction to RAP documentation....................................................................................4
1.1
Scope........................................................................................................................4
1.2
Changes to RAP documentation (M3).....................................................................4
2
Study objectives and design ................................................................................................5
2.1
Study objectives.......................................................................................................5
2.2
Study design and treatment......................................................................................6
3
First interpretable results (FIR) ...........................................................................................8
4
Interim analyses...................................................................................................................8
4.1
Interim and Second CSRs........................................................................................8
5
Statistical methods: Analysis sets........................................................................................8
6
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
7
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
7.1
Primary parameter .................................................................................................10
7.2
Supportive analyses for the primary parameter.....................................................11
7.3
Secondary efficacy variables .................................................................................11
7.4
Exploratory efficacy variables...............................................................................12
8
Statistical methods for safety and tolerability data............................................................13
List of tables
Figure 2-1
Study Design Schematic .........................................................................7
Table 5-1
Protocol deviation severity codes and analysis sets................................9
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Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics &
Programming input into the Clinical Study Report (CSR) for trial “CVAY736X2201”. 
Module 3 (M3) provides the description of the statistical methodology used to analyze the 
data, Module 7 (M7) details the presentation of the data, including shells of summary tables, 
figures and listings, and Module 8 (M8) contains programming specifications e.g. for derived 
variables and derived datasets, to support the creation of CSR outputs.
1.2
Changes to RAP documentation (M3)
Refer to corresponding guidances and Translational Sciences (TSc) RAP Addendum template 
for detailed information on the requirements of documenting changes to RAP documentation.
For the statistical methodology (M3), any major changes occurring before database lock to 
the statistical methodology should be reflected in the RAP M3 documentation via version 
control (new document version to be approved by the trial team as the original module.
Major changes include, but are not limited to, changes in protocol that affect study design and 
statistical methodology. 
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file / 
note in RAP Addendum or within the CSR itself.  Minor changes include, but are not limited 
to, change in statistical model.  Corrections of typographical errors or modification of spelling 
(from English to American, for example) do not need to be incorporated into the RAP M3 
documentation.


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Study objectives and design 
2.1
Study objectives
Primary Objectives

To compare the effect of a single i.v. dose VAY736 versus placebo on the clinical 
disease activity of primary Sjögren’s syndrome patients as measured by the change of 
a modified EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) between 
base line and Week 12.

To assess the safety and tolerability of a single i.v. dose VAY736 in patients with 
primary Sjögren’s syndrome as measured by adverse events (AEs).
Secondary Objectives

To evaluate the effect of a single i.v. dose VAY736 versus placebo on self-reported
outcomes in pSS patients at 12 weeks compared to baseline as measured by the 
EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI), the Short Form 
(36) Health Survey (SF-36) and the Multidimensional Fatigue Inventory (MFI) 
Questionnaire.

To determine the changes in the physician global assessment of the patient’s overall
disease activity between baseline and Week 12 as recorded by a visual analog scale 
(VAS)

To determine the changes in the patients global assessment of their disease activity
between baseline and Week 12 as recorded by a VAS

To determine the pharmacokinetics following a single dose i.v. VAY736 in pSS 
patients
Exploratory Objectives
High resolution ultrasound of parotid salivary glands as measured by the 
following parameters:
Parotid thickness and staging
Parotid blood flow with contrast agent (optional)
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Salivary gland function using the salivary flow (unstimulated and stimulated)
Lacrimal gland function using the Ocular Staining Score
Serum evidence of B cell hyperactivity,
 

To assess the immunogenicity following a single i.v. dose of VAY736 in pSS patients

To measure the effect of a single i.v. dose VAY736 on leukocyte subsets,
 
 
2.2
Study design and treatment
This is a double-blind, randomized, placebo-controlled, parallel-group, non-confirmatory
study to assess the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics 
and clinical efficacy of VAY736 administered intravenously as a single dose in pSS patients.
The patients will be enrolled in 2 sequential cohorts:

3 mg/kg cohort (Cohort 1): 6 patients randomized to receive a single dose of VAY736 
at a starting dose of 3.0 mg/kg or placebo at a 2:1 ratio; approximately 4 patients in 
this cohort will receive a 3.0 mg/kg dose of VAY736 and approximately 2 patients 
will receive placebo.

10 mg/kg cohort (Cohort 2): 20 patients randomized to receive a single dose of 
VAY736 at a dose of 10.0 mg/kg or 3.0 mg/kg or placebo at a 6:1:3 ratio, respectively. 
Around 12 patients will receive 10 mg/kg of VAY736 in this cohort and around 6 will 
receive placebo. Approximately 2 patients will receive 3.0 mg/kg in this cohort to 
maintain a level of blinding regarding the dose received.
Between Cohort 1 and Cohort 2 recruitment will be paused and a safety review will be
conducted by the VAY736 project team and the principle investigators.
The single doses of 3 - 10 mg/kg are based on the two highest doses safely administered in
Part 1 of the SAD phase I study recently completed in RA patients. This study will enroll 
around 26 patients with primary Sjögren’s syndrome. At least 24 subjects are expected to 
complete the study.
Subjects that are prematurely withdrawn from the study for reasons other than safety will be 
replaced on a case by case basis. Data from the withdrawn patients will still be used in the 
primary analysis as much as possible but the sponsor will use replacement patients to obtain
complete data on at least 24 patients.
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At Week 24 the blinding was broken to confirm treatment allocation. Investigators will follow
the guidance below:

If a patient received VAY736 and their B cell recovery was demonstrated at Week 24,
then patients should have returned for their End of Study visit approximately 4 weeks later.

Those patients who did not meet the criteria for B cell recovery at Week 24, will return to 
the site every 8 weeks until Week 52, then after Week 52, every 24 weeks until 2 years
post dose (Week 100) and afterwards every 48 weeks, until B cell recovery is
demonstrated and the End of Study visit may be scheduled.

If a patient received placebo, at Week 24 they were offered the option of receiving open-
label VAY736 (10 mg/kg) in a separate treatment arm.
o
Patients that consented to open-label VAY736 treatment would have restarted the 
study at Day 1 (within 4 weeks [+ 2 week window] of Week 24 visit);
o
Patients that did not consent to receive open-label VAY736 treatment would have 
returned to the site for End of Study visit as per Assessment schedule.
Patients will not be informed of their treatment allocation until after all of the assessments
scheduled for Week 24 have been completed.
A study design schematic is provided in Figure 2-1.
Figure 2-1
Study Design Schematic


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First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
The study FIR template can be found in CREDI in the study RAP folder [file name] 
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be marked as “Key” in the M9.1 Tracking sheet output 
list. 
4
Interim analyses 
Prior to this amended RAP two interim analyses have been performed, firstly when 25 and 
secondly when all 27 subjects had completed the Week 12 visit in order to assess the effect of 
VAY736 on the primary endpoints. For these subjects the efficacy endpoints (along with 
relevant safety data) were examined as a preliminary evaluation of therapeutic effects.
In addition, an interim safety review was performed between Cohort 1 and Cohort 2.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study.
4.1
Interim and Second CSRs
An interim CSR will be produced after all patients have completed up to Week 52
assessments or have completed the study before Week 52. Efficacy data up to each patients 
week 52 visit will be summarized in this interim CSR(see below for more details regarding 
the figures), while listings will have all data up to the DB freeze. All safety data will be listed 
and summarized up to the interim CSR freeze date. At the end of the study after all patients 
have had B cell recovery a second CSR will be produced describing the data from Week 52 
onwards and including all end of study assessments.
The following rules will be used for the presentation of the data for the Week-52 interim CSR,
1) For the majority of PD summary figures (such as boxplots etc.), only data up to week 
24 will be included. The exception includes B cell count data visualization which will 
show all the data.
2) For other PD visualizations such as overlaid individual plots, they will include all 
available PD data up to week 52. 
3) For AEs and conmeds, the summaries where applicable will be done for the double-
blinded period and open-label period separately.
4) For summary tables for PD/safety lab/VS/ECG the PD tables end at Week 52 visits; 
safety data may include data beyond.
5) For all outputs which include “uncleaned” data, a footnote will be added “All data up 
to 05Oct2016 (the last Week 52 visit) has been cleaned and data afterwards hasn’t 
been fully cleaned yet”. 


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5
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
All subjects that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set.
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 experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data, who received any 
study drug and experienced no protocol deviations with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 5-1
Protocol deviation severity codes and analysis sets
Protocol deviation severity code
Safety 
analysis set
PK analysis 
set
PD analysis 
set
Code
Text
5
Exclude subject from all safety analysis
-
-
-
8
Exclude from all analyses
-
-
-
20
Exclude subject from PK analysis set
+
-
+
22
Exclude subject from PD analysis set
+
+
-
23
Exclude subject from PK and PD analysis set
+
-
-
49
Report relevant protocol deviation – include 
subject in all analysis sets
+
+
+
+ = include in analysis set, - = exclude from analysis set, NA = not applicable
6
Statistical methods for Pharmacokinetic (PK) parameters
VAY736 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as 
zero. Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic 
and geometric), median, minimum and maximum. Concentrations below LLOQ will be 
treated as zero in summary statistics. A geometric mean will not be reported if the dataset 
includes zero values.
Pharmacokinetic parameters will be listed by treatment and subject. Descriptive summary 
statistics will include mean (arithmetic and geometric), SD, and CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented.
Modeling of the PK data may be performed as appropriate. During modeling of the
pharmacokinetics of the study drug, the broad principles outlined in the FDA Guidance for
Industry: Population Pharmacokinetics will be followed. Subjects with missing PK parameters
(e.g., Cmax, AUClast, AUCinf) in some but not all periods will be included in a mixed model


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analysis assuming missing at random. This modelling of the PK data will be performed by the 
Novartis PKist. 
PK/PD modeling will be used to explore the relationship between extent and duration of B 
cell depletion and the pharmacokinetic profile of VAY736. The PK/PD modelling will be 
performed internally at Novartis. Overlaid individual B cell counts with PK concentrations
will be provided by Covance.
7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Primary parameter
The primary aim of this study is to evaluate the effect of a single i.v. dose VAY736 on the 
clinical disease activity of primary Sjögren’s syndrome patients as measured by the ESSDAI 
at Week 12 compared to baseline. The statistical analysis model will include data on the 
ESSDAI from all timepoints at which it was recorded (baseline, Weeks 6, 12 and 24) but the 
primary comparison is made for Week 12.
The ESSDAI is an established disease outcome measure for Sjögren’s syndrome that will be 
applied to the study patients at baseline and again at Weeks 6, 12 and 24.  The instrument 
contains 12 organ-specific domains contributing to disease activity. For each domain, features 
of disease activity are scored in 3 or 4 levels according to their severity. These scores are then 
summed across the 12 domains in a weighted manner to provide the total score.
It is assumed that the ESSDAI will follow an approximate normal distribution. If, on blinded 
review of the data, this assumption appears to not be met, alternative statistical methods may 
be applied, e.g. data may be log transformed with changes from baseline in the log 
transformed data being analyzed.
A positive sign of therapeutic effects will be considered to be a difference of at least 5 points 
in the change from baseline between VAY736 and placebo with a moderate level of evidence. 
Additionally there should be a high level of evidence that is a difference between VAY736
and placebo. The two active doses will be pooled for the primary efficacy analysis (unless 
there is evidence of inferiority of the 3 mg/kg dose to the 10 mg/kg dose). These criteria will 
be evaluated by calculating Bayesian posterior probabilities as follows:
Pr (θVAY736,12w-θplacebo,12w > 0 | data) > 90% and
Pr (θVAY736,12w-θplacebo,12w > 5 | data) > 50%
where θ means change from baseline in ESSDAI at 12 weeks.
It is assumed that Yijt, the observed change from baseline in ESSDAI for subject i receiving
treatment j (VAY736 or placebo) at time t, follows a normal distribution N(θjt, σ2), It is 
further assumed that θjt follows a standard non-informative prior Normal distribution, p(θjt, σ2) 
= 1/σ2.
The statistical model will be a repeated measures fitting terms for treatment by timepoint and 
baseline by timepoint using the SAS procedure PROC MCMC. Estimates of the difference 
between VAY736 and placebo at each timepoint will be derived from this model and 
presented together with 95% credible intervals. The estimates of the posteriors probabilities of 
the efficacy criteria being met will be provided.


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Patients with missing ESSDAI at baseline will not be included in the analysis. Patients with 
missing data at one or more timepoints post baseline will be included in the analysis. The 
planned mixed effects model assumes that missing values are missing at random. The 
reasonableness of this assumption will be checked during the blinded review of the data and if 
necessary further methods may be applied.
Summary statistics will be provided for absolute and changes from baseline in ESSDAI by 
treatment and timepoint. Mean (SD) plots for absolute and changes from baseline in ESSDAI 
will also be provided. Overlaying individual profiles will also be provided by treatment.
7.2
Supportive analyses for the primary parameter
The primary analysis uses a standard mixed model repeated measures approach where 
timepoints are considered as factors. This was chosen since the time course of ESSDAI
changes following a single dose of VAY736 or placebo is not known. Supportive analyses
will attempt to model the time effect to better describe changes over time, the model may
include the following covariates: baseline, treatment, time, treatment by time interaction, 
treatment by time square interaction, as well as a random intercept and a random slope for 
each patient. Time will be modeled as a continuous variable. The model may be simplified if 
there are problems with convergence. The treatment by time square interaction will be 
included if it improves the fit.
Potential differences in efficacy between the 3 mg/kg dose and the 10 mg/kg dose of VAY736 
may be explored.
7.3
Secondary efficacy variables
Secondary efficacy variables supporting the exploratory objectives are:

EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI) change from 
baseline.

Change in physician global assessment of the patient’s overall disease activity 
between baseline and Week 12 as recorded by a visual analog scale (VAS)

Change in the patient’s global assessment of their disease activity between baseline 
and Week 12 as recorded by a VAS

Change from baseline for each domain of the Short Form (36) Health Survey (SF-36).

Change from baseline for each dimension of the Multidimensional Fatigue Inventory 
(MFI) Questionnaire.
The secondary efficacy variables will be analyzed using a repeated measures model with the 
same factors as the primary efficacy variable but will use a frequentist rather than Bayesian 
approach.
During the conduct of the study it has been noted that the ESSPRI score has been recorded as
1 to 10 rather than 0 to 10 which would lead to an underestimate of the outcomes. The 
Principal Investigator has confirmed that the scale still provides a reliable detection of relative 
changes.
The ESSPRI statistical analyses will be rerun after transforming the results as per the below to 
assess the impact:


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1. Use a linear transformation to change the 1-10 scale to a 0-10 scale 
New scale score = 10 x (Old scale score – 1)/9
(i.e. 1 becomes 0, 2 becomes 1.111, 3 becomes 2.222 etc.)
2. Recode 1 to 0 and leave the rest of the scores the same (the rationale is that a score of 
1 indicates zero activity but for scores above 1 it is not possible to say what they really 
should be)
The statistical analysis will be provided for both the untransformed and transformed data 
(only untransformed data was used in the first 2 interim analyses).
7.4
Exploratory efficacy variables
Exploratory efficacy variables supporting the exploratory objectives are:

Ultrasound parameters including gland thickness and staging (de Vita score), parotid 
blood flow with contrast agent (vascularization index and perfusion AUC) parotid 
elasticity from sonoelastography (shear wave and velocity). De Vita responders 
(defined as at least a 1 point reduction from baseline in the mean of the left and right 
values)

Results of histological and the immunohistochemistry staining of lymphocyte subsets 
in salivary gland biopsies

Salivary flow rates

Ocular Staining Score

Flow cytometry 
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Time to B cell event endpoints will be summarized by treatment group, based on the results 
from the previous IAs there was no B cell depletion for placebo subjects therefore no Kaplan-
Meier estimates or log-rank tests among treatment groups will be performed. The B cell 
depletion AUC (area under curve, calculated using the linear trapezoidal rule) over time at 
Week 12 and 24 will be explored for the relationship with change from baseline PRO 
parameters at corresponding time points. Baseline B cell count will also be explored for such 
relationship. The AUC and baseline B cell count will be log transformed prior to analysis.
For ultrasound parameters where both the left and right side of glands have been measured, 
the mean of the two sides will be taken for summary statistics and other planned statistical 
analyses, including the correlation among changes from baseline in ultrasound parameters and 
also correlation between changes from baseline in ultrasound parameters with changes from 
baseline in PRO parameters.
8
Statistical methods for safety and tolerability data
All data for background demographic variables will be listed and summarized by treatment.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed.
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Data for study drug administration and concomitant therapies will be listed by treatment
group and subject.
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameters) will be 
created.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged.
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data, including pregnancy tests, will be listed by treatment, subject, and 
visit/time and if normal ranges are available abnormalities will be flagged. Summary statistics 
will be provided by treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject. The 
number and percentage of subjects with adverse events will be tabulated by body system and 
preferred term with a breakdown by treatment. A subject with multiple adverse events within 
a body system is only counted once towards the total of this body system. Boxplots to 
visualize trends in longitudinal safety data (vitals, ECG, lab parameters) will be created.
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