Clinical trial NCT02775916
Conditions: Primary Sjögren's Syndrome
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-01; Completion date: 2017-05-17
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Study is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary therapeutic efficacy of oral administrations of CDZ173 in patients with primary Sjögren's syndrome.

Detailed description:
This study is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary therapeutic efficacy of oral administrations of CDZ173, a selective PI3K delta inhibitor, for 12 weeks, in patients with primary Sjögren's syndrome. Data from this study will provide the basis for further development of the compound for the treatment of primary Sjögren's syndrome.

Arms: arm 1: Capsule arm 2: Capsule matching Placebo
Interventions: intervention 1: CDZ173 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
CDZ173
Clinical Trial Protocol CCDZ173X2203
A randomized, double-blind, placebo-controlled, 
parallel group study to assess the safety, tolerability, 
pharmacokinetics and preliminary efficacy of CDZ173 
in patients with primary Sjögren’s syndrome
Authors:
 
Document type:
Amended Protocol version
EUDRACT number:
2014-004616-12
Version number:
v01 (Clean)
Development phase:
II
Release date:
15-Sep-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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Amended Clinical Trial Protocol Version 01 (Clean)
Protocol No. CCDZ173X2203
Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements. See also Site Operations Manual for further details on the method of reporting a 
SAE.

Complete SAE report 

Submit SAE report to Novartis Drug Safety and Epidemiology (DS&E) within 24 hours 
after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual. 


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Amended Clinical Trial Protocol Version 01 (Clean)
Protocol No. CCDZ173X2203
Table of contents
Site Operations Manual (SOM)...........................................................................................2
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
Protocol synopsis...............................................................................................................14
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.1.1
Phosphoinositide 3-kinases ...................................................................18
1.1.2
Phosphoinositide 3-kinase delta............................................................18
1.1.3
Relevant data summary.........................................................................18
1.2
Study purpose ........................................................................................................23
2
Study objectives.................................................................................................................24
2.1
Primary objective(s)...............................................................................................24
2.2
Secondary objective(s)...........................................................................................24
2.3
Exploratory objective(s) ........................................................................................24
3
Investigational plan ...........................................................................................................26
3.1
Study design...........................................................................................................26
3.2
Rationale of study design.......................................................................................28
3.3
Rationale of dose/regimen, duration of treatment .................................................29
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................30
3.6
Risks and benefits..................................................................................................30
4
Population..........................................................................................................................31
4.1
Inclusion criteria ....................................................................................................31
4.2
Exclusion criteria...................................................................................................32
5
Restrictions for study subjects...........................................................................................35
5.1
Contraception requirements...................................................................................35
5.2
Prohibited treatment...............................................................................................35
5.2.1
Other investigational therapies..............................................................35
5.2.2
Vaccination ...........................................................................................35
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Amended Clinical Trial Protocol Version 01 (Clean)
Protocol No. CCDZ173X2203
5.2.5
Corticosteroids ......................................................................................36
5.3
Drugs to be used with caution ...............................................................................37
 
 
 
5.4
Dietary restrictions and smoking...........................................................................38
5.4.1
Dietary restrictions................................................................................38
5.4.2
Smoking ................................................................................................38
6
Treatment...........................................................................................................................39
6.1
Study treatment......................................................................................................39
6.1.1
Investigational treatment.......................................................................39
6.2
Treatment arms ......................................................................................................39
6.3
Permitted dose adjustments and interruptions of study treatment.........................39
6.4
Treatment assignment and randomization.............................................................40
6.5
Treatment blinding.................................................................................................40
6.6
Emergency breaking of assigned treatment code ..................................................41
6.7
Treatment exposure and compliance .....................................................................41
6.8
Recommended treatment of adverse events ..........................................................41
6.9
Rescue medication.................................................................................................42
6.10
Concomitant treatment...........................................................................................42
7
Discontinuation and study completion ..............................................................................42
7.1
Discontinuation of study treatment........................................................................42
7.2
Study completion and post-study treatment ..........................................................43
7.3
Lost to follow-up ...................................................................................................43
7.4
Withdrawal of informed consent ...........................................................................44
7.5
Replacement of early withdraws or discontinuations............................................44
7.6
Study Stopping rules..............................................................................................44
7.7
Early study termination by the sponsor .................................................................44
8
Procedures and assessments ..............................................................................................45
8.1
Informed consent procedures.................................................................................48
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8.2
Subject screening...................................................................................................48
8.3
Subject demographics/other baseline characteristics.............................................48
8.3.1
Hepatitis/HIV screening........................................................................49
8.3.2
Tuberculosis testing ..............................................................................49
8.3.3
Alcohol test, Drug screen......................................................................49
8.4
Efficacy..................................................................................................................49
8.4.1
ESSPRI..................................................................................................50
8.4.2
ESSDAI.................................................................................................50
8.4.3
SF-36.....................................................................................................50
8.4.4
MFI........................................................................................................50
8.4.5
Global assessments (VAS) of disease activity......................................50
8.4.6
Patient-Reported Outcome....................................................................51
8.5
Safety.....................................................................................................................52
8.5.1
Physical examination ............................................................................52
8.5.2
Vital signs..............................................................................................52
8.5.3
Height and weight .................................................................................52
8.5.4
Laboratory evaluations..........................................................................52
8.5.5
Pregnancy and assessments of fertility .................................................54
8.5.6
Other safety evaluations........................................................................54
8.6
Pharmacokinetics...................................................................................................54
8.7
Other assessments..................................................................................................55
9
Safety monitoring ..............................................................................................................58
9.1
Adverse events.......................................................................................................58
9.2
Serious adverse event reporting.............................................................................59
9.2.1
Definition of SAE .................................................................................59
9.2.2
SAE reporting........................................................................................60
9.3
Infection Monitoring..............................................................................................61
9.4
Liver safety monitoring .........................................................................................62
9.5
Renal safety monitoring.........................................................................................65
9.6
Pregnancy reporting...............................................................................................66
9.7
Early phase safety monitoring ...............................................................................67
10 Data review and database management.............................................................................67
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10.1
Site monitoring ......................................................................................................67
10.2
Data collection.......................................................................................................67
10.3
Database management and quality control............................................................68
10.4
Data Monitoring Committee..................................................................................69
10.5
Adjudication Committee........................................................................................69
11 Data analysis......................................................................................................................69
11.1
Analysis sets ..........................................................................................................69
11.2
Subject demographics and other baseline characteristics......................................69
11.3
Treatments .............................................................................................................70
11.4
Analysis of the primary variable(s) .......................................................................70
11.4.1
Variable(s).............................................................................................70
11.4.2
Statistical model, hypothesis, and method of analysis..........................70
11.4.3
Handling of missing values/censoring/discontinuations.......................70
11.4.4
Supportive analyses...............................................................................71
11.5
Analysis of secondary and exploratory variables ..................................................71
11.5.1
Efficacy / Pharmacodynamics...............................................................71
11.5.2
Safety.....................................................................................................71
11.5.3
Pharmacokinetics ..................................................................................72
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................72
11.5.5
Other assessments .................................................................................73
11.6
Sample size calculation..........................................................................................74
11.7
Interim analyses .....................................................................................................74
12 Ethical considerations........................................................................................................75
12.1
Regulatory and ethical compliance........................................................................75
12.2
Responsibilities of the investigator and IRB/IEC..................................................75
12.3
Publication of study protocol and results...............................................................75
13 Protocol adherence ............................................................................................................75
13.1
Protocol Amendments ...........................................................................................76
14 References .........................................................................................................................77
17 Appendix 3: Blinding and Unblinding ..............................................................................82
18 Appendix 4: Sample Log Table.........................................................................................83
19 Appendix 5: Sample labeling and shipping information...................................................84
20 Appendix 6: ESSDAI ........................................................................................................85
21 Appendix 7: ESSPRI.........................................................................................................86
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22 Appendix 8: SF-36 ............................................................................................................87
23 Appendix 9: MFI...............................................................................................................88
List of tables
Table 8-1
Assessment schedule.............................................................................45
Table 9-1
Liver Event and Laboratory Trigger Definitions ..................................63
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers...64
Table 9-3
Specific Renal Alert Criteria and Actions.............................................66
List of figures
 
Figure 3-1
Study design..........................................................................................28
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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANA
Anti-nuclear Antibody
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
b.i.d.
twice a day
BM
Biomarker
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive protein
CO2
carbon dioxide
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTRD
Clinical Trial Results Database
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
ESSDAI
EULAR Sjögren’s syndrome disease activity index
ESSPRI
EULAR Sjögren’s syndrome patient reported index
EULAR
European league against rheumatism
DMARDs
Disease-modifying anti-rheumatic drugs
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Protocol No. CCDZ173X2203
DMC
Data Monitoring Committee
DSMB
Data safety monitoring board
FIH
First in Human
FDA
Food and Drug Administration
GCP
Good Clinical Practice
γ-GT
Gamma-glutamyl transferase
h
hour
HV
Healthy Volunteer
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL
Interleukin
i.v.
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
LFT
Liver function test
LDH
lactate dehydrogenase
LLQ
lower limit of quantification
LLN
lower limit of normal
MAD
Multiple ascending dose
MedDRA
Medical dictionary for regulatory activities 
MFI
Multidimensional fatigue inventory questionnaire
mg
milligram(s)
ml
milliliter(s)
NCDS
Novartis Clinical Data Standards
NTI
narrow therapeutic index
OC/RDC
Oracle Clinical/Remote Data Capture
o.d.
once a day
PA
posteroanterior
PD
pharmacodynamic(s)
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Protocol No. CCDZ173X2203
PGA
Physician global assessment
PI3Kδ
Phosphoinositide 3-kinases delta
PK
pharmacokinetic(s)
p.o.
oral(ly)
PoC
Proof of concept
pSS
primary Sjögren’s syndrome
RAP
Reporting and analysis plan
RBC
red blood cell(s)
REB
Research Ethics Board
RF
Rheumatoid factor
SAD
Single ascending dose
SAE
serious adverse event
s.c.
subcutaneous
SF-36
Short form 36
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
SOM
site operations manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
VAS
Visual analog scale
WBC
white blood cell(s)
WHO
World Health Organization
WoCBP
Women of child bearing potential


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to time ‘t’ where t is a defined time point after administration 
[mass x time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x time 
/ volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
F
Bioavailability of a compound. Fabs is the absolute bioavailability, i.e. the 
fraction (or percentage) of the administered extravascular dose systemically 
available. Frel is the relative bioavailability, i.e. the bioavailability relative 
to a reference.
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]
T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]
Vss
The volume of distribution at steady state following intravenous 
administration [volume]


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Protocol No. CCDZ173X2203
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amended Clinical Trial Protocol Version 01 (Clean)
Protocol No. CCDZ173X2203
Protocol synopsis
Protocol number
CCDZ173X2203
Title
A randomized, double-blind, placebo-controlled, parallel group study to 
assess the safety, tolerability, pharmacokinetics and preliminary efficacy of 
CDZ173 in patients with primary Sjögren’s syndrome
Brief title
Safety, tolerability, pharmacokinetics and preliminary efficacy
study of 
CDZ173 in patients with primary Sjögren’s syndrome
Sponsor and Clinical 
Phase
Novartis 
Phase 2
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
This study is designed to evaluate the safety, tolerability, pharmacokinetics 
and preliminary therapeutic efficacy of oral administrations of CDZ173, a 
selective PI3K delta inhibitor, for 12 weeks, in patients with primary Sjögren’s 
syndrome. Data from this study will provide the basis for further development 
of the compound for the treatment of primary Sjögren’s syndrome.
Primary Objective(s)

To assess the safety and tolerability of CDZ173 in patients with primary 
Sjögren’s syndrome.

To compare the effect of CDZ173 versus placebo on the patient-reported 
outcomes of primary Sjögren’s syndrome patients after 12 weeks of 
treatment
Secondary 
Objectives

To assess the pharmacokinetics of CDZ173 in primary Sjögren’s 
syndrome patients

To evaluate the effect of CDZ173 versus placebo on clinical disease 
outcomes in primary Sjögren’s syndrome patients after 12 weeks of 
treatment

To evaluate the changes in the physician global assessment of the 
patient’s overall disease activity after 12 weeks of treatment.

To evaluate the changes in the patients global assessment of their 
disease activity after 12 weeks of treatment
Study design
This is a randomized, double-blind, placebo-controlled, parallel group,
non-confirmatory study.
Population
Male or female patients with primary Sjögren’s syndrome, aged 18 to 75 
years. It is planned to enroll approximately 27 patients.
Key Inclusion 
criteria

Diagnosis of primary Sjögren’s syndrome according to revised EU/US 
consensus criteria

Moderate to severe disease activity by ESSDAI score ≥ 6 at screening 
visit;

ESSPRI at screening visit ≥5
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Key Exclusion 
criteria

Secondary Sjögren’s syndrome (presence of another connective tissue 
disease)

Patients having received the following treatments related to 
randomization time-point:
- Oral or i.v. cyclophosphamide within 6 months;
- i.v. corticosteroid bolus with dose > 1 mg/kg within 3 months;
- Rituximab and other B cell depleting agents within 12 months; for 
patients who received such drug, their B cell count should be within 
normal range
- Belimumab within 6 months;
- Any other biologic within 1 month or five times the half-life;
- Any other immunosuppressives such as systemic cyclosporine A or 
Mycophenolate within 3 months;

History or current diagnosis of ECG abnormalities indicating significant 
risk of safety for patients;
 
 

History of malignancy of any organ system except localized basal cell 
carcinoma of the skin;

History of ongoing, chronic or recurrent infectious disease or evidence of 
tuberculosis infection;

History of immunodeficiency diseases;

Any live vaccines (this includes any attenuated live vaccines) starting 
from 6 weeks prior to randomization.

Female participants need to agree to use highly effective contraception 
(according to ICH M3) 
Investigational and 
reference therapy
CDZ173 70 mg b.i.d.; matching placebo
Efficacy 
assessments

EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI)

EULAR Sjögren’s syndrome disease activity index (ESSDAI)

Short Form (36) Health Survey (SF-36)

Multidimensional Fatigue Inventory (MFI) Questionnaire

Physician’s and Patient’s assessment of global disease activity (Visual 
Analog Scale, VAS)
Key safety 
assessments

Physical examination

Vital signs

Safety Laboratory(Hematology, Biochemistry, Urinalysis)

Electrocardiogram (ECG)

Adverse Events
 
 
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Data analysis
The primary efficacy analysis will be based on a longitudinal mixed model of 
ESSPRI as a function of baseline ESSPRI, baseline intake of steroids 
(yes/no, which is a stratification factor for the randomization), treatment, time 
as a continuous variable (linear and quadratic terms), interaction between 
treatment and time, as well as a random intercept, random slope and random 
quadratic effects by subject to account for within-subject correlations. 
The difference between active treatment and placebo in change from 
baseline visit in ESSPRI after 12 weeks treatment will be estimated from the 
model and presented with 80% confidence intervals. Simpler models will also 
be considered in case the pre-specified model does not fit the data well.
The following criteria will be considered indicative of treatment efficacy:
- Statistically significant decrease in ESSPRI after 12 weeks on treatment 
compared to placebo (at one-sided 10% level)
- Estimated mean reduction in ESSPRI after 12 weeks treatment of 1 point or 
more than on placebo
The decrease of 1 point is considered clinically relevant as 0.67 – 1 points 
have been published to be the minimal clinically important improvement. 
In the absence of a standard of care with demonstrated long-term efficacy, no 
confirmation is available that a decrease of 1 point will translate into a 
long-term benefit.
Key words
CDZ173, PI3K pathway, primary Sjögren’s syndrome


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1
Introduction
1.1
Background
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease of unknown etiology. 
It is characterized by lymphoid infiltration and progressive destruction of exocrine glands 
(Youinou and Pers 2012). Current hypotheses of the underlying cause of pSS describe a viral 
triggering infection of the exocrine epithelial cells, resulting in release of autoantigens 
(Nocturne and Mariette 2013). Plasmacytoid dendritic cells are activated, resulting in release 
of type 1 interferons and upregulation of toll-like receptors and other innate immune 
responses leading to B cell activation. Plasmacytoid dendritic cells also release IL-12, leading 
to T cell activation and generation of Th1- and Th17-mediated inflammation and tissue 
destruction. Together, the activated B cells and T cells form ectopic lymphoid structures 
ranging from loose aggregates of lymphocytes to germinal center-like structures wherein 
plasmablasts and plasma cells generate autoantibodies (e.g., ANA, anti-SSA, anti-SSB, 
rheumatoid factor) and leading to immune complex formation.
Primary Sjögren’s syndrome is a common disorder, second only to rheumatoid arthritis (RA) 
in prevalence as a systemic autoimmune disease. The disease affects mainly women with a 
female/male ratio of 9:1 and can occur at any age. 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). Most 
patients (reported as frequently as in 85% of patients) experience profound and disabling 
fatigue, described as an ever-present, fluctuating, and uncontrollable lack of energy 
(Mengshoel et al 2014). Disease impact on quality of life (QOL) measures is substantial and 
comparative studies demonstrate pSS QoL scores quantitatively worse than in congestive 
heart failure or many cancers (Segal et al 2009; 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 ineffective, and no pharmacologic intervention is effective against the severe, disabling 
fatigue. Although small trials with the B cell depleting agent rituximab have demonstrated a 
degree of therapeutic efficacy in approximately 50% of pSS patients, no proper, large 
randomized controlled trials have shown clear efficacy in pSS. Thus, a disease modifying 
agent that prevents secretory gland destruction and addresses extra-glandular disease 
manifestations would introduce a significant advance for the treatment of pSS.


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1.1.1
Phosphoinositide 3-kinases
Phosphoinositide 3-kinases (PI3K) are lipid kinases that are crucial for intracellular signal 
transduction. Activated through tyrosine kinase coupled receptors and recruited to the plasma 
membrane, their principal function is the generation of phosphatidylinositol-3,4,5-
trisphosphate (PIP3). PIP3 serves as an important cellular second messenger specifically 
activating Akt (via Phosphoinositide-dependent protein kinase [PDK1]) and regulating a 
multitude of cellular processes (Kandel and Hay 1999). PI3K are classified according to their 
structural and functional properties into three classes (IA & B, II and III). All class IA PI3K 
are heterodimeric molecules composed of an 85 kD regulatory subunit (p85) and one of three 
different 110 kD catalytic subunits (p110α, p110β and p110δ).  
1.1.2
Phosphoinositide 3-kinase delta
PI3Kδ is primarily expressed in hematopoietic cells and is functionally relevant in the 
adaptive (particularly B cells) and the innate immune system. Specifically, PI3Kδ has been 
shown to contribute to key elements of autoimmune pathophysiology such as B lymphocyte 
activation, cytokine secretion, antigen presentation and autoantibody production. Blockade of 
PI3Kδ impedes B cell activation and lymphocyte germinal center formation as well as 
immune cell trafficking, therefore supporting the rationale that PI3Kδ–targeted therapy has a 
strong potential in treating autoimmune diseases, notably also pSS. In addition, specifically 
targeting PI3Kδ should help to avoid potential side effects associated with ubiquitously 
expressed PI3Kα and β isoforms (Hirsch et al 2000; Li et al 2000; Sasaki et al 2000; 
Patrucco et al 2004; Clayton et al 2002; Jou et al 2002).
CDZ173 is an oral, low molecular weight compound that selectively inhibits the lipid kinase 
PI3Kδ and may therefore be a valid treatment option in pSS.
1.1.3
Relevant data summary
 
1.1.3.1
Preclinical data
 
 
 
 
 
 
 
 
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1.1.3.2
Teratogenicity and reproductive toxicity data
 
 
 
 
 
 
 
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1.1.3.3
Human safety and tolerability data
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.1.3.4
Human pharmacokinetic data
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.1.3.5
Human pharmacodynamic data
 
 
 
 
 
 
1.2
Study purpose
This study is designed as a proof of concept study of CDZ173 in primary Sjögren’s syndrome. 
The purpose of the present study is to evaluate the safety, tolerability, pharmacokinetics and 
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preliminary therapeutic efficacy of CDZ173 in patients with pSS. The study outcome will 
provide data for the further development of CDZ173 in the treatment of pSS.
2
Study objectives
2.1
Primary objective(s)
Objective
Endpoint

To assess the safety and tolerability of 
CDZ173 in patients with primary 
Sjögren’s syndrome  

AEs, vital signs, ECGs, safety 
laboratory parameters (hematology, 
biochemistry, urinalysis) 

To compare the effect of CDZ173 versus 
placebo on the patient reported outcome of
primary Sjögren’s syndrome patients after 
12 weeks of treatment (study week 13)

Change in EULAR Sjögren’s Syndrome 
Patient Reported Index (ESSPRI)
2.2
Secondary objective(s)
Objective
Endpoint

To assess the pharmacokinetics of 
CDZ173 in primary Sjögren’s syndrome 
patients

Single dose (Day 1) CDZ173 PK 
parameters (including but not limited to 
Cmax and AUC), and trough evaluation 
after multiple doses (Days 8, 15, 29, 57 
and 85)

To evaluate the effect of CDZ173 versus
placebo on outcomes in primary 
Sjögren’s syndrome patients after 12 
weeks of treatment (study week 13)

EULAR Sjögren’s Syndrome Disease 
Activity Index (ESSDAI), 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 after 12 weeks of 
treatment (study week 13)

Physician’s visual analog scale (VAS)

To evaluate the changes in the patients 
global assessment of their disease 
activity after 12 weeks treatment (study 
week 13)

Patient’s visual analog scale (VAS)
2.3
Exploratory objective(s)
 
 
 
 
 
 
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3
Investigational plan
3.1
Study design
This is a double-blind, randomized, placebo-controlled, parallel design, non-confirmatory
study to assess the safety, tolerability, pharmacokinetics and preliminary clinical efficacy of 
multiple oral doses of CDZ173 (70 mg b.i.d.) in patients with pSS.
The study will consist of a 4-week screening period, a baseline period prior to randomization,
a 12-week treatment period and a 4-week follow-up period (no study drug or study visits) 
before the End of Study visit. The total duration for each patient in the study will be 
approximately 21 weeks.
Approximately 27 patients will be randomized (2:1) to a 12 week treatment receiving either 
CDZ173 or placebo. Randomization will be stratified according to baseline glucocorticoid 
intake (yes/no).
For the entire duration of the treatment period (12 weeks), patients will receive a b.i.d. dosing 
regimen to be administered at approximately 12 h intervals.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, biochemistry and urinalysis) as well as adverse event and 
serious adverse event monitoring.
Other assessments to be completed are outlined in the Assessment schedule.
Screening and Baseline
For each patient there will be a screening period of up to 28 days (Day -28 to Day -2). 
The screening visit (V1) may be split over 2 days if it is in the best interest of the patient or 
for logistical reasons.
Subjects who meet the eligibility criteria at screening visit (V1) will be admitted to baseline 
evaluations. The baseline visit (V2) will occur at Day -1, but may be extended up to Day 1 to 
enable all assessments to be completed prior to study drug administration on Day 1 (V3). 
Assessments to be completed at Screening and Baseline are outlined in the 
Assessment schedule.
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Randomization and 12 week treatment period
Eligible patients (according to Inclusion and Exclusion criteria in Section 4), will be 
randomized (via IRT) to receive either CDZ173 or placebo as twice daily (b.i.d.) oral doses 
for 12 weeks. Study treatment will be initiated on Day 1 (Visit V3).
During Day 1 (V3), patients will undergo various pre-dose procedures (including PK and PD
and biomarker baseline samples collection) prior to receiving the study drug. Patients will 
remain at the site for approximately 8 hours post dose for various safety, PK and PD and 
biomarker assessments at timepoints as outlined in the Assessment schedule.
Patients will then be able to return home to continue their daily treatment regimen
(self-administration). 
Patients will return to the study site at approximately weekly intervals for the first three weeks 
(V4, Week 2 and V5, Week 3), then fortnightly for V6 (Week 5) followed by approximately 
monthly visits for V7 (Week 9) and V8 (Week 13). At each study visit, patients will undergo 
assessments with various scales/questionnaires, as well as safety, PK and PD and biomarker
sampling as indicated in the Assessment schedule and described in Section 8. Patients will be 
asked to take their morning dose of study drug at the site on these visit days.
All study visits during the treatment period will be ambulatory. However, for logistical 
reasons, it may be necessary for patients to come to the site the evening before their scheduled 
assessment visits, or to remain at the site following the visit (e.g. transport restrictions, long 
travel times from home to site). In these instances, the patients may stay overnight at the site, 
but this would not be considered as an SAE.
The ambulatory visits may be conducted within an allowed time window as indicated in the 
Assessment schedule.
Patients will be provided with a patient diary to record study drug self-administration, 
Adverse Events and concomitant medication use
during the treatment period. The 
Investigator/site staff may contact the patients during the study to ensure compliance/monitor 
safety by telephone or other means, if it is deemed appropriate.
Follow up and end of study visit (EoS)
After the last day of dosing, patients will enter a 4-week follow-up period without study drug 
treatment. Patients will then be asked to return to the site at Week 17 for the End-of-Study
visit. At this visit, patients will undergo final assessments as indicated in the 
Assessment schedule. Upon completion of this visit, patients will be discharged from the 
study.


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Figure 3-1
Study design
3.2
Rationale of study design
CDZ173 is an oral, low molecular weight compound that selectively inhibits the lipid kinase 
PI3Kδ, an important mediator of immune cell activation and germinal center formation. 
The essential role of PI3Kδ in the adaptive as well as the innate immune system strongly 
supports the rationale for the PI3Kδ targeted intervention in autoimmune diseases.
The interference with germinal center formation further supports expected efficacy in patients 
with pSS where ectopic germinal centers in salivary glands are considered pathogenically 
important. This study will be conducted in patients with active pSS, where no established 
clinically effective disease modifying treatment has been proven effective against the 
underlying disease. 
A randomized, placebo-controlled, double-blind approach is used to eliminate potential bias 
in reporting safety and clinical efficacy data. Patients will be randomized to CDZ173 or 
placebo in a 2:1 ratio in order to minimize exposure to placebo and to gather mor e data on 
CDZ173. Stratified randomization is done in order to limit imbalances between active and 
placebo arms in baseline intake of oral corticosteroids. 
After the double-blind period, the patients will enter a follow-up period; for which a duration 
of 4 weeks was chosen to allow sufficient time for safety monitoring.
In addition to safety, efficacy estimated by the EULAR Sjögren’s Syndrome Patient Reported
Index (ESSPRI) is chosen as a key endpoint of the study (Seror et al 2011). A decrease of 1.7
points was observed at week 16
in a small open-label study with rituximab 
(Meiners et al 2012). In a publication the group of Seror reported 0.67 – 1 ESSPRI points to 
be the minimal clinically important improvement (Seror et al 2016). In addition to the 
ESSPRI, efficacy estimated by the EULAR Sjögren’s Syndrome Disease Activity Index 
(ESSDAI) is chosen as a second disease specific endpoint of the study. The ESSDAI assesses 
organ involvement in patients with pSS and has been shown to be sensitive to suggest efficacy 
of rituximab treatment in a randomized controlled trial (Moerman et al 2014). Further efficacy 
assessments include diseases-independent outcome variables (SF-36, MFI, patients’ and 
Screening
CDZ173: 70 mg b.i.d
PLACEBO: b.i.d
Follow-up
-4                              -1   1         2           3  
5                   9                   13                                17
week
End of Study
R
A
Key: B: Baseline; R: Randomization; A: assessments (PROs, PK etc) at site
A
A
A
A
A
A
B
A
Up to 4 weeks 
12 weeks Treatment 
4 weeks 


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physicians’ global assessments) 
 
3.3
Rationale of dose/regimen, duration of treatment
CDZ173 will be administered orally for 12 weeks at a dose of 70 mg b.i.d. and be compared 
to placebo, also dosed b.i.d.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4
Rationale for choice of comparator
Placebo to CDZ173 will be used as a comparator to provide objective evidence of potential 
AEs and other safety data as well as clinical efficacy and PD data generated from patients 
exposed to experimental therapy. Since there is no established clinically effective disease 
modifying treatment for patients with pSS, and considering the relatively limited duration of 
the trial, use of placebo is considered justified.
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3.5
Purpose and timing of interim analyses/design adaptations
 
 
 
 
 
 
 
 
3.6
Risks and benefits
The PI3K pathway has been identified as a key pathway in inflammation and autoimmunity in
preclinical models. Its inhibition by CDZ173 is therefore expected to result in a clinical 
benefit in patients with active primary Sjögren’s syndrome (pSS).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, defined stopping rules and by prohibiting concomitant medication that 
possibly may lead to significant drug-drug interactions.
A maximum of 420 mL of blood is planned to be collected over a period of about 21 weeks, 
from each subject as part of the study. Additional samples for monitoring of any safety 
findings would be in addition to this. This is not considered to be a risk for this population.
Women of child bearing potential should be informed that taking the study drug may involv e 
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.
There may be unknown risks of CDZ173 which may be serious and unforeseen.
4
Population
The study population will be comprised of male and female patients with active primary 
Sjögren’s syndrome.
Approximately 27 patients will be randomized to participate in the study.
The investigator must ensure that all patients being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at screening
and 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 entry criterion excludes a subject from enrollment into the study.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed;
2. Male or female patient, aged 18 to 75 years, inclusive;
3. Diagnosis of primary Sjögren’s syndrome according to revised EU/US consensus criteria 
(Vitali et al 2002). In the event of new criteria being released, the 2002 criteria version 
will remain as the reference for diagnostic inclusion criteria;
4. Moderate to severe disease activity as determined by ESSDAI score ≥6 at screening visit;
5. ESSPRI at screening visit ≥5;
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8. Patient must be able to communicate well with the investigator, to understand and comply 
with the requirements of the study.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Secondary Sjögren’s syndrome. Patients with laboratory or clinical signs of another 
connective tissue disease (e.g. systemic lupus erythematous) but not fulfilling the 
diagnostic criteria for that disease, may be eligible at the Investigators discretion;
2. Use of other investigational drugs at the time of enrollment, or is within 5 half-lives of 
using other 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;
4. Patients having received the following treatments (within in the specified timeframe) prior 
to randomization:

Oral or i.v. cyclophosphamide treatment within 6 months of randomization;

i.v. corticosteroid bolus with a dose > 1 mg/kg within 3 months of randomization;

Rituximab or other B cell depleting drug within 12 months of randomization. For 
patients who received such drug, their B cell count should be within normal range;

Belimumab within 6 months of randomization;

Any other biologic within 1 month of randomization or five-times the half-life, 
whichever is longer;

Any other immunosuppressive such as systemic cyclosporine A or mycophenolate 
within 3 months of randomization;

If the patient is on oral glucocorticoid treatment at Screening, the dose must NOT 
exceed 10 mg prednisone or equivalent per day, and must be stable for at least 2 
weeks prior to randomization and for the duration 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 on 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;
5. Require regular or intermittent use of medications that, as judged by the Investigator, can 
cause dry mouth in the patient, (such as antidepressants, anticholinergics, anti-Parkinson 
agents, and diuretics);
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7. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in 
case of participation in the study. The investigator should make this determination in 
consideration of the subject’s medical history and/or clinical or laboratory evidence of any 
of the following:

Uncontrolled hypertension (≥160/95 mmHg)

Uncontrolled diabetes (insulin dependent or non-insulin dependent)

Congestive heart failure (New York Heart Association status of class III or IV)

Severe chronic obstructive pulmonary disease (GOLD stage 3-4)

Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding

Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel 
resection

Pancreatic injury or pancreatitis

Liver disease or liver injury as indicated by abnormal liver function tests such as AST 
(SGOT), ALT (SGPT), alkaline phosphatase, or serum bilirubin. The Investigator 
should be guided by the following criteria: ALT must NOT exceed 1.5 times upper 
limit of normal (ULN)

History of renal injury/renal disease (e.g. renal trauma, glomerulonephritis, or one 
kidney only) or presence of impaired renal function as indicated by a serum creatinine 
level exceeding 1.5 mg/dL (133 μmol/L)

Evidence of urinary obstruction or difficulty in voiding at screening
8. Clinically significant abnormal hematology laboratory values at screening:

Total white blood cell count (WBC) outside the range of 2.0-15.0 x 109/L

Platelets <100 x 109/L

Hemoglobin <9.0 g/dL

Lymphocyte count < 0.8 x 109/L

Neutrophil count <1.5 x 109/L
 
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11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG serum test
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of study medication and for 2 days after stopping study treatment. Highly 
effective contraception methods (according to ICH M3) 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), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment;

Male sterilization (at least 6 month prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient;

Use of oral, injected or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS) or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception

In case of use of oral contraception women should have been stabile 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) or tubal ligation at 
least six weeks before screening. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone 
level assessment she is considered of not being of child bearing potential
13. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases
14. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by a positive QuantiFERON TB-Gold test at Screening. If presence of 
latent tuberculosis is established then treatment according to local country guidelines must 
have been completed before patient can be considered for enrollment
15. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) 
test result at Screening
16. A positive Hepatitis B surface antigen or Hepatitis C test result at Screening
17. Donation or loss of 400 mL or more of blood within 8 weeks before randomization
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18. History or evidence of ongoing alcohol or drug abuse, within the last 12 months before 
randomization
19. Any live vaccines (this includes any attenuated live vaccines) starting from 6 weeks 
before study entry, during the study and up to 7 day after the last dose of CDZ173 should 
be excluded
Note: In the case where a safety laboratory assessment at screening is outside of the range 
specified above, the assessment may be repeated once prior to randomization. If the repeat 
value remains outside of the specified ranges, the subject is excluded from the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for study subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must
be informed and reminded of the following restrictions:
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4.2) for details of contraception requirements for the 
study. 
5.2
Prohibited treatment
5.2.1
Other investigational therapies
Other investigational therapies must not be used while the patient is on the study. If such 
agents are required for a patient then the patient must be permanently discontinued from the 
treatment portion of the study.
5.2.2
Vaccination
Live/Attenuated Vaccination: The study drug is considered to decrease activities of cells of 
the immune system, thus from 6 weeks prior to randomization, until 7 days after cessation of 
study treatment, live vaccines (incl. attenuated viruses) are not permitted.
Dead vaccines: Due to the decreased activities of the immune cells, use of dead vaccines is 
expected to be less effective or ineffective. Patients should be advised that their vaccination 
may be ineffective if administered within the timeframe specified above. However, patients 
will not be discouraged from receiving dead vaccines, including the seasonal influenza 
vaccination.
Patients and physicians are encouraged to plan required vaccinations outside this window.


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5.2.5
Corticosteroids
 
 
If a systemic corticosteroid dose 
corresponding to a daily prednisone equivalent > 10 mg is deemed required for longer than 5 days, 
then the patient will be discontinued from study treatment but will continue in the study.
Systemic dosing of corticosteroids corresponding to a daily prednisolone ≤10 mg is known to 
be a weak inducer only and is therefore allowed. Patients taking oral systemic corticosteroids 
have to be on a stable dose of ≤10 mg/d prednisone or equivalent for at least 2 weeks before 
randomization, and are allowed to continue on a stable dose. Topical applications (e.g., rash), 
inhaled sprays (e.g., obstructive airways diseases or allergic rhinitis), or eye drops are also 
allowed.
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5.3
Drugs to be used with caution
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.4
Dietary restrictions and smoking
5.4.1
Dietary restrictions

Patients should be instructed to take the dose of CDZ173 daily in the morning and in the 
evening, at approximately the same time each day, except on the days blood collection is 
scheduled at the clinic, at which time the patients should take their doses at the clinic. 

The morning dose of CDZ173 should be taken at approximately the same time each day 
when most convenient for the patient. Patients may take CDZ173 irrespective of food 
intake.

The evening dose should be taken approximately 12 hours after the morning dose. 
Patients may take CDZ173 irrespective of food intake. 

CDZ173 should be taken with a glass of water and consumed over as short a time as 
possible. Patients should be instructed to swallow the capsules whole and not to chew 
them

If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose.

Missed doses should not be made up.
5.4.2
Smoking
It is recommended to reduce or completely refrain from smoking. Smoking status at screening 
will be recorded in the CRF. 
 
 
This restriction does not apply to nicotine gum 
or electronic cigarettes.
 
 
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6
Treatment
6.1
Study treatment
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatment are outlined in Section 3 of the Site Operations 
Manual.
6.1.1
Investigational treatment
The investigational drug, CDZ173 (70 mg and matching placebo capsules) will be prepared 
and supplied by Novartis. Study drug will be provided in blinded packaging in a way that the 
patient can take the medication home for dosing. Resupply of medication may be required 
during the study due to shelf-life. Study treatment assignment will be done by an IRT system.
The Investigator, the patient, and the clinical trial team of the Sponsor directly involved in the 
study will be blinded.
6.2
Treatment arms
Patients will be randomized to CDZ173 or placebo in a 2:1 ratio in order to minimize exposure 
to placebo and to gather more data on CDZ173. Stratified randomization is done by baseline intake 
of oral corticosteroids in order to limit imbalances between active and placebo arms.
Study treatments are defined as:

CDZ173 70 mg as oral capsules , b.i.d. for 12 weeks (84 days)

CDZ173 matched placebo, oral capsules, b.i.d. for 12 weeks (84 days)
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted, except in the following 
case below.
 
 
However, if study drug dosing was for any reason interrupted for cumulatively more t han 28 
doses (i.e., 14 days, whether consecutive or not), then the patient will be discontinued from 
study treatment but will continue in the study. These changes must be recorded on the Dosage 
Administration Record CRF.
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6.4
Treatment assignment and randomization
At Baseline/Randomization visit, all eligible subjects will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms. The investigator or his/her delegate 
will contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the 
patient to a treatment arm and will specify a unique medication number for the package of 
study drug to be dispensed to the patient. The randomization number will not be 
communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of patient numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).
Randomization will be stratified by use of corticosteroids (yes/no). The randomization scheme 
for patients will be reviewed and approved by a member of the Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of patients.
The investigator will enter the screening number and medication number in the eCRF.
6.5
Treatment blinding
This is a double blind study: subjects, investigator staff, persons performing the assessments, 
and data analysts will remain blind to the identity of study treatments.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor. 
The Interim Analysis Team, which can be unblinded to the results at this point, may 
communicate interim analysis results (e.g. evaluation of efficacy and safety criteria,
evaluation of PoC criteria or information needed for planning/modifying another study) to 
relevant Novartis teams for information, consulting and/or decision purposes. The Interim 
Analysis Team is defined in the SOM, and includes at a minimum the Trial Statistician, 
Trial Programmer and the Trial Medical Expert.
Unblinding will only occur in the case of patient emergencies (see Section 6.6), at the time of 
the interim analysis and at the conclusion of the study.


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6.6
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and an email with an onscreen display of the medication 
confirming this information. The system will automatically inform the Novartis monitor for 
the site and the Study Team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. If appropriate, the investigator will inform the subject how to 
contact his/her backup in cases of emergency when he/she is unavailable.
6.7
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with CDZ173, as detailed in Section 8.6.
Subjects will provide pre- and post-dose blood samples up to 7 hours after the first dose 
administration (Day 1, Visit 3), pre-and post-dose blood samples up to 3 hours post dose on
Day 8 (Visit 4), and pre-dose blood samples on Day 15, Day 29, Day 57 and Day 85 (Visit 5, 
Visit 6, Visit 7 and Visit 8), as reported in the Assessment schedule.
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the subject. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
6.8
Recommended treatment of adverse events
No medications are currently recommended to manage adverse events associated with 
CDZ173. AEs should be treated according to established medical practice, and the judgement 
of the investigator. 
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
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6.9
Rescue medication
There is no established, approved immunosuppressive treatment for pSS. Patients may receive
NSAIDs, paracetamol, or symptomatic care at the discretion of the treating physician as
outlined in Section 6.10. Rescue medicine is to be provided by the study center or personal
physician.
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies in the eCRF after start of study drug.
6.10
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. The salivary 
stimulants should be stopped within 48 hours prior to, and during assessment of clinical 
disease outcome measurements. Artificial tears and artificial saliva are to be provided by the 
study center or personal physician.
Concomitant use of corticosteroids is allowed at a dose of max 10 mg per day (prednisone or 
equivalent) and no immunosuppressives such as systemic cyclosporine, cyclophosphamide, 
mycophenolate or azathioprine are allowed. Stable dose of methotrexate (up to 25 mg per 
week) and/or antimalarials are permitted. Any other drug with a potential immunosuppressive 
effect that is not specifically mentioned in the Inclusion/Exclusion criteria should be discussed 
with the Sponsor on a case by case basis.
The investigator should instruct the subject to notify the study site about any new medications 
he/she takes after the start of the study drug.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies section of the 
CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being.
Study treatment must be discontinued under the following circumstances:

Subject withdraws consent

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
The subject experiences a drug-related serious adverse event

Absolute QTcF (or QTcB) >500 msec, as confirmed by repeat ECG measurements 
performed as soon as possible

Diarrhea of CTCAE grade ≥ 2 on more than 3 consecutive days

Diarrhea of CTCAE Grade 3 or higher 

Diarrhea or abdominal pain with accompanying fever assessed to be related to a 
gastrointestinal infection

Increase of methotrexate dose and/or corticosteroid dose and/or chloroquine during 12 
weeks of dosing (see Section 6.10).
The patient will be discontinued from study treatment and will continue in the study if
deviating from the prescribed dose regimen for study treatment:

More than 28 missed doses of study treatment cumulatively (i.e., 14 days, whether 
consecutive or not)
Discontinuation of study treatment will be at the discretion of the Investigator, under the 
following circumstances:

Any protocol deviation or adverse event that results in a significant risk to the patient’s safety

Use of prohibited treatment other than described under Concomitant Treatment, please see 
also Section 5.2
The appropriate personnel from the site and Novartis will assess whether study treatment
should be discontinued for any subject whose treatment code has been broken inadvertently 
for any reason.
Subjects who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent. They should return for all assessments as 
presented in the Assessment schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, email and letter) should be made to contact them.
7.2
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no f urther 
study treatment will be made available to them. Study completion is defined as when the last 
subject completes their End of Study visit, and any repeat assessments associated with this 
visit have been documented and followed-up appropriately by the Investigator, or in the event 
of an early study termination decision, the date of that decision.
The 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.
7.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.


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7.4
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore and/or does not want any further visits or assessments and/or does not want any 
further study related contact and/or 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. All biological 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.
7.5
Replacement of early withdraws or discontinuations
The sponsor may replace patients who withdrew or discontinued from study treatment before 
study week 13.
7.6
Study Stopping rules
The study will be put on temporary hold and safety data will be reviewed if any of the 
following criteria are met, and no further enrollment will take place pending a full safety 
review conducted by the sponsor:

Two or more subjects experience a drug-related serious adverse event

Three or more subjects report CTCAE (current version) Grade 3 or higher adverse events 
within the same organ class that are considered to be related to study drug

The sponsor considers that the number and/or severity of adverse events justify 
discontinuation of the study

The sponsor requests it
7.7
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
subjects must be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.








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8.1
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research. 
Novartis will review the Investigators proposed informed consent form to ensure it complies 
with the ICHE6 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.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
 
 
 
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.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Subject screening
In general it is permissible to re-screen a patient if s/he fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis. 
Information on what data should be collected for screening failures is outlined in the Site 
Operations Manual.
8.3
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.
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Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, the diagnoses and not symptoms will be recorded.
Medications, over-the-counter drugs and significant non-drug therapies (including physical 
therapy and blood transfusions) prior to the start of the study will also be recorded.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3.1
Hepatitis/HIV screening
All patients will be screened for Hepatitis B surface antigen (HBsAg). Screening for Hepatitis 
C will be based on HCV antibodies.
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a 
second technique available at the laboratory, e.g. Western Blot.
Appropriate counseling will be made available by the Investigator in the event of a positive 
finding. Notification of state and federal authorities, as required by local law, will be the 
responsibility of the Investigator.
Results will be available as source data and will not be recorded within the CRF.
8.3.2
Tuberculosis testing
In order to evaluate a possible infection or latent infection with tuberculosis, a Quantiferon 
Gold® test will be performed and read at screening.
A positive QuantiFeron test at screening will exclude the subjects from the participation in the 
study. Results will be available as source data and will not be recorded within the (e)CRF.
8.3.3
Alcohol test, Drug screen
Subjects will be tested for substances of abuse (e.g., alcohol, amphetamines, barbiturates,
benzodiazepines, cannabinoids, cocaine, and opiates).
Results will be available as source data and will not be recorded within the (e)CRF.
8.4
Efficacy
In addition to assessments for safety, PK and PD, exploratory clinical efficacy measurements
will include components of the ESSDAI and of the ESSPRI and other patient-based
assessments, along with imaging, histopathology and functional assessments of the exocrine
glands. 
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8.4.1
ESSPRI
The ESSPRI (Appendix 7) is an established disease outcome measure for Sjögren’s syndrome.
It consists of a questionnaire developed to assess the patients' symptoms in primary Sjögren's 
syndrome and covers the three key subjective areas of discomfort, i.e., dryness, pain and 
fatigue (Seror et al 2011). The full questionnaire has 21 questions. Subsequently, it was noted 
that the first three questions, Likert scales ranging from 0 – 10, capture the essence of the 
ESSPRI. This abbreviated version was used to define the “minimal clinically important 
improvement” (0.67 – 1) and the “patient-acceptable symptom state” (<5) (Seror et al 2016).
Study subjects in the present study will be asked to complete the full ESSPRI questionnaire. 
However the mean of the first three questions is used for the primary analysis and for the 
assessment of eligibility.
8.4.2
ESSDAI
The ESSDAI (Appendix 6) 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.
For assessments not listed in the protocol as mandatory tests but which may be needed to
estimate ESSDAI, including radiography, high resolution computer tomography (HRCT),
lung function test (DLCO, FVC), estimated glomerular filtration rate (eGFR),
electromyography (EMG), muscle (or any other) biopsy, it is at the investigator’s discretion to
have these assessed based on the signs and symptoms of the patient so to provide correct
ESSDAI readout. 
8.4.3
SF-36
The Short Form Health Survey (SF-36) is a survey evaluating individual patients’ health
status which also monitors and compares patients’ disease burden (Appendix 8).
The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general 
health perceptions, physical role functioning, emotional role functioning, social role
functioning, mental health), which are the weighted sums of the questions in their section.
8.4.4
MFI
The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to 
measure fatigue covering the following dimensions: General Fatigue, Physical Fatigue,
Mental Fatigue, Reduced Motivation and Reduced Activity (Appendix 9).
8.4.5
Global assessments (VAS) of disease activity
8.4.5.1
Physician’s global assessment
The physician’s global assessment of disease activity will be performed using 100 mm VAS
ranging from no disease activity to maximal disease activity, after the question “Considering


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all the ways the disease affects your patient, draw a line on the scale for how well his or her
condition is today”. 
The investigator will then measure the distance in mm from the left edge of the scale and the
value will be entered on the eCRF.
8.4.5.2
Patient’s global assessment
The patient’s global assessment of disease activity will be performed using 100 mm VAS
ranging from no disease activity to maximal disease activity, after the question on how well
the patient is doing with the disease considering all aspects affected by the disease.
The investigator will then measure the distance in mm from the left edge of the scale and the
value will be entered on the eCRF.
8.4.6
Patient-Reported Outcome
Refer to Section 8.4.1, Section 8.4.2, Section 8.4.3 and Section 8.4.4 for patient-reported
Outcome.
The patients will be asked to complete a paper copy of the questionnaires or VAS scale in
their local language. The printed copy will serve as source data and the patients’ responses
will be transcribed into the eCRF.
Completed questionnaires and VAS scale will be reviewed and examined by the Investigator
before the clinical examination for responses which may indicate potential AEs or SAEs.
The Investigator should review not only the responses to the VAS scale, but also for any
unsolicited comments written by the patient.
If the occurrence of AEs or SAEs is confirmed, the Investigator should record the events as
per instructions given in Section 9 Investigators should not encourage the patients to change
the responses reported on the VAS scale.
 
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8.5
Safety
8.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and/or pelvic exams may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded in the CRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History CRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event 
must be appropriately recorded on the Adverse Event CRF.
8.5.2
Vital signs
Vital signs include blood pressure (BP), pulse measurements, and body temperature.
After the patient has been sitting for 3 minutes, with back supported and both feet placed on
the floor, systolic and diastolic BP will be measured using an automated validated device. 
The body temperature will be measured as indicated in the Assessment schedule according to
local regulations. The measurement will be conducted at the same anatomical location 
throughout the study participation.
8.5.3
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.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2.
8.5.4
Laboratory evaluations
A central laboratory will be used in this study. Central laboratory information, including 
collection, shipment of samples and reporting of results, may be found in the laboratory 
manual. 
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In the case of a laboratory assessment that is listed in the eligibility criteria is outside of a 
protocol-specified range at screening and/or at the baseline visit, the assessment may be 
repeated once prior to randomization. If the repeat value remains outside of protocol-specified 
ranges, the patient is excluded from the study.
In the case of a laboratory range is not specified by the protocol, but the laboratory is outside 
the reference range at screening and/or baseline visit, a decision regarding whether the result 
is of clinical significance or not shall be made by the Investigator, and shall be based, in part, 
upon the nature and degree of the observed abnormality. The assessment may be repeated 
once prior to randomization.
In all cases, the Investigator must document in the source documents the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the patient to continue in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
8.5.4.1
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.
8.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, 
chloride, creatinine, CK, hsCRP, gamma-GT, glucose, LDH, inorganic phosphorus, lipase, 
amylase, magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, TSH, T3, T4, 
urea/BUN and uric acid will be measured.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal,
direct and indirect reacting bilirubin should be differentiated.
8.5.4.3
Urinalysis
Dipstick urine tests will be performed measuring leucocytes, nitrite, pH, protein, glucose, 
ketones, urobilinogen, bilirubin, blood/ hemoglobin.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be
sent for microscopic analysis of WBC, RBC and casts to the central or local laboratory.
 
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8.5.4.8
Electrocardiogram (ECG)
ECGs are assessed to ensure patient safety. Details of all procedures relating to ECG 
collection and reporting will be described in the SOM. The following measurements will be
reported:

PR interval, QRS duration, heart rate, RR, QT, QTc
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Clinically significant abnormalities should be recorded on the relevant section of the medical
history/Current medical conditions/AE eCRF page as appropriate.
8.5.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have regular pregnancy tests 
during the study. 
Serum pregnancy tests will be performed at screening, baseline and at the End of Study. At all 
other times urine pregnancy tests may be used.
If a urine pregnancy test is performed and is found to be positive, this will require immediate
interruption of the study drug, until a serum β-hCG is performed, and found to be negative. 
If positive, the patient must be discontinued from the study medication.
When performed at screening and at baseline, the result must be received before the patient
may be dosed.
8.5.6
Other safety evaluations
8.5.6.1
Infections
All occurrences of infections must be carefully monitored by the investigator (see also
Section 9.3).
8.6
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment schedule.
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In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol.
Further details on sample collection, numbering, processing and shipment can be found in the 
Site Operations Manual.
Pharmacokinetic (PK) samples will be obtained and evaluated in all patients.
 
 
PK samples remaining after completion of the determination of parent may be used for 
exploratory assessment of metabolites or other bioanalytical purposes (e.g. cross check 
between different sites, stability assessment). 
 
 
 
 
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
 
 
 
 
PK parameters will be calculated as per Novartis Guidance on Standardization of 
Pharmacokinetic Parameters. 
 
 
 
 
 
8.7
Other assessments
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9
Safety monitoring
9.1
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 patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results 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 patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for liver related events are included in
Section 9.4.
Adverse events must be recorded on the Adverse Events CRF for patients that pass screening 
and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. the Common Toxicity Criteria (CTC) AE grade (version 4.03)
If CTC-AE grading does not exist for an adverse event, use:
1=mild, 
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2=moderate, 
3=severe 
4=life threatening* (see Section 9.2 for definition of a serious adverse event (SAE))
*Note: There may be cases where a CTCAE with a grade of 4 (life-threatening) may not 
necessarily be an SAE (e.g. certain laboratory abnormalities in the absence of meeting 
other seriousness criteria).
CTC-AE grade 5 (death) is not used, but is collected in other CRFs (e.g. Study 
Completion, Death/Survival).
2. its relationship to the study treatment (no/yes).
3. its duration (start and end dates) or if the event is ongoing at the end of study.
4. whether it constitutes a serious adverse event (SAE) See Section 9.2 for definition of SAE
5. action taken regarding investigational treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (e.g. further observation only) 

investigational treatment dosage increased/reduced 

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). 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.
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

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
constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or
development of dependency or abuse.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 9.2.2.
9.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence as 
described below. Any SAEs experienced after this should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment. 
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the 
Site Operations Manual.


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Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department, notifying the Clinical Trial Leader. Contact information is listed 
in the Site Operations Manual. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure 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.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.   
Note:  SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
9.3
Infection Monitoring
All infections that develop during the study will be reported as AEs. Investigators are 
requested to specifically ask about infections at each visit, in particular bacterial enterocolitis. 
Treatment and additional evaluations will be performed at the discretion of the investigator. 
The investigator should consider early treatment with specific antimicrobial therapy on the 
basis of clinical diagnosis or suspicion thereof in consultation with infectious disease experts, 
as appropriate.


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WBC will be assessed at every visit. If the neutrophil count falls below 1000 per μl, then 
weekly assessments of WBC are recommended.
The investigator should remind the patient of the risk of infections and to instruct them to 
promptly report any symptoms of infections to the investigator.
9.4
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 9-1 and Table 9-2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed in Table 9-2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug (refer to Section 7.1, if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 


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the procedures performed should be recorded as appropriate in the CRF, including the liver 
event overview CRF pages.
Table 9-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
Liver laboratory triggers
3 x ULN < ALT / AST 5 x ULN
1.5 x ULN < TBL 2 x ULN
Liver events
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity * 


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Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-
up monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit


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Criteria
Actions required
Follow-up monitoring
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study drug interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
*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
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.
9.5
Renal safety monitoring
Renal events are defined as one of the following:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status

new onset (≥1+) proteinuria, hematuria or glucosuria; or as a

doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio 
(PCR) (if applicable).
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study:

Serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter 

Urine dipstick triggers that will require follow up and repeat assessments of the abnormal 
laboratory parameter


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Table 9-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Serum creatinine increase  50 % 
compared to baseline
Follow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold
Albumin-creatinine ratio (ACR) ≥ 30 mg/g 
or ≥ 3 mg/mmol;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR )≥ 150 mg/g 
or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until one of the following:
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline) 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.
9.6
Pregnancy reporting
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. The study drug must be discontinued, though the patient may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The patient may continue all other protocol assessments. 
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on an SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.


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9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
in Section 7.
The Sponsor will advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if 
possible) of any new, clinically relevant safety information reported from another site during 
the conduct of the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the patients will be disclosed.
10.2
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, 


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by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
After database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
assessment schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
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, or CRO working on behalf of Novartis, who will make the correction 
to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data in reference to dispensing of study drug(s) to the subject and 
all IRT recorded dosage changes will be tracked using Interactive Response Technology 
(IRT). The system will be supplied by a vendor, who will also manage the database. The 
database will be sent electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.


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10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The full analysis set will include all subjects that received any study drug.
The safety analysis set will include all subjects that received any study drug. The PK analysis 
set will include all subjects with at least one valid (i.e. not flagged for exclusion) PK 
concentration measurement, who received study drug and no protocol deviations with relevant 
impact on PK data.
The PD analysis set will include all subjects that received study drug and had no protocol 
deviations with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
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11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
Summaries and listings of cumulative exposure to study drug (cumulative dose received over 
the treatment period) will be provided.  
11.4
Analysis of the primary variable(s)
The primary aims of this study are to assess safety in patients with pSS and to investigate the 
effect of CDZ173 on efficacy (as measured by the ESSPRI) at study week 13. The statistical 
analysis model will include ESSPRI data from all time points up to study week 13 and 
summaries of safety and tolerability will be provided. 
11.4.1
Variable(s)
The primary efficacy variable is the ESSPRI change from baseline. 
11.4.2
Statistical model, hypothesis, and method of analysis
It is assumed that the ESSPRI will follow an approximately normal distribution. If this 
assumption appears not to be met, alternative statistical analysis methods may be applied. 
These will be described in the Reporting and Analysis Plan (RAP). 
The primary efficacy analysis will be based on a longitudinal mixed model of ESSPRI as a 
function of baseline ESSPRI, baseline intake of steroids (yes/no, which is a stratification 
factor for the randomization), treatment, time as a continuous variable (linear and quadratic 
terms), interaction between treatment and time, as well as a random intercept, random slope 
and random quadratic effects by subject to account for within-subject correlations. 
An unstructured covariance matrix for the random effects will be fitted along with an 
independent error matrix. The difference between active treatment and placebo in change 
from baseline in ESSPRI at study week 13 will be estimated from the model and presented 
with 80% confidence intervals. Simpler models will also be considered in case the 
pre-specified model does not fit the data well.
The following criteria will be considered indicative of treatment efficacy:

Statistically significant decrease in ESSPRI at week 13 visit on treatment compared to 
placebo (at one-sided 10% level)

Estimated mean reduction in ESSPRI at week 13 visit of 1 point or more than on placebo
(see Section 3.2)
11.4.3
Handling of missing values/censoring/discontinuations
All subjects with a baseline ESSPRI and at least one post-baseline ESSPRI will be included in 
the primary analysis. The primary analysis method provides unbiased estimates of the 
treatment effect under the assumption that data are missing at random (MAR). Guidelines for 
subject discontinuation should ensure that this assumption is reasonable. If a substantial 
proportion (e.g. more than 15%) of subjects discontinue before week 13 visit, alternative 
methods to account for missing data may be considered.


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11.4.4
Supportive analyses
Simpler models may be considered, including simpler covariance structures. If the time course 
doesn’t appear to be quadratic, time may be modeled as a categorical variable. 
11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy / Pharmacodynamics
 
11.5.2
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, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit. 
A longitudinal PK-QT model using all available data will be used to see if there is any 
concentration-dependent increase in QT. This model may include data from other studies 
exploring CDZ173 and may be reported in a separate report. The model will include a random 
subject effect to account for the within-patient correlations. In case the direct PK-QT model 
doesn’t fit the data appropriately, alternative models taking into account potential hysteresis 
will be used.    
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit.
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Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
Infections
The frequency of infections will be tabulated. 
11.5.3
Pharmacokinetics
The pharmacokinetics of CDZ173 will be evaluated in patients in the PK analysis set.
CDZ173 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as 
zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values. Pharmacokinetic parameters will be calculated by 
non-compartmental methods as described in Section 8.6 and will be listed by treatment and 
subject.
 
 
 
 
 
 
 
 
 
11.5.4
Pharmacokinetic / pharmacodynamic interactions
Relationships between exposure and selected PD variables will be explored by a graphical 
approach and descriptive statistics of exposure and PD variables will be provided. 
Additional analysis such as exposure-response models will be performed, if warranted.
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11.5.5
Other assessments
11.5.5.1 Imaging biomarkers
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tial Information
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11.6
Sample size calculation
A total of approximately 27 patients will be recruited into the study. Patients will be 
randomized in a 2:1 ratio to either CDZ173 (n=18) or placebo (n=9) treatment groups. This 
number is based firstly on the assumed treatment effect in the primary endpoint ESSPRI and 
secondly on an assumed drop-out rate of 10% (i.e. 3 patients).
With 24 patients for the analysis of the primary efficacy variable (16 in the CDZ173 treated 
group and 8 in the placebo group), the study would have around 10% chance of having a 
false-positive result, i.e. of meeting both efficacy criteria when the true difference between 
CDZ173 and placebo is zero ESSPRI points. 
The power of the study is 86% (when the true difference between CDZ173 and placebo is 2 
points in ESSPRI). 
The criteria for success are assumed to be the efficacy criteria defined in Section 11.4.2.
These calculations assume that the change from baseline in ESSPRI is approximately 
normally distributed with a standard deviation of 2. This estimate of the standard deviation is 
based on a study of rituximab in patients with pSS (Meiners et al 2012).
The calculated numbers come from simulations done in R version 3.2.2.
11.7
Interim analyses
 
 
 
 
 
 
 
 
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
12.3
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.
13
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 must 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.


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13.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL 
should be informed and (serious) adverse event reporting requirements (Section 9) followed 
as appropriate.


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14
References
Available upon request.
Clayton E, Bardi G, Bell SE, et al (2002) A crucial role for the p110delta subunit of
phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 196(6):753-63.
Flinn IW, Kahl BS, Leonard JP et al (2014) Idelalisib, a selective inhibitor of 
phosphatidylinositol 3-kinase-, as therapy for previously treated indolent non-Hodgkin 
lymphoma, Blood; 123(22), 3406-13.
Hirsch E, Katanaev VL, Garlanda C, et al (2000) Central role for G protein-coupled
phosphoinositide 3-kinase gamma in inflammation. Science. 287(5455):1049-53.
Jou ST, Carpino N, Takahashi Y, et al (2002) Essential, nonredundant role for the
phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell
Biol. (24):8580-91.
Kandel ES, Hay N (1999) The regulation and activities of the multifunctional serine/threonine 
kinase Akt/PKB. Exp. Cell Res.; 253 (1): 210-229.
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.
Li Z, Jiang H, Xie W, et al (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in 
chemoattractant-mediated signal transduction. Science; 287(5455):1046-9.
Meiners PM, Arends S, Brouwer E, et al (2012) Responsiveness of disease activity indices
ESSPRI and ESSDAI in patients with primary Sjögren’s syndrome treated with rituximab.
Ann Rheum Dis; 71:1297-302.
Mengshoel AM, Norheim KB, Omdal R (2014) Primary Sjögren’s Syndrome: Fatigue Is an
Ever-Present, Fluctuating, and Uncontrollable Lack of Energy. Arthritis Care Res; 66: 1227-1232.
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.
Nocturne G and Mariette X. Nat Rev Rheumatol 2013; 9:544-556.
Patrucco E, Notte A, Barberis L, et al (2004) PI3Kgamma modulates the cardiac response to 
chronic pressure overload by distinct kinase-dependent and -independent effects. Cell; 
118:375-87.
Pijpe J, Kalk WW, Bootsma H, et al (2007) Progression of salivary gland dysfunction in
patients with Sjögren’s syndrome. Ann Rheum Dis; 66:107-12.


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Sasaki T, Irie-Sasaki J, Jones RG, et al (2000) Function of PI3Kgamma in thymocyte
development, T cell activation, and neutrophil migration. Science; 287(5455):1040-6.
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.
Seror R, Ravaud P, Mariette X, et al (2011). EULAR Sjogren's Syndrome Patient Reported 
Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome. 
Ann Rheum Dis; 70:968-72.
Seror R, Bootsma H, Saraux A, et al (2016) Defining disease activity states and clinically 
meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's 
syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum 
Dis; 75:382-389.
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.
Youinou P, Pers JO (2012) Latest update on the primary Sjögren’s syndrome. Presse Med; 41 
(9 pt 2):e437-439.


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17
Appendix 3: Blinding and Unblinding
Please refer to Site Operations Manual.


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18
Appendix 4: Sample Log Table
Please refer to Site Operations Manual.


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19
Appendix 5: Sample labeling and shipping information
Sample labeling and shipping instructions will be provided in a separate laboratory manual.


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20
Appendix 6: ESSDAI
Will be provided as a separate document.


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21
Appendix 7: ESSPRI
Will be provided as a separate document.


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22
Appendix 8: SF-36
Will be provided as a separate document.


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23
Appendix 9: MFI
Will be provided as a separate document.

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
CDZ173
CCDZ173X2203
A randomized, double-blind, placebo-controlled, parallel 
group study to assess the safety, tolerability, 
pharmacokinetics and preliminary efficacy of CDZ173 in 
patients with primary Sjögren’s syndrome
Statistical Analysis Plan (SAP)
Author:
 
Document type:
SAP Documentation – NIBR 
Document status:
Final Version 2
Release date:
30-June-2017
Number of pages:
16
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary objectives...................................................................................5
1.3.2
Secondary objectives...............................................................................5
1.3.3
Exploratory objectives ............................................................................5
1.4
Study design and treatment......................................................................................6
2
First interpretable results (FIR) ...........................................................................................6
3
Interim analyses...................................................................................................................7
4
Statistical methods: Analysis sets........................................................................................7
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................8
5.1
Variables..................................................................................................................8
5.2
Descriptive analyses ................................................................................................9
5.2.1
Graphical presentation of results.............................................................9
6
Statistical methods for pharmacodynamic (PD) parameters ...............................................9
6.1
Primary objective.....................................................................................................9
6.1.1
Variables .................................................................................................9
6.1.2
Descriptive analyses..............................................................................10
6.1.3
Statistical model, assumptions and hypotheses.....................................10
6.2
Secondary objectives .............................................................................................12
6.2.1
Variables ...............................................................................................12
6.3
Exploratory objectives...........................................................................................12
7
Statistical methods for safety and tolerability data............................................................12
7.1.1
Variables ...............................................................................................13
7.1.2
Descriptive analyses..............................................................................13
7.1.3
Graphical presentation ..........................................................................14
8
Statistical methods for Biomarker data .............................................................................14
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List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................7
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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCDZ173X2203”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v00 (original protocol) 
dated 26 January 2016. 
1.3
Study objectives
1.3.1
Primary objectives

To assess the safety and tolerability of CDZ173 in patients with primary Sjögren’s 
syndrome (pSS).

To compare the effect of CDZ173 versus placebo on the patient reported outcome 
(ESSPRI) of pSS patients after 12 weeks of treatment (study week 13).
1.3.2
Secondary objectives

To assess the pharmacokinetics of CDZ173 in pSS patients.

To evaluate the effect of CDZ173 versus placebo on clinical disease outcomes 
(ESSDAI, SF-36, MFI) in pSS patients after 12 weeks of treatment (study week 13).

To evaluate the changes in the physician global assessment of the patient's overall
disease activity after 12 weeks of treatment (study week 13).

To evaluate the changes in the patients’ self-reported global assessment of their 
disease activity after 12 weeks treatment (study week 13).
1.3.3
Exploratory objectives
 
 
 
 
 
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1.4
Study design and treatment
This is a double-blind, randomized, placebo-controlled, parallel design, non-confirmatory
study to assess the safety, tolerability, pharmacokinetics and preliminary clinical efficacy of
multiple oral doses of CDZ173 (70 mg b.i.d.) in patients with pSS.
The study will consist of a 4-week screening period, a baseline period prior to randomization,
a 12-week treatment period and a 4-week follow-up period (no study drug or study visits)
before the End of Study visit. The total duration for each patient in the study will be
approximately 21 weeks.
Approximately 27 patients will be randomized (2:1) to a 12 week treatment receiving either
CDZ173 or placebo. Randomization will be stratified according to baseline glucocorticoid
intake (yes/no).
For the entire duration of the treatment period (12 weeks), patients will receive a b.i.d. dosing
regimen to be administered at approximately 12 h intervals.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical
laboratory evaluations (hematology, biochemistry and urinalysis) as well as adverse event and
serious adverse event monitoring.
Other assessments to be completed are outlined in the Assessment schedule in the protocol.
The study design is summarized in Figure 1-1 below:
Figure 1-1
Study Design
2
First interpretable results (FIR)
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3
Interim analyses 
 
 
 
 
4
Statistical methods: Analysis sets
For subjects for whom the actual treatment received does not match the randomized treatment,
the treatment actually received will be used for the analysis.
All subjects that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available baseline and post-dose PD 
data, who received any study drug and experienced no protocol deviations with relevant 
impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
Protocol deviations: 
Exclude subject completely 
from all (safety) analysis 
sets
I1
ICF not obtained
I2
ICF was signed after the other screening 
procedures; ICF wrong version was obtained.
S1
If Patient did not take the drug ever
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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these Protocol 
deviations: 
Exclude subject from PK 
analysis set 
I1
ICF not obtained
I2
ICF was signed after the other screening
procedures; ICF wrong version was obtained.
  S1
If Patient did not take the drug ever
Subjects are excluded from PD analysis in case of these Protocol 
deviations:
Exclude subject from PD 
analysis set
  S1
If Patient did not take the drug ever
  
E1
Secondary Sjögren’s syndrome
I1
ICF not obtained
I2
ICF was signed after the other screening
procedures; ICF wrong version was obtained.
I3
Diagnosis of primary Sjögren’s syndrome
I4
ESSDAI at screening/baseline ≥6
I5
ESSPRI at screening/baseline ≥5
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
The following plasma pharmacokinetic parameters will be determined using the actual
recorded sampling times on Day 1 and non-compartmental method(s) with Phoenix
WinNonlin (Version 6.2 or higher): Cmax, Tmax, AUC0-7h and AUClast. Other PK
parameters may be added as appropriate. After multiple doses, PK will be summarized in 
terms of trough concentration (Ctrough). 
PK parameters will be calculated as per Novartis Guidance on Standardization of
Pharmacokinetic Parameters. The linear trapezoidal rule will be used for AUC calculation.
Regression analysis of the terminal plasma elimination phase for the determination of T1/2
will include at least 3 data points after Cmax. If the adjusted R2 value of the regression
analysis of the terminal phase will be less than 0.75, no values will be reported for T1/2,
AUCinf and CL/F. The extrapolated part of the AUCinf will not contribute to more than 20%
of total AUC.


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5.2
Descriptive analyses
The pharmacokinetics of CDZ173 will be evaluated in patients in the PK analysis set.
CDZ173 plasma concentration data will be listed by treatment, subject, and visit/sampling
time point. Descriptive summary statistics will be provided by treatment and visit/sampling
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as
zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and
geometric), median, minimum and maximum. An exception to this is Tmax where median,
minimum and maximum will be presented. Concentrations below LLOQ will be treated as
zero in summary statistics and for PK parameter calculations. A geometric mean will not be
reported if the dataset includes zero values. Pharmacokinetic parameters will be listed by 
treatment and subject.
 
5.2.1
Graphical presentation of results
Arithmetic mean (SD) and geometric mean (95% CI) plasma concentration data will be 
plotted over time.
Overlaying individual plasma concentration-time profiles will be generated along with 
concentration versus time profiles for individual subjects.
Relationships between exposure (average Ctrough over time) and selected PD variables, 
 
 will be 
explored by a graphical approach and descriptive statistics of exposure and PD variables will 
be provided.
6
Statistical methods for pharmacodynamic (PD) parameters
6.1
Primary objective
6.1.1
Variables 
The primary aims of this study are to assess safety in patients with pSS and to investigate the
effect of CDZ173 on efficacy (as measured by the ESSPRI) at study week 13. The statistical
analysis model will include ESSPRI data from all time points up to study week 13. The 
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primary efficacy variable is the ESSPRI change from baseline (based on the mean of the 
below first 3 questions from the questionnaire):

How severe has your dryness been during the last 2 weeks?

How severe has your fatigue been during the last 2 weeks?

How severe has your pain been during the last 2 weeks?
The other questions will be listed but not summarized. The safety and tolerability, as 
described in Section 7, will be summarized.
6.1.2
Descriptive analyses
Summary statistics will be provided for baseline, as well as for absolute and percent change 
from baseline in ESSPRI, by treatment and timepoint.
6.1.3
Statistical model, assumptions and hypotheses
It is assumed that the ESSPRI will follow an approximately normal distribution. 
A positive sign of therapeutic effects will be considered to be a reduction of at least 1 point
in the change from baseline between CDZ173 and placebo with a moderate level of evidence. 
Additionally there should be a high level of evidence that is a difference between CDZ173
and placebo. These criteria will be evaluated by calculating Bayesian posterior probabilities as 
follows:
Pr (θCDZ173,13w-θplacebo,13w < 0 | data) > 90% and
Pr (θCDZ173,13w-θplacebo,13w < -1 | data) > 50%
where θ means change from baseline in ESSPRI at 13 weeks.
It is assumed that Yijt, the observed change from baseline in ESSPRI for subject i receiving
treatment j (CDZ173 or placebo) at time t, follows a normal distribution N(θjt, σ2), It is further 
assumed that θjt follows a standard non-informative prior Normal distribution, p(θjt, σ2) = 1/σ2.
The statistical model will be a repeated measures model fitting terms for treatment by 
timepoint and baseline by timepoint using the SAS procedure PROC MCMC. Estimates of the 
difference between CDZ173 and placebo at each timepoint will be derived from this model 
and presented together with 95% credible intervals. The estimates of the posterior
probabilities of the efficacy criteria being met will be provided.
Patients with missing ESSPRI at baseline will not be included in the analysis. Patients with
missing data at one or more timepoints post baseline will be included in the analysis. The 
planned model assumes that missing values are missing at random. The reasonableness of this 
assumption will be checked during the blinded review of the data and if necessary further 
methods may be applied.


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6.1.3.1
Model checking procedures
Diagnostic output from the PROC MCMC model will be reviewed.
6.1.3.2
Handling of missing values/censoring/discontinuations
All subjects with a baseline ESSPRI and at least one post-baseline ESSPRI will be included in
the primary analysis. The primary analysis method provides unbiased estimates of the
treatment effect under the assumption that data are missing at random (MAR). Guidelines for
subject discontinuation should ensure that this assumption is reasonable. If a substantial
proportion (e.g. more than 15%) of subjects discontinue before week 13 visit, alternative
methods to account for missing data may be considered.
Follow up visits from subjects who discontinued will not be included in the analysis.
For patients where treatment was withdrawn PD summary statistics and all the analysis using 
the PD analysis set will only include data that was measured <= 7 days after the treatment was 
stopped, i.e. data longer than 7 days after treatment discontinuation will be excluded. For 
individual figures using the PD analysis set all the data will be displayed but the lines will be 
solid up to the treatment discontinuation + 7 days and for subsequent time points the line 
should be dotted, i.e. the data that is excluded from the summary stats/analysis should be 
presented dotted.
If a subject took a prohibited medication then a footnote will be added to detail this in all PD
outputs to explain that data after the usage make be affected by the medication.
6.1.3.3
Supportive analyses
The supportive analysis will be based on a longitudinal mixed model of change from baseline 
in ESSPRI as a function of baseline ESSPRI, baseline intake of steroids (yes/no, which is a 
stratification factor for the randomization), treatment, time (days from first treatment) as a 
continuous variable (linear and quadratic terms), interaction between treatment and time, as 
well as a random intercept, random slope and random quadratic effects by subject to account 
for within-subject correlations.
An unstructured covariance matrix for the random effects will be fitted along with an
independent error matrix. The difference between active treatment and placebo in change
from baseline in ESSPRI at study week 13 will be estimated from the model and presented
with 80% and 95% confidence intervals (estimates will also be provided corresponding to the 
other visits where ESSPRI was assessed). Simpler models will also be considered in case the
pre-specified model does not fit the data well.
Simpler models may be considered, including simpler covariance structures. If the time course
does not appear to be quadratic, time may be modelled as a categorical variable.
The following criteria will be considered indicative of treatment efficacy:

Statistically significant decrease in ESSPRI at week 13 visit on treatment compared to
placebo (at one-sided 10% level) 

Estimated mean reduction in ESSPRI at week 13 visit for CDZ173 of 1 point or more 
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6.1.3.4
Graphical presentation of results
Lsmean (SE) and individual profiles will be produced by treatment and time.
6.2
Secondary objectives
6.2.1
Variables 
Secondary efficacy variables supporting the secondary objectives are:

Change from baseline in ESSDAI 

Change from baseline in SF-36 for both physical and mental component 

Change from baseline in MFI 

Change from baseline in Physician and Patient VAS of global disease activity 
There was a scaling problem with the printed batch for the CRF sheets for the VAS scale in 
Hungary. The line that is printed and which is marked by either the patient or the phy sician 
should be 100mm long, but in the Hungarian site both VAS scales only measured 95mm 
therefore both VAS scales for the Hungarian site will be transformed by multiplying by 1.053 
to get comparable results to the German site.
In the listings both the actual measurement and the value based on a length of 100mm will be 
presented with the transformed results based on a length of 100mm used in all other VAS 
outputs.
The key timepoint is the week 13 visit.
6.3
Exploratory objectives
 
 
 
 
 
 
 
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7
Statistical methods for safety and tolerability data
7.1.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.1.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
Baseline concomitant medication related to pSS will be summarized by treatment group.
Summaries and listings of cumulative exposure to study drug (cumulative dose received over 
the treatment period) will be provided.
Heatmaps of exposure will be provided.
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.
In the protocol it was stated to use a longitudinal PK-QT model to check for concentration-
dependent increase in QT. If this pooled analysis is done it will be presented in a separate 
report.
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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. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
Heatmaps of neutropenia and rashes will be presented.
Liver and renal events will be listed and summarized using frequency tables.
Other safety evaluations
Immunogenicity
All immunogenicity results will be listed by subject and visit/time.
Infections
The frequency of infections will be tabulated.
7.1.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for Biomarker data
Biomarker data (except for hypothesis-free platforms), change from baseline and percentage 
changes from baseline will be listed by treatment, subject, and visit/time.
 
 
 
Summary statistics will be provided by treatment and visit/time. In the summary tables, the 
frequency (n, %) of values below the LLOQ and above the ULOQ, respectively, will be 
included.
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