An Adaptive Phase 2 Randomized Double-blind, Placebo-controlled Multi-center Study to Evaluate the Safety and Efficacy of Multiple LOU064 Doses in Patients With Moderate to Severe Sjögren's Syndrome (LOUiSSe)
Phase: PHASE2
Conditions: Sjögren Syndrome
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
LOU064
Clinical Trial Protocol CLOU064E12201
An adaptive Phase 2 randomized double-blind, 
placebo-controlled multi-center study to evaluate the 
safety and efficacy of multiple LOU064 doses in 
patients with moderate to severe Sjögren’s Syndrome 
(LOUiSSe)
Document type:
Amended Protocol Version
EUDRACT number:
2018-004387-54
Version number:
v04 Clean (incorporating amendment 04)
Clinical Trial Phase:
II
Release date:
12-Feb-2021
Property of Novartis/sponsor
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018
ClinicalTrials.gov Identifier: NCT04035668

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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................21
1
Introduction .......................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose ..................................................................................................................25
2
Objectives and endpoints...................................................................................................26
3
Study design ......................................................................................................................27
4
Rationale............................................................................................................................30
4.1
Rationale for study design .....................................................................................30
4.2
Rationale for dose/regimen and duration of treatment ..........................................31
4.3
Rationale for choice of control drug (placebo)......................................................32
4.4
Purpose and timing of interim analyses/design adaptations..................................32
4.5
Risks and benefits..................................................................................................34
4.5.1
Blood sample volume............................................................................37
4.6
Rationale for Public Health Emergency mitigation procedures ............................37
5
Study Population ...............................................................................................................37
5.1
Inclusion criteria ....................................................................................................38
5.2
Exclusion criteria...................................................................................................38
6
Treatment...........................................................................................................................42
6.1
Study treatment......................................................................................................42
6.1.1
Investigational and control drugs..........................................................42
6.1.2
Additional study treatments ..................................................................42
6.1.3
Treatment arms/group ...........................................................................43
6.2
Other treatment(s)..................................................................................................43
6.2.1
Concomitant therapy.............................................................................43
6.2.2
Prohibited medication ...........................................................................44
6.2.3
Rescue medication ................................................................................46
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6.2.4
Restriction for study subjects................................................................46
6.3
Subject numbering, treatment assignment, randomization....................................46
6.3.1
Subject numbering ................................................................................46
6.3.2
Treatment assignment, randomization ..................................................46
6.4
Treatment blinding.................................................................................................47
6.5
Dose escalation and dose modification..................................................................49
6.6
Additional treatment guidance...............................................................................49
6.6.1
Treatment compliance...........................................................................49
6.6.2
Recommended treatment of adverse events..........................................49
6.6.3
Emergency breaking of assigned treatment code..................................49
6.7
Preparation and dispensation.................................................................................50
7
Informed consent procedures ............................................................................................50
8
Visit schedule and assessments .........................................................................................51
8.1
Screening ...............................................................................................................58
8.1.1
Eligibility screening ..............................................................................58
8.1.2
Information to be collected on screening failures.................................58
8.2
Subject demographics/other baseline characteristics.............................................59
8.3
Efficacy..................................................................................................................59
8.3.1
EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI).........59
8.3.2
Physician Global Assessment Scale (PhGA) ........................................60
8.3.3
EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI)..........60
8.3.4
FACIT-Fatigue......................................................................................60
8.3.5
EQ5D.....................................................................................................60
8.3.6
Appropriateness of efficacy assessments..............................................60
8.4
Safety.....................................................................................................................61
8.4.1
Laboratory evaluations..........................................................................62
8.4.2
Electrocardiogram (ECG) .....................................................................63
8.4.3
Pregnancy 
.................................................63
8.4.4
Appropriateness of safety measurements..............................................64
8.5
Additional assessments..........................................................................................64
8.5.2
Other Assessments ................................................................................66
8.5.3
Pharmacokinetics ..................................................................................67
9
Study discontinuation and completion ..............................................................................68
9.1
Discontinuation and completion............................................................................68
9.1.1
Study treatment discontinuation and study discontinuation..................68
9.1.2
Withdrawal of informed consent...........................................................70
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9.1.3
Lost to follow-up...................................................................................70
9.1.4
Study stopping rules..............................................................................71
9.1.5
Early study termination by the sponsor.................................................71
9.2
Study completion and post-study treatment ..........................................................71
10 Safety monitoring and reporting........................................................................................72
10.1
Definition of adverse events and reporting requirements......................................72
10.1.1
Adverse events ......................................................................................72
10.1.2
Serious adverse events ..........................................................................73
10.1.3
SAE reporting........................................................................................74
10.1.4
Pregnancy reporting ..............................................................................75
10.1.5
Reporting of study treatment errors including misuse/abuse................75
10.2
Additional Safety Monitoring................................................................................76
10.2.1
Liver safety monitoring.........................................................................76
10.2.2
Renal safety monitoring........................................................................77
11 Data Collection and Database management......................................................................78
11.1
Data collection.......................................................................................................78
11.2
Database management and quality control............................................................78
11.3
Site monitoring ......................................................................................................79
12 Data analysis and statistical methods ................................................................................79
12.1
Analysis sets ..........................................................................................................80
12.2
Subject demographics and other baseline characteristics......................................80
12.3
Treatments .............................................................................................................80
12.4
Analysis of the primary endpoint(s) ......................................................................81
12.4.1
Definition of primary endpoint(s).........................................................81
12.4.2
Statistical model, hypothesis, and method of analysis..........................82
12.4.3
Handling of missing values/censoring/discontinuations.......................84
12.4.4
Sensitivity and Supportive analyses......................................................84
12.5
Analysis of secondary endpoints ...........................................................................84
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................85
12.5.2
Safety endpoints....................................................................................85
12.5.3
Pharmacokinetics ..................................................................................86
12.6
Analysis of exploratory endpoints.........................................................................87
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12.7
Interim analyses.....................................................................................................88
12.7.1
Timing of analyses ................................................................................88
12.7.2
Purpose of analyses...............................................................................88
12.7.3
Maintenance of study integrity..............................................................88
12.7.4
Decision criteria for interim analyses ...................................................89
12.8
Sample size calculation..........................................................................................89
13 Ethical considerations and administrative procedures ......................................................89
13.1
Regulatory and ethical compliance........................................................................89
13.2
Responsibilities of the investigator and IRB/IEC..................................................90
13.3
Publication of study protocol and results...............................................................90
13.4
Quality Control and Quality Assurance.................................................................90
14 Protocol adherence ............................................................................................................91
14.1
Protocol amendments.............................................................................................91
15 References .........................................................................................................................92
16 Appendices ........................................................................................................................95
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................95
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................96
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....100
16.4
Appendix 4: ESSDAI ..........................................................................................102
List of tables
Table 2-1
Objectives and related endpoints ..........................................................26
Table 6-1
Investigational and control drug............................................................42
Table 6-2
Treatments against dryness of eyes/mouth ...........................................44
Table 6-3
Prohibited Medication...........................................................................44
Table 6-4
 Blinding levels............................................................................48
Table 8-1
Assessment Schedule ............................................................................52
Table 8-2
Assessments and Specifications............................................................61
Table 8-3
Laboratory Evaluations .........................................................................62
Table 8-4
PK sampling schedule...........................................................................68
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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................76
Table 12-1
Non-compartmental pharmacokinetic parameters ................................86
Table 16-1
Liver event and laboratory trigger definitions ......................................96
Table 16-2
Follow up requirements for liver events and laboratory triggers..........97
Table 16-3
Specific Renal Alert Criteria and Actions...........................................100
Table 16-4
Renal Event Follow Up.......................................................................101
Table 16-5
The EULAR Sjögren’s syndrome disease activity index (ESSDAI): 
domain and item definitions and weights............................................102
List of figures
Figure 3-2
Study flow chart and visit schedule ......................................................28
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List of abbreviations
ACR
American College of Rheumatology
AD
Atopic Dermatitis
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
anti-HBc
Hepatitis B core antibody
Anti-TNF-α mAb
Anti-Tumor Necrosis Factor-alpha monoclonal antibody
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
AUC
area under the curve
AV-Block 
atrioventricular block
BCR
B cell receptor
BCRP
Breast Cancer Resistance Protein
bid
twice a day (for Latin: “bis in die”)
BMI
Body Mass Index
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CK
creatinine kinase
cm
Centimeter
CMO&PS
Chief Medical Office & Patient Safety
CNS
central nervous system
COA
Clinical outcome assessments
CRF/eCRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CSR
Clinical study report
CSU
Chronic Spontaneous Urticaria
COVID-19
Coronavirus disease 2019
CV
coefficient of variation
CYP
Cytochrome P450
DDE
Direct Data Entry
DDI
Drug-drug interactions
DIN
Drug Inducted Nephrotoxicity
DMARDs
disease-modifying antirheumatic drugs
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
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EMG
Electromyography
EOS
End of Study
EQ-5D
EuroQual 5 dimensions (Standard instrument to measure the health-related 
quality of life)
(e)SAE
(Electronic) Serious Adverse Event
eSource
Electronic Source
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren's Syndrome Patient Reported Index
EULAR
European League against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
Full Analysis Set
FDA
Food and Drug Administration (US Agency for drug and food control)
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
Hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HRCT
high resolution computer tomography
i.v.
Intravenous
IA
Interim analysis
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IMP
investigational medicinal product
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
kg
Kilogram
LDH
lactate dehydrogenase
LFT
Liver function test
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mAb
monoclonal antibody
MATE1
Multidrug and toxin extrusion protein 1
MCP-Mod
Multiple Comparison Procedure – Modelling
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed effect Model Repeat Measurement
MRT
mean residence time
ng
Nanogram
NOAC
Novel Oral Anti-Coagulant
NSAID
Nonsteroidal Anti-Inflammatory Drug
NTI
Narrow Therapeutic Index
PD
Pharmacodynamic(s)
P-gp
P-glycoprotein
PhGA
Physician global assessment scale
PK
Pharmacokinetic(s)
PNS
peripheral nervous system
PT
prothrombin time
PTT
partial thromboplastin time
PXR
Pregnane-X-Receptor
qd
once a day (for Latin “quaque die”)
OAT3
Organic anion transporter 3
OATP1B1
Organic anion transporting polypeptide 1B1
OCT1
Organic cation transporter 1 (liver)
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
RF
rheumatoid factor
ROTEM
Rotational thromboelastometry
RoW
Rest of World
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SjS
Sjögren's Syndrome
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SOM
Site Operations Manual
SS
Safety Set
SUSAR
Suspected Unexpected Serious Adverse Reactions
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TBL
total bilirubin
TEC
tyrosine-protein kinase
Tfh
follicular T helper cell
ULN
upper limit of normal
UTI
Urinary Tract Infection
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
XLA
X-linked agammaglobulinemia
µL
Microliter

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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
End of the clinical 
trial
The end of the clinical trial is defined as the date of last visit of the last subject 
or at a later point in time as defined by the protocol.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication 
number
A unique identifier on the label of medication kits
Mis-randomized 
subjects
Mis-randomized subjects are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently randomized 
into the study
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in subjects with established disease and in 
those with newly-diagnosed disease
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis

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Perpetrator Drug
A drug which affects the pharmacokinetics of the other drug
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Randomization 
number
A unique identifier assigned to each randomized subject
Run-in Failure
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject’s intervention or other 
treatment)
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first subject
Study treatment
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Victim drug
The drug that is affected by the drug-drug interaction
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data

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Protocol summary
Protocol number
CLOU064E12201
Full Title
An adaptive Phase 2 randomized, double-blind, placebo-controlled 
multicenter study to evaluate the safety and efficacy of multiple LOU064 
doses in patients with moderate to severe Sjögren’s Syndrome 
(LOUiSSe)
Brief title
A Phase 2 study to evaluate the safety and efficacy of LOU064 in 
patients with Sjögren’s Syndrome (SjS)
Sponsor and Clinical 
Phase
Novartis. Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
This study with LOU064 is an adaptive phase 2 study designed to 
establish safety and efficacy 
 of 
LOU064 in patients with moderate to severe SjS to allow further 
development of the compound for treatment of this disease.
Primary Objective(s) 
Secondary Objectives
Objective 2: To evaluate the efficacy of LOU064 compared to placebo with 
respect to change from baseline on patient and physician-reported 
outcomes (ESSPRI, FACIT-F, EQ-5D, PhGA) over time.
Objective 3: To evaluate the efficacy of LOU064 compared to placebo with 
respect to change from baseline in ESSDAI over time.
Objective 4: To evaluate the safety and tolerability of LOU064 by reporting 
the occurrence of treatment emergent AEs (both serious and non-
serious), abnormal vital signs, laboratory and ECG values during the 
study.
Objective 5: To assess PK parameters of LOU064 (Cmax, AUC, Tmax 
and MRT and others as needed) at steady state.
Study design
This is an adaptive phase 2 randomized, double-blind, placebo-
controlled, multi-center, 
 study to evaluate the 
safety and efficacy of multiple LOU064 doses in patients with moderate 
to severe Sjögren's Syndrome (SjS) over 24 weeks of treatment. Total 
study duration for each patient will be up to 35 weeks.
Study Population
Female and male patients aged 18 to 75 years with moderate to severe 
SjS; a total of approximately 252 patients will be enrolled.
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Key Inclusion criteria

Male or female patients aged 18 to 75 years at screening

Classification of Sjögren's Syndrome according to the 2016
ACR/EULAR criteria at screening

Screening ESSDAI (based on weighted score) ≥5 from 8 defined
domains (biologic, hematologic, articular, cutaneous, glandular,
lymphadenopathy, renal, constitutional). Patients with involvement of
one or more of the remaining 4 domains are eligible but scores of
these domains will not contribute to the assessment for eligibility, but
will be part of the overall ESSDAI score for that subject

Screening ESSPRI ≥ 5

Seropositive for anti-Ro/SSA antibodies at or within 3 months prior to
screening

Unstimulated whole salivary flow rate of > 0 mL/min at screening
Key Exclusion criteria

Sjögren’s Syndrome overlap syndromes where another
autoimmune disease constitutes the primary illness

Rituximab or other B cell depleting drug within 12 months of
Screening. For subjects who received such drug, their B cell count
should be within normal range.

Prior treatment with any of the following within 6 months of baseline

CTLA4-Fc Ig (abatacept)

Anti-TNF-α mAb

Intravenous Ig

Plasmapheresis

i.v. or oral cyclophosphamide

i.v. or oral cyclosporine A

Required regular use of medications known to cause, as a major
side effect, dry mouth / eyes, and which have not been on a stable
dose for at least 30 days prior to Screening, or any anticipated
change in the treatment regimen during the course of the study.

Significant bleeding risk or coagulation disorders, including but not
limited to:

Requirement for anti-platelet or anticoagulant medication (for
example, warfarin, or clopidogrel or Novel Oral Anti-Coagulant -
NOAC) other than acetylsalicylic acid (up to 100 mg/d)

History of gastrointestinal or intracerebral or otherwise severe
prior bleeding events, including in association with use of
Nonsteroidal Anti-Inflammatory Drug (NSAID)

Screening CBC laboratory values as follows:

Hemoglobin levels below 10 g/dL

Total leukocyte count less than 3,000/µL

Platelets less than 100,000/µL

Neutrophil count ≤ 1,500/ µL

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Study treatment
LOU064 hard gelatin capsules
Placebo hard gelatin capsules
Efficacy assessments

ESSDAI, ESSPRI, FACIT-F, EQ-5D, PhGA
Pharmacodynamic 
assessments

Pharmacokinetic 
assessments

PK parameters AUCtau, AUC0-4h, Cmax, Tmax and MRT and
others as needed
Key safety 
assessments

Adverse event monitoring

Physical examinations

Monitoring of laboratory markers in blood and urine

Central ECG assessment

Additional liver and renal safety monitoring
Other assessments
Data analysis
The change from baseline in ESSDAI, 
ESSPRI, FACIT-F, EQ-5D and PhGA will be analyzed using a MMRM 
including treatment group, visit, treatment group by visit interaction, 
stratification factor baseline ESSDAI (<10 or ≥10) and geographic region 
as fixed factors as well as baseline value of variable analyzed as a 
covariate. The estimated means per dose and visit and the differences 
between LOU064 treatment groups and placebo will be derived together 
with 2-sided 95% confidence intervals.
Key words
Sjögren's Syndrome, ESSDAI, BTK inhibitor, LOU064, adaptive trial 
design
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1
Introduction
1.1
Background
Sjögren’s syndrome (SjS) is a systemic autoimmune disease of unknown etiology characterized 
by lymphoid infiltration and progressive destruction of exocrine glands (Brito-Zerón et al 2016). 
Although the disease primarily affects the lacrimal and salivary glands, the inflammatory 
process can target any organ with approximately 15 % of patients showing severe 
extraglandular manifestations (Baldini et al 2014). The clinical presentation is most often 
primarily characterized by exocrinopathy of salivary and lacrimal glands presenting with 
dryness of the mouth and eyes. However, symptoms can be very heterogeneous and range 
beyond dryness to also include musculoskeletal pain and fatigue affecting nearly all patients, to 
severe, extra-glandular and systemic involvement (characterized by peri-epithelial lymphocytic 
infiltration and immune complex deposition) in a more limited subset. The mechanism 
underlying the development of SjS is the destruction of the epithelium of the exocrine glands, 
as a consequence of autoreactive B cells and T cells (Brito-Zerón et al 2016). The high 
prevalence of autoantibodies, especially against Ro/SSA, even at a very early stage suggests that 
autoreactive B cells participate in the pathomechanism of SjS (Nocturne and Mariette 2018). 
The B-cell pathology also results in an increased risk for malignant transformation, with B-cell 
lymphomas occurring at a 10-fold elevated lifetime risk in 5% of SjS patients 
(Baldini et al 2014).
SjS has an estimated prevalence of 0.3 to 1 per 1,000 persons (Qin et al 2015) and is second 
only to rheumatoid arthritis as a systemic autoimmune disease. The disease affects mainly 
women with a female/male ratio of 9:1 and can occur at any age. A major effect of the symptoms 
in SjS is a severe impact on quality of life and productivity, often caused by disabling fatigue 
associated with the disease (Mariette and Criswell 2018). There are also a number of potentially 
severe systemic complications including arthritis, cutaneous vasculitis, peripheral neuropathy, 
glomerulonephritis, interstitial nephritis, biliary cholangitis, obstructive bronchiolitis and others, 
involving multiple organ systems and affecting 20-40% of patients (Seror et al 2014).
Clinical features of Sjögren’s syndrome can be divided into medically evaluable and 
patient-symptomatic manifestations. At the present time, there is no single assessment tool that 
can capture disease activity of both these clinical manifestations of SjS. Therefore, the 
“European League Against Rheumatism (EULAR) Sjoegren Syndrome (SS) Patient Reported 
Index” (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI) are widely accepted as 
well validated, gold-standard measures of symptomatic and systemic manifestations of SjS, 
respectively, and will be used in this study to measure the effectiveness of LOU064 
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In terms of current treatment landscape, there are no internationally approved systemic therapies 
available for SjS. As far as dryness of mouth and eyes is concerned, treatment for SjS patients 
is limited to symptomatic care. Steroids and typical DMARDs are mostly ineffective, and no 
pharmacologic intervention is effective against the severe, disabling fatigue. The lack of 
effective treatment options underscores the need to evaluate newer therapeutic approaches for 
this highly debilitating disease. Because the pattern of B cell autoreactivity is to some extent 
similar to systemic lupus and rheumatoid arthritis, recently, B cell depletion therapy using the 
anti-CD20 monoclonal antibody (mAb) rituximab has been evaluated for both glandular and 
extra-glandular manifestations of SjS as well as for lymphoma management with varying 
degree of success. However, this approach is currently not an approved treatment of SjS. 
The insufficient efficacy of rituximab could be related to incomplete B cell depletion in the 
affected tissues (Brito-Zerón et al 2016) which may be better addressed by using a 
BTK-inhibitor and which will be evaluated in this study.
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a member of the TEC 
kinase family. BTK is expressed in cells of both the adaptive and innate immune system 
including B cells, macrophages, basophils, mast cells and thrombocytes. BTK is indispensable 
for signaling through the Fc epsilon receptor (FcεR1 for IgE) and the activating Fc gamma 
receptors (FcγR for IgG), as well as the B cell antigen receptor (BCR). BTK inhibition has been 
shown to be an effective concept to treat B cell malignancies. The covalent BTK inhibitors 
ibrutinib (Imbruvica®) and acalabrutinib (Calquence®) are approved for the treatment of certain 
B cell malignancies (Thompson and Burger 2018). BTK inhibition has shown promising 
efficacy on B cell autoimmunity in preclinical and clinical studies (Tan et al 2013;
Whang and Chang 2014; Satterthwaite 2017; Rip et al 2018). In addition, BTK levels were 
shown to be increased in circulating B cells of a significant percentage of patients with SjS, in 
association with high serum rheumatoid factor (RF) levels (Corneth et al 2017). Thus BTK 
inhibition is a potentially promising therapeutic option for the treatment of SjS.
1.2
Purpose
This study with LOU064 is an adaptive phase 2 study designed to establish safety and efficacy 
 of LOU064 in subjects with moderate to severe SjS to allow 
further development of the compound for treatment of this disease.
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)


Change from baseline in ESSDAI at Week 
24
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the efficacy of LOU064
compared to placebo with respect to change
from baseline on patient- and physician-
reported outcomes over time

Change from baseline in ESSPRI, FACIT-F,
EQ-5D and PhGA over time


Change from baseline in ESSPRI at Week
24

To evaluate the efficacy of LOU064
compared to placebo with respect to change
from baseline in ESSDAI over time

Change from baseline in ESSDAI over
time

To evaluate the safety and tolerability of
LOU064

Safety endpoints will include

Occurrence of treatment emergent
adverse events (both serious and non-
serious) during the study

Occurrence of treatment emergent
abnormal vital signs, laboratory and
ECG during the study

To assess PK parameters of LOU064

PK parameters AUC, Cmax, Tmax and
MRT and others as needed
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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Objective(s)
Endpoint(s)
3
Study design
This is an adaptive phase 2 randomized, double-blind, placebo-controlled, multi-center, 
 study to evaluate the safety and efficacy of multiple LOU064 doses in 
patients with moderate to severe Sjögren's Syndrome (SjS). In this study, moderate to severe 
SjS is defined as Sjögren's Syndrome according to ACR/EULAR criteria and an ESSDAI of at 
least 5 (in 8 out of 12 domains - see Section 5.1 and Section 16.4 for details) and an ESSPRI of 
at least 5. In case study subjects receive certain concomitant therapy for their underlying disease 
and still meet entry criteria, they will remain on this therapy provided it remains stable until the 
end of the study (for details, see Section 6.2.1).
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Study Conduct
Each individual study subject will first undergo a screening period of up to 6 weeks, a treatment 
duration of 24 weeks and a follow-up period of 30 days post last administration of study 
treatment, before the End of Study visit. The total duration for each subject in the study, 
including Screening, will be up to 35 weeks (see Figure 3-2).
Figure 3-2
Study flow chart and visit schedule
For the entire duration of the treatment period (24 weeks), subjects will receive twice-daily 
doses of LOU064 or placebo, regardless of selected dosing regimen, so that the blind is 
maintained for subjects, investigators and site staff throughout 
study. 
For further details, please refer to Section 6.1.3 and Section 6.4.
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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.
Screening
After signing informed consent, subjects will be assessed for ESSDAI and ESSPRI as well as 
completing safety and other assessments to evaluate eligibility. For logistical reasons, 
assessments may be performed on different days, during the 6 week screening period, if deemed 
appropriate by the Investigator. Subjects that fail screening, may be re-screened for one further 
occasion.
Baseline
Eligible subjects will return for the Baseline visit on Day 1. Subjects may reside overnight at 
the site for logistical reasons, although this would not be considered a hospital admission. 
Eligibility must be confirmed prior to randomization and required baseline assessments must 
be completed prior to dosing on Day 1. If preferred by the site for scheduling purposes, some 
Baseline assessments may be carried out on the evening prior to Day 1.
Treatment
Subjects will be randomized to the respective treatment arms per study part.
Subjects will return to the site at approximately 4-weekly intervals, with an additional visit at 
the end of Week 2 (Day 15). At the study visits, subjects will undergo ESSDAI and ESSPRI 
assessments as well as other scales/questionnaires, safety and various PK, 
sample collections as indicated in the Assessment Schedule and described in Section 8. 
Subjects will be asked to take their morning dose of the study drug at the site on these days. 
Subjects will return their used drug supply packs for compliance and accountability assessment 
and will receive a new supply of study drug for the next 4 week treatment period.
All study visits will be ambulatory, however, for logistical reasons, it may be necessary for 
subjects to come to the site the evening before their scheduled assessment visit. In these 
instances, the subjects may stay overnight at the site, but this would not be considered a hospital 
admission.
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Subjects may be contacted by the Investigator/site staff during the study to ensure 
compliance/monitor safety by telephone or other means, if it is deemed appropriate or necessary 
by the Investigator.
Follow up and End of Study visit (EoS)
After the last day of dosing, subjects will enter a 30-day follow-up period without study drug 
treatment. Subjects will then be asked to return to the site at Week 29 for the End-of-Study visit. 
At this visit, subjects will undergo final assessments as indicated in the Assessment schedule 
(Table 8-1) 
Upon completion of this visit, subjects will be discharged from the study.
4
Rationale
4.1
Rationale for study design
The study is blinded for study subjects, investigators/site staff and sponsor staff until final 
database lock (except where indicated in Section 6.4) to reduce potential bias in the assessment 
of subjective readouts.
Treatment allocation is done by a stratified randomization procedure to achieve an equal 
distribution of disease severity among the different treatment groups.
The control group is placebo on top of standard care because there is no approved treatment to 
be used as active comparator for moderate to severe Sjögren's Syndrome. However, all subjects 
can continue with their current immunomodulatory therapy, if on a stable dose and as described 
in Section 6.2.1.
Two different dosing regimens (qd vs. bid) will be evaluated in 
 the study in line with 
the known pharmacological features (PK and PD) of LOU064 (as described in Section 4.2 and 
Investigator's Brochure).
The study treatment duration is 24 weeks, which is consistent with earlier studies conducted in 
this condition and is expected to allow a meaningful assessment of the safety and efficacy in 
SjS. 
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4.2
Rationale for dose/regimen and duration of treatment
The highest dose planned for this study (100 mg bid or qd) has demonstrated a maximal effect 
for LOU064 based on predicted BTK occupancy in blood (B-cell blockade) and tissues, and 
inhibition of CD63 up-regulation in basophils (IB). This dose is therefore expected to provide 
maximum clinical effect in tissue, including lymphatic tissue for SjS. In Phase 1, doses up to 
600 mg both as single and multiple doses and 200 mg as twice daily dose had been tested in 
human volunteers and proven to be safe (Section 5.2 in the IB).
Dose/regimen 
The extent of BTK inhibition required for optimal clinical efficacy still needs to be established. 
However, it has been hypothesized that 70% inhibition for ~90% of each dosing period at steady 
state may be appropriate (Herman et al 2018) which would be exceeded clearly by both the 
qd- and bid regimen tested in 
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the dose 
(100 mg) is tested in a qd and in a bid
regimen and compared to placebo. Due to the covalent nature of the binding of LOU064 to 
intracellular BTK, the duration of the treatment effect  is dependent on the turn-over rate of the 
BTK molecule. 
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4.3
Rationale for choice of control drug (placebo)
Comparator treatment will be placebo to provide objective evidence of potential AEs and other 
safety data, as well as clinical efficacy and PD data generated from subjects treated with 
LOU064 during the 24-week trial. Since there is no approved systemic treatment for SjS, the 
use of placebo is justified. Current standard-of-care for SjS patients is limited to symptomatic 
care for the mucosal signs and symptoms (dryness) and steroids and conventional DMARDs 
are often ineffective. No pharmacologic intervention is effective against the severe, disabling 
fatigue associated with SjS. Requirements for continuation of concomitant therapy throughout 
the study are described in Section 6.2.1.
4.4
Purpose and timing of interim analyses/design adaptations
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4.5
Risks and benefits
Study subjects suffering from Sjögren’s Syndrome are not considered to be a specific risk 
population for COVID-19 infections unless caused by immunosuppressive medication. 
Treatment with LOU064 (remibrutinib) is expected to lead to an immunomodulatory effect with 
potential therapeutic consequences for the underlying immunological condition. Due to this 
immunomodulatory effect, a potential risk for the acquisition of infections in general cannot be 
excluded. This is however not considered to be specific for any viral infection including 
Coronavirus. It is still unclear whether the susceptibility for any viral infection during treatment 
with remibrutinib is increased. For established COVID-19 infections, initial reports on patients 
suffering from hematological malignancies and being chronically treated with a 
BTK-antagonist have reported relative mild disease courses (Thibaud et al 2020) and 
BTK-inhibitors are even considered to prevent lung injury in COVID-19 disease 
(Treon et al 2020). Several clinical studies have recently been initiated to test the effect of 
registered BTK-inhibitors on Coronavirus infections (NCT04375397, NCT04382586, 
NCT04380688). The most crucial measure to prevent study subjects from infection with 
Coronavirus is to decrease any potential exposure to the virus. Subjects with a known or 
suspected history of an ongoing, chronic or recurrent infectious disease (which includes 
Coronavirus infections) are excluded from this protocol according to Exclusion criterion #8. 
Based on these considerations, it is not considered that the COVID-19 pandemic changes the 
overall risk-benefit assessment for this study.
So far, no SjS patients have been treated with LOU064, and no reports about treatment of SjS 
patients with other BTK inhibitors have been published. Safety experience with LOU064 in 
humans is so far limited and primarily based on Phase 1 and 2 clinical studies and safety profiles 
from other BTK inhibitors. As of 04-Aug-2020, approximately 525 subjects (healthy volunteers 
and patients suffering from CSU, asthma, SjS or atopic dermatitis (AD), respectively) have 
been exposed to LOU064 at doses ranging from 0.5 mg to 600 mg or placebo. Administration 
of LOU064 did not raise any significant safety signal. A summary of AEs and pre-clinical safety 
data can be found in the IB.
Based on a thorough review of safety information currently available in the literature together 
with an assessment of safety data obtained from both clinical and preclinical experience with 
LOU064 as well as safety profiles from other BTK inhibitors, the following potential risks are 
considered for LOU064 and require close monitoring in the proposed study. When comparing 
the safety risks between the approved BTKi (e.g., ibrutinib and acalabrutinib) and LOU064, the 
relevance and importance of the study patient populations must be taken into consideration.

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
Infections: BTK is an important signaling node downstream of cell surface receptors and
expressed in several immune cells of the adaptive and innate system, including B cells,
macrophages and mast cells/basophils. Therefore, LOU064 has the potential to increase
the risk of infections. Patients with X-linked agammaglobulinemia (XLA) – a genetic
defect associated with a lack of BTK – suffer from recurrent bacterial and enteroviral
infections which may be associated with neutropenia (Kumar et al 2006). However, in
XLA, BTK-deficiency leads to impaired B cell and plasma cell development and in turn to
a nearly complete absence of immunoglobulins. In adult patients, BTK inhibition
primarily interferes with B cell activation but not plasma cell function and is therefore not
associated with a marked decrease of immunoglobulins (Hendriks et al 2014;
Sun et al 2015; Nutt et al 2015). Administration of ibrutinib and acalabrutinib is
associated with a risk of infection in patients suffering from B cell malignancies
(Acalabrutinib SmPC 2017; Ibrutinib SmPC 2013). All patients participating in LOU064
clinical studies will be monitored closely for signs and symptoms of infections while in
the study. Patients with a known history of chronic recurrent or active ongoing history of
infections will be excluded from the study.

Impaired platelet function: BTK is a signaling kinase in one of several platelet activation
pathways. In the prescribing information for both ibrutinib and acalabrutinib,
bleeding/bruising events are very common, affecting approximately 50% of patients with
hematologic malignancies. Warnings on hemorrhagic events including deaths have also
been described (Acalabrutinib SmPC 2017; Ibrutinib SmPC 2013). Compared to other
drugs in the same class, LOU064 demonstrated a higher selectivity for BTK vs. other TEC
kinases. Therefore bleeding may be less a safety concern when compared to ibrutinib and
acalabrutinb because these may be more caused by inhibiting other tyrosine kinases than
BTK. Patients receiving LOU064 must be closely monitored for any signs and symptoms
of bleeding while in the study. Subjects with a known history of bleeding disorder and
subjects taking medication that is known to increase the bleeding risk (other than
acetylsalicylic acid) must be excluded from the study (see details in Section 5.2).

Myelomodulation: The role of BTK inhibition in myelomodulation is not fully
understood. Treatment emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia
and anaemia) were reported in patients with hematologic malignancies treated with
ibrutinib and acalabrutinb (Acalabrutinib SmPC 2017; Ibrutinib SmPC 2013). Therefore,
patients must be closely monitored for signs and symptoms of cytopenia while in the
study, and those with a history of hematological disorders or with markedly altered
hematologic parameters at baseline will be excluded from the study.

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
Risk of cardiovascular origin:
For ibrutinib, atrial fibrillation was described for 3% to 6% of 
subjects across multiple trials, which might be associated with Na-channel inhibition 
(Ibrutinib SmPC 2013). For acalabrutinib, both atrial fibrillation and atrial flutter of any 
grade were reported in 3% of patients (Acalabrutinib SmPC 2017). Therefore, ECG 
monitoring will be implemented in this study. In addition, patients with a known history or 
current diagnosis of ECG abnormalities indicating a significant safety risk will be 
excluded from the study.

Drug-drug interactions:
Please refer to the current IB (Section 5.1.5) for information on drug-drug interactions of 
LOU064.  
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
Reproductive toxicity:
For ibrutinib and acalabrutinib, embryofetal toxicity in animals is 
reported (Acalabrutinib SmPC 2017; Ibrutinib SmPC 2013). Highly effective methods of 
contraception must be practiced for women of child-bearing potential while taking study 
treatment and for 7 days after stopping study medication.
Women of child-bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study, they must adhere to the contraception requirements 
outlined in the exclusion criteria. If there is any question that the subject will not reliably 
comply, they should not enter or continue in the study.
In summary, SjS patients may benefit from treatment with LOU064 due to the effect on B-cells 
and autoantibodies. Additionally, this study will help improve the scientific understanding of 
LOU064 in the management of SjS and offer the potential of developing an innovative drug 
that could potentially improve the quality of life for SjS patients beyond the conventional 
treatment modalities currently available to them.
Potential risks are mitigated by compliance with inclusion/exclusion criteria, study procedures, 
close clinical monitoring and study drug discontinuation rules. As with investigational drugs in 
general, not all safety risks are known. Patients and investigators participating in this study will
be informed should important new safety information become available.
4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of 
24 weeks for the treatment period plus the 6 week screening and the 30 days follow-up 
period from each subject as part of the study. Additional samples may be required for safety 
monitoring.
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and central laboratory manual.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.
5
Study Population
The study population will consist of adult male and female Sjögren's Syndrome (SjS) patients 
with ESSDAI ≥ 5 derived from 8 of 12 domains.
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Subjects who drop out after they have been randomized will not be replaced.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria at the time 
of screening evaluations unless otherwise noted.
1. Signed informed consent must be obtained before any study assessment is performed.
2. Male or female patients aged 18 to 75 years
3. Classification of Sjögren's Syndrome according to the 2016 ACR/EULAR criteria
(Shiboski et al 2017).
4. Screening ESSDAI (based on weighted score) ≥5 derived from 8 domains (biologic,
hematologic, articular, cutaneous, glandular, lymphadenopathy, renal, constitutional).
Subjects with involvement of one or more of the remaining 4 domains are eligible but
scores of these domains will not contribute to the assessment for eligibility, but will be
part of the overall ESSDAI for that subject.
5. Screening ESSPRI ≥ 5
6. Seropositive for anti-Ro/SSA antibodies at or within 3 months prior to screening
7. Unstimulated whole salivary flow rate of > 0 mL/min.
8. Able to communicate well with the Investigator to understand and comply with the
requirements of the study.
5.2
Exclusion criteria
Subjects fulfilling any of the following criteria (at the time of screening evaluations unless 
otherwise noted) are not eligible for inclusion in this study.
1. Sjögren’s Syndrome overlap syndromes where another autoimmune disease constitutes the
primary illness, specifically

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


2.
3. Rituximab or other B cell depleting drug within 12 months of Screening. For subjects who
received such drug, their B cell count should be within normal range.
4. Current use of prednisone or equivalent > 15mg/d or dose change within 2 weeks prior to
baseline.
5. Prior treatment with any of the following within 6 months of baseline

CTLA4-Fc Ig (abatacept)

Anti-TNF-α mAb

Intravenous Ig

Plasmapheresis

i.v. or oral cyclophosphamide

i.v. or oral cyclosporine A
6. Disease-modifying antirheumatic drugs (DMARDs) or kinase inhibitors within 3 months
prior to baseline are not allowed
7. Required regular use of medications known to cause, as a major side effect, dry mouth /
eyes, and which have not been on a stable dose for at least 30 days prior to Screening, or
any anticipated change in the treatment regimen during the course of the study.
8. HIV, Hepatitis C, Hepatitis B (HBsAg positive). If HBsAg is negative and anti-HBc
positive, patient can be included if HBV-DNA is negative and patient is monitored during
the study for HBsAg and HBV-DNA.
Known or suspected history of an ongoing, chronic or recurrent infectious disease
including but not limited to opportunistic infections (e.g. tuberculosis, atypical
mycobacterioses, listeriosis or aspergillosis).
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9. History of live attenuated vaccine within 6 weeks prior to baseline or requirement to
receive these vaccinations at any time during study drug treatment
10. Major surgery within 8 weeks prior to screening or surgery planned prior to end of study
11. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular
tachycardia, and clinically significant second or third degree AV-block without a
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes

Resting heart rate (12 lead ECG) < 50 bpm

Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) at pretreatment (screening)
or inability to determine the QTcF interval
12.
13. Significant bleeding risk or coagulation disorders, including but not limited to:
b. Requirement for anti-platelet or anticoagulant medication (for example, warfarin, or
clopidogrel or Novel Oral Anti-Coagulant - NOAC) other than acetylsalicylic acid (up
to 100 mg/d)
c. History of gastrointestinal, intracerebral or otherwise considered severe bleeding, eg
in association with use of Nonsteroidal Anti-Inflammatory Drug (NSAID)
14.
15.
16.
17.
18. Screening CBC laboratory values as follows:

Hemoglobin levels below10 g/dL

Total leukocyte count less than 3,000/µL

Platelets less than 100,000/µL

Neutrophil count ≤ 1,500/ µL
19.
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6
Treatment
6.1
Study treatment
The investigational drug will be provided by Novartis as appropriately blinded labeled bottles. 
 the bottles will contain capsules with either 50 mg active substance (LOU064) or 
matching Placebo.
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, dispensing and taking study treatment are outlined in the 
SOM.
6.1.1
Investigational and control drugs
Novartis Global Clinical Supply (GCS) will provide IMP supplies as detailed in the table below 
(Section 6.1).
Supplies will be provided in a double-dummy manner. 
Table 6-1
Investigational and control drug
Investigational/Co
ntrol Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply type
Sponsor
LOU064 50 mg
Hard Gelatin 
Capsule
Oral
Double-blind 
supply
Novartis Pharma 
AG 
LOU064 0 mg
(Placebo)
Hard Gelatin 
Capsule
Oral
Double-blind 
supply
Novartis Pharma 
AG 
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
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6.1.3
Treatment arms/group
 subjects will be assigned on Day 1 to one of the following 3 treatment arms in a ratio 
of 1:1:1

LOU064 100 mg bid

LOU064 100 mg qd

Placebo
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Forms.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study.
Low-dose steroids (up to maximally 15 mg/day prednisone or equivalent) are allowed and study 
subjects must be on a stable dose for at least 2 weeks prior to randomization.
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Concomitant treatment may include standard of care for dry eye and dry mouth symptoms, such 
as the use of artificial tears and artificial salvia/salivary stimulants (e.g. cevimeline, pilocarpine) 
at the discretion of the treating physician. Amount and frequency of use should be recorded. 
Please refer to Table 6-2 for guidance on suggested treatment time interval prior to assessment 
of clinical disease outcome measurements. Artificial tears and artificial saliva are to be provided 
by the study center or personal physician.
Table 6-2
Treatments against dryness of eyes/mouth
Treatment Type
Time interval prior outcome 
assessment
Artificial tears or other topical ophthalmic medications
4 hrs
Artificial saliva
4 hrs
Pilocarpine
12 hrs
Cevimeline or other salivary stimulants
24 hrs or 5x half-life whichever is longer
6.2.2
Prohibited medication
Use of treatments displayed in the below table is not allowed in study periods as indicated.
Table 6-3
Prohibited Medication
Medication
Prohibition period
Action to be taken
Use of other investigational 
drugs
5 half-lives or within 30 days of 
baseline or until 
pharmacodynamic effect has 
disappeared prior to baseline 
(whichever is longer) until end 
of study
Discontinue study treatment
Routine use of systemic 
corticosteroids (>15mg/d 
prednisone or equivalent)
14 days prior to baseline until 
end of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
Rituximab or other B cell 
depleting drug
Within 12 months prior to 
screening until end of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
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Medication
Prohibition period
Action to be taken
Other immunosuppressive 
medication with or without 
known effect on SjS including 
but not limited to cyclosporine 
A, cyclophosphamide, 
tacrolimus, leflunomide and 
mycophenolate mofetil or 
azathioprine, 
hydroxychloroquine / 
chloroquine and methotrexate 
in doses above those given in 
Section 6.2.1.
Within 6 months prior to 
baseline until end of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
Intravenous (i.v.) 
immunoglobulins or 
plasmapheresis
Within 6 months prior to 
baseline until end of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
Live attenuated vaccine
6 weeks prior to baseline until 
end of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
Moderate and strong inhibitors 
of CYP3A4 (see Section 16.6)
From screening until end of 
study
If LOU064 treatment is 
interrupted during the study to 
allow for transient treatment of 
CYP3A4 inhibitors (e.g. 
erythromycin) it may be 
resumed > 48hrs after the 
intermittent treatment has been 
stopped
Co-medication with moderate 
and strong CYP3A4 inhibitor is 
not allowed and subjects may 
interrupt LOU064 treatment if 
respective co-medication is 
required or cannot be replaced
Drugs which are substrates for 
efflux transporters P-gp and 
BCRP and are classified as 
sensitive substrates or have a 
narrow therapeutic index (NTI)
From screening until end of 
study
Co-administration may either 
be avoided and respective 
drugs (list to be provided) 
dosed in a staggered approach 
(3hrs after LOU064)
Moderate and strong inducers 
of CYP3A4 (see Section 16.6)
From screening until end of 
study
Subject's may be withdrawn
from the study as the efficacy 
of LOU064 is compromised by
concomitant use of CYP3A4 
inhibitors 
Any drug known to prolong QTc 
interval
5 half-lives or until 
pharmacodynamic effect has 
disappeared prior to baseline 
(whichever is longer) until end 
of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
Anti-platelet or anticoagulant 
medication (for example, 
warfarin/VKAs, or clopidogrel or 
Novel Oral Anti-Coagulant -
NOAC) other than 
acetylsalicylic acid (up to 100 
mg/d)
From screening until end of 
study
Subject's withdrawal from the 
study may be required on a 
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Medication
Prohibition period
Action to be taken
Newly installed DMARDs or 
other immune suppressive 
agents or changes in an 
existing DMARD regimen 
(hydroxychloroquine / 
chloroquine or methotrexate)
From 3 months prior to 
baseline until end of study
Subject's withdrawal from the 
study may be required on a 
case-by-case basis
6.2.3
Rescue medication
There is no established, approved immunosuppressive treatment for SjS. Patients may receive 
nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, or symptomatic care at the 
discretion of the treating physician as outlined in Section 6.2.1. Each concomitant drug must be 
individually assessed against all exclusion criteria and prohibited medication (Table 6-3). 
When in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If any of the medications 
listed in Table 6-3 is deemed a necessary rescue therapy, the investigator must follow the actions 
to be taken outlined in this table. Any potential rescue medication is to be provided by the study 
center or personal physician. Patients should be encouraged to come for the end-of-study visit 
even when discontinued permanently from study medication.
There is no specific rescue medication for LOU064. LOU064 is eliminated within a few hours 
from the body and no specific antidote is necessary. Pharmacodynamic activity of LOU064 
may take longer as the elimination time because of the covalent binding to the BTK-molecule. 
However, any direct immunosuppressive activity is not expected to take more than a few days.
6.2.4
Restriction for study subjects
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see 
‘Subject numbering’ section in the SOM.
6.3.2
Treatment assignment, randomization
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 subject fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization 
number to the subject, which will be used to link the subject to a treatment arm and will specify 
a unique medication number for the first package of study treatment to be dispensed to the 
subject. Randomisation will occur once eligibility is confirmed and prior to dosing; this will 
occur on Day 1 as per Assessment Schedule (Table 8-1), but may be performed on Day -1, if 
preferred by the site for logistical reasons.
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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject 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 Novartis Global Clinical Supply 
(GCS) using a validated system that automates the random assignment of medication numbers 
to packs containing the study treatment.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
6.4
Treatment blinding
 is subject and investigator-blinded. Subjects and investigators will remain blinded to the 
study treatment throughout the study, except where indicated below in  Table 6-4.
The identity of the treatments will be concealed by the use of study drug that are all identical in 
packaging, labeling, schedule of administration, appearance, taste and odor. To keep the dosing 
schedule blinded, there will be a morning and an evening dose for all subjects.
The following unblinded sponsor roles are required for this study: Unblinded sample analyst(s) 
(PK). The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Unblinding will occur in the case of subject emergencies and at the conclusion of the study.
Following final database lock all roles may be considered unblinded. See the Table 6-4 for an 
overview of the blinding/unblinding plan.
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Table 6-4
 Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Subjects/Patients
B
B
UI
Site staff
B
B
UI
Drug Supply and 
Randomization Office
UI
UI
UI
Unblinded sponsor staff (see 
text for details)
B
B
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
Independent committees 
used for assessing interim 
results
B
B
UI
All other sponsor staff not 
identified above
B
B
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
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6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted. Study subjects are 
treated according to their allocation in the randomization process.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator and site staff 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. Compliance will be assessed by the investigator 
and/or study personnel at each visit using information provided by the subject for hard gelatin 
capsule 
 counts at visits where new supply is provided to 
the subject. This information - including any missed doses - must be captured in the source 
document at each visit.
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs).
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
6.6.3
Emergency breaking of assigned treatment code
Breaking the randomization code will only be undertaken when it is required for subject's safety. 
Blinding codes may also be broken after a participant discontinues study treatment due to 
disease progression if deemed essential to allow the investigator to select the participant’s next 
treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
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to treat a study subject 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 subject, he/she must provide the requested subject identifying information 
and confirm the necessity to break the treatment code for the subject. The investigator will then 
receive details of the investigational drug treatment for the specified subject and a fax or email 
confirming this information. The system will automatically inform the 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 dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
After emergency unblinding the subject will not receive further study treatment and will be 
withdrawn from the study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs Section 6.1.1.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, delivery of IMP directly to a participant’s home may be permitted (if allowed by Local 
or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. The dispatch of IMP from the site to the participant’s 
home remains under the accountability of the Investigator. Each shipment/provisioning will be 
for a maximum of one-month supply. In this case, regular phone calls or virtual contacts (every
4 weeks or more frequently if needed) will occur between the site and the participant for 
instructional purposes, safety monitoring, drug accountability, investigation of any adverse 
events, ensuring participants continue to benefit from treatment and discussion of the 
participant´s health status until the participants can resume visits at the study site.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC)-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (eg all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
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Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the ICH Good Clinical Practice (GCP) guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the subject.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
8
Visit schedule and assessments
The assessment schedule lists all of the assessments and when they are performed. All data 
obtained from these assessments must be supported in the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented by the investigator 
as the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits for the duration of the disruption 
until it is safe for the participant to visit the site again.
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Table 8-1
Assessment Schedule
Period Screening
Treatment
Visit Name Screening Baseline Week 
2
Week 4
Week 
8
Week 
12
Week 
16
Week 
20
Week 24
Days
-42
1
15
29
57
85
113
141
169
Time (post-dose)
-
-
-
pre-dose
0h
0.5h
1h
2h
3h
4h
-
-
-
-
pre-dose 0h 0.5h 1h
2h 3h
Informed consent
X
X
Inclusion / 
Exclusion criteria
X
Demography
X
Medical 
history/current 
medical 
conditions
X
Prior therapy for 
Sjögren's 
Syndrome
X
Contact IRT
S
Drug dispensation 
at site
S
S
S
S
S
S
Dose 
administration
X
X
X
X
X
X
X
HIV screen
X
Hepatitis screen / 
monitoring
X
X1
X1
X1
X1
X1
X1
S
Physical 
Examination
S
S
S
S
S
S
S
S
S 
Vital Signs
X
X
X
X
X
X
X
X
X
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Period Screening
Treatment
Visit Name Screening Baseline Week 
2
Week 4
Week 
8
Week 
12
Week 
16
Week 
20
Week 24
Days
-42
1
15
29
57
85
113
141
169
Time (post-dose)
-
-
-
pre-dose
0h
0.5h
1h
2h
3h
4h
-
-
-
-
pre-dose 0h 0.5h 1h
2h 3h
Body 
Temperature
X
X
X
X
X
Body Height
X
Body Weight 13
X
ESSDAI
X
X
X
X12
X
X
X
X
X12
ESSPRI
X
X
X
X12
X
X
X
X
X12
Anti-Ro/SSA
X
X
X12
X
X12
PhGA - VAS
X
X
X12
X
X
X
X
X12
FACIT-Fatigue
X
X
X12
X
X
X
X
X12
EQ5D
X
X
X12
X
X
X
X
X12
Hematology
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
Coagulation 
Panel
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
PK blood 
collection
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
X2
X
X2
X2
X
X
X
X
X2
X2
X4
X
X
X12
X
X
X
X
X5, 
12
X
X
X12
X
X12
Salivary flow rate 
(unstimulated)
X
X
X
X12
X
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Period Screening
Treatment
Visit Name Screening Baseline Week 
2
Week 4
Week 
8
Week 
12
Week 
16
Week 
20
Week 24
Days
-42
1
15
29
57
85
113
141
169
Time (post-dose)
-
-
-
pre-dose
0h
0.5h
1h
2h
3h
4h
-
-
-
-
pre-dose 0h 0.5h 1h
2h 3h
X
X
X8
X
X
X8
X
X
X8
X
X
X
X8
X
X
X
X8
X
X
Pregnancy
X
X
X
X
X
X
X
X
X
Study completion 
information
Concomitant 
medications
X
Adverse Events
X
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Period
Treatment
Follow Up
Visit Name
Week 24
Week 29/EOS15
Days
169
199
Time (post-dose)
4h
-
Informed consent
Inclusion / Exclusion criteria
Demography
Medical history/current medical conditions
Prior therapy for Sjögren's Syndrome
Contact IRT
Drug dispensation
Dose administration at site
HIV screen
Hepatitis screen / monitoring
Physical Examination
S
Vital Signs
X
Body Temperature
Body Height
Body Weight
ESSDAI
X
ESSPRI
X
Anti-Ro/SSA
PhGA - VAS
X
FACIT-Fatigue
X
EQ5D
X
Hematology
X
Clinical Chemistry
X
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Period
Treatment
Follow Up
Visit Name
Week 24
Week 29/EOS15
Days
169
199
Time (post-dose)
4h
-
Coagulation Panel
X
Urinalysis
X
PK blood collection
X
Electrocardiogram (ECG)
X
X
Salivary flow rate (unstimulated)
X
Pregnancy Commercially Confidential Information
X
Study completion information
X
Concomitant medications
X
Adverse Events
X
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X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Hepatitis B monitoring only for subjects who were HBsAg negative and anti-HBcAb positive with a negative HBV DNA test at Screening.
2
3
4
5
6 SjS symptom section is to be completed weekly and dosing compliance section daily. SjS symptom section only until EOS visit.
7 at selected sites only
8 to be taken pre-dose
9
10 Serum pregnancy test will be done at Screening and EOS. For remaining visits urine pregnancy test will be performed.
11
12 Suggested time point but assessment can be done at any time during the visit
13 Note that monitoring of weight loss is part of the constitutional domain of ESSDAI. While body weight is only captured in the CRF for screening, 
measurements have to be done if required for the assessment of ESSDAI
14 
15 Mandatory to all participants, including those who have discontinued the study prematurely.
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8.1
Screening
It is permissible to re-screen a subject if she/he fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis. Patients can be 
re-screened only once and no study-related re-screening procedure should be performed prior 
to written re-consent by the patient.

Tests for HIV, Hepatitis B and HCV do not need to be repeated if they satisfied eligibility
criteria in the initial screening, and have been conducted within 12 weeks prior to planned
date of randomization.

If tested positive in screening anti-Ro/SSA, results do not need to be repeated in re-
screening.
In the case where a safety laboratory or ECG assessment at screening is outside of the range 
specified in the exclusion criteria, the assessment may be repeated once prior to randomization. 
If the repeat value remains outside of the specified ranges, the subject must be excluded from 
the study.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the SOM.
8.1.1
Eligibility screening
Subjects will be screened for HIV, Hepatitis C and for Hepatitis B surface antigen (HBsAg) and 
Hepatitis B core antibody (anti-HBcAb). HBsAg negative and anti-HBcAb positive subjects 
with a negative HBV DNA test are eligible for randomization but will be monitored every 4 
weeks throughout the study treatment phase for HBsAg and HBV DNA. Any subject testing 
positive for HBsAg or HBV DNA during this monitoring process will need to be discontinued 
from the study.
Positive anti-Ro/SSA results obtained as part of routine medical care and within 3 months prior 
to screening can be used to satisfy inclusion criterion, and do not need to be repeated at 
screening.
Additional information and guidance are provided in the SOM.
8.1.2
Information to be collected on screening failures
Subjects who sign an informed consent form and are subsequently found to be ineligible prior 
to Day 1, will be considered a screen failure. The reason for screen failure will be recorded on 
the appropriate Case Report Form. In addition, only the CRFs related to the following 
assessments should be completed: informed consent, demography, and inclusion/exclusion 
criteria. The CRF for adverse events (AEs) should be completed for any Serious Adverse Events 
(SAEs) that occurred during the screening period. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
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If the subject fails to be randomized, the IRT should be notified within 2 days of the screen fail 
that the subject was not randomized. Subjects who are randomized and fail to start treatment, 
e.g. subjects randomized in error, will be considered as mis-randomized. The reason for
mis-randomization will be recorded on the appropriate Case Report Form.
8.2
Subject demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Demographic and baseline characteristic data to be collected on all subjects include: age, sex, 
race, ethnicity, source of patient referral, relevant medical history/current medical condition 
present before signing informed consent where possible, diagnoses and not symptoms will be 
recorded. Prior therapy for Sjögren's Syndrome will also be recorded.
Investigators will 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
Efficacy
Clinical efficacy measurements related to primary and secondary objectives are outlined below.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, Clinical Outcomes Assessment (COA) data may be collected remotely (e.g., via web 
portal) depending on local regulations, technical capabilities and following any applicable 
training in the required process.
8.3.1
EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI)
ESSDAI (Section 16.4) is a validated disease outcome measure for Sjögren’s Syndrome that 
will be applied to the study subjects. 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. The domains (weights) are as follows: constitutional 
(3), lymphadenopathy (4), glandular (2), articular (2), cutaneous (3), pulmonary (5), renal (5), 
muscular (6), PNS (5), CNS (5), hematological (2), and biological (1). The maximum possible 
score is 123.
To calculate ESSDAI, all 12 organ domains must be individually assessed at every scheduled 
timepoint (from screening visit till end of study). Domain assessments will be entered into a 
tablet (provided by a central vendor) and ESSDAI score will be calculated by the software. 
At screening, the ESSDAI subscore from 8 pre-selected domains listed in the inclusion criterion 
#7, will be calculated to determine patient's eligibility. 
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.

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8.3.2
Physician Global Assessment Scale (PhGA)
The physician’s global assessment scale is used for the Investigator to rate the disease activity 
of their patient using 100 mm VAS ranging from “no disease activity” (0) to “maximal disease 
activity” (100).
To enhance objectivity, the physician must not be aware of the specific patient’s patient reported 
outcome assessments, when performing his own assessment on that patient. Therefore this 
assessment must be done prior to viewing the patient’s reported outcomes.
8.3.3
EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI)
ESSPRI is an established disease outcome measure for Sjögren’s Syndrome (Seror et al 2011). 
It consists of three of domains of dryness, pain and fatigue. The subject can assess severity of 
symptoms they experience on a single 0-10 numerical scale for each of the three domains. 
The ESSPRI score is defined as mean of scores from the three scales: (dryness + pain + fatigue) 
/3. ESSPRI will be applied to the study subjects at screening, baseline and during study 
treatment as per study assessment schedule (Table 8-1).
8.3.4
FACIT-Fatigue
The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 
13-item, easy-to-administer tool that measures an individual’s level of fatigue during their usual
daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale
(0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much) Webster et al 2003.
8.3.5
EQ5D
EQ-5D is a standardized instrument which measures the health-related quality of life. 
The EQ-5D consists of a descriptive system and the EQ VAS scale.
The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. This can be used as a quantitative measure of health 
outcome that reflects the patient’s own judgement. The scores on these five dimensions can be 
presented as a health profile or can be converted to a single summary index number (utility) 
reflecting preferability compared to other health profiles.
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale with 0 
representing 'Worst imaginable Health State' and 100 'Best imaginable Health State'.
8.3.6
Appropriateness of efficacy assessments
Efficacy measures in this study are primarily based on ESSDAI (EULAR SS Disease Activity 
Index) measuring organ-specific disease criteria, and on ESSPRI (European League Against 
Rheumatism [EULAR] Sjoegren Syndrome [SS] Patient Reported Index) measuring the 
patient's subjective disease impact. Both instruments are widely accepted and validated, 
gold-standard measures of systemic and symptomatic manifestations of SjS, respectively.

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ESSDAI is a systemic disease activity index that classifies disease activity in 3-4 levels, over 
each of 12 differentially weighted domains (biologic, hematologic, articular, glandular, 
cutaneous, constitutional, lymphadenopathy, renal, pulmonary, PNS, CNS and muscular). 
A composite weighted score provides an accurate assessment of disease activity, with a good 
sensitivity to change, as validated in multiple cohort studies (Seror et al 2015). The ESSPRI 
tool, on the other hand, is a patient reported composite score of symptoms of dryness, limb pain 
and fatigue evaluated on 0-10 visual analog scale, during the preceding 2 weeks 
(Seror et al 2011). Patient reported scores have poor sensitivity to change in disease activity, 
but among available tools, ESSPRI has been reported to have significantly better sensitivity. 
A recent prospective study reported poor correlation between systemic and patient scores, 
suggesting that the two indices evaluate complementary components of disease activity, 
therefore underscoring the importance of evaluation of both parameters to arrive at an accurate 
assessment of disease activity and change thereof (Seror et al 2015).
8.4
Safety
Safety assessments are specified below with the assessment schedule (Table 8-1) detailing when 
each assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
The methods, assessment, specification, and recording for each assessment will be detailed in 
the SOM.
Table 8-2
Assessments and Specifications
Assessment
Specification
Physical
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.
The investigator should ask the patient for and pay attention to presence 
of signs and symptoms of infection.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse 
Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure (BP) and pulse measurements. After the 
subject has been sitting for five minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be 
measured using an automated validated device, with an appropriately 
sized cuff.
Clinically notable vital signs are defined in Section 16.1.
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 Temperature
Measured as per local default e.g. oral or ear/tympanic measurement.
The methods for each assessment and data recording details are specified in the SOM.

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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for 
safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual.
All abnormal lab results must be evaluated for criteria defining an adverse event but only 
reported as such if the criteria are met (please refer to Section 10.1.1). For those lab adverse 
events, repeated evaluations are mandatory until normalization of the result(s) or until the result 
is no longer considered to be clinically significant. Clinically notable laboratory findings are 
defined in Section 16.1.
Table 8-3
Laboratory Evaluations
Test Category
Test Name
Hematology
Hemoglobin, Hematocrit, Mean Corpuscular Hemoglobin (MCH), Mean
Corpuscular Hemoglobin Concentration (MCHC), Mean Corpuscular Volume 
(MCV), Red Blood Cells (RBC), White Blood Cells (WBC) plus differential 
count (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Bands), Platelets
Chemistry
Sodium, Potassium, Bicarbonate, Creatinine, Urea, Uric Acid, Chloride, 
Albumin, Calcium, Alkaline Phosphatase, total Bilirubin (if elevated above 1.5 
times, direct and indirect Bilirubin will be differentiated), LDH, GGT, AST, 
ALT, Amylase, Lipase, CK, glucose, Total Cholesterol, Triglycerides; total 
Protein, Immunoglobulins quantitative (IgG, IgA, IgM, IgE); C-reactive Protein 
(CRP). Special clinical laboratory evaluations serum markers of B cell 
hyperactivity including but not limited to β2-microglobulin, free 
immunoglobulin light chains and complement (C3, C4, CH50).
Urinalysis
Urinalysis: leucocytes, nitrite, pH, protein, glucose, ketones, urobilinogen, 
bilirubin, blood/hemoglobin. If positive for protein, nitrite, leucocytes and/or 
blood, sample will undergo microscopic analysis of WBC, RBC and casts.
Coagulation
Prothrombin time (PT), International normalized ratio [INR]), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time (APTT)
Serology
Hepatitis serology: hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (anti-HBc), HBV-DNA if applicable; hepatitis C virus antibody 
(HCVAb); HCV-RNA if applicable (see Section 8.1.1)
Human immunodeficiency virus antibody (HIV Ab)
Hepatitis 
monitoring
HBsAg, HBV-DNA
Pregnancy Test
Serum / Urine pregnancy test (see Section 8.4.3)

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8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
technical manual provided by the core laboratory.
Standard 12-lead ECGs must be recorded after 10 minutes rest in the supine position according 
to the ECG investigator manual. See Section 1.2 of the SOM for recommendation on the 
ordering of assessments. The Fridericia QT correction formula (QTcF) should be used for 
clinical decisions.
Triplicate 12-lead ECGs are to be collected for central analysis as follows:

Day 1: before administration of the first dose of study medication

Week 4 and Week 24: before administration of study medication and 1h after
administration of the study medication (study medication will be taken at the study site;
ECG recording will be accompanied by taking samples for PK analysis (see
Section 8.5.3)).
Single 12-lead ECGs will be recorded at Screening, Week 2, Week 8, Week 12, Week 16, 
Week 20 and EOS.
For any ECGs with treatment emergent abnormalities, two additional ECGs must be performed 
to confirm the abnormal finding and copies forwarded to the central ECG laboratory for 
assessment. A monitoring or review process should be in place for clinically significant ECG 
findings throughout the study and especially at baseline before administration of study 
treatment.
In the event that a clinically significant ECG abnormality is identified at the site (eg severe 
arrhythmia, conduction abnormality of QTcF > 500 ms or QTcF prolongation> 60 ms), a copy 
of the assessment is sent to the core laboratory for expedited review if applicable, and the ECG 
is repeated to confirm the diagnosis. If the subject is hemodynamically compromised, the 
investigator or a medically qualified person must initiate appropriate safety procedures without 
delay (for example cardioversion).
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or AEs as appropriate.
8.4.3
Pregnancy 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Serum pregnancy test will be done at Screening and EOS and for remaining visits urine 
pregnancy test can be performed. Additional pregnancy testing might be performed if requested 
by local requirements. A positive urine test requires immediate interruption of study drug 
and needs to be confirmed with a serum test. If positive, the subject must be discontinued from 
the study treatment. Highly effective method of birth control must be used for women of 
child-bearing potential (see exclusion criteria definitions, Section 5.2).
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If participants cannot visit the site to have pregnancy tests, urine pregnancy test kits may be 
used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first, and only if the test result is negative are they to proceed with administration of the study 
treatment. A communication process should be established with the participant so that the Site 
is informed and can verify the pregnancy test results (e.g., following country-specific measures).
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
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8.5.2
Other Assessments
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8.5.3
Pharmacokinetics
PK samples will be collected at the visits and time points defined in the assessment schedule 
(Table 8-1). Follow instructions outlined in the laboratory manual regarding sample collection, 
numbering, processing and shipment. 
PK samples (blood) will be obtained in all subjects and at all dose levels. They will be evaluated 
in all subjects, except the placebo group. 
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Concentrations will be expressed in mass per volume units (ng/mL) and will refer to the free 
base. 
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol. The following PK parameters will be determined from the blood concentration time 
data using the actual recorded sampling times and non-compartmental method(s) with Phoenix 
WinNonlin (Version 6.4 or higher): Cmax, Tmax, AUC. 
The PK of LOU064 will be characterized at Week 4 and Week 24 across all treatment arms. 
 Proposed sampling 
schedule and rationale is given in Table 8-4. Detailed PK sampling schedule is given in 
Table 8-1.
Table 8-4
PK sampling schedule
Time
Sample
Comment
Day 1
no PK assessment
Week 4
Pre-dose, 
0.5h/1h/2h/3h/4h/post-dose
Early Steady-state “full” PK profile baseline 
PK assessment, which allows 
synchronization of parallel cardiovascular 
investigations, which may be driven by 
initial high blood exposures (Cmax) at the 
primary endpoint/interim analysis
Week 24 (last day, 
last dose
Pre-dose, 
0.5h/1h/2h/3h/4h/post-dose
Assess steady-state + intra-subject 
variability + putative time dependent effects 
on PK, 
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject's decision

Pregnancy
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
Use of prohibited treatment as per recommendations in the prohibited treatment section
(Section 6.2.2)

Any situation in which study participation might result in a safety risk to the subject, e.g.
required surgical interventions associated with a risk of clinically significant bleeding

Following emergency unblinding

Emergence of the following AEs:

AEs including severe or serious hypersensitivity reactions for which continued
exposure to the study drug would be detrimental

Abnormal liver laboratory results requiring discontinuation (see Section 16.2)

Abnormal renal laboratory results requiring discontinuation (see Section 16.3)

Platelets < 75 000/mm3

Any other laboratory abnormalities that in the judgment of the investigator, taking
into consideration the subject’s overall status, prevents the subject from continuing
participation in the study

Patient received a live virus vaccination during the study
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, they should return for the assessments 
indicated in the assessment schedule (Table 8-1). If they fail to return for these assessments 
for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact 
the subject/pre-designated contact as specified in the lost to follow-up section (Section 9.1.3). 
This contact should preferably be done according to the study visit schedule (Table 8-1).
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section (see Section 6.6.3).

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9.1.1.1
Replacement policy
Subjects will not be replaced on study.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not want any further visits or assessments, and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. However, subjects still retain the right to object to the further use of personal 
data. Study treatment must be discontinued and no further assessments conducted, and the data 
that would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the subject’s study discontinuation should be made as detailed in the 
assessment table (Table 8-1).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
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 must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
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9.1.4
Study stopping rules
The study may be put on hold pending a full safety data review, if any of the following criteria 
are met:

If an unexpected frequency (in different subjects) of similar study-treatment related SAEs
are reported

Two or more other clinically significant, severe events (in different subjects) that preclude to
continue dosing and which are considered study drug related, including but not limited to
o
development of recurrent/opportunistic infection,
o
spontaneous bleeding events (except minor bleeding like self-limiting
epistaxis),
o
drug related renal or liver events meeting the event criteria as detailed in
Section 10.2.1 and Section 10.2.2,
o
neutropenia <1,000/microl, anemia <8g/dl, thrombocytopenia <75.000/microl,
o

The Sponsor considers that the number and/or severity of AEs, abnormal safety
monitoring tests or abnormal laboratory findings justify putting the study on hold.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed.
9.1.5
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, futility outcome 
, practical reasons (including slow enrollment), or for regulatory or medical reasons. 
In making the decision to terminate, Novartis will always consider the welfare and safety of 
subjects. Should early termination be necessary, subjects must be seen as soon as possible and 
treated as a prematurely withdrawn subject. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as the date when the last subject finishes their Study Completion 
visit and any repeat assessments associated with this visit have been documented and followed-
up appropriately by the Investigator or, in the event of an early study termination decision, the 
date of that decision. All randomized and/or treated subjects should have a safety follow-up call 
conducted 30 days after last administration of study treatment (in case of early study termination 
and EOS visit not performed). The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3 and 
in SOM). Documentation of attempts to contact the subject should be recorded in the source 
documentation.
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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments (such as e.g. Patient-reported Outcomes).
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression
of underlying illness (i.e. progression of the study indication) the assessment of causality
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a
lack of efficacy or progression of underlying illness are not caused by the trial drug, they
happen in spite of its administration and/or both lack of efficacy and progression of
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a
single subject
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not
recovered/not resolved must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. Action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

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
Drug interrupted/withdrawn
6. Its outcome i.e., its recovery status or whether it was fatal
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued for at least 30 days following the last dose of study 
treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. See Section 16.1, Section 16.2 and Section 16.3 for alert ranges for 
laboratory and other test abnormalities.
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for subjects that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

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
routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
No pre-specified study endpoints are considered to be exempted from SAE reporting.
1. Screen Failures (eg a subject who is screened but is not treated or randomized): SAEs
occurring after the subject has provided informed consent until the time the subject is
deemed a Screen Failure must be reported to Novartis/sponsor within 24-hours of learning
of its occurrence.
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until
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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. A SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety 
(CMO&PS) Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment must be stopped, and the trial 
participant must be asked to read and sign pregnancy consent form to allow the Study Doctor 
ask about her pregnancy. To ensure subject safety, each pregnancy occurring after signing the 
informed consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. A minimum of 12 months 
of the newborn must be followed up.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. Information 
will be collected at three time points after the estimated date of delivery and for a period of 
12 months.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please 
see Section 10.1.1, Section 10.1.2 and Section 10.1.3.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject 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.
Please also refer to Section 16.2 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-2 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Section 16.2.

Repeat liver chemistry tests (ALT, AST, Total Bilirubin (TBL), PT/INR, ALP and GGT)
to confirm elevation. These liver chemistry repeats will be performed using the central
laboratory. If results will not be available from the central laboratory, then the repeats can
also be performed at a local laboratory to monitor the safety of the subject. If a liver event
is subsequently reported, any local liver chemistry tests previously conducted that are
associated with this event should have results recorded on the appropriate eCRF.

If the initial elevation is confirmed, close observation of the subject will be initiated

Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event. These investigations can include based on
investigator’s discretion: serology tests, imaging and pathology assessments,
hepatologist’s consultancy

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
Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and
special diets

Exclusion of underlying liver disease

Obtaining a history of exposure to environmental chemical agents

Considering gastroenterology or hepatology consultations
All follow-up information, and the procedures performed must be recorded as appropriate in 
the eCRF.
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the course of the study period:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Any one of the following:

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR

New onset dipstick proteinuria ≥ 3+, OR

New onset dipstick hematuria ≥ 3+ (after excluding menstruation, Urinary Tract
Infection (UTI), extreme exercise, or trauma)
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
as defined in Table 16-3 in Section 16.3 should be monitored and followed up by the 
investigator or designated trial staff as summarized in Table 16-4.
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11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Laboratory samples and ECG will be processed centrally and the results will be sent 
electronically to Novartis.
Subjects will fill in their electronic/paper diary data at home. The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to Novartis.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.

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Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis representative will review the protocol and data capture requirements (i.e. eCRFs) 
with the investigators and their staff. During the study, Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The field 
monitor will visit the site to check the completeness of subject records, the accuracy of data 
capture / data entry, the adherence to the protocol and to Good Clinical Practice, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/delegated CRO/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.
12
Data analysis and statistical methods
The final analyses will be conducted after all subjects have finished the study. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented as the number and percent of patients in each category.
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If not otherwise specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed.
The baseline value is defined as the last assessment prior to first dose administration. In case 
the scheduled baseline assessment value is missing, the screening value if available will be used 
instead.
12.1
Analysis sets
 the following analysis sets will be used in this trial:
Full Analysis Set (FAS): comprises all subjects to whom study treatment has been assigned. 
Following the intent-to-treat principle, subjects will be analyzed according to the treatment 
assigned to at randomization and the strata they actually belong to in case of misallocation of 
strata during the randomization process. 
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized subjects are treated as screen failures.
Unless otherwise specified, mis-randomized subjects (randomized by mistake in IRT) will be 
excluded from the FAS. The FAS will be used for summaries of subject disposition and analysis 
sets, and for all efficacy variables, unless otherwise stated.
Safety Set (SS): includes all subjects who received at least one dose of study medication. 
Subject will be analyzed according to treatment received and the strata they actually belong to 
in case of misallocation of strata during the randomization process. The safety set will be used 
in the analysis of all safety variables.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for Safety Set and Full Analysis Set.
The following demographic variables and baseline disease characteristics will be summarized 
by treatment group:

Gender, age, race, ethnicity, weight, height, BMI and disease duration

ESSDAI and number of subjects per ESSDAI stratum, ESSPRI, PhGA, EQ-5D,
unstimulated salivary flow, 
 use 
of DMARDs (split by type), and percentage of subjects with history of prior biologics
treatment use.
Relevant medical histories and current medical conditions at baseline will be summarized 
combined by system organ class and preferred term, and by treatment group.
12.3
Treatments
Analyses of study treatment will be based on the Safety Set.
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of subjects with exposure of at least certain thresholds (e.g. any exposure, ≥1 week, 
≥2 weeks, ≥4 weeks, ≥8 weeks, etc) as well as cumulative exposure will be displayed.
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Prior and concomitant medication
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered.
Prior and concomitant medications will be summarized in separate tables. Medications will be 
presented in alphabetical order, by Anatomical Therapeutic Classification (ATC) codes and 
grouped by anatomical main group. Tables will show the overall number and percentage of 
patients receiving at least one treatment of a particular ATC code and at least one treatment in 
a particular anatomical main group.
The number and percentage of subjects receiving systemic therapies for SjS as prior and 
concomitant background medication will be presented separately by preferred term.
12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The following estimand framework is adopted for the primary analysis.


Variable of interest: Change from baseline in ESSDAI total score after 24 weeks of study 
drug administration. This will be defined as the Week 24 visit ESSDAI value minus the 
baseline ESSDAI value with negative values indicating improvement in disease status

Treatment of interest: The randomized treatment (LOU064 or placebo) on top of allowed
concomitant medication

Intercurrent events: Regardless whether early termination from the study, interruption of
study treatment, or intensified concomitant treatment (local and systemic) has occurred

Summary measure: Difference in mean change from baseline in ESSDAI total score at
Week 24 visit between placebo and LOU064
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12.4.2
Statistical model, hypothesis, and method of analysis
12.4.2.1 Repeated measures analysis
 a repeated measures model will be fitted to 
the changes from baseline in ESSDAI up to Week 24 visit. The change from baseline in 
ESSDAI is assumed to be normally distributed.
A mixed effect model for repeated measurements (MMRM) will be fitted to the changes from 
baseline in ESSDAI for all time points until Week 24 visit including the following fixed factors

treatment group

visit

treatment group by visit interaction

actual stratification factor using baseline ESSDAI score <10 or ≥10

geographic region
and baseline ESSDAI as a continuous covariate. An unstructured variance-covariance matrix 
will be fitted to model the dependency between repeated observations. Graphical checks on the 
model assumptions of normality of the data will be provided.
The mean treatment effects will be estimated at Week 24 visit.
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12.4.3
Handling of missing values/censoring/discontinuations
Missing baseline value
If the baseline ESSDAI total score is missing, the screening value (if available) will be used to 
impute the baseline value. If neither the ESSDAI total score at baseline nor the ESSDAI 
total score at screening can be calculated due to missing domain scores, then the baseline 
ESSDAI total score is calculated using combination of baseline visit domain scores (where 
those are not missing) and screening domain scores (where the baseline analogs are missing) if 
they are available, and otherwise the baseline ESSDAI total score is set to missing.
Other missing data
For post-dose time points with missing data in one of the domains of the ESSDAI, the ESSDAI 
total score will be set to missing.
The MMRM utilized for the primary analysis implicitly imputes missing data under a missing 
at random assumption. The reasonableness of this assumption will be checked during the 
blinded review of the data and, if necessary, further methods may be applied.
12.4.4
Sensitivity and Supportive analyses
12.5
Analysis of secondary endpoints
For the analysis of the secondary endpoints of ESSDAI, ESSPRI, FACIT-F, EQ-5D and PhGA, 
the same population and a similar estimand framework as for the primary endpoint 
(Section 12.4.1) will be adopted. Descriptive summary statistics will include all subjects in the 
Full Analysis Set.
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12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Efficacy analysis 
The change from baseline over time for secondary efficacy endpoints (ESSDAI, ESSPRI, 
FACIT-F, EQ-5D and PhGA) will be presented by treatment group and visit. Summary statistics 
will be presented for original results and mean change from baseline, together with adjusted 
mean change from baseline and 95% confidence interval estimated from 
 MMRM 
 
. Differences in change from baseline between 
LOU064 treatment groups and placebo, along with associated 95% confidence intervals, will 
be presented by visit. 
12.5.2
Safety endpoints
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG) will be summarized by 
treatment for all subjects in the safety set.
Adverse events
All information obtained on AEs will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent AEs (events started after the 
first dose of study medication or events present prior to start of double-blind treatment but 
increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related AEs, deaths, serious adverse 
events, and other significant AEs leading to discontinuation. A subject with multiple AEs within 
a primary system organ class is only counted once towards the total of the primary system organ 
class.
Laboratory data
The summary of laboratory evaluations will be presented for four groups of laboratory tests 
(hematology, serum chemistry, urinalysis and coagulation). Descriptive summary statistics for 
the change from baseline to each study visit will be presented. These descriptive summaries 
will be presented by test group, laboratory test and treatment group. Change from baseline will 
only be summarized for subjects with both baseline and post baseline values.
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Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign, treatment group and visit/time. Change from baseline will only be summarized 
for subjects with both baseline and post-baseline values. Shifts with respect to normal ranges 
and number and percentage of notable abnormalities will also be summarized.
ECG
Summary statistics will be provided by treatment and visit/time.
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each subject 
during the study. Frequency tables will be produced for the number and percentage of subjects 
with notable QT and QTcF intervals and with noteworthy PR, QRS and Heart Rate interval or 
changes from baseline.
12.5.3
Pharmacokinetics
Descriptive summary statistics for PK concentration data will be provided by treatment and 
visit/sampling time point, 
. Summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. 
Descriptive summary statistics for pharmacokinetic parameters will be provided by treatment. 
Summary statistics include mean (arithmetic and geometric), SD, and CV (arithmetic and 
geometric), median, minimum, and maximum. An exception to this is Tmax where median, 
minimum, and maximum will be presented.
Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast and AUC0-4h
The AUC from time zero to the last measurable concentration sampling 
time (tlast) (ng x h/mL). As the proposed sampling time is up to 4 hr 
AUClast will be equivalent to AUC0-4 hr if blood concentrations can be 
measured up to 4 hr
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state 
(ng x h/mL).
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid 
drug concentration after single dose administration (ng/mL
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body 
fluid drug concentration after single dose administration (h)
MRT
Mean residence time of the analyte in the central compartment (h)
T1/2
The elimination half-life
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The PK profile of LOU064 will be characterized but not limited to the PK parameters listed 
above. 
12.6
Analysis of exploratory endpoints
Analyses of exploratory endpoints will be performed using Full Analysis Set.
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12.7
Interim analyses
12.7.1
Timing of analyses
12.7.2
Purpose of analyses
12.7.3
Maintenance of study integrity
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12.7.4
Decision criteria for interim analyses
12.8
Sample size calculation
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Council for  Harmonisation (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki.
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13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
in EudraCT. In addition, after study completion (defined as last patient last visit) and 
finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to investigators at the trial 
investigator meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.

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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
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15
References
References are available upon request
Acalabrutinib SmPC (2017) (Internet) Available from 
<https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf> 
(Accessed 05-Mar-2019)
Baldini C, Pepe P, Quartuccio L, et al (2014) Primary Sjogren's syndrome as a multi-organ 
disease: impact of the serological profile on the clinical presentation of the disease in a large 
cohort of Italian patients. Rheumatology (Oxford) p. 839-44.
Barendregt PJ, Visser MR, Smets EM, et al (1998) Fatigue in primary Sjögren's syndrome. 
Ann. Rheum. Dis. p. 291-5.
Brito-Zerón P, Retamozo S, Gheitasi H, et al (2016) Treating the Underlying Pathophysiology 
of Primary Sjögren Syndrome: Recent Advances and Future Prospects. Drugs p. 1601-1623.
Corneth OBJ, Verstappen GMP, Paulissen SMJ, et al (2017) Enhanced Bruton's Tyrosine 
Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune 
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Sjögren syndrome with rituximab: a randomized trial. Ann. Intern. Med. p. 233-42.
Hendriks RW, Yuvaraj S, Kil LP (2014) Targeting Bruton's tyrosine kinase in B cell 
malignancies. Nat. Rev. Cancer p. 219-32.
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immunodeficiency diseases. Clin. Dev. Immunol. p. 223-59.
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Rev Rheumatol p. 133-145.
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Nutt SL, Hodgkin PD, Tarlinton DM, et al (2015) The generation of antibody-secreting 
plasma cells. Nat. Rev. Immunol. p. 160-71.
Qin B, Wang J, Yang Z, et al (2015) Epidemiology of primary Sjögren's syndrome: a 
systematic review and meta-analysis. Ann. Rheum. Dis. p. 1983-9.
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Immune Cell Signaling and Systemic Autoimmunity. Crit. Rev. Immunol. p. 17-62.
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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The following specific criteria have been identified for this study. Should these criteria be met, 
a re-test should be done within 5 days after the first assessment based on investigator’s clinical 
judgement. Discontinuation of the study treatment should be considered if the abnormal 
hematology parameter is confirmed:
Hemoglobin: < 10 g/dl
Platelets: < 75 000/mm3
White blood cells: 3 000/mm3
Neutrophils: < 1 500/mm3
For all other laboratory assessments, the central laboratory will flag laboratory values falling 
outside of the normal ranges on the central laboratory report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the eCRF.
Notable values for vital signs and change from baseline will be summarized.
Notable values are defined as follows: heart rate of < 50 and > 100 bpm; systolic blood pressure 
of < 90 and ≥ 140 mmHg; diastolic blood pressure of < 60 and ≥ 90 mmHg.
For ECGs a notable QTc value is defined as a QTc (Fridericia’s) interval of greater than 450 
msec for males or greater than 460 msec for females – all such ECGs will be flagged by the 
central CRO’s cardiologist and require assessment for clinical relevance by the investigator.

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16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
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*
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver
neoplasms TBL: total bilirubin; ULN: upper limit of normal

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Table 16-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study
treatment immediately

Hospitalize, if clinically
appropriate

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study
treatment immediately

Hospitalize if clinically
appropriate

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR > 1.5

Discontinue the study
treatment immediately

Hospitalize, if clinically
appropriate

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48
hours

If elevation persists,
continue follow-up
monitoring

If elevation persists for
more than 2 weeks,
discontinue the study drug

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)

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Criteria
Actions required
Follow-up monitoring
> 3 × ULN accompanied by 
symptomsb

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)

Repeat LFT within 48 
hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit

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Criteria
Actions required
Follow-up monitoring
Jaundice

Discontinue the study
treatment immediately

Hospitalize the patient

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment
interruption or
discontinuation

Hospitalization if clinically
appropriate

Establish causality

Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.

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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase ≥ 50 % +

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation
unless other causes are diagnosed and
corrected

Consider patient hospitalization and
specialized treatment
New onset dipstick proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation
unless other causes are diagnosed and
corrected
New onset hematuria ≥ 3+ on urine dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain,
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other diseases or
causes, e.g., dehydration due to delirium, tumor lysis

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Table 16-4
Renal Event Follow Up
Assess, document and record in CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until 

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio
stabilization at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event

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16.4
Appendix 4: ESSDAI
Table 16-5
The EULAR Sjögren’s syndrome disease activity index (ESSDAI): 
domain and item definitions and weights
Domain [weight]
Activity level
Description
Constitutional [3]
Exclusion of fever of 
infectious origin and 
voluntary weight loss
No = 0
Low = 1 
Moderate = 2
Absence of the following 
symptoms
Mild or intermittent fever (37.5–
38.5°C)/night sweats and/or 
involuntary weight loss of 5-10% 
of body weight
Severe fever (>38.5°C)/night 
sweats and/or involuntary weight 
loss of >10% of body weight
Lymphadenopathy [4]
Exclusion of infection
No = 0
Low = 1
Moderate = 2 
High = 3
Absence of the following features
Lymphadenopathy ≥1 cm in any 
nodal region or ≥2 cm in inguinal 
region
Lymphadenopathy ≥2 cm in any 
nodal region or ≥3 cm in inguinal 
region, and/or splenomegaly 
(clinically palpable or assessed 
by imaging)
Current malignant B-cell 
proliferative disorder
Glandular [2]
Exclusion of stone or 
infection
No = 0
Low =1
Moderate = 2
Absence of glandular swelling
Small glandular swelling with 
enlarged parotid (≤3 cm), or 
limited submandibular or 
lachrymal swelling
Major glandular swelling with 
enlarged parotid (>3 cm), or 
important submandibular or 
lachrymal swelling
Articular [2]
Exclusion of osteoarthritis
No = 0
Low = 1
Moderate = 2
High = 3
Absence of currently active 
articular involvement
Arthralgias in hands, wrists, 
ankles and feet accompanied by 
morning stiffness (>30 min)
1–5 (of 28 total count) synovitis
≥6 (of 28 total count) synovitis

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Domain [weight]
Activity level
Description
Cutaneous [3]
Rate as ‘no activity’ stable 
long-lasting features 
related to damage
No = 0
Low = 1
Moderate = 2 
High = 3
Absence of currently active 
cutaneous involvement
Erythema multiforma
Limited cutaneous vasculitis, 
including urticarial vasculitis, or 
purpura limited to feet and ankle, 
or subacute lutaneous lupus
Diffuse cutaneous vasculitis, 
including urticarial vasculitis, or 
diffuse purpura, or ulcers related 
to vasculitis
Pulmonary* [5]
Rate as ‘no activity’ stable 
long-lasting features 
related to damage, or 
respiratory involvement not 
related to the disease 
(tobacco use, etc)
No = 0
Low = 1 
Moderate = 2 
High = 3
Absence of currently active 
pulmonary involvement
Persistent cough or bronchial 
involvement^ with no 
radiographic abnormalities on 
radiography Or radiological or 
HRCT evidence of interstitial 
lung disease with no 
breathlessness and normal lung 
function test
Moderately active pulmonary 
involvement, such as interstitial 
lung disease shown by HRCT 
with shortness of breath on 
exercise (NYHA II) or abnormal 
lung function tests restricted to 
70%>DLCO≥40% or 
80%>FVC≥60%
Highly active pulmonary 
involvement, such as interstitial 
lung disease shown by HRCT 
with shortness of breath at rest 
(NHYA III, IV) or with abnormal 
lung function tests DLCO<40% or 
FVC<60%

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Domain [weight]
Activity level
Description
Renal [5]
Rate as ‘no activity’ stable 
long-lasting features 
related to damage and 
renal involvement not 
related to the disease.
If biopsy has been 
performed, please rate 
activity based on 
histological features first
No = 0 
Low = 1 
Moderate = 2 
High = 3
Absence of currently active renal 
involvement with proteinuria <0.5 
g/day, no haematuria, no 
leucocyturia, no acidosis, or 
long-lasting stable proteinuria 
due to damage
Evidence of mild active renal 
involvement, limited to tubular 
acidosis without renal failure or 
glomerular involvement with 
proteinuria (between 0.5 and 1 
g/day) and without haematuria or 
renal failure (GFR ≥60 ml/min)
Moderately active renal 
involvement, such as tubular 
acidosis with renal failure (GFR 
<60 ml/min) or glomerular 
involvement with proteinuria 
between 1 and 1.5 g/day and 
without haematuria or renal 
failure (GFR ≥60 ml/min) or 
histological evidence of extra-
membranous glomerulonephritis 
or important interstitial lymphoid 
infiltrate
Highly active renal involvement, 
such as glomerular involvement 
with proteinuria >1.5 g/day or 
haematuria or renal failure (GFR 
<60 ml/min), or histological 
evidence of proliferative 
glomerulonephritis or 
cryoglobulinaemia-related renal 
involvement
Muscular* [6]
Exclusion of weakness due 
to corticosteroids
No = 0
Low = 1 
Moderate = 2 
High = 3
Absence of currently active 
muscular involvement
Mild active myositis shown by 
abnormal EMG or biopsy with no 
weakness and creatine kinase 
(N<CK≤2N)
Moderately active myositis 
confirmed by abnormal EMG or 
biopsy with weakness (maximal 
deficit of 4/5), or elevated 
creatine kinase (2N<CK≤4N)
Highly active myositis shown by 
abnormal EMG or biopsy with 
weakness (deficit ≤3/5) or 
elevated creatine kinase (>4N)
PNS* [5]
No = 0
Low = 1 
Absence of currently active PNS 
involvement

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Domain [weight]
Activity level
Description
Rate as ‘no activity’ stable 
long-lasting features 
related to damage or PNS 
involvement not related to 
the disease
Moderate = 2 
High = 3
Mild active peripheral nervous 
system involvement, such as 
pure sensory axonal 
polyneuropathy shown by NCS 
or trigeminal (V) neuralgia
Moderately active peripheral 
nervous system involvement 
shown by NCS, such as axonal 
sensorimotor neuropathy with 
maximal motor deficit of 4/5, 
pure sensory neuropathy with 
presence of cryoglobulinamic 
vasculitis, ganglionopathy with 
symptoms restricted to 
mild/moderate ataxia, 
inflammatory demyelinating 
polyneuropathy (CIDP) with mild 
functional impairment (maximal 
motor deficit of 4/5 or mild 
ataxia) Or cranial nerve 
involvement of peripheral origin 
(except trigeminal (V) neuralgia)
Highly active PNS involvement 
shown by NCS, such as axonal 
sensorimotor neuropathy with 
motor deficit ≤3/5, peripheral 
nerve involvement due to 
vasculitis (mononeuritis 
multiplex, etc), severe ataxia due
to ganglionopathy, inflammatory 
demyelinating polyneuropathy 
(CIDP) with severe functional 
impairment: motor deficit ≤3/5 or 
severe ataxia
CNS* [5]
Rate as ‘no activity’ stable 
long-lasting features 
related to damage or CNS 
involvement not related to 
the disease
No = 0
Moderate = 2
High = 3
Absence of currently active CNS 
involvement
Highly active CNS features, such 
as cerebral vasculitis with 
cerebrovascular accident or 
transient ischaemic attack, 
seizures, transverse myelitis, 
lymphocytic meningitis, multiple 
sclerosis-like syndrome with 
motor deficit

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Domain [weight]
Activity level
Description
Haematological [2]
For anaemia, neutropenia, 
and thrombopenia, only 
autoimmune cytopenia 
must be considered 
Exclusion of vitamin or iron 
deficiency, drug-induced 
cytopenia
No = 0
Low = 1 
Moderate = 2 
High = 3
Absence of auto-immune 
cytopenia
Cytopenia of auto-immune origin 
with neutropenia 
(1000<neutrophils<1500/mm3), 
and/or anaemia 
(10<haemoglobin<12 g/dl), 
and/or thrombocytopenia 
(100000<platelets<150000/mm3) 
Or lymphopenia 
(500<lymphocytes<1000/mm3)
Cytopenia of auto-immune origin 
with neutropenia 
(500≤neutrophils≤1000/mm3), 
and/or anaemia 
(8≤haemoglobin≤10 g/dl), and/or 
thrombocytopenia 
(50000≤platelets≤100000/mm3) 
Or lymphopenia (≤500/mm3)
Cytopenia of auto-immune origin 
with neutropenia (neutrophils 
<500/mm3), and/or or anaemia 
(haemoglobin <8 g/dl) and/or 
thrombocytopenia (platelets 
<50000/mm3)
Biological [1]
No = 0
Low = 1 
Moderate = 2
Absence of any of the following 
biological features
Clonal component and/or 
hypocomplementaemia (low C4 
or C3 or CH50) and/or 
hypergammaglobulinaemia or 
high IgG level between 16 and 
20 g/l
Presence of cryoglobulinaemia 
and/or 
hypergammaglobulinaemia or 
high IgG level >20 g/l, and/or 
recent onset 
hypogammaglobulinaemia or 
recent decrease of IgG level (<5 
g/l)
^ Based on the EULAR ESSDAI user guide (Seror et al 2015), an inconsistency was observed 
under the pulmonary domain. The description column of the low disease activity for the pulmonary 
domain has been modified from “persistent cough or bronchial involvement” to “persistent cough 
due to bronchial involvement”.

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Confidential
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Amended Protocol Version v04 (Clean)
Protocol No. CLOU064E12201
Commercially Confidential Information