Clinical trial NCT02291029
Conditions: Primary Sjögren's Syndrome
Keywords: Sjögren's syndrome, CFZ533, ESSDAI
Sponsor: Novartis Pharmaceuticals
Start date: 2014-10-22; Completion date: 2018-06-29
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study did evaluate the safety,tolerability and preliminary therapeutic efficacy of multiple doses of intravenous infusion of CFZ533 monoclonal antibody in patients with primary Sjögren's syndrome(pSS)

Detailed description:

Arms: arm 1: multiple doses of CFZ533 intravenous infusion arm 2: multiple doses of placebo intravenous infusion arm 3: multiple doses of CFZ533 s.c. injection arm 4: multiple doses of placebo s.c. injection arm 5: multiple doses of CFZ533 s.c. injection arm 6: Single dose of CFZ533 i.v. infusion and multiple doses of CFZ533 s.c. injection
Interventions: intervention 1: CFZ533 active - Cohort 1 intervention 2: CFZ533 placebo- Cohort 1 intervention 3: CFZ533 active - Cohort 2 intervention 4: CFZ533 placebo - Cohort 2 intervention 5: CFZ533 active -Cohort 3 intervention 6: CFZ533 active - Cohort 3
Intervention descriptions: intervention 1: multiple doses of CFZ533 s.c. injection intervention 2: multiple doses of placebo s.c. injection intervention 3: multiple doses of CFZ533 intravenous infusion intervention 4: multiple doses of placebo intravenous infusion intervention 5: multiple doses of CFZ533 s.c. injection intervention 6: Single dose of CFZ533 i.v. infusion and multiple doses of CFZ533 s.c. injection

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CFZ533
Clinical Trial Protocol CCFZ533X2203
A multi-center, randomized, double-blind, placebo-
controlled, parallel groupstudyto assess thesafety, 
tolerability, pharmacokinetics and preliminaryefficacy of 
CFZ533 in patients with primarySjögren’ssyndrome
Document type:
Amended Protocol Version
EUDRACT number:
2013-004808-19
Version number:
v07Clean(incorporating amendment 07)
Developmentphase:
II
Release date:
24-May-2017
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 SAEoccurring in a subject from consent until 30 days after the last study visitmust 
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 faxedby the investigator to the local Novartis Chief Medical Office 
& Patient Safety (CMO&PS)Departmentwithin 24hoursof learning of the occurrence of 
the SAE even if the SAE does not appearto be drug-related. Theoriginal SAE form, together 
with the fax confirmation sheet, must be kept with the case report forms at the study site.
For SAEs recorded electronicallyin the Novartis clinical data capture system, information 
should be entered, saved and e-signed within 24 hours of awareness of the SAE. 
Thesedata will automatically be submitted to Novartis Drug Safety & Epidemiology.
More details in Section 7
Personal Data
of this protocol.


Novartis
Confidential
Page 3
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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...............................................................................................................25
Assessment schedule –Cohort 1.......................................................................................29
Assessment schedule-Cohort 2........................................................................................31
Assessment scheduleCohort 3..........................................................................................34
1 Introduction.......................................................................................................................36
1.1
Background............................................................................................................36
1.1.1
Physiology of CD40/CD40L co-stimulation.........................................36
1.1.2
CD40/CD40L co-stimulation: a target for primary Sjögren’s 
syndrome...............................................................................................37
1.1.3
CFZ533: mechanism of action..............................................................38
1.1.4
Clinical data for otheranti-CD40 monoclonal antibodies....................38
1.1.5
Relevant data summary.........................................................................39
1.2
Study purpose........................................................................................................46
2 Study objectives.................................................................................................................46
2.1
Primary objectives.................................................................................................46
2.2
Secondary objectives.............................................................................................47
3 Investigational plan...........................................................................................................49
3.1
Study design..........................................................................................................49
3.2
Rationale for study design.....................................................................................53
3.3
Rationale for dose/regimen, duration of treatment................................................
Corporate Confidential Information
54
Corporate Confidential Information


Novartis
Confidential
Page 4
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
3.4 
Rationale for choice of comparator.......................................................................58
3.6
Risks and benefits..................................................................................................58
3.6.1
Potential benefit....................................................................................58
3.6.2 
Potential risks associated with exposure to CFZ533 and their 
mitigation..............................................................................................58
4 Population..........................................................................................................................61
4.1
Inclusion criteria....................................................................................................62
4.2
Exclusion criteria...................................................................................................62
5 Treatment...........................................................................................................................65
5.1 
Protocol requested treatment.................................................................................65
5.1.1
Investigational treatment.......................................................................65
5.1.2
Additional study treatment....................................................................66
5.2
Treatment arms......................................................................................................66
5.3
Treatment assignment............................................................................................67
5.4
Treatment blinding.................................................................................................68
5.5
Treating the subject................................................................................................68
5.5.1
Subject numbering................................................................................68
5.5.2
Dispensing the study treatment.............................................................69
5.5.3
Handling of study treatment..................................................................70
5.5.4
Instructions for prescribing and taking study treatment........................70
5.5.5
Permitted dose adjustments and interruptions of study treatment........71
5.5.6
Recommended treatment of adverse events..........................................71
5.5.7 
Rescue medication................................................................................72
5.5.8
Concomitant treatment..........................................................................72
5.5.9
Prohibited treatment..............................................................................73
5.5.10
Discontinuation of study treatment.......................................................73
5.5.11
Withdrawal of consent ..........................................................................75
5.5.12
Loss to follow-up..................................................................................75
5.5.13
Emergency breaking of assigned treatment..........................................75
5.5.14
Study completion and post-study treatment..........................................76
5.5.15
Early study termination.........................................................................76
6 Visit assessments...............................................................................................................77
6.1
Dietary, fluid and other restrictions.......................................................................77
6.2 
Subject demographics/other baseline characteristics.............................................77
6.3
Treatment exposure and compliance.....................................................................
Corporate Confidential Information
78


Novartis
Confidential
Page 5
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.4
Efficacy / Pharmacodynamic assessments.............................................................78
6.4.1
ESSDAI.................................................................................................78
6.4.2
ESSPRI..................................................................................................78
6.4.3
SF-36 –Cohorts 1 and 2 only...............................................................79
6.4.4
MFI –Cohorts 1 and 2 only..................................................................79
6.5
Safety.....................................................................................................................81
6.5.1
Physical examination............................................................................81
6.5.2
Vital signs.............................................................................................82
6.5.3
Height and weight.................................................................................82
6.5.4
Laboratory evaluations..........................................................................82
6.5.6
Electrocardiogram (ECG).....................................................................84
6.5.7
Pregnancy..............................................................................................84
6.5.8
Other safety assessments.......................................................................85
6.6
Pharmacokinetic assessments................................................................................85
6.6.1
PK Blood collection and processing.....................................................85
6.6.2
Pharmacokinetic analytical method......................................................86
6.6.3
Pharmacokinetic parameters.................................................................86
6.7
Other assessments..................................................................................................86
7 Safety monitoring..............................................................................................................89
7.1
Adverse events.......................................................................................................89
7.2
Serious adverse event reporting.............................................................................91
7.3
Liver safety monitoring.........................................................................................91
7.4
Pregnancy reporting...............................................................................................92
7.5
Early phase safety monitoring...............................................................................92
8 Data review and database management.............................................................................
Corporate Confidential Information
93
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 6
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
8.1
Site monitoring......................................................................................................93
8.2 
Data collection.......................................................................................................93
8.3
Database management and quality control............................................................94
8.4
Data Monitoring Committee..................................................................................94
8.5
Adjudication Committee........................................................................................94
9 Data analysis......................................................................................................................95
9.1
Analysis sets..........................................................................................................95
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(s).......................................................................95
9.4.1
Variable(s).............................................................................................95
9.4.2
Statistical model, hypothesis, and method of analysis..........................95
9.4.3
Handling of missing values/censoring/discontinuations.......................96
9.4.4
Supportive analyses...............................................................................96
9.5
Analysis of secondary and exploratory variables..................................................96
9.5.1
Efficacy / Pharmacodynamics...............................................................96
9.5.2
Safety....................................................................................................97
9.5.3
Pharmacokinetics..................................................................................98
9.5.4
Pharmacokinetic / pharmacodynamic interactions................................98
9.6 
Sample size calculation..........................................................................................99
9.7
Power for analysis of key secondary variables....................................................100
10 Ethical considerations......................................................................................................101
10.1 Regulatory and ethical compliance......................................................................101
10.2 Informed consent procedures...............................................................................102
10.3 Responsibilities of the investigator and IRB/IEC................................................102
10.4 Publication of study protocol and results............................................................103
11 Protocol adherence..........................................................................................................103
11.1 Protocol Amendments.........................................................................................103
12 References.......................................................................................................................104
14 Appendix 2: Sample labeling and shipping information.................................................
Corporate Confidential Information
113
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 7
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
15 Appendix3: Liver event definitions and follow-up requirements..................................114
16 Appendix 4: ESSDAI......................................................................................................117
17 Appendix 5: ESSPRI.......................................................................................................121
18 Appendix 6: Blinding and unblinding.............................................................................124
List of tables
Table 5-1
Study drug CFZ533 (lyophilisate)........................................................65
Table 5-2
Study drug CFZ533 (liquid in vial).......................................................66
Table 5-3
Prohibited treatment..............................................................................73
Table 9-1
Probability of observing a certain number of adverse events in the 
study given assumed underlying rates.................................................100
Table 9-2
Estimated difference in AE rates when observing a certain number 
of adverse events in the study.............................................................100
Table 15-1 
Liver Event Definitions.......................................................................114
Table 15-2
Liver Event Follow Up Requirements................................................115
Table 16-1
The EULAR Sjögren’s syndrome disease activity index (ESSDAI): 
domainand item definitions and weights............................................117
Table 18-1
Blinding levels Cohorts 1 and 2..........................................................124
Table 18-2 
Blinding levels Cohort 3.....................................................................125
List of figures
Figure 1-1
Relationship between CD40 receptor occupancy by CFZ533 and 
functional activity (CFZ533 inhibition of CD154-induced 
expression of CD69) in human whole blood cultures...........................40
Figure 3-1
Study Design Cohort 1 and Cohort2....................................................50
Figure 3-2
Study Design Cohort 3..........................................................................
Corporate Confidential Information
50
Corporate Confidential Information


Novartis
Confidential
Page 8
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANA
antinuclear antibody
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
b.i.d.
twice a day
BMI
Body Mass Index
BUN
blood urea nitrogen
ca. 
Latin term ‘circa’ (signification:about)
CD-ROM
compact disc –read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CRF
Case Report/Record Form (paper or electronic)
CO2
carbon dioxide
CRO
Contract Research Organization
C-SSRS
Columbia Suicide Severity Rating Scale
CTC
Common Toxicity Criteria
CV
coefficient of variation
DMARD
Disease-modifying anti-rheumatic drug
DMC
Data Monitoring Committee
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
ESSDAI
EULAR Sjögren’sSyndrome Disease Activity Index
ESSPRI
EULAR Sjögren’s Syndrome Patient Reported Intensity
EULAR
The European League Against Rheumatism
Fab
Antigen binding fragmentof an antibody


Novartis
Confidential
Page 9
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Fc
Crystalizeable fragmentof an antibody
FDA
Food and Drug Administration
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
i.v.
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
KLH
Keyhole Limpet Hemocyanin
LFT
Liver function test
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
LLN
lower limit of normal
MedDRA
Medical dictionary for regulatory activities 
MFI
Multidimensional Fatigue Inventory Questionnaire
mg
milligram(s)
ml
milliliter(s)
OC/RDC
Oracle Clinical/Remote Data Capture
o.d.
once a day
PA
posteroanterior
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
p.o.
oral(ly)
pSS
primary Sjögren’s syndrome
PTT
partial thromboplastin time
q1w
(or Q1W) once every week 
RBC
red blood cell(s)
REB
Research Ethics Board


Novartis
Confidential
Page 10
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
RO
Receptor occupancy
SAE
serious adverse event
s.c.
subcutaneous
SF-36
Short Form (36) Health Survey
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TDAR
T cell dependent antibody response
ULN
upper limit of normal
ULQ
upper limit of quantification
VAS
Visual Analog Scale
WBC
white blood cell(s)
WHO
World Health Organization


Novartis
Confidential
Page 11
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma concentration-time curve from time zero to time 
‘t’ where t is a defined time point after administration [mass x time / volume]
AUCtx-ty
The area under the plasma concentration-time curve from time ‘x’to time 
‘y’ where ‘time x’ and ‘time y’aredefined time pointsafter administration.
Cmax
The observed maximum plasma concentration following drug administration 
[mass / volume]
Cmin
The observed minimum plasma concentration following drug administration
Ctrough
The observed plasma concentration that is just prior to the beginning of, or 
at the end of a dosing interval 
Tmax
The time to reach the maximum concentration after drug administration 
[time]
ss (subscript) Indicate that the parameter is defined at steady state


Novartis
Confidential
Page 12
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Any drug (an active drug or an inactive drug, such as a 
placebo) which is used as a comparator to the drug being tested 
in the trial.
Enrollment
Point/time of subject entry into the study at which informed 
consent must be obtained (i.e.,prior to starting any of the 
procedures described in the protocol)
Investigational drug
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 
andis 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 includesany placebos, any active controls, as well as 
approved drugs used outside of their indication/approved 
dosage ortested in a fixed combination.
Investigational treatment generally does not include
protocol-specified concomitant background therapies when 
these are standardtreatments in that indication.
Medication number
A unique identifier on the label of each study drug package in 
studies that dispense study drug using an IRT system
Protocol
A written account of all the procedures to be followed in a 
trial,which describes all the administrative, documentation, 
analytical and clinical processes used in the trial.
Part
A single component of a study which contains different 
objectives or populations within that single study. Common 
parts within a study are: a single dose part and a multiple dose 
part, or a part in patients with established disease and in those 
with newly-diagnosed disease.
Period
A minor subdivision of the study timeline; divides phases 
intosmaller 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.


Novartis
Confidential
Page 13
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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.
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 
subjectas 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.
Subject Number
A number assigned to each subject who enrolls into the study.
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the
drug being tested in the study.


Novartis
Confidential
Page 14
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 15
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 16
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 17
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 18
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 19
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 20
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 21
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 22
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 23
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 24
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 25
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Protocol synopsis
Protocol number
CCFZ533X2203
Title
A multi-center, randomized, double-blind, placebo-controlled, parallel group 
study to assess the safety, tolerability, pharmacokinetics and preliminary 
efficacy of CFZ533 in patients with primary Sjögren’s syndrome
Brief title
Safety, pharmacokinetics and preliminary efficacy study of CFZ533 in 
patients with primary Sjögren’s syndrome
Sponsor and Clinical 
Phase
Novartis
Phase 2
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This study is designed to evaluate the safety, tolerability, pharmacokinetics, 
pharmacodynamics, and preliminary therapeuticefficacy of multiple doses of 
CFZ533 monoclonal antibody in patients with primary Sjögren’s syndrome 
(pSS), which will provide data for furtherdevelopment of CFZ533 inthe 
treatment of pSS.
Primary Objectives
To assess the safety and tolerability of multiple intravenous infusionsof 
CFZ533 in patientswith primary Sjögren’s syndrome as measured by 
adverse events (AEs).
To compare the effect of multipleintravenous infusionsof CFZ533 versus 
placebo on the clinical disease activity of primary Sjögren’s syndrome 
patients as measured by the change of theEULAR Sjögren’s Syndrome 
Disease Activity Index (ESSDAI) after 12 weeks treatment.
Secondary 
Objectives
To assess the safety and tolerability of multiple subcutaneous doses of 
CFZ533in patients with primary Sjögren’s syndrome as measured by 
adverse events (AEs).
To compare the effect of multiple subcutaneousdosesof CFZ533 versus 
placeboontheclinicaldiseaseactivityofprimary Sjögren’ssyndrome 
patientsasmeasured bythechangeoftheEULARSjögren’sSyndrome 
DiseaseActivityIndex(ESSDAI)after12weekstreatment.
To assess the pharmacokinetics of multiple subcutaneous doses and 
multiple intravenous infusionsof CFZ533 in primary Sjögren’s syndrome 
patients.
To evaluate the effect of multiple subcutaneousdoses and multiple 
intravenous infusions of CFZ533 versus placebo on self-reported 
outcomes in primary Sjögren’s syndrome patients after 12 weeks 
treatment 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 evaluate the changes in the physician global assessment of the 
patient’s overall disease activity as recorded by a visual analog scale 
(VAS) after 12 weeks treatment.
To evaluate the changes in the patients global assessment of their 
disease activity as recorded by a VAS after 12 weeks treatment.


Novartis
Confidential
Page 26
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Study design
Randomized, double-blind, placebo-controlled, non-confirmatory study in 
approximately 12patients in Cohort 1and30 patients in Cohort 2, andopen-
labelrandomized study in approximately
 24patientsin Cohort 3
Population
Male and female patients with primary Sjögren’s syndrome, age 18 to 
75years(inclusive).
Inclusion criteria
Diagnosis of primary Sjögren’s syndromeaccording to revised EU/US 
consensus criteria(Vitali et al 2002)
Moderate to severe disease activity with ESSDAI score ≥ 6
Presence of autoantibodies at screening as determined by any of the 
following:
Elevated serum titers of ANA (≥ 1:160) and positive rheumatoid 
factor (RF), or,
Positive anti-SSA 
Stimulated whole salivary flow rate >0 mL/minfor Cohort 1 and 2; and 
unstimulated whole salivary flow rate > 0 mL/minfor Cohort 3.
If the pat
ient 
is on ora
l g
lucocort
ico
id treatment at screen
ing, the dose must 
NOT exceed10 mg predn
isone or equ
iva
lent per day, and must be stab
le for 
at 
least 2 weeks pr
ior to random
izat
ion and for the durat
ion of the study;
If the patient is on chloroquine or hydroxychloroquine at screening, the 
dose must be stable for at least 4 weeks prior to randomization and for 
the duration of the study;
If the patient is treated with oral or parenteral methotrexate at screening, 
the dose must NOT exceed 25 mg per week for at least 3 months prior to 
randomization and must be stable for the duration of the study.
If the patient is treated with oral azathioprine at screening, the dose must 
NOT exceed 100 mg per day for at least 3 months prior to randomization 
and must be stable for the duration of the study.
Exclusion criteria
Secondary Sjögren’s syndrome
Use other investigational drugs at the time of enrollment, or is within five 
half-lives of using other investigational drugs or longer if required by local 
regulations, at the time of enrollment
History of hypersensitivity to study drugor to drugs of similar chemical 
classes
Patientshave receivedtreatment with:
Cyclosphosphamide within 6 months;
Corticosteroid bolus i.v.dose > 1 mg/kg within 3 months
Rituximab within 12 months
Belimumab within 6 months;
Any other biologic within 1 month or five times the half-life
Any other immunosuppressives such as cyclosporine A or 
mycophenolate within 3 months
Patients where the primary cause of sicca symptoms is attributable to a 
medication used regularly or intermittently rather than to primary 
Sjögren’s syndrome
At significant risk for thromboembolic events
Pancreatic injury or pancreatitis
History or presence of medically significant cardiac condition
Clinically significant systemic viral,bacterial or fungal infection within 
30days of randomization


Novartis
Confidential
Page 27
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Condition that would result in a significantly elevated risk for infections
History or evidence of tuberculosis
Significant surgical, medical, psychiatric or additionalphysical condition
Investigational and 
reference therapy
Cohort 1:
CFZ533 
 for injection and matching placebo
CFZ533: 
 administered subcutaneously
.
Control: CFZ533 placebo
Cohort 2:
CFZ533 
 for injection and matchingplacebo
CFZ533:  
 administered by intravenous infusion.
Control: CFZ533 placebo
Cohort 3:
CFZ533 
 for injection
CFZ533  
 s.c. once per week for 4 weeks, followed by  
 s.c. 
once per week for 9weeks
CFZ533  
 i.v. at Day 1, followed by  
 s.c., starting at Day 8
once per week for 12weeks
Efficacyand 
pharmacodynamic
assessments
EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)
Safety assessments
All Cohorts:
Physical examination
Vital signs
Laboratory evaluations: hematology, clinical chemistry, urinalysis
Electrocardiogram (ECG)
Pregnancy testing
Adverse event
Serious adverse event
Other assessments
All Cohorts:
Pharmacokinetics of CFZ533
EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI)
Physician’s and Patient’s assessment of global disease activity(VAS)
Cohorts 1 and 2:
Short Form (36) Health Survey(SF-36)
Multidimensional Fatigue Inventory (MFI) Questionnaire
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information
C
 
 
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 28
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Data analysis
Cohorts 1 and 2:
A longitudinal model describing ESSDAI change from baseline over time will 
be fitted for the controlled part of the study (up to Week 13) with the following 
covariates: baseline ESSDAI, baseline prednisone dose, treatment(placebo,
CFZ533
 s.c.or CFZ533 
 i.v), time as a continuous factor 
and a quadratic time effect, as well as a random intercept, a random slope 
and a random quadratic effect for subject. The change from baseline in 
ESSDAI at Week 13will be estimated from the model for alltreatments.
Inference will be made in the frequentist framework. The results from the 
primary analysis will be assessed against the following efficacy criteria to 
support internal decision making:
a statisticallysignificant reduction in ESSDAI at Week 13in the CFZ533 
group compared to placebo, at the one-sided 10% significance level, and,
an estimatedmean reduction in ESSDAI in the CFZ533 group to be 
5points or greater than placebo.
A positive sign of efficacy will be considered if both criteria are met.
Cohort 3:
Descriptive statistics and graphical displays will be used to summarize the PK 
concentrations in each treatment arm.
Key words
CFZ533, anti-CD40, primary Sjögren’s syndrome


Novartis
Confidential
Page 29
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Assessment schedule–Cohort 1
Study phase
Screening Baseline
End of Study
Visit Numbers (internal use only)
Visit 1
Visit 2
V7
V11
V14
V777*
Week
Week 11
Week 19
Week 29 
Week 33
Day
Day -28 to -2 Day -1
Day 71
Day 127
Day 197
Day 225
Hour
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Obtain informed consent
X
Inclusion /Exclusion criteria
X 
X
Relevant med history and current conditions
X 
X
Demography
X
Physical examination
X 
X 
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3 X
X
X
Hepatitis and HIV screen
X
Pregnancy test
X4
X4
X
X
X
X
X
X
X
X4
Purified protein derivative (PPD) skin test or 
Quantiferon test
Alcohol and drug screen
X
X
X
Drug administration 
X
X
X
X
X
X
X
X
Concomitant meds/Therapies
Adverse Events5
Comments
Vital signs and body measurements:
   Body height
X
   Body weight
X
X
X
   Body temperature
X 
X 
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3 X
X
X
   Blood pressure / Pulse rate
X
X 
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3
X
X3 X
X
X
ECG evaluation
X
X
X
X
X
X
X 
X
X
X
Hematology, Blood chemistry, Urinalysis
X 
X
X
X
X
X
X
X
X 
X
X
X
X 
X
X
X
X
X
X
X
X 
X
X
X
Coagulation test
X 
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
Day 113
Day 141
X
Day 1
Day 15
Day 29
Day 57
 Day 85
As required
Day 99
Week 15
Week 17
Week 21
Day 169
Weeks -4 to -1
Week 3
Week 5
Week 9
Week 25 
Follow-Up Period1
As required
As required
V3
V4
V5
V6
V82
V9
V10
V12
Open-Label Period1
Placebo-Controlled Period1
V132
Week 1
Week 13
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 30
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Assessment schedule–Cohort 1(continued)
Study phase
Screening Baseline
End of Study
Visit Numbers (internal use only)
V
isit 1
V
isit 2
V7
V11
V14
V777*
Week
Week 11
Week 19
Week 29 
Week 33
Day
Day -28 to -2 Day -1
Day 71
Day 127
Day 197
Day 225
Hour
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
Pre- 
dose 0 6
ESSDAI
X
X
X6
X6
X6
X6
X6
X6
X6
X
X
X
ESSPRI, MFI, SF-36
X
X6
X6
X6
X6
X
X
X
VAS A
ssessments by Investigat
or and Patient
X
X6
X6
X6
X6
X6
X6
X6
X
X
X
Ultrasound
X8
X6
X
X
X6
X
X
X6
X
X
X
X
X
X
X8
X
X
X
X
X
X
X
PK blood collection 
X
X
X 
X X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X
X
X
X
X 
X
X
X
Leukocyte subsets
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
X
X 
X
X
X
X
X 
X 
X X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X
X
X
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X
X
X
X 
X
X
X
X
X
X X
X
X
X
X
X
X
X
X 
X
Study completion 
inf
ormation
X
2 V
isit
 8 
is the end of placebo-cont
rolled period and the start of open-label period, V
isit
 13 is the end of open-label period and the start of follow-up 
period 
5 Serious A
dverse Ev
ents reporting 
is requird from signing 
the inf
ormed consent until 
30 days after study completion
6 These pre-dose assessments can be done one day before the dosing 
or within 6 hours post dosing
 This assessment can be performed at screening 
V6
V82
Week 25 
Day 169
Follow-Up Period1
V132
Week 13
Week 15
Week 17
Week 21
V9
V10
V12
Open-Label Period1
Placebo-Controlled Period1
V3
V4
V5
Weeks -4 to -1
Week 1
Week 3
Week 5
Week 9
4  These should use serum pregnancy test
* Patients who discontinue 
the study should complet
e these assessments
Day 113
Day 141
Day 1
Day 15
Day 29
Day 57
 Day 85
Day 99
1 Placebo-Controlled Period includes Day 1 (Week 1) to complet
ion 
of pre-dose assessments on Day 85 (Week 13). Open-Label Period includes Day 85 (dosing,
 Week 13) to complet
ion of assessments on Day 169 (Week 25). Follow-Up 
Period includes Week 25 - Week 32.
3 The post-dose 6 h assessments should include 
assessing inject
ion 
site(s) and vit
als before dismissing the subject from clinic
al site
X
Corporate Confidential 
Information
Corporate Confidential Information
Corporate Confidential 
Information
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 31
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Assessment schedule-Cohort 2
Study phase
Screening Baseline*
End of Study
Visit Numbers (internal use only)
Visit 1
Visit 2
V7
V11
V14
V7773
Week
Week 11
Week 19
Week 29 
Week 33
Day
Day -28 to -2
Day -1
Day 71
Day 127
Day 197
Day 225
Hour
Pre- 
dose 0
Post-
dose 
2h4 
Pre- 
dose 0
Post-
dose 
2h4
Pre- 
dose 0
Post-
dose 
2h4
Pre- 
dose 0
Post-
dose 
2h4 
Pre- 
dose 0
Post-
dose 
2h4 
Pre- 
dose 0
Post-
dose 
2h4 
Pre- 
dose 0
Post-
dose 
2h4 
Pre- 
dose 0
Post-
dose 
2h4
Obtain informed consent
X
Inclusion /Exclusion criteria
X
X
Relevant med history and current conditions
X
X
Demography
X
Physical examination
X
X 
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
Hepatitis and HIV screen
X
Pregnancy test
X6
X6
X
X
X
X
X
X
X
X6
Purified protein derivative (PPD) skin test or 
Quantiferon test
Alcohol and drug screen
X
X
X
Drug administration 
X
X
X
X
X
X
X
X
Concomitant meds/Therapies
Adverse Events7
Comments
Vital signs and body measurements:
   Body height
X
   Body weight
X
X
X
X
X
X
X
X
X
X
   Body temperature
X
X 
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
   Blood pressure / Pulse rate
X
X 
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
ECG evaluation
X
X
X
X
X
X
X
X
X
X
Hematology, Blood chemistry, Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Follow-Up Period
1
As required
As required
V3
V4
V5
V6
V82
V9
V10
V12
Open-Label Period
1
Placebo-Controlled Period
1
V132
Week 1
Week 13
Week 15
Week 17
Week 21
Day 169
Weeks -4 to -1
Week 3
Week 5
Week 9
Week 25 
Day 113
Day 141
X
Day 1
Day 15
Day 29
Day 57
 Day 85
As required
Day 99
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 32
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Assessment scheduleCohort 2 (continued)
Study phase
Screening Baseline*
End of Study
Visit Numbers (internal use only)
Visit 1
Visit 2
V7
V11
V14
V777
3
Week
Week 11
Week 19
Week 29 
Week 33
Day
Day -28 to -2 Day -1
Day 71
Day 127
Day 197
Day 225
Hour
Pre- 
dose 0
Post-
dose 
2h
4 
Pre- 
dose 0
Post-
dose 
2h
4
Pre- 
dose 0
Post-
dose 
2h
4
Pre- 
dose 0
Post-
dose 
2h
4 
Pre- 
dose 0
Post-
dose 
2h
4 
Pre- 
dose 0
Post-
dose 
2h
4 
Pre- 
dose 0
Post-
dose 
2h
4 
Pre- 
dose 0
Post-
dose 
2h
4 
ESSDAI
X
X
X
8
X
8
X
8
X
8
X
8
X
8
X
8
X
X
X
ESSPRI, MFI, SF-36
X
X
8
X
8
X
8
X
8
X
X
X
VAS Assessments by Investigator and Patient
X
X
8
X
8
X
8
X
8
X
8
X
8
X
8
X
X
X
Ultrasound
X
9
X
8
X
X
X
8
X
X
X
8
X
X
X
X
X
X
X
9
X
X
X
X
X
X
X
PK blood collection
10 
X
X
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
X
X
X
X
Leukocyte subsets
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X 
X
X
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
Study completion information
X
Week 9
Day 113
Day 141
Day 1
Day 15
Day 29
Day 57
 Day 85
Day 99
X
V4
V5
Weeks -4 to -1
Week 1
Week 3
Week 5
V6
V8
2
Week 25 
Day 169
Follow-Up Period
1
V13
2
Week 13
Week 15
Week 17
Week 21
V9
V10
V12
Open-Label Period
1
Placebo-Controlled Period
1
V3
Corporate Confidential 
Information
Corporate Confidential Information
Corporate Confidential 
Information


Novartis
Confidential
Page 33
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
2 Visit
 8 
is the end of placebo-cont
rolled 
period 
and the start of open-label 
period,
 Visit
 13 is the end of open-label period 
and the start of follow-up period 
3 Pat
ients who discontinue 
the study should complet
e these assessments
4 This 
is 2 hours after the end of 
i.v. 
infusion
5 The post-dose 2 h assessments should include 
assessing inf
usion 
site and v
itals before dismissing the subject from clinical site
6 These should use serum pregnancy test
7 Serious Adverse Events reporting 
is required from signing 
the inf
ormed consent until 
30 days after study complet
ion
8These pre-dose assessments can be done one day before the dosing
9 This assessment can be performed at screening 
10 PK samples should be taken from the other arm which has not been used for i.v. 
infusion
*  Baseline 
safety evaluat
ion 
results must be available prior to dosing 
and meeting 
eligibility
 criteria  
1 Placebo-Controlled 
Period includes Day 1 (Week 1) to complet
ion of pre-dose assessments on Day 85 (Week 13). Open-Label Period includes Day 85 (dosing,
 Week 13) to 
complet
ion 
of assessments on Day 169 (Week 25). Follow-Up 
Period includes Week 25 - Week 32.
Corporate Confidential Information


Novartis
Confidential
Page 34
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Assessment scheduleCohort 3
Study phase
Screening
Baseline
End of 
Study
8
Visit Numbers
V1
V2
V4
V5
V6
V8 
V9 
V10
V12
V13
V14
V16
V17
V18
V777
Week
w 2
w 3
w 4
w 6 w 7
w 8
w 10
w 11
w 12
w 15 w 17 w 19
w 21
Day
1
-28 to -2
-1
8
15
22
36
43 
50
64 
71 
78
99
113 
127 
141
Hour
Pre-
dose 0
Post- 
dose     
1 h
Pre-
dose
0
Pre-
dose 0
Pre-
dose 0
Obtain informed consent
X
Inclusion /Exclusion criteria
X
X
Med history and current conditions
X
X
Demography
X
Physical examination
X
X
X
3
X
X
X
X 
X 
X 
X
Hepatitis and HIV screen
X
Pregnancy test
X
X
X
X
X 
X 
X 
X 
X
TB (PPD) skin test/ Quantiferon test
X
Alcohol and drug screen
X
X
Concomitant meds/Therapies
Adverse Events
Comments
Vital signs and body measurements:
    Body height
X
    Body weight
X
X
    Body temperature
X
X 
X
X
3
X
2
X
2
X
2
X
X
2
X
2
X
2
X
X
2
X
2
X
2
X
X
X
    Blood pressure / Pulse rate
X
X
X
X
3
X
X
X
X
X
ECG evaluation
X
X
X
X
X
X
X
Hematology, Blood chemistry, Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESSDAI
X
X
X
X
X
X
ESSPRI
X
X
X
X
X
VAS by Investigator
X
X
X
X
X
VAS by Patient
X
X
X
X
X
X
X
X
X
PK blood collection 
X
X
7
X
2
X
2
X
2
X
X
2
X
2
X
2
X
X
2
X
2
X
2
X 
X 
X 
X 
X
X
X
2
X
X
X
X
X 
X
X
X
X
X
2
X
X
2
X
X
2
X 
X 
X 
X 
X
X
X
X
X
X
X
X
Drug administration
6
X
X
X 
X
X 
X 
X 
X 
X 
X 
X 
X
X
Study completion information
X
Treatment Period
V11
w 9
57
As required
Follow-up Period
V15
w 13
85
V7
w 5
w -4 to -1
1
29
V3
w 1
As required
As required
X
4
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential Information
Corporate Confidential 
Information


Novartis
Confidential
Page 35
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
1 Visit windows are specified in Section 6
2Pre-dose
3Postdoseassessments should include assessing injection sites, body temperature and vitals before 
dismissing the subject from clinical site.
4Unstimulated salivary flow can be assessed at screening or baseline
6In treatment arm 1, subjects will receive CFZ533  
 s.c. at Visits 3, 4, 5, 6, and then
 s.c.
at Visits 7, 8, 9, 10, 11, 12, 13, 14 and 15.
   In treatment arm 2, subjects will receive CFZ533 
i.v. at Visit 3, and then 
 s.c.at 
Visits 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14and15
7This post-dose PK sample isfor treatment arm 2 first dose (i.v.) only. Thesample is taken at 1 hour 
after the end of the i.v.infusion. No post-dose PK sample is collected after s.c. injections at Visit 3in 
treatment arm 1.
8
Corporate Confidential Information
Patients who discontinue the study should complete these assessments


Novartis
Confidential
Page 36
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
1
Introduction
1.1
Background
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease of unknown etiology. 
Itischaracterized by lymphoid infiltration and progressive destruction of exocrine glands 
(Youinou and Pers 2012).pSS is a common disorder, second only to rheumatoid arthritis (RA) 
in prevalence as a systemic autoimmune disease. The disease affects mainly women witha 
female/male ratio of 9:1 and can occur at any age. Although primarily organ-specific for the 
lacrimal,salivary and other exocrine 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.
Secretory gland failure can lead to disturbance of vision (lacrimal gland), swallowing difficulty and 
poor dentition (salivary gland) and sexual dysfunction (vaginal dryness). Further, many(reported as 
frequently as in 85% of patients)experience profound and disabling fatigue. Disease impact 
on quality of life (QOL) measures is substantial and comparative studies demonstrate 
pSSQoL scores quantitatively worse than in congestive heart failure or many cancers
(Segaletal2009;Kuenstner et al 2002;Komaroff et al 1996).Moreover, 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.
Treatment for pSS patients is limited to symptomatic care for the mucosal signs and 
symptoms. Glucocorticoids and typical disease-modifying anti-rheumatic drugs (DMARDs)
are mostly ineffective, and no pharmacologic intervention is effective against the severe, 
disabling fatigue. Despite a lack of convincing evidence of efficacy andbased on anecdotal 
evidence as well as experience from similar autoimmune diseases such as systemic lupus 
erythematosus, antimalarials (Tishler et al 2008), methotrexate (Winzer and Aringer2010) or 
azathioprine (Kaufmanetal1999
Corporate Confidential Information
) are sometimes used, in particularfor the treatment of 
extraglandular symptoms such as renal or joint involvement.
Although small trials with the B cell depleting agent rituximab havedemonstrated adegree of 
therapeutic efficacy, no proper, large randomized controlled trials have shown clear efficacy
with regard to extra-glandular and glandular disease manifestations.A disease modifying 
agentthat prevents secretory gland destruction and addresses extra-glandular disease 
manifestations would introduce a game-changing advance for the treatment of chronic pSS.


Novartis
Confidential
Page 37
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
1.1.2
CD40/CD40L co-stimulation: a target for primary Sjögren’s syndrome
The CD40-CD154 co-stimulation pathway has long been considered as a target for the 
treatment of autoimmune diseases (Toubi and Shoenfeld 2004). Humans or rodents with 
loss-of-function or null mutants of CD40 fail to mount T-cell dependent immune response, do 
not undergo affinity maturation or differentiate into memory B cells. Further, pharmacological 
inhibition of CD40-CD154 interactions has been demonstrated to reduce/ameliorate 
autoimmune disease pathology in pre-clinical and clinical studies and can prolong allograft 
survival in non-human primates.Using monoclonal antibodies to target CD154 has been 
hampered by the occurrence of thromboembolic complications (Kawai et al 2000) so an 
alternative approach is to target the receptor, CD40. 
Several lines of evidence suggest that immune mediated pathology driven by or closely 
related to the CD40-CD154 pathway is essential in pSS. A hallmark of pSS is B cell 
hyper-reactivity such as formation of germinal center like structures (observed in 18-59% of 
patients), autoantibodies such asSSA, SSB or RF (Vossenkämper et al 2012). T cells 
predominate in pSS lesions, and are capable of provoking B cell hyperactivity and 
Igsecretion, and are directly involved in destruction of glands through Fas and 
perforin-mediated cytotoxicity (Manganelli and Fietta 2003). A portion of pSS patients have 
elevated serum sCD154; and T and B cell infiltrates of salivary glands show upregulation of 
CD40 and CD154.
Furthermore, CD40/CD154 mediated tissue inflammation may also contribute to pSS 
pathogenesis. Epithelial cell lines derived from pSS patients have constitutively up-regulated 
surface CD40 (Dimitriou et al 2002). Increased levels of micro-particles derived from 
platelets and also from leukocytes together with elevated sCD154 concentrations havebeen 
reported in pSS sera (Sellam et al 2009
Corporate Confidential Information
).


Novartis
Confidential
Page 38
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
1.1.4
Clinical data for other anti-CD40 monoclonal antibodies
CFZ533 is closely related to another Novartis compound, lucatumumab (HCD122).
DespitesharingidenticalCDR regions, the two antibodies can be differentiated by the 
engineered presence of a N297A mutation into the 1 Fc region ofCFZ533, rendering it 
Fc-silent.Incontrast, HCD122 has an unmutated Fc region and unlike CFZ533,is able to 
mediate ADCC. In phase I/II studies of lucatumumab in patients (n=approx. 164) with 
malignancies such as chronic lymphocytic leukemia, non-Hodgkin’s or Hodgkin’s 
lymphomas and myeloma, the most common reported grade 1 and 2 events occurred during 
the infusion and included chills (44%), pyrexia (33%), nausea (31%) and fatigue (26%). 
Themost commonly reported grade 3 or 4 adverse events, regardless of study drug 
relationship, were lipase elevations, dyspnea, and anemia. The majority of the adverse events 
was reversible and manageable; most were mild or moderate in severity. Elevations in lipase 
and amylase were observed but were primarily transient in nature and did not require medical 
intervention, were asymptomatic and imaging studies were negative for pancreatitis. 
Suchelevations, which are usually rare events and not typically associated with a fully-human 
IgG1 monoclonal antibody in clinical trials, are likely linked to the potent ADCC activity of 
the compound and CD40 expression of the ductal mucosa and liver parenchyma 
(Vostersetal2004). Of note, there were no thromboembolic complications in any of the 
Phase I/II studies with lucatumumab.
Recently published data (Goldwater et al 2013
Corporate Confidential Information
) also suggested a favorable safety and 
tolerability profile for the anti-human CD40 antagonist ASKP1240monoclonal antibody in 
the first-in-human, phase I study which evaluated single ascending doses of intravenous 
ASKP1240 (0.00003 –10 mg/kg) in healthy volunteers. There was no evidence of cytokine 
release syndrome or thromboembolic events. The antagonism of the CD40/CD154 interaction 
with ASKP1240 was overall safe and well tolerated at the doses tested.


Novartis
Confidential
Page 39
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 40
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 41
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 42
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 43
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 44
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 45
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 46
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
1.2
Study purpose
This study is designed to evaluate the safety, tolerability, pharmacokinetics, 
pharmacodynamics,and preliminary therapeutic efficacy of multiple doses of CFZ533 
monoclonal antibodyin patients withprimary Sjögren’s syndrome (pSS). The study outcome 
will provide data for further development of CFZ533in treatment of pSS.
2
Study objectives
2.1
Primary objectives
To assess the safety and tolerability of multiple intravenous infusionsof CFZ533 in 
patients with primary Sjögren’s syndrome as measured by adverse events (AEs).

Corporate Confidential Information
To compare the effect of multiple intravenous infusionsof CFZ533versus placebo on 
theclinical disease activity of primary Sjögren’s syndrome patients as measured by 
thechange of theEULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) after 
12weeks treatment.


Novartis
Confidential
Page 47
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
2.2
Secondary objectives
To assess the safety and tolerability of multiple subcutaneousdoses of CFZ533in patients 
with primary Sjögren’s syndrome as measured by adverse events (AEs).
To compare the effect of multiple subcutaneous doses of CFZ533versus placebo on 
theclinical disease activity of primary Sjögren’s syndrome patients as measured by 
thechange of theEULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) after 
12weeks treatment.
To assessthe pharmacokinetics ofmultiple subcutaneousdoses and multiple intravenous 
infusionsof CFZ533in primary Sjögren’s syndromepatients.
To evaluate the effect of multiple subcutaneousdosesand multiple intravenous infusions
of CFZ533 versus placebo on self-reported outcomes in primary Sjögren’s syndrome 
patients after 12 weekstreatment 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 evaluatethe changes in the physician global assessment of the patient’s overall disease 
activity as recorded by a visual analog scale (VAS)after 12 weeks treatment.

Corporate Confidential Information
To evaluatethe changes in the patients global assessment of their disease activity as 
recorded by a VASafter 12 weeks treatment.


Novartis
Confidential
Page 48
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 49
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
3
Investigational plan
3.1
Study design
This is a double-blindfollowed by open-label, randomized, placebo-controlled, parallel-group, 
non-confirmatory study to assess the safety, tolerability, pharmacokinetics, and preliminary 
clinical efficacy of multiple doses of CFZ533 in the followingCohorts1 and 2:
Cohort 1: 
 CFZ533 administered subcutaneouslyin patientswithpSS, in a double-
blind and placebo-controlledfashion, followed by open-label treatment;
Cohort 2:
 CFZ533 administered by intravenous infusionin patientswith pSS, in 
a double-blind and placebo-controlledfashion, followed by open label treatment.
These cohorts will be followed by an open label, randomized, parallel group, 
non-confirmatory part of Cohort 3:

Corporate Confidential Information
Cohort 3: 
In treatment arm 1,CFZ533 will be given at  
 s.c. weekly on 4 occasions 
(loading regimen),followed by  
 s.c. weekly on 9 occasions (maintenance 
regimen starting on study Day 29).  
In treatment arm 2, the loading regimen will bea single i.v. dose of  
 CFZ533 
(on study Day 1), this will be followed by 
 s.c. weekly on 12 occasions 
(maintenance regimen starting on study Day8).
Thestudy will randomizeapproximately 68patients with primary Sjögren’s syndrome.
InCohorts 1 and 2, therandomization will be stratified by baseline intake of oral 
corticosteroids (yes/no).There will be no stratification in Cohort 3.
The study comprisesthree periodsfor Cohort 1 and Cohort 2: 
1) placebo-controlled period(from Day 1, Week 1 tocompletion ofpre-doseassessments on 
Day 85, Week 13), during which 4 doses of CFZ533or placebo will be administered on 
top of the standard of care therapy, (e.g.,low dose corticosteroid) that is necessary to treat 
pSS; 
2) open-label period(from dosing on Day 85, Week 13 to completion of assessments on 
Day 169, Week 25), when all patients will receive 4doses of open-label CFZ533 
treatment, and 
3) follow-up period (Weeks 25 –32), when patients will be followed up without study 
medication.


Novartis
Confidential
Page 50
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Figure 3-1
Study Design Cohort 1 and Cohort 2
Cohort 3 comprises two periods:
1. open-label treatment period (from dosing on Day 1, Week 1 to last dose and completion 
of assessments on Day 85, Week 13),
2. follow-up period (from Week 13 after completion of last dose to Day 141, Week 21), 
when patients will be followed up for 8 weeks without study medication.
In the open-label treatment period, treatment arm 1 dosing starts with CFZ533 
 s.c. 
q1w for 4weeks;in treatment arm 2, dosing starts with CFZ533 
i.v. on Day 1.
Following that, dosing continues with CFZ533  
 s.c. q1w for 4 weeks (treatment arm 1) 
and 9 weeks (treatment arm 2), respectively. 
Figure 3-2
Study Design Cohort 3
Week            -4 to -2                -1   1                                  5                                  9            
13                                17                               21
Day             -28 to -2                -1  1         8      15    22     29     36     43    50      57   64     71    78     85               99            113           127           141
End of 
Treatment
Maintenance
Maintenance
Follow-up
Follow-up
End of 
Study
Visits
Baseline
Screening  
Corporate Confidential Information
Randomization 11
Corporate 
Confidential 
Information
Corporate Confidential 
Information
Corporate Confidential Information
Corporate 
Confidential 
Information


Novartis
Confidential
Page 51
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Cohort 1
This cohort will randomize approximately 12 patients. For each patient, there will be a 
screening periodfrom Day -28to Day -2. Patientswho meet the eligibilitycriteria at 
screening will be admitted to baselineevaluations. Baselineevaluationsmay be started from
Day -6to allow completion of assessments on Day -1 prior to the treatment on Day 1. 
Allbaseline safety evaluation results must be available prior to dosingand meetingeligibility 
criteria. Eligiblepatients will enter the placebo-controlled period on Day 1 (Week 1) and will 
be randomized at a 2:1 ratio to receive treatment with either CFZ533or placebo.On Day 1, a 
dose of 
 CFZ533orplacebo will be administered by subcutaneousinjection(s.c.), 
followed by PK, pharmacodynamics (PD) and safety assessments for up to6hours. Patients 
will be discharged from the site on the same dayafter completion of all assessments provided 
there are no safety concerns.
Patients willreturn to the study center to receivethree s.c. doses of either CFZ533 or placebo 
(same as they have receivedon Day 1) on Day 15(Week 3), Day 29(Week 5) and Day 57
(Week 9) respectively.Safety and efficacy assessments will be conducted in these visits, 
On Day 85(Week 13), after safety and other assessmentsthatare assessments for the end of 
placebo-controlled period,allpatients will enter the open-label period and receive an 
open-label s.c. dose of 
 CFZ533. This is followed bythree open-labels.c. doses of 
CFZ533 
on Day 99 (Week 15), Day 113 (Week 17)and Day 141 (Week 21)
respectively. Safety and efficacy assessments will be conducted in these visits, PK and 
biomarker samples will be collected. The blind of the controlled period will be maintained for 
the investigator and the patient until the end of the study.
On Day 169 (Week 25),patientswill have assessments for the end of open-label period and 
enter follow-up period with no study medication administered. Patients will return to the study 
center for safety monitoringduring this period.
The end ofstudy visit will occur on Day225 (Week 33), which will include study completion 
evaluations followed by discharge from the study.
Cohort 2
Approximately 12 subjects would have been enrolled in Cohort 1, Cohort 2 will begin 
enrollment to randomize approximately 30 patients to have approximately 24 patients 
completing 12 weeks treatment.The study design for Cohort 2 is identical as Cohort 1 with 
the exception of the dosing regimen to include multiple intravenous dosing of 
 
CFZ533followed by PK, pharmacodynamics (PD) and safety assessments for up to 2 hours
after the end ofthe infusion.  Additionally, body weight will be measured at every dosing visit 
to calculate the drug dosage according to the subject’s actual weight (in Cohort 1, subject’s 
baseline weight was used throughout study).  
Corporate Confidential Information


Novartis
Confidential
Page 52
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Cohort 3
All new patients enrolled after Protocol Amendment 6 will be allocated to Cohort 3. Cohort 3 
will randomize approximately 24patients to have approximately 20 patients(10in treatment 
arm1, 10 in treatment arm2) completing a 12-week treatment.
Patients can remain on their standard of care therapies provided that the treatments are 
maintained at a constant level during the study.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis, pregnancy test, blood 
coagulation), adverse event and serious adverse event monitoring.
All s.c. injectionsandi.v. infusions will take place in a monitored facility.Patientswill be 
monitored closelyfor at least 6hour afters.c.injectionin Cohort 1,2 hours aftercompletion 
ofi.v. infusionin Cohort 2. In Cohort 3, the patients will be monitored forat least 1 hour after 
the completionof i.v. infusion and 30 minutes after s.c. injection,or longer at the discretion of 
the Investigator for vital signs, and signs or symptoms of adverse eventsincluding 
development of an injectionreaction. Treatment of injection sitereactionand allergic 
reactions is described underSection 5.5.6
Corporate Confidential Information
.Pharmacokinetic, pharmacodynamic, and safety 
assessments will be made for up to6hoursafter s.c. injection in Cohort 1,2 hours after the 
completion of i.v. infusion in Cohort 2, or 1 hour after the completion of the i.v. infusionand 
30 minutes after thes.c. injectionin Cohort 3.Subjects will be discharged after these 
assessments,at the discretion of the Investigator, following satisfactory review ofsafety data.
PK assessmentwill include measurements of free CFZ533in plasma. 


Novartis
Confidential
Page 53
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
3.2
Rationale forstudy design
This study will be conducted in patients with active pSS for which no existing treatment has 
been proven effective against the underlying disease. 
 
Cohorts 1 and 2
Two different doses 
 of CFZ533 will be assessed in two 
separate cohorts.
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 CFZ533 or placebo in a 2:1 ratio in order to minimize exposure 
to placebo and to gather more data on CFZ533. Stratified randomization is done in order to 
limit imbalances between active and placebo arms in baseline intake of oral corticosteroids.
Theopen-labelperiod will administer CFZ533 to all patients including those who were 
administered placebo in the placebo-controlled period. This would provide potential treatment 
benefit to these patients, and collect further safety and efficacy
 data for CFZ533 in pSS patients.
After the open-label period, patients will entera follow up period for which a duration of 
8weeks (12 weeks after the last dosing with CFZ533) was chosento allow sufficient time for 
monitoring safety and exploring duration of response.
In addition to safety, efficacy estimated by the EULAR Sjogren’s Syndrome Disease Activity 
Index (ESSDAI) is chosen as a key endpoint of the study. The ESSDAI has been shown to be 
responsive in a retrospective analysis of a randomized controlled trial on rituximab, and was 
suggested to be a sensitive tool to assess efficacy of rituximab treatment 
(Moermanetal2014).The authors reported a significant lower ESSDAI in the rituximab 
group compared to the placebo group at week 12 and week 24, demonstrating some 
effectiveness in reducing disease activity in this small study. 
Cohort 3
Corporate Confidential Information
Because of the key objective ofthis cohort, no placebo control is required, and open-label 
treatment is justified. In Cohort 3, two treatmentarms areimplemented to assess whether two
loading regimens(multiple s.c. doses in treatment arm1, or single i.v. administrationin 
treatment arm2), followed by a maintenance regimen (multiple s.c. doses, both arms),areset 
to 12 weeks (Day 1 to Day 85) to establish steady state conditions for CFZ533 concentrations 
in plasma at a level similar to trough concentrations observed in Cohort2 
 
The follow-up period isset to 8 weeks (Day85 to Day141), 
(i)to follow the elimination of CFZ533 under conditions where the target is fully 
saturated (slow elimination), and under incomplete CD40 saturation (rapid 
elimination), and 
(ii)to characterize the capacity of the target mediated elimination pathway for CFZ533 
after 12-week treatment.
Corporate Confidential Information
Corporate 
Confidential 
Information


Novartis
Confidential
Page 54
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
3.3
Rationale fordose/regimen, duration of treatment
No previous experience with an anti-CD40 blocking agent exists in human primary Sjögren’s 
syndrome.
 
 
 
 
 
 
 
 
 
Cohort 1 (subcutaneous 
The 2-week dosing interval at the start is meant to ensure full CD40 saturation on peripheral 
Bcells as well as complete suppression of CD40-CD154 interaction in tissues after 
subcutaneous administration. By the end of the 12-week treatment period, clinically 
meaningful changes in the primary endpoint and in other key efficacy and biomarker readouts 
are expected to occur. Based on published results with a single cycle of rituximab, significant 
clinical responses in pSS patients can be detected as early as at week 5, with maximum effect 
shown at week 12 (Meijeretal2010). During the additional 12-week open label extension 
period, further data regarding longer termefficacy and safety of CFZ533 will be collected.
Cohort 2 (intravenous -
Corporate Confidential Information
The 
 i.v. regimen is introduced to offer higher plasma exposures throughout the 
treatment period, in order to ensure complete and sustained CD40 pathway blockade intarget 
tissues, in conditions where higher CD40 expression is likely.This regimen is supported by 
 
recently published data from ASKP1240.
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 55
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 56
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Data from ASKP1240, a monoclonal antibody blocking CD40: A recent analysis of 
disclosed PK/efficacy data from Astellas’ anti-CD40 antibody ASKP1240 in solid organ 
transplantation (Harland et al 2015
Corporate Confidential Information
) demonstrated that efficient target mediated antibody 
clearance in tissue, could result in loss of CD40 blockade and likely loss of efficacy, as a 
consequence of a significant increase of target expression in target tissues. The proposed 
intravenous regimen is aiming tosaturate, throughout the entire treatment period, CD40 
elimination pathways,in conditions where higher CD40 expression is likely.
 
 
  
Corporate 
Confidential 
Information


Novartis
Confidential
Page 57
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Cohort 3
Corporate Confidential Information
Based on results from Cohorts1 and 2 
an efficient 
dosing regimen in patients with pSS mayrequire a loading regimen (i.v.or s.c.), providing 
early full CD40 saturation and minimal targetmediated disposition followed by a s.c.
maintenance regimen.
In Cohort 3, the dose/regimen in treatment arm 1 and in treatment arm 2 were set to assess 
whether a loading regimen (i.v. or s.c.), followed by a s.c. maintenance regimen is able to 
deliver steady state plasma concentrationssimilar to the i.v.regimentested in Cohort 2, and 
has the ability to overcome target mediated disposition of CFZ533via the s.c.route.
Corporate Confidential Information


Novartis
Confidential
Page 58
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
3.4
Rationale for choice of comparator
In studyCohorts 1 and 2, the placebo to CFZ533will be used as comparator to provide 
objective evidence of potential AEs and other safety data, as well as clinical efficacy and 
PDdata generated from patients exposed to the experimental therapy. Since there is no 
established, clinically effective disease modifying treatment for patients with pSS, potential 
treatment with placebo (on top ofstandard of care therapy, if necessary) is justified.
3.6
Risks and benefits
3.6.1
Potential benefit
To date, no evidence-based, systemic therapy has been available for pSS patients. Based on 
the established role of both B cells and T cells in pSS pathogenesis, CFZ533, via the 
inhibitionof T cell dependent B cell functions, autoantibody production, ectopic germinal 
center formation along with a concurrent blockade of the parenchymal CD40 mediated 
signaling in salivary glands, has a potential therapeutic benefit.
If CFZ533 has clinical efficacy, all patients participating in the present trial can experience 
this benefit as placebo patientsin Cohorts 1 and 2will be switched to CFZ533 after 12weeks 
(in the open-label period). However, CFZ533 has never been used in patients with pSS,so at 
this stage, no statement can be made of its efficacy in treating this disease.
3.6.2
Potential risks associated with exposure to CFZ533and their 
mitigation
Corporate Confidential Information
Currently, limited data exists regarding the use of agents that block the CD40/CD154pathway. 
 
 
 The current IB (Section 6, Investigator Guidance) also provides
detailed instructions regarding the risks and their mitigation.
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 59
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Acutehypersensitivity
Hypersensitivity or infusion reactions can manifest with itching, flushing, headache, 
nausea/vomiting, hypotension, urticaria, bronchospasm, or angioedema. 
 
 
 
 
 
Infections
Corporate Confidential 
Information
Subjects treated with CFZ533 may be at an increased risk of infection. CD40 ligation is 
linkedto the functional activity of antigen presentation, as well as T-cell priming, B-cell 
differentiation, antibody production and immune memory. Administration of CFZ533 is 
expected to result in general immunosuppression with a decreased capacity to mount a 
response to novel immunogens, including those of bacterial, viral, fungal and parasitic origin 
when full receptor occupancy has been achieved.
Although the ability to mount a primary immune response will be affected by CFZ533, the 
memory B-cell repertoire and immune recall response should remain intact and protective. 
Inaddition, subjects will have adequate preformed antibody to maintain protective humoral 
response for extended periods of time (months).
Subjects enrolled in the current studywillbe monitored regularly and carefully for signs and 
symptoms which might indicate a severe infection.Subjects willbe informed to contact the 
study physician if they present with signs and symptoms of an infection such as fever, nausea, 
myalgia, headache,arthralgia, chills, diarrhea, stiff neck, and malaise for further assessment 
and treatment if necessary.
Corporate Confidential Information


Novartis
Confidential
Page 60
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Vaccination
Vaccination of subjects during treatment with CFZ533 and prior to clearance of the antibody
is likely to result in therapeutic failure (i.e., non-protective antibody titers) due to the 
pharmacologic activity of the antibody. For subjects participating in this study, all 
vaccinations should be up to date based on local guidelines. Administration of live attenuated 
agents will be prohibitedreceiving CFZ533 treatment in the current study.
Immunogenicity
 
 
Extrapolation of immunogenicity risks from healthy subjects to pSS 
patients is unknown and blood samples will be collected during this trial to assess this.
Thrombosis
There is a minimalrisk for thromboembolic complications when targeting this co-stimulatory 
pathwaywith this anti-CD40 mAb. 
 
 
 
 
 
Although the risk is hypothetical, hematologic and coagulation parameters will be regularly
monitored in the current study. Furthermore, patients with conditions such as 
anti-phospholipid syndrome where the risk is already high will be excluded.
Systemic inflammationand potential kidney injury
Corporate Confidential Information
Although not expected in this clinical study, the investigator will monitor for signs, symptoms 
and laboratory results consistent with clinically significant inflammation as well as for 
changes in renal function and signs ofacute kidney injuryasper local practice.
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 61
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Lymphadenopathy
The investigator will pay special attention to lymph nodes in patients during physical 
assessments including unusual lymphadenopathy
in the absence of infection.
 
Lymphoproliferative disorders
 
 
 The clinician should monitor hematology regularly for changes 
consistent with a lymphoproliferative disorder.
4
Population
The study population will be comprised of male and femalesubjects with active primary 
Sjögren’s syndrome.
A total of approximately 12 subjects for Cohort1, 30subjectsfor Cohort 2,and 24subjects 
for Cohort 3 are planned to be randomized to participate in the study. 
Approximately10subjects are expected to complete the placebo-controlled period inCohort 1,
approximately 24 subjects are expected to complete the placebo-controlled period in Cohort 2, 
and approximately 20subjects are expected to complete the treatment period in Cohort 3.
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all inclusion/exclusion criteria at 
screeningand baseline. A relevant record (e.g.,checklist) of the eligibility criteria must be 
stored with the source documentation at the study site.
Deviation from any
Corporate Confidential Information
entry criterion excludes a subject from enrollmentinto the study.
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 62
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill allof the following criteria:
1. Written informed consent must be obtained before any assessment is performed;
2. Male and female patients 18 to 75years of age included;
3. Subjects must have a body weight of 50 –150 kg (inclusive);
4. Diagnosis of primary Sjögren’s syndromeaccording to revised EU/US consensus criteria 
(Vitalietal2002);
5. Moderate to severe disease activity as determined by ESSDAI score ≥6;
4.2
Exclusion criteria
Subjects fulfilling any
Corporate Confidential Information
of the following criteria are not eligible for inclusion in this study:
1. Secondary Sjögren’s syndrome. Patients with laboratory or clinical signs of another 
connective tissue disease(e.g.,systemic lupus erythematous) may be eligible at the 
investigators discretion;
2. Use other investigational drugs at the time of enrollment, or is within five half-lives of 
usingother investigational drugs or longer if required by local regulations, at the time of
enrollment;
3. History of hypersensitivity to study drug or to drugs of similar chemical classes;


Novartis
Confidential
Page 63
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
4. Patients having received the following treatments (within given timeframe before 
randomization):
Oral or i.v. cyclosphosphamide treatment within 6 months;
i.v. corticosteroid bolus with dose > 1 mg/kg within 3 months;
Rituximabwithin 12months. For patient who received rituximab earlier, B cell count 
should be within normal range;
Belimumab within 6 month;
Any other biologic within 1 month or five times the half-life, whichever is longer;
Any other immunosuppressives (despite methotrexate, glucocorticoids, and 
hydroxychloroquine on stable doses as described in the inclusion criteria 8, 9, 10, 11) 
such as cyclosporine A or mycophenolate within 3months;
11.Signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection 
within 30 days of randomization;
12.Any condition, that would result in a significantly elevated risk for infections, as judged 
by the investigator, e.g.,:
Vaccinations as required based on local guidelines are not up to date;

Corporate Confidential Information
Any form of clinically relevant immunodeficiency.
Corporate Confidential Information


Novartis
Confidential
Page 64
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
20.Pregnantor nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test
21.Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unlessthey are using highly effective methods of contraception 
during the studyand for 12 weeksafterthe last study treatment. Highly effective 
contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment, 
confirmed by medical documentation. In case ofoophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment.
Male sterilization (at least 6 months prior to screening, with the appropriate 
post-vasectomy documentation of the absence of sperm in the ejaculate).For female 
subjects on the study the vasectomized male partner should be the sole partner for that 
subject
Corporate Confidential Information
.


Novartis
Confidential
Page 65
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g.,age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomyor tubal ligationat 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearingpotential.
No additional exclusions may be applied bythe investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The investigational drug,CFZ533and matching placebo will be prepared by Novartis and 
supplied to the Investigator site as open-label bulk medication.
Cohorts 1 and 2
The dosage form of the supplied drug is lyophilisate in vial and needs to be reconstituted with 
water for injection (USP or equivalent), provided by the investigator’s site. Theplacebo 
control selected for this study isa mixture of inactive excipients, matching the composition of 
the CFZ533 
for injection.
Table 5-1
Study drug CFZ533(lyophilisate)
Name
CFZ533
Formulation 
Lyophilisate in vial(powder for solution for injection)
Appearance before reconstitution 
White lyophilized cake
Appearance after reconstitution 
Opalescent to clear, colorless solution
Unit dose 
Packaging 
6 mL Type I glass vials
Corporate Confidential Information
*The vials contain a 20% overfill to allow a complete withdrawalof the labeled amount of CFZ533
Corporate Confidential Information


Novartis
Confidential
Page 66
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
After reconstitution ofthe lyophilized powder with 1.0 mL water for injection, the resulting 
solution contains
 CFZ533 and the excipients L-Histidine, Sucrose and 
Polysorbate 20, pH 6.0 ± 0.5.
Cohort 3
The dosage form of the supplied drug is a ‘ready to use’ aqueous buffered sterilesolution also 
referred to as CFZ533 Concentrate for infusion/solution for injection (liquid in vial).
Thispresentation hasthe same composition as the reconstituted powder.The same overfill of 
20% is included to allowcomplete removal of the intended dose.There is no placebo for this 
cohort.
Table 5-2
Study drug CFZ533 (liquid in vial)
Name
CFZ533
Formulation 
Solution for infusion/solution for injection
Appearance
Opalescent to clear, colorless solution
Unit dose 
*The vials contain a 20% overfill to allow a complete withdrawalof the labeled amount of CFZ533
Clinical suppliesare 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 CFZ533 vials, and preparation of CFZ533 and 
placebo(in Cohorts 1 and 2)injection are described in thePharmacy Manual, provided as a 
separate document.
Of note, CFZ533vials require storage between 2-8°C.
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
The study will have three cohorts. 
In the placebo-controlled periodof Cohorts 1 and 2, all subjects will be randomized in a 2:1 ratio to 
one of the following two treatment arms, defined as:
Cohort 1
CFZ533 active: multiple dosesof  
 CFZ533s.c.injection
CFZ533 placebo: multipledosesof placebo s.c. injection
In the open-label period, all subjects will receive CFZ533 active treatment of multiple s.c. 
dosing  
.
Corporate Confidential Information


Novartis
Confidential
Page 67
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Cohort 2
CFZ533 active: multiple doses of  
 CFZ533i.v. infusion
CFZ533 placebo: multipledosesof placebo i.v. infusion
In the open-label period, all subjects will receive CFZ533 active treatment of multiple i.v. 
dosing 
Cohort 3
In the open-label Cohort 3, the subjects will be randomized in a 1:1 ratio to one of the 
following two treatment arms:
Treatment arm 1: CFZ533 will be given 
 weekly on 4 occasions (Days1, 8, 
15 and 22; loading regimen), followed by 
 s.c. weekly on 9 occasions 
(maintenance regimen starting on study Day 29, last dose on Day 85).
Treatment arm 2: CFZ533 
 i.v. onDay 1, followed by 
c. weekly on 
12occasions (maintenance regimen starting on study Day 8, last dose on Day85).
The 
 s.c doses will consist of 4injections or 2injectionsof 1mLCFZ533 
 respectively.
5.3
Treatment assignment
Randomization numbers will be assigned in ascending, sequential order to eligible subjects 
(see Section 5.5.1for details). The investigator will enter the randomization number on the eCRF.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
Arandomization list for each cohort 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. 
Therandomization scheme for subjects will be reviewed and approved by a member of the 
Novartis IIS Randomization Group.
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:
The site designee will complete a Randomization Request form and email to the Novartis 
designee.
On receivingthe Randomization Request form, 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 email back.
On receiving the allocated randomization number, the unblinded pharmacist or authorized 
designee will use the information on the completedform to ensure that the patient receives 
the correct study medication, according to the provided randomization list.
Corporate Confidential Information


Novartis
Confidential
Page 68
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
After inclusion of each new patient, the site designee will countersign the Randomization 
Request form, and 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
Cohorts 1 and 2 aredouble-blind: 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 6. Randomization data are kept strictly confidential 
until the time of unblinding for the respective person(s). Furtherinformation regarding 
blinding (and unblinding) is presented in Appendix 6.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, taste and odor.
An unblinded pharmacist at the investigator site will prepare the study treatment for injection
from the bulk open-labeled supplies.
The blind of the controlled periodof the study will be maintained in the open-label periodfor 
the investigator and the patient until the end of the study.
The PK/PDbioanalystswill be unblinded during the clinical study, but will not provide 
individual PK/PDdata prior to database lock, to maintain the study blind.
The necessary safety review may lead to the Novartis study team being inadvertently 
unblinded;however,this information will not be communicated to the investigator.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.11) and at the 
time of the interim analysis and at the conclusion of the study.
Cohort 3 will be open-label.However, subjects andinvestigator staff remain blinded to the 
study treatment allocation (dosing arm) until first dosing. Furtherinformation regarding 
blinding (and unblinding) is presented in Appendix 6.
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 
(or0002), the screening numbers will be 2001, 2002, 2003 in an ascending order.


Novartis
Confidential
Page 69
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 first dose of 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) as soon as this is available.
Cohort 1
Subjects will be assigned randomization numbers 5101-5130 in the first stratum 
(baselineintake of oral corticosteroids = yes) and randomization numbers 5201-5230 in the 
second stratum (baseline intake of oral corticosteroids = no).
Replacement subjects will be assigned randomization numbers 6101-6130in the first stratum 
and 6201-6230 in the second stratum. If a subject requires a replacement, the replacement 
subject will be assigned a randomization number corresponding to the original subject 
(e.g.,Subject 6103 would replace Subject 5103).Replacements are envisaged only for subjects 
dropping out for reasons other than safety without at least one post-baselineESSDAI result.
Cohort 2
Subjects will be assigned randomization numbers 5601-5630 in the first stratum 
(baselineintake of oral corticosteroids = yes) and randomization numbers 5701-5730 in the 
second stratum (baseline intake of oral corticosteroids = no).
Replacement subjects will be assigned randomization numbers 6601-6630 in the first stratum 
and 6701-6730 in the second stratum. If a subject requires a replacement, the replacement 
subject will be assigned a randomization number corresponding to the original subject 
(e.g.,Subject 6603 would replace Subject 5603). Replacements are envisaged onlyfor subjects 
dropping out for reasons other than safety without at least one post-baseline ESSDAI result.
Cohort3
Subjects will be assigned randomization numbers 5801-5840.
5.5.2
Dispensing the study treatment
The investigational drug, CFZ533
lyophilisatein vialsand matching placebo
(Cohorts1 and 2),or CFZ533liquid in vialsin Cohort 3
 
will be prepared by Novartis and supplied to the investigatorsiteas 
open labeled bulk medication.
For preparation of the study medication, a copy of the randomization schedule will be sent to 
theunblindedpharmacist at the Investigator’s siteor to the dispensing contractor.
Appropriate documentation of the subject specific dispensing process must be maintained.
Corporate Confidential Information


Novartis
Confidential
Page 70
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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.
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. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective 
Novartis CPO Quality Assurance. 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 during 
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. 
Unlessspecifically 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 (e.g.,an 
un-blinded monitor), the Investigator will provide a copy of the drug accountability ledgerto 
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 destructionorhave the unused and partly useddrug 
supplies as well as the empty containers destroyed by the site’s pharmacist, providing a drug 
destruction certificate.
5.5.3.2 Handling of other study treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
CFZ533,or matching placebo(Cohorts 1 and 2only),will be administered as an s.c. injection
in Cohort 1, i.v. infusion in Cohort 2, or i.v. infusion and s.c. injection in Cohort 3by the 
study center personnel following the instructions and using the material as described and 
specified in the Pharmacy Manual.
In Cohort 1, the subjectswill be weighed at the baseline visit and this weightvalue 
will be used for studymedication preparationand the calculation of the dose.
In Cohort 2, the dose for administration to subjectswill be calculated from the 
individual subjects’ body weight obtained atthe mostrecentpre-dose visit.


Novartis
Confidential
Page 71
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
In Cohort 3, the i.v. dose (Day1) for administration to subjects randomized to 
treatment arm2will be calculated from the individual subject’s body weight obtained 
at Baseline visit.All s.c. doses in this cohort
 are administered as flat 
doses (not adjusted to body weight)
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 eCRF.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted in this study; in case of an 
AE or for any reason (e.g.,non-compliance, operational hurdle) resulting in a deviation from 
the required dosing scheme, consultation and agreement with Novartis will be necessary to 
decide whether the subject can continue or needs to be withdrawn from the study. Any change 
in dosingmust be recorded on the Dosage Administration Record eCRF.
In case of notable adverse events, SAEs including loss of efficacy and/orassociated PK/PD 
data collected during the study, changes to a different dosing scheme level may be considered 
and implemented via a protocol amendment.
Uponreview data at interim analysis, dose adjustment for study drug may occur. This will be 
implemented via a protocol amendment.Details are provided in Section 9.8.
5.5.6
Recommended treatment of adverse events
Parenteral administration of monoclonal antibodies can be associated with acute, severe 
reactions (occurring within the first few hours post dose) secondary to hypersensitivity, 
immunogenicity, or ADCC-mediated cell depletion. Although such events are more likely to 
occur during intravenous administration (infusion reaction), they cannot be fully excluded 
when the antibody is administered as a subcutaneous injection.
Injection site reactions can also be noted during or after subcutaneous administration and are 
usually less severe than infusion reactions, however, may still require medical attention and 
treatment.
In this study, CFZ533 will be administered as intravenous infusionandsubcutaneous injection. 
 
Patients will be monitored at the site for at least 6 hours post dose or longer in Cohort 1, at 
least 2 hours post dose or longer in Cohort 2, and at least 1 hourafter i.v.infusionand 
30minutes afters.c.injectionsin Cohort 3at the discretion of the Investigator to ensure 
adequate safety monitoring. In case of any signs of an acute reaction, clinical treatment will 
be provided as determined by the treating physician on a case-by-case basis and depending on 
the severity, using symptomatic treatment, anti-histamines, NSAIDs, acetaminophen, 
intravenous fluids, corticosteroids, or adrenaline.
Corporate Confidential Information


Novartis
Confidential
Page 72
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
For the management of allergic reaction, anaphylaxis and cytokine release, it is recommended 
to follow the guidelines by the National Cancer Institute Common Toxicity Criteria 
(NCI-CTCAE/v4.03, Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
When using CFZ533 in a subcutaneous dosing form, plasmapheresis will likely be of limited 
benefit to decrease the systemic concentration of CFZ533.
Use of rescue medication must be recorded on the Concomitant medications / Significant 
non-drug therapies eCRF after start of study drug.
5.5.7
Rescue medication
There is no established, approved immunosuppressive treatment for pSS. Patients may receive 
NSAIDs, paracetamolorsymptomatic care at the discretion of the treating physician as 
outlined in Section5.5.8. Rescue medicine is to be provided by the study center or 
personalphysician.Use of rescue medication must be recorded on the Concomitant 
medications/Significant non-drug therapies eCRF after start of study drug.
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. Forassessments in 
Cohorts 1 and 2, the salivary stimulantsshould be stoppedwithin 12hours prior to, or during 
assessment of clinical disease outcome measurements. Artificial tears and artificial saliva are 
to beprovided by the study center or personal physicianif needed, and should not be used
4hours prior to, or during assessment of clinical disease outcome measurements.
Currently, concomitant use of corticosteroidsis allowed at a dose of max 10 mg per 
day(prednisone or equivalent) and no immunosuppressives such as cyclosporine,
cyclophosphamide, or mycophenolateare allowed. Stable dose of methotrexate(up to 25 mg 
per week), azathioprine (up to 100 mg per day)and/or antimalarials are permitted.Any other 
drug with a potential immunosuppressiveeffect that is not specifically mentioned in the 
Inclusion/Exclusion criteria, should be discussed with the Sponsor on a case by case basis. 
If,based on the patient condition(such as severe extraglandular manifestation,or major 
disease worsening)a corticosteroid dose above 10 mg (prednisone or equivalent) per day or 
animmunosuppressivemedicationis necessary, the patient may have to be withdrawn from 
the study. This will be decided on the basis of a case by case evaluation by both the 
investigator and Sponsor.
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 criteriaprior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the eCRF.
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.


Novartis
Confidential
Page 73
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
5.5.9
Prohibited treatment
Use of the treatments displayed in the table below are NOT allowed after the start of study 
druguntil at least four weeks after the last administration of study drug.
Table 5-3
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
Immune suppressive agents
Withdrawal may be required on a case-by-case basis
Any medication that, as judged by the Investigator, is 
the primary cause of drymouth in the patients 
Withdrawal may be required on a case-by-case basis
Live vaccination
Withdrawal immediately
5.5.10
Discontinuation of study treatment
Study “Stopping rules”
The following stopping rules, based on potential toxicities, will serve as the basis for placing 
the study on hold. Although the stopping criteria do not incorporate an absolute requirement 
for causality, the potential relationship between an adverse event and CFZ533 will be 
evaluated carefully on a case-by-case basis between the Sponsor and the Investigator.
Following a review of the adverse event(s), a decision to permanently discontinue enrollment 
or re-initiate dosing will be made jointly by the Investigator and Sponsor.
As a guidance, dose limiting toxicities (DLTs) will be assessed according to the 
standardizedtoxicity grading scale, the NCI Common Toxicity Criteria for Adverse Events 
(NCI-CTCAE/v4.03, Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
Any study treatment related death,
1. Two (2) or more subjects presenting with a serious adverse event that is related to the 
study treatment,
2. One (1) subjectpresenting with study treatment related cytokine release syndrome,
3. One (1) subject presenting with a study treatment related thromboembolic event that is at 
least of moderate severity,
4. More thanone (1)allergicreaction of Grade 3 severity of the NCI-CTCAE/v4.03 Criteria 
within the first 5 treated subjects or an incidence of >20% thereafter,
5. Any treatment-related, Grade 3 or higher event ofthe NCI-CTCAE/v4.03 Criteria 
considered drug relatedbythe Investigator with the followingexceptions:
1. Events not requiring treatment, and diagnostic procedures involving elective or 
non-urgent hospital admission,
2. Disease Specific Events that are due to the patients underlying pSS diagnosis,
3. AEs/SAEs unrelated to the experimental compound as determined by the Investigator 
or Novartis


Novartis
Confidential
Page 74
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6. Two (2) ormore subjects presenting with:
4. Progressive renal insufficiency or acute kidney injury defined as a Grade 2 increase in 
serum creatinine (1.5 X ULN) in the setting of euvolemia at any time during the study,
5. Emergent hypogammaglobulinemia defined as a reduction in total serum IgG or IgM 
concentration by 50% or more from baseline,
6. Severe systemic infection or opportunistic infectionthat requires treatment, 
e.g.,sepsis, urosepsis, mycoses, pneumonia.
7. Clinically significant (according to the Investigator) and study drug-related, persisting 
changes from baseline in vital signs, electrocardiograms, orrelevant, persistent changes in 
laboratory parameters, which are not consistent with existing co-morbidities, in more than 
one (1) subjectwithin the first 5 treated subjects oran incidence of >20% thereafter.
8. Other clinically significant changes or effects in the opinion of the Investigator or Sponsor 
that are deemed unsafe to continue dosing.
In addition, all blinded safety data, including disease specific events, will beevaluated by the 
Sponsor and Investigatorcontinuouslyand at scheduled meetings. Thestudy may be put on 
hold pending further data analysis, and the decisionto adjust the dose or modify the 
medication if the following 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.
Individual subject withdrawal
Subjectsmay voluntarily discontinue the studyfor any reason at any time.
The Investigator should discontinue study treatment for a givensubject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being.
Study treatment mustbe discontinued under the following circumstances:
Subject withdraws consent,
Pregnancy,
CTCAE Grade 3-4allergic reaction,
Major worsening of primary Sjögren’ssyndrome as judged by the Investigator 
(e.g.,severe CNS or renal complications, or increase from baseline in ESSDAI of at least 
7points after more than 8 weeks of treatment(as a guidance),
Acute, severe infection as judged by the investigator,
Significant changes in standard coagulation test, such as prothrombin time (PT)or
activated partial thromboplastin time (aPTT),suggesting an increased risk for 
hypercoagulabilityor any signor symptomof a thromboembolic event.
Discontinuation of study treatment will be at the discretion of the Investigator, under the 
following circumstances:
Any other protocol deviation that results in a significant risk to the subject’s safety


Novartis
Confidential
Page 75
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
The appropriate personnel from the site and Novartis will assess whether studytreatment 
should be discontinued for any subject whose treatment code has been broken inadvertently 
for any reason.
Subjectswho discontinue study treatmentshould NOT be considered withdrawn from the 
studyUNLESS they withdraw their consent (see Section 5.5.11). They should return for the 
assessments indicated by an asterisk (*) in the assessment table. If they fail to return for these 
assessments for unknown reasons, every effort should be made to contact them as specified in 
Section5.5.12.
5.5.11
Withdrawal of consent
Subjects may voluntarily
 withdraw consent to participate in the study for any
 reason at any
 time.
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material.
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. Allbiological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
5.5.12
Loss to follow-up
For 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. A subject should not be considered lost to follow-up until his/her scheduled end of 
study visit would have occurred.
Subjects dropping out for reasons other than safety without at least one post-baseline ESSDAI 
result will be replaced by an equal number of newly enrolled subjects.
5.5.13
Emergency breaking of assigned treatment
Cohorts 1 and 2: 
Emergency unblinding in Cohorts 1 and 2 should only be undertaken when it is essential to 
treat the subject safely and efficaciously. Most often,study treatmentdiscontinuation 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. Allcode 
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 


Novartis
Confidential
Page 76
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 eCRF.
Theinvestigator 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 code break cardsin 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 study drug should be discontinued for a given 
subject and, if applicable, whether the subject can continue intothe next trial phase 
(e.g.,anunblinded extension).
Cohort 3 will be open-label.
5.5.14
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.
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.
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.15
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 
ensurethat adequate consideration is given to the protection of the subject’s interests. 
Theinvestigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


Novartis
Confidential
Page 77
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6
Visit assessments
The full Assessment scheduleis presented at the end of the synoptic section, above.
Subjects should be seen for all visits on the designated day with an allowed “visit window” as 
shown below:
1. Baseline visit assessments(V2, Day -1, Week -1)can be started from Day -6. 
2. VisitV3 (Day 1,Week 1) should occur within 7days after the Baseline visit (V2, Day -1, 
Week -1)
3. Subsequent visits starting from V4 up to V12in Cohorts1 and 2, orfrom V4up to V15in 
Cohort 3, inclusive: ±3day
4. Visits V13 , V14 and V777in Cohorts 1 and 2, orV16, V17, V18 and V777:±7days
Every effort shouldbe made to take the pharmacokinetic samplesat the protocol specified 
time. When assessments are scheduled to be performed at the same time-point, thesewill be 
taken after the pharmacokinetic sampleand other blood samples.
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs.
At a minimum, subjects will be contacted for safety evaluations during the 30 days following 
the last study visit or following the last administration of study treatment if there are 
post-treatment follow-up visits (whichever is later), including a final contact at the 30-day 
point. Documentation of attempts to contact the subjectshould berecorded in the source 
documentation.
6.1
Dietary, fluid and other restrictions
Subjects should maintain their usual diet and life habits during the entire study.
6.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects include: 
date of birth, age, sex, race, predominant ethnicity.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
The date of original diagnosis of primary Sjögren’s syndrome shouldbe recorded.
Hepatitis screen, HIV screen
All subjectswill be screened for Hepatitis B surface antigen (HBsAg). Screening for 
HepatitisC will be based on HCV antibodies.


Novartis
Confidential
Page 78
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 eCRF.
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 eCRF.
6.3
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated withCFZ533, as detailed in Section 6.6.
6.4
Efficacy / Pharmacodynamic assessments
Exploratory clinical efficacy measurements will include components of the ESSDAI and 
ofthe ESSPRI and other patient-based assessments,
 
 
6.4.1
ESSDAI
The ESSDAI (Appendix 4) is an established disease outcome measure for Sjögren’s syndrome.
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 5
Corporate Confidential Information
) is an established disease outcome measure for Sjögren’s syndrome 
that will be applied to the study patients.
Corporate Confidential Information


Novartis
Confidential
Page 79
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.4.3
SF-36–Cohorts 1 and 2 only
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, 
generalhealth perceptions, physical role functioning, emotional role functioning, social role 
functioning, mental health), which are the weighted sums of the questions in their section.
6.4.4
MFI–Cohorts 1 and 2 only
Corporate Confidential Information
The Multidimensional FatigueInventory (MFI) is a 20-item self-report instrument designed to 
measure fatiguecovering the following dimensions: General Fatigue, Physical Fatigue, 
Mental Fatigue, Reduced Motivation and Reduced Activity.


Novartis
Confidential
Page 80
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 81
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.5
Safety
6.5.1
Physical examination
Corporate Confidential Information
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 the eCRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History eCRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event 
must be appropriately recorded on the Adverse Event eCRF.


Novartis
Confidential
Page 82
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.5.2 
Vital signs
Vital signs include blood pressure (BP) and pulse measurements. After the subject has been 
sitting for at least 3 minutes, with back supported and both feet placed on the floor, systolic 
and diastolic BP will be measured using a validated device, with an appropriately sized cuff. 
Incase the cuff sizes available are not large enough for the subject’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used.
If heart-rateor blood pressureis out-of-range at screening orbaseline, the Investigator may 
obtain two additional readings,so that a total of up to three consecutive assessments are made, 
with the subject seated quietly for approximately five minutes preceding each repeat 
assessment. Atleast the last reading mustbe within the ranges provided above in order for 
the subject to qualify.
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 rangeat screening or baseline, the assessment may be 
repeated once prior to randomization. If the repeat value remains outside of protocol-specified 
ranges, the subjectis 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 or baseline, a decision regarding whether the 
result isof 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 subjectto 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.
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.


Novartis
Confidential
Page 83
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.5.4.2 Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, chloride, 
creatinine, CK, -GT, glucose, LDH, inorganic phosphorus, lipase, amylase, magnesium, 
potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUNand 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.
6.5.4.3 Urinalysis
A midstream urine sample (approximately30 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 or blood, the sample will be sent 
for microscopic analysis of WBC, RBC and casts.
6.5.4.4 Coagulation test
Prothrombin time (PT), activated partial thromboplastin time (aPTT)will be measured. 
Additional parameters, e.g.,INR, may be assessed at Investigator’s discretion.
6.5.4.5 C-Reactive Protein (CRP)
C-reactive protein (CRP) will be assessed.
6.5.4.6 Auto-antibodies
ANA, Rheumatoid factor (RF), anti-SSA, anti-SSB,and anti-dsDNAantibodies will be 
assessed.
6.5.4.7 Serum IgG and IgM
Corporate Confidential Information
Serum totalimmunoglobulinG (IgG) and M (IgM)will be assessed in the study.


Novartis
Confidential
Page 84
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.5.6
Electrocardiogram (ECG)
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs, appropriately signed, should be 
collected and archived at the study site.
Each ECG tracing should be labeled with study number, subject initials,subject number, date 
and time, be appropriately signed and dated to confirm review and filedin the study site 
source documents. For any ECGs with subject safety concerns, two additional ECGs should 
be performed to confirm the safety finding. Clinically significant ECG findings prior to 
dosing with investigational treatment must be discussed with the Sponsor.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate.
The eCRF will contain:
date and time of ECG
heart rate
PR interval
QT uncorrected
QTcF
QRS duration.
6.5.7
Pregnancy
Corporate Confidential Information
Pregnancy tests are required of all female subjects regardless of reported reproductive/ 
menopausal status.
Serum pregnancy tests will be performed at screening, baseline and at the end of the study. 
Atall other times urine pregnancy tests may be used.
If a urine pregnancy test is performed and is found to be positive, this will require 
immediateperforming 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 atbaseline, the result of this test must be received before 
the subject may be dosed.


Novartis
Confidential
Page 85
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
6.5.8
Other safety assessments
6.5.8.1 PPD skin test or QuantiFeron test
A purified protein derivative (PPD) skin test will be performed and read at screening or within 
6months prior to randomization in order to evaluate theinfection with tuberculosis(TB). 
Thetest dose is bioequivalent to 5 tuberculin units (or as according to local standard practice) 
of standard PPD injected intra-dermally 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 
≥5mm 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.
T-SPOT or other types ELISPOT assays basedon interferon-gamma release may also be used 
for tuberculosis diagnosis as per local practice.
Results will be available as source data and willnot be recorded within the eCRF.
6.5.8.2 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 eCRF.
6.6
Pharmacokinetic assessments
See Sample log tables 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.In Cohort 2(i.v. regimen) and Cohort3,treatment arm2 (i.v. dose 
on Day1), the PK, PD and IG samples should be taken from adifferent arm thanthe oneused 
for i.v. infusion.
All samples will be given a unique sample number and a collection number (as listed in the 
blood log Appendix 1). The actual sample collection date andtime will be entered on the 
PKblood collection page of the eCRF. Sampling problems will be commented in the eCRFs.


Novartis
Confidential
Page 86
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
The details of sample processing, handling, storage, and shipment will be described in a 
separate laboratory manual.
6.6.2
Pharmacokinetic analytical method
The analytical method to assess free CFZ533 concentrations (target based ELISA assay) will 
be described in a separate laboratory manual.
6.6.3
Pharmacokinetic parameters
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
If data permit, the following pharmacokinetic parameters (non-exhaustive list) of CFZ533will 
be determined using the actual recorded sampling times and non-compartmental method(s) 
with WinNonlin Pro (Version 5.2 or higher): Cmax’s, Cmin’s, Ctrough’s, Tmax, and AUCs
from the plasma concentration-time data.
Concentrations below the LLOQ will be treated as zero for PK parameter calculations. 
Thelinear trapezoidal rule will be used for AUC calculation. 
Corporate Confidential Information
6.7
Other assessments


Novartis
Confidential
Page 87
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 88
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 89
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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.Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
For all subjects who have signed informed consent and are entered into the study will have all 
adverse events occurring after informed consent is signedrecorded on the Adverse Event 
eCRF.
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.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patientswith 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subjectand identifying adverse events. Alert ranges for liver related eventsare included in 
Appendix 3.Adverse events must be recorded on the Adverse Events eCRF under the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. the severity grade:
mild:
usually transient in nature and generally not interfering with normal 
activities
moderate:
sufficiently discomforting to interfere with normal activities
severe:
prevents normal activities
2. its relationship to thestudy treatment (no/yes), or indistinguishable
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported
4. whether it constitutes a serious adverse event (SAE)
5. action taken regarding studytreatment
6. its duration (e.g.,start and end date)
7. whether it constitutes a serious adverse event (SAE)
8. action taken regarding studytreatment
9. whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)


Novartis
Confidential
Page 90
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
10.its outcome.
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 isunrelated 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 
thefollowing: 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 eCRF.
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.


Novartis
Confidential
Page 91
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
7.2
Serious adverse event reporting
To ensure subjectsafety, every SAE, regardless of causality, occurring after the subjecthas 
provided informed consent and until 30 days after the last study visitmust be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30days period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the eventoccurs. 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 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to study treatmentcomplete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours after awarenessof the SAEto the local 
Novartis Drug Safety and Epidemiology Department. The telephone and fax number of the 
contact persons in the local department of Drug Safety and Epidemiology, specific to the site, 
are listed 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 apreviously reported SAE.
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 
subjectcontinued 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 or Package Insert 
(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 EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure subjectsafety 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 elevated liver function tests LFTs.


Novartis
Confidential
Page 92
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs.
Please refer to Table 15-1-Appendix 3forcomplete definitions of liver events.
Any liver event which meets the criteria for a “medically significant” event should follow the 
standard procedures for SAE reportingas described in Section 7.2.
Every liver event as definedin Table 15-1-Appendix 3should be followed up by the 
investigator or designated personnelat the trial site, as summarized below and detailed in 
Table 15-2-Appendix 3.
Repeating the LFT to confirm elevation as appropriate
Discontinuation of the investigational drug if appropriate
Hospitalization of the subjectif 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 eCRF.
7.4
Pregnancy reporting
To ensure subjectsafety, each pregnancy occurring while the subjectis 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. 
Pregnancyfollow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatmentany pregnancy outcome.
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
7.5
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor 
ofany clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Suchevaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and allInvestigators. 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical sites are participating in the clinical study, the Sponsor will advise 
the Investigators at all sites in writing (e-mail) of any new, clinically relevant safety 
information reported from another site during the conduct of the study in a timely manner.


Novartis
Confidential
Page 93
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
subjectrecords, the accuracy of entries on the eCRFs, 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 eCRFs 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 eCRF 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 eCRFs are 
performed according tothe 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 
transfer of the data to Novartisorthe 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 eCRF is not considered as source.
In general the eCRF is not used as source. If the eCRF will be used as source (i.e.,no prior 
written or electronic record of data), then the protocol must clearly identify these data.


Novartis
Confidential
Page 94
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
8.3
Database management andquality 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)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 faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
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. At the conclusion of a 
non-IRT study, the occurrence of any emergency code breaks will be determined after return 
ofall code break reports and unused drug supplies to Novartis. Theoccurrence 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. 
 
 
8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
Corporate Confidential Information
Not required.
Corporate Confidential 
Information


Novartis
Confidential
Page 95
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
9
Data analysis
9.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment 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 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 bytreatment group and subject.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group andsubject.
9.4
Analysis of the primary variable(s)
The primary aimsof this study are to assess the safety of multiple intravenous infusionof
CFZ533 in patientswith pSS,and to investigate theeffect of multiple intravenous infusionof
CFZ533 based on ESSDAI at Week 13.Statistical analysis model will include data on the
ESSDAI from all timepointsup to Week 13and will provide thecomparison at Week 13.
Summaries of safety and tolerability data will beprovided as detailed inSection 9.5.2.
9.4.1
Variable(s)
The primary efficacy variable is the ESSDAI change from baseline.
9.4.2
Statistical model, hypothesis, and method of analysis
It is assumed that the ESSDAI will follow an approximate normal distribution. If this 
assumption appears to not be met, alternative statistical methods maybe applied. These will 
be described full in the Reporting and Analysis Plan (RAP).
The analysis of the data for primary variable will be conducted combining data from both 
Cohorts1 and 2. As a result, the three treatments under consideration would be Placebo 
(pooled), CFZ533 
 s.c.and CFZ533 
 i.v. A longitudinal model 
describing ESSDAIchange from baseline over time will be fitted for thecontrolled part of the 


Novartis
Confidential
Page 96
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
study (upto Week 13) with the following covariates: baseline ESSDAI, baseline prednisone 
dose, treatment(three as mentioned above), time as a continuous factor and a quadratic time 
effect, as well as a random intercept, a random slope and a random quadratic effect for subject. 
Anunstructured covariance matrix for the random effects will be fitted along with an 
independent error matrix. The change from baseline in ESSDAI at Week13(end of 
placebo-controlled period)will be estimated from the model for alltreatments and the 
difference between treatments to placebo will be presented along with 80% confidence 
intervals. Inference will be done in the frequentist framework.
The results from the primary analysis will be assessed against the following efficacy criteria
to support internal decision making(inference is done in the frequentist framework):
astatistically significant reductionin ESSDAI at Week 13in the CFZ533
 
i.v.group compared to placebo,at the one-sided 10% significance level, and
an estimated meanreduction in ESSDAI in the CFZ533
 i.v.group to be 
5points or greaterthan placebo.
The decrease of 5 points was chosen because it is in the range ofwhat was observed at 
week12 in a small open-label studywith rituximab(Meiners et al 2012).A positive sign of 
efficacywill be considered if both criteria are met.
ESSDAI data after Week 12 will be summarized using descriptive statistics and displayed 
graphically. ESSDAI data from cohort 3 will also be summarized using descriptive statistics. 
More detailswill be described in the RAP.
9.4.3
Handling of missing values/censoring/discontinuations
All subjects with a baseline ESSDAI and at least one post-baseline ESSDAI will be included 
in the primary analysis.The planned mixed effects model assumes that missing values are 
missing at random.The guidelines for subject discontinuation given in Section 5.5.10should 
ensure that the missingness mechanism is as close as possible to missing at random.
9.4.4
Supportive analyses
Other models than the one specified in Section 9.4.2may be considered: time would be 
modeled as categorical variableif the time course doesn’t appear to be quadratic.
Simpler covariances than the unstructured one may also be considered if needed.
Corporate Confidential Information


Novartis
Confidential
Page 97
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 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 andsubject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred termwith 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.
Infections
Corporate Confidential Information
The frequency of infections will be tabulated and compared between treatment groups with 
Fisher’s exact test.


Novartis
Confidential
Page 98
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
9.5.3 
Pharmacokinetics
Plasma CFZ533concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summary statistics will beprovided by treatment and visit/sampling 
time point, includingthe 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 6.6.3and 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. 
Anexception to this is Tmax where median, minimum and maximum will be presented.
A dose-independent, model-based analysis considering both i.v. and s.c.PK data may be 
performed as appropriateand will be reported in a separate, standalone modeling and 
simulation report. During modeling of PK data, the broad principlesoutlined in the FDA 
Guidance forIndustry: Population Pharmacokinetics,will be followed. 
9.5.4
Pharmacokinetic / pharmacodynamic interactions
Corporate Confidential Information
PK/PD analysis
 
willbe explored graphically.Modeling of s.c. and i.v. PK/PD data using 
a population approach may be performed as appropriate and will be reported in a separate, 
standalone report.
These data will be summarized by cohort, treatment and subject. Descriptive statistics will 
also be provided such as mean, median, standard deviation, minimum and maximum, by time 
point, treatment and cohort.
Corporate Confidential Information


Novartis
Confidential
Page 99
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
9.6
Sample size calculation
Cohorts 1 and 2
With 24 patients in the analysisof the primary efficacy variable (16 in the CFZ533 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 CFZ533and
placebo is zero. Additionally the chances of meeting both the efficacy criteria remain below
10% for true differences between CFZ533and placebo of less than 2 points.
The study would have approximately 83% chance of meeting both the efficacy criteria, when
the true difference between CFZ533and placebo is 7 points.
In case the true difference between CFZ533 and placebo is only 5 points, thestudy would 
have approximately 51% chance of meeting both the efficacy criteria.These calculations 
assume that the primary efficacy variable, ESSDAI, follows a normaldistribution with a 
standard deviation of 5. This estimate of the standard deviation is based ona study of 
rituximab in patients with primary Sjögren’s syndrome(Meiners et al 2012) inwhich the 
observed standard deviation ranged from 5 at baseline to 3-7 post baseline.
With 24 patients(16 in the CFZ533 group and8 in the placebo group),the study would have 
around 38% power (resp. 70% power) to detect an increase of 30% (resp.42%) in the 
infection rate in the CFZ533 group, assuming a background rate of 5% on placebo.
The probabilities to observe a certain number of adverse events in each treatment arm, with 
this sample size, given assumed event rates, are given in Table 9-1
Corporate Confidential Information
below:


Novartis
Confidential
Page 100
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Table 9-1
Probability of observing a certain number of adverse events in the 
study given assumed underlying rates
Underlying true 
adverse event rate
(in both treatment 
arms)
Probability to 
observe at least 
4/16 patients with 
AEs on active arm
Probability to 
observe at least 
2/8 patients with 
AEs on placebo
Probability to 
observe at least 
8/16 patients with 
AEs on active arm
Probability to 
observe at least 
4/8 patients with 
AEs on placebo
20%
0.402
0.497
0.007
0.056
35%
0.866
0.831
0.159
0.294
50%
0.989
0.965
0.598
0.637
The estimated difference in AE rates along with 90% confidence intervals, given a certain 
number of observed adverse events in each treatment arm, are given in Table 9-2below:
Table 9-2
Estimated difference in AE rates when observing a certain number of 
adverse events in the study
Number of patients with AE 
observed on active arm (out of 16)
Number of patients with AE 
observed on placebo (out of 8)
Estimated differencein AE rates 
along with the 90% confidence 
interval
4
2
0 (-0.308, 0.308)
8
2
0.25 (-0.075, 0.575)
12
2
0.5 (0.192, 0.808)
Calculations have been made withR 2.8.1 and NQuery 7.0.
Cohort 3
With data from 10 patients in a treatment arm, the 90% confidence interval of
PKconcentrations at a given time-point is expected to be within 86% to 116% of the observed 
geometric mean with 90% coverage probability. A coefficient of variation of 20% was 
assumedin this calculation. With coefficients of variation of 30%, 40% and 50%, the 90% 
confidenceintervals are expected to be within 80% to 149%, 75% to 133%and 70%to 142% 
of theobserved geometric mean, respectively.
To allow for a drop-out rate of 15%, approximately 24 patients will be recruited into this cohort.
Sample size calculations were performed using NQuery 7.0 based on log-transformed
PKconcentrations.
9.7
Power for analysis of key secondary variables
Cohorts 1 and 2
With 24 patients (16 in the CFZ533 group and 8 in the placebo group),the study would have 
approximately 83%chance of detecting a decrease of 2 points in the ESSPRI, assuming a 
normal distributionwith a standard deviation of 2 for the variable. The standard deviation is 
based on Meiners et al (2012), in which the observed standard deviation ranged from 2.2 at 
baseline to 1.9-2.2 to post baseline.
Calculations have been made with NQuery 7.0.


Novartis
Confidential
Page 101
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
10
Ethical considerations
10.1
Regulatory and ethical compliance
Corporate Confidential Information
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.


Novartis
Confidential
Page 102
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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. Ifincapable of doing so, 
after such consent has been provided by a legally acceptable representative of the subject. 
Incases where the subject’s representative gives consent, the subject should be informed 
about the study to the extent possible given his/her understanding. If the subject is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
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.
10.3
Responsibilities of the investigator and IRB/IEC
Corporate Confidential Information
Before initiating a trial, the investigator/institution should obtain approval/favorable 
opinionfrom the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for 
thetrial protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 


Novartis
Confidential
Page 103
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
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 protocol and 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
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. 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 amendmentthat 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. 
Onlyamendments 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 
10working days or less, if required by local regulation.


Novartis
Confidential
Page 104
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
12
References
Available upon request
De Vita S, Lorenzon G, Rossi G, et al(1992) Salivary gland echography in primary and 
secondary Sjögren’s syndrome. Clin Exp Rheumatol; 10:351–6.
DimitriouID, Kapsogeorgou EK, Moutsopoulos HM, et al(2002) CD40 on salivary gland 
epithelial cells: high constitutive expression by culturedcells from Sjögren’s syndrome 
patients indicating their intrinsic activation.Clin Exp Immunol;127(2):386-92.
Goldwater R, Keirns J, Blahunka P, et al(2013)A Phase 1, randomized ascending single-dose 
study of antagonist anti-human CD40 ASKP1240 in healthy subjects. Am J Transplant;
13:1040-6.
Harland R, Klintmalm G, Yang H, et al. (2015) ASKP1240 in De Novo Kidney Transplant 
Recipients. Am J Transplant;15(S3):Abstract # 3012.
KaufmanI, Schwartz D, Caspi D, et al (1999)Sjögren
's syndrome -not just Sicca: renal 
involvement in Sjögren
's syndrome. Ann Rheum Dis.58:253-6.
Kawai T, Andrews D, Colvin RB,et al (2000) Thromboembolic complications after treatment 
with monoclonal antibody against CD40 ligand. Nat Med;6:114.
Komaroff AL, Fagioli LR, Doolittle TH, et al(1996) Health status in patients with chronic 
fatigue syndrome and in general population and disease comparison groups. Am J Med;
101:281-90.
Kuenstner S, Langelotz C, Budach V,et al (2002) The comparability of quality of life scores. 
A multititrait multimethod analysis of the EORTC QLQ-C30, SF-36 and FLIC questionnaires. 
Eur J Cancer;38:339-48.
ManganelliP, Fietta P (2003)Apoptosis and Sjögren syndrome. Semin Arthritis Rheum. 
33(1):49-65.
Meijer JM, Meiners PM, Vissink A, et al(2010) Effectiveness ofrituximab treatment in 
primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis 
Rheum;62:960-8.
Meiners PM, Arends S, Brouwer E, et al(2012) Responsiveness of disease activity indices 
ESSPRI and ESSDAI in patients withprimary Sjögren’s syndrome treated with rituximab.
Ann Rheum Dis;71:1297-302.
Moerman RV, Arends S, Meiners PM, et al(2014) EULAR Sjögren’s Syndrome Disease 
Activity Index (ESSDAI) is sensitive to show efficacy of rituximab treatment in a randomised 
controlled trial. Ann Rheum Dis;73:472-4.
PijpeJ, Kalk WW, Bootsma H,et al(2007)Progression of salivary gland dysfunction in 
patients with Sjögren’s syndrome.Ann Rheum Dis;66:107-12.


Novartis
Confidential
Page 105
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Segal B, Bowman SJ, Fox PC, et al (2009) Primary Sjögren’s Syndrome: health experiences 
and predictors of health quality among patients in the United States. Health Qual Life 
Outcomes;May 27; 7:46.
Sellam J, Proulle V, Jüngel A, et al(2009) Increased levels of circulating microparticles in 
primary Sjögren’s syndrome, systemic lupus erythematosus and rheumatoid arthritis and 
relation with disease activity. Arthritis Res Ther;11:R156.
Seror R, Ravaud P, Bowman SJ, et al (2011) Corrections to Seror Ret al69(6):1103. Ann 
Rheum Dis 70:880 doi:10.1136/ard.2009.110619corr1.
TishlerM, Yaron I, Shirazi I, et al(2008) Hydroxychloroquine treatment for primary 
Sjögren
's syndrome: its effect on salivary and serum inflammatory markers. Scand J 
Rheumatol. 37:213-8.
Toubi E, Shoenfeld Y(2004)The role of CD40-CD154 interactions in autoimmunity and the 
benefit of disrupting this pathway. Autoimmunity;37:457-64.
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.
Vossenkämper A, Lutalo PM, Spencer J(2012) Translational Mini-Review Series on B cell 
subsets in disease. Transitional B cells in systemic lupus erythematosus and Sjögren’s 
syndrome: clinical implications and effects of B cell-targeted therapies. Clin Exp Immunol;
167:7-14.
Vosters O, Beuneu C, Nagy N, et al(2004) CD40 expression on human pancreatic duct cells: 
role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines. 
Diabetologia;47:660-8.
Winzer M, Aringer M. (2010) Use of methotrexate in patients with systemic lupus 
erythematosus and primary Sjögren
's syndrome. Clin Exp Rheumatol.28 (5 Suppl 61):S156-9.
Youinou P,Pers JO (2012) Latest update on the primary Sjögren’s syndrome. Presse Med; 
41(9 pt 2):e437-439.


Novartis
Confidential
Page 106
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 107
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 108
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 109
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 110
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 111
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 112
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 113
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
14
Appendix 2: Sample labeling and shipping information
Sample labeling and shipping instructions will be provided in a separate laboratory manual.


Novartis
Confidential
Page 114
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
15
Appendix 3: Liver event definitions and follow-up 
requirements
Table 15-1
Liver Event Definitions
Definition/ threshold
Adverse event of special 
interest
Laboratory values
ALT or AST > 3 x ULN
ALP > 2 x ULN
TBL > 1.5 x ULN
Medically significant event 
(SAE)
Laboratory values
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction])
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction])
TBL > 3 x ULN
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and
TBL > 2 x ULN [mainly conjugated fraction] withoutnotable 
increase in ALP to > 2 x ULN)
Adverse events
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders –severe events only”* or any“Hy’s law case” PT
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms.


Novartis
Confidential
Page 115
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Table 15-2
Liver Event Follow Up Requirements
Criteria
Event type
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize, if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolution
c(frequency at 
investigator discretion)
ALT or AST
> 8 x ULN
Medically 
significant
Repeat LFT within48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolution
c(frequency at 
investigator discretion)
> 5to ≤ 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists for more 
than 2 weeks, discontinue the 
study drug
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolution
c(frequency at 
investigator discretion)
> 3 x ULN
accompanied by 
symptoms
b
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolution
c(frequency at 
investigator discretion)
> 3 to ≤ 5 x ULN 
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Investigator & Novartis
Repeat LFT once or twice in the 
week
If elevation persists, establish 
causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 3 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
ALP (isolated)
> 5 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, report to 
Novartis as an SAE
Establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit


Novartis
Confidential
Page 116
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Criteria
Event type
Actions required
Follow-up monitoring
> 2 to ≤5 x ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Investigator & Novartis
Repeat LFT once or twice in the 
weekIf elevation persists, 
establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 2 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
TBL (isolated)
> 3 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolution
c(frequency at 
investigator discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 3 x ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Novartis
Repeat LFT once or twice in the 
weekIf elevation persists, 
establish causality
investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 1.5 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
Preferred terms
Jaundice
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize the patient
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolution
c(frequency at 
investigator discretion)
“Drug-related 
hepatic 
disorders -severe 
events only” SMQ 
AE
Medically 
significant
Discontinue the study drug 
hospitalization if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
Investigator discretion
a
Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN
b
General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia
c
Resolution is defined as an outcome of one of the following: return to baseline values, stable values at three 
subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a maximum of 6 months, liver 
transplantation, and death.


Novartis
Confidential
Page 117
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
16
Appendix 4: ESSDAI
Table 16-1
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 (37.5–8.5°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 (>30min)
1–5 (of 28 total count) synovitis
≥6 (of 28 total count) synovitis


Novartis
Confidential
Page 118
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Domain [weight]
Activity level
Description
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 cutaneous lupus
Diffuse cutaneous vasculitis, including urticarial vasculitis, or diffuse purpura, or ulcers related to 
vasculitis
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 radiographyor 
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 DL
CO<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


Novartis
Confidential
Page 119
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Domain [weight]
Activity level
Description
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 (deficit ≤3/5) or elevated 
creatine kinase (>4N)
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 4/5or 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
Moderate = 
2**
High = 3
Absence of currently active CNS involvement
Moderately active CNS features, such as cranial nerve involvement of central origin, optic neuritis or 
multiple sclerosis-like syndrome with sy
mptoms restricted to pure sensory impairment or confirmed 
cognitive impairment
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


Novartis
Confidential
Page 120
Amended Protocol Version v07 Clean
Protocol No. CCFZ533X2203
Domain [weight]
Activity level
Description
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/mm
3), and/or or anaemia 
(haemoglobin <8 g/dl) and/or thrombocytopenia (platelets <50000/mm
3)
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; DL
CO, 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, peripheralnervous system.
*Clinical investigator subjective scoring based on availability of concurrent clinical data.
**Seror et al 2011
***CH100 may be used instead of CH50




Novartis
Confidential
Page 122
Amended Protocol Version v07Clean
Protocol No. CCFZ533X2203
8. *How severe has your nasal drynessbeen 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) drynessbeen 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 drynessbeen 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.
11.*Among the following symptoms, please identify the one you consider the mostin 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 leastin 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 mostin need of improvement to 6: the leastin 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


Novartis
Confidential
Page 123
Amended Protocol Version v07Clean
Protocol No. CCFZ533X2203
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 Sjögren’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


Novartis
Confidential
Page 124
Amended Protocol Version v07Clean
Protocol No. CCFZ533X2203
18
Appendix 6: Blinding and unblinding
Randomization data are kept strictly confidential, and are accessible only to authorized 
personnel, until unblinding of the trial as described in the table below.
Table 18-1
Blinding levelsCohorts 1 and 2
Time or Event
Role
1 
2 
3 
4 
5 
6 
7
Drug Supply
UI 
UI 
UI 
UI 
UI 
UI 
UI
Randomization Office
UI 
UI 
UI 
UI 
UI 
UI 
UI
Investigational site unblinded pharmacist
UI 
UI 
UI 
UI 
UI 
UI 
UI
Subject
B 
B 
B
UI
B 
B
UI
Treating Physician
B 
B 
B
UI
B 
B
UI
Primary Investigator
B 
B 
B
UI
B 
B
UI
Unblinded Physician for safety monitoring1
B 
B
UI 
UI 
UI 
UI 
UI
Study Monitor
B 
B 
B
UI
B 
B
UI
Clinical Trial Leader
B 
B 
B
UI 
UI 
UG 
UI
Data Manager
B 
B 
B
UI
B 
B
UI
PK Bioanalytics
B
UI 
UI 
UI 
UI 
UI 
UI
PK Expert
B 
B 
B
UI 
UI 
UG 
UI
Statistician
B 
B 
B
UI 
UI 
UI 
UI
Translational Medicine Expert
B 
B 
B
UI 
UI 
UG 
UI
Modeler
B 
B 
B
UI 
UI 
UI 
UI
Programmer
B 
B 
B
UI 
UI 
UI 
UI
Novartis decision teams
B 
B 
B
UI 
UG 
UG 
UI
1Note that although the unblinded physician for safety monitoring is permitted to be unblinded, (s)he will not be 
provided with the randomization list until the interim analysis, in order to prevent accidental unblinding of other 
investigational site staff.
UG
Allowed to be unblinded on treatment group level
UI
Allowed to be unblinded on individual patient level
B
Remains blinded
1
Generation of randomization list, QC and lock randomization list
2
Patient allocation to treatment
3
Treatment administration
4
Safety emergency event (unblinding of a single subject)
5
Interim analysis (all patients included in the analysis have completed the study)
6 
Interim analysis (some patients included in the analysis have not yet completed the study)
7
Database lock


Novartis
Confidential
Page 125
Amended Protocol Version v07Clean
Protocol No. CCFZ533X2203
Table 18-2
Blinding levelsCohort 3
Time or Event
Role
1 
2 
3 
4 
5 
6 
7
Drug Supply
UI 
UI 
UI 
UI 
UI 
UI 
UI
Randomization Office
UI 
UI 
UI 
UI 
UI 
UI 
UI
Investigational site unblinded pharmacist
UI 
UI 
UI 
UI 
UI 
UI 
UI
Subject
B 
B
UI 
UI 
UI 
UI 
UI
Treating Physician
B 
B
UI 
UI 
UI 
UI 
UI
Primary Investigator
B 
B
UI 
UI 
UI 
UI 
UI
Unblinded Physician for safety monitoring1
B 
B
UI 
UI 
UI 
UI 
UI
Study Monitor
B 
B
UI 
UI 
UI 
UI 
UI
Clinical Trial Leader
B 
B
UI 
UI 
UI 
UI 
UI
Data Manager
B 
B
UI 
UI 
UI 
UI 
UI
PK Bioanalytics
B
UI 
UI 
UI 
UI 
UI 
UI
PK Expert
B 
B
UI 
UI 
UI 
UI 
UI
Statistician
B 
B
UI 
UI 
UI 
UI 
UI
Translational Medicine Expert
B 
B
UI 
UI 
UI 
UI 
UI
Modeler
B 
B
UI 
UI 
UI 
UI 
UI
Programmer
B 
B
UI 
UI 
UI 
UI 
UI
Novartis decision teams
B 
B
UI 
UI 
UI 
UI 
UI
1Note that although the unblinded physician for safety monitoring is permitted to be unblinded, (s)he will not be 
provided with the randomization list until the interim analysis, in order to prevent accidental unblinding of other 
investigational site staff.
UG
Allowed to be unblinded on treatment group level
UI
Allowed to be unblinded on individual patient level
B
Remains blinded
1
Generation of randomization list, QC and lock randomization list
2
Patient allocation to treatment
3
Treatment administration
4
Safety emergency event (unblinding of a single subject)
5
Interim analysis (all patients included in the analysis have completed the study)
6 
Interim analysis (some patients included in the analysishave not yet completed the study)
7
Database lock


Novartis
Confidential
Page 126
Amended Protocol Version v07Clean
Protocol No. CCFZ533X2203
Corporate Confidential Information

SAP_001.pdf: 
Clinical Development
CFZ533
CCFZ533X2203
A multi-center, randomized, double-blind, placebo-
controlled, parallel group study to assess the safety, 
tolerability, pharmacokinetics and preliminary efficacy of 
CFZ533 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:
FinalV03
Release date:
05-SEP-2018
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
TSc RAP Module 3
CCFZ533X2203
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
2.1.1
Primary objectives...................................................................................5
2.1.2
Secondary objectives...............................................................................5
2.2
Study design and treatment......................................................................................7
3 First interpretable results (FIR)...........................................................................................9
5 Statistical methods: Analysis sets......................................................................................10
6 Statistical methods for Pharmacokinetic (PK) parameters................................................10
6.1
Pharmacokinetic parameters..................................................................................10
6.2
Analysis of pharmacokinetics................................................................................10
7 Statistical methods for Pharmacodynamic (PD) parameters.............................................11
7.1
Analysis of the primary variable............................................................................11
7.1.1
Statistical model, hypothesis, and method of analysis..........................11
Handling of missing values/censoring/discontinuations.......................................12
Supportive analysis................................................................................................12
7.2
Analysis of secondary and exploratory variables..................................................13
8 Pharmacokinetic / pharmacodynamic interactions............................................................13
9 Statistical methods for safety and tolerability data............................................................13
11 Reference list.....................................................................................................................16
List of tables
Figure 2-1
Study design Cohort 1 and Cohort 2.......................................................8
Figure 2-2
Study design Cohort 3.............................................................................8
Table 4-1
Probabilities of various decisions at the interim analysis.......................9
Table 5-1
Protocol deviation severity codes and analysis sets..............................
Corporate Confidential Information
10
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 3
TSc RAP Module 3
CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 4
TSc RAP Module 3
CCFZ533X2203
1
Introduction to RAPdocumentation
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 “CCFZ533X2203”. 
Module 3 (M3) provides the description of the statistical methodologyused 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 designand 
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.


Novartis
Confidential
Page 5
TSc RAP Module 3
CCFZ533X2203
2
Study objectives and design 
2.1
Study objectives
2.1.1
Primary objectives
To assess the safety and tolerability of multiple subcutaneous doses and multiple 
intravenous infusionof CFZ533 in patients with primary Sjögren’s syndrome(pSS)as 
measured by adverse events (AEs).
To compare the effect of multiple intravenous infusionof CFZ533 versus placebo on the 
clinical disease activity of pSSpatients as measured by the change of an EULAR 
Sjögren’s Syndrome Disease Activity Index (ESSDAI) after 12 weeks treatment.
2.1.2
Secondary objectives
To assess the safety and tolerability of multiple subcutaneous dosesof CFZ533 in patients 
with pSS as measured by AEs.
To compare the effect of multiple subcutaneous doses of CFZ533 versus placebo on the 
clinical disease activity of pSS patients as measured by the change of an ESSDAI after 12 
weeks treatment.
To assess the pharmacokinetics of multiple subcutaneous doses and multiple intravenous 
infusion of CFZ533 in pSSpatients.
To evaluate the effect of multiple subcutaneous dosesand multiple intravenous infusions
of CFZ533 versus placebo on self-reported outcomes in pSSpatients after 12 weeks 
treatment 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 evaluate the changes in the physician global assessment of the patient’s overall disease 
activity as recorded by a visual analog scale (VAS) after 12 weeks treatment.

Corporate Confidential Information
To evaluate the changes in the patients global assessment of their disease activity as 
recorded by a VAS after 12 weeks treatment.


Novartis
Confidential
Page 6
TSc RAP Module 3
CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 7
TSc RAP Module 3
CCFZ533X2203
2.2
Study design and treatment
This is a double-blind followed by open-label, randomized, placebo-controlled, parallel-group, 
non-confirmatory study to assess the safety, tolerability, pharmacokinetics, and preliminary 
clinical efficacy of multiple doses of CFZ533 in the following Cohorts 1 and 2:
Cohort 1: 
 CFZ533 administered subcutaneously in patients with pSS, in a 
doubleblind and placebo-controlled fashion, followed by open-label treatment;
Cohort 2:  
 CFZ533 administered by intravenous infusion in patients with pSS, in
a double-blind and placebo-controlled fashion, followed by open label treatment.
These cohorts will be followed by an open label, randomized, parallel group, non-
confirmatory part of Cohort 3:

Corporate Confidential Information
Cohort 3 (patients with pSS):
In treatment arm 1 CFZ533 will be given at 
 s.c. weekly on 4 occasions (loading 
regimen), followed by 
 s.c. weekly on 9 occasions (maintenance regimen starting 
on study day 29). In treatment arm 2,the loading regimen will consist of a single i.v. dose 
of  
 CFZ533 (on study day 1), followed by  
 s.c. weekly on 12 occasions
(maintenance regimen starting on study day 8).
The study will randomize approximately 68 patients with primary Sjögren’s syndrome. In 
Cohorts 1 and 2, the randomization will be stratified by baseline intake of oral corticosteroids 
(yes/no). There will be no stratification in Cohort 3.
The study comprises three periods for Cohort 1 and Cohort 2:
1) placebo-controlled period(from Day 1, Week 1 to completion of pre-dose assessments on
Day 85, Week 13), during which 4 doses of CFZ533 or placebo will be administered on
topof the standard of care therapy, (e.g., low dose corticosteroid) that is necessary to treat 
pSS;
2) open-label period (from dosing on Day 85, Week 13 to completion of assessments on Day 
169, Week 25), when all patients will receive 4 doses of open-label CFZ533 treatment, 
and
3) follow-up period (Weeks 25 –32), when patients will be followed up without study
medication.
An illustration of the study design for Cohorts 1 and 2 is provided in Figure 2-1.


Novartis
Confidential
Page 8
TSc RAP Module 3
CCFZ533X2203
Figure2-1
Study designCohort 1 and Cohort 2
Cohort 3, comprises two periods, namely:
1. open-label treatment period (from dosing on Day 1, Week 1 to last dose and completionof 
assessments on Day 85, Week 13),
2. follow-up period (from Week 13 to Day 141/Week 21), when patients will be followedup 
for 8 weeks without study medication.
In the open label period, treatment arm 1 dosing starts with CFZ533 
 s.c. q1w for4 
weeks, whereas in treatment arm 2, dosing starts with CFZ533 
 i.v. on Day 1.In 
both arms maintenance dosing then continues with CFZ533 
 s.c. q1w for 4 weeks 
(treatment arm 1) or9 weeks (treatment arm 2).
An illustration of thestudy design for Cohort3is provided in Figure 2-2.
Figure2-2
Study design Cohort 3
Corporate Confidential 
Information
Corporate Confidential 
Information
Corporate Confidential 
Information
Corporate Confidential 
Information
Corporate Confidential Information


Novartis
Confidential
Page 9
TSc RAP Module 3
CCFZ533X2203
3
First interpretable results (FIR)
Corporate Confidential Information
First interpretable results (FIR) willbe provided for this trialbut not as fully as usual due to 
interim analyses that have already occurred. 
 
The template shows the analysis/ resultsto be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be marked as “Key” in the Tracking sheet output list. 
Corporate Confidential Information
Corporate Confidential Information


Novartis
Confidential
Page 10
TSc RAP Module 3
CCFZ533X2203
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 safetyanalysis set.
The 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.
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
6.1
Pharmacokinetic parameters
If data permits, the following pharmacokinetic parameters will be determined using the actual 
recorded sampling times and non-compartmental analysis: Cmax, Cmax,ss, Ctrough, 
Ctrough,ss and AUC’s from the CFZ533 plasma concentration-time data.Concentrations 
below the LLOQwill 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 (but not 
including Cmax). If the adjusted R2value of the regression analysis of the terminal phase is
less than 0.75, T1/2, AUCinf, Vz/F and CL/F will be excluded and indicated as missing
values.
6.2
Analysis of pharmacokinetics
Plasma CFZ533 concentration data will be listed by cohort, treatment, subject, and 
visit/sampling time point. Descriptive summary statistics will be provided by cohort, 
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 


Novartis
Confidential
Page 11
TSc RAP Module 3
CCFZ533X2203
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. 
Concentrations below LLOQwill be treated as zeroin summary statistics. A geometric mean 
will not be reported if the dataset includes zero values.
Pharmacokinetic parameters will be listed by cohort, 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.
. During any modeling of PK data, the broad principles outlined in theFDA
Guidance for Industry: Population Pharmacokinetics, will be followed.
7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Analysis of the primary variable
7.1.1
Statistical model, hypothesis, and method of analysis
The primary efficacy variable is the ESSDAI change from baseline.
It is assumed that the ESSDAI will follow an approximate normal distribution.If this 
assumption appears to not be met, alternative statistical methods maybe applied. For example, 
data may be log transformed with changes from baseline in the log transformed data being 
analyzed.
The analysis of the data for the primary variable from Cohorts 1 and 2 differs from that 
proposed in the protocol in that it will not be conducted combining placebo data from those 
two cohorts.Being in two separate consecutive cohorts, one s.c. and the other i.v., they are not 
now considered similar enough to combine. As a result, the active treatments under 
consideration, 
 areeach 
compared to their respective matching placebo treatments within each cohort.Cohort 3 simply 
compares two alternative loading regimes.
For each of cohorts 1 and 2, alongitudinal model describing ESSDAIchange from baseline 
over time will be fitted upto Week 13with the following fixed effect terms: baseline ESSDAI, 
treatmentgroup, visit, and interaction between treatment group and visit. In the first instance 
anunstructured variance-covariance matrix will be fitted;if there are issues with convergence 
then other variance-covariance matrices will be investigated. The change from baseline in 
ESSDAI at Week 13 (end of placebo-controlled period) will be estimated from the model. 
Inference will be done in the frequentist framework.
For Cohorts 1 and 2 the results from the primary analysis will be assessed against the 
following efficacy criteria:
astatistically significant reductionin ESSDAI at Week 13in the CFZ533
 
i.v. group compared to placebo,at the one-sided 10% significance level, and

Corporate Confidential Information
an estimated meanreduction in ESSDAI in the CFZ533
 i.v. group to be 
5points or greater than placebo.
Corporate Confidential Information


Novartis
Confidential
Page 12
TSc RAP Module 3
CCFZ533X2203
The decrease of 5 points was chosen because it is in the range of what was observed at 
week12 in a small open-label study with rituximab (Meiners et al 2012).A positive sign of 
efficacy will be considered if both criteria are met.
In Cohorts 1 and 2,ESSDAI data after Week 13, where there is no longer a placebo treatment,
will be examined similarly. It will also be summarized using descriptive statistics of both 
absolute values and changes from baseline and the raw data displayed graphicallyfor 
individual patients and for visit treatment means.Graphs will also be used to display modelled 
treatment effects over time.
ESSDAI data from Cohort 3 up to Week 13 and then to Week 21 will also be analyzed in a 
similar way to the data from each of Cohorts 1 and 2, but withtwo active treatment groups
instead of comparison with control. It will also be summarized with descriptive statisticsand 
plots similarly.
Handling of missing values/censoring/discontinuations
All subjects with a baseline ESSDAI and at least one post-baseline ESSDAI will be included 
in the primary analysis. The planned modelsassume that missing values are missing at 
random. The guidelines for subjectdiscontinuation provided in the protocol should ensure that 
the missingness mechanism isas close as possible to missing at random.The reasonableness 
of this assumption will be checked and if necessary further methods may be applied.
Supportive analysis
The Bayesian analyses proposed in the protocol for the interim analysis of Cohort 1 will serve 
as supportive to the main frequentist analysis abovewhen applied in a similar manner to 
Cohorts 1 and 2.
TwoBayesian posterior probabilities as follows will be calculated for Cohorts 1 and 2:
Pr (θCFZ533,13w-θ
placebo,13w <0 | data)
Pr (θCFZ533,13w-θ
placebo,13w <-5 | data)
where θ means change from baseline in ESSDAI at Week 13.
It is assumed that Y
ijt, the observed change from baseline in ESSDAI for subject i receiving
treatment j (CFZ533or placebo) at time t, follows a normal distribution N(θjt, σ
2),It is further 
assumed that θ
jtfollows a standard non-informative prior Normal distribution,p(θjt, σ
2) = 1/σ
2.
Thisstatistical model will be a repeated measures Bayesian analysis with baselineas a 
covariate using PROC MCMC. Example SAS code is provided in the RAP Module 8.
Estimates of the difference between CFZ533and placebo at each timepoint will be derived
from this model and presented together with 95% credible intervals.
If required, further frequentist supportive analyses will attempt to model the time effect to 
better describe changes over time. If so,the model may include the following covariates: 
baseline, treatment, time, treatment by time interaction, treatment by time squaredinteraction, 
as well as a random intercept and a random slope for each patient. Time may be modeled as a 
continuous variable. The model may be simplified if there are problems with convergence, 
including a simpler variance-covariance matrix. The treatment by time squaredinteraction 
will be included if it improves the fit.


Novartis
Confidential
Page 13
TSc RAP Module 3
CCFZ533X2203
8
Pharmacokinetic / pharmacodynamic interactions
Modeling of PK/PD data using a population approach may be performed as appropriate by the 
Novartis PK group and reported in a separate standalone report.
These data will be summarized by cohort, treatment and subject. Descriptive statistics will 
also be provided,such as mean, median, standard deviation, minimum and maximum, by 
cohort, treatment and time point. 
9
Statistical methods for safety and tolerability data
Corporate Confidential Information
All data for background and demographic variables will be listed by cohort, treatment group 
and subject. Summary statistics will be provided by treatment groupwithin cohort.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by cohort, treatment group and subject.
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by cohort, treatment group and subject.
Plots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
All vital signs will be listed by cohort, treatment, subject and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by cohort, treatment and visit/time.


Novartis
Confidential
Page 14
TSc RAP Module 3
CCFZ533X2203
Corporate Confidential Information
All ECG data will be listed by cohort, treatment, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by cohort, treatment and visit/time.
All laboratory data will be listed by cohort, treatment, subject and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
cohort, treatment and visit/time.Individual B-cell and neutrophil countsover time by cohort, 
treatment groupwill be presented graphically.
All information obtained on adverse events will be displayed by cohort, 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 treatmentwithin cohort. A subject with multiple 
adverse events within a body system is only counted once towards the total of this body 
system.
The frequency of patients who have had infections by Week 13 will be tabulated and 
compared between treatment groups within Cohorts 1 and 2 with Fisher’s Exact test.
Immunogenicity results will be listed by cohort, treatment, subject and visit/sampling time 
point. No descriptive summary statistics will be provided.


Novartis
Confidential
Page 15
TSc RAP Module 3
CCFZ533X2203
Corporate Confidential Information


Novartis
Confidential
Page 16
TSc RAP Module 3
CCFZ533X2203
11
Reference list
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. 
Corporate Confidential Information
Ann Rheum Dis;71:1297-302.