Conditions: Sjogren Syndrome Mixed Connective Tissue Disease
Keywords: Sicca Syndrome Sjogren Syndrome Connective Tissue Disease, Mixed MCTD Sharp Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This study was a basket trial designed to establish safety, tolerability and efficacy of MHV370 in Sjögren's Syndrome (SjS) and Mixed Connective Tissue Disease (MCTD).

Detailed description:
This was a randomized, participant and investigator blinded, placebo-controlled, multi center parallel group basket study to evaluate the safety, tolerability and efficacy of MHV370 in participants with Sjögren's Syndrome (SjS) or with Mixed Connective Tissue Disease (MCTD). Participants first underwent a screening period of up to 6 weeks, followed by a treatment duration of 24 weeks and a follow-up period of 4 weeks. Total study duration for each participant was up to 34 weeks. Participants with SjS were randomized in a 1:1 ratio to MHV370 or placebo and participants with MCTD were randomized in a 1:1 ratio to MHV370 or placebo.

Arms:
arm 1: SjS participants randomized in the MHV370 arm will be treated with MHV370 for 24 weeks. Double-blind supply will be used. arm 2: SjS participants randomized in the placebo arm will be treated with placebo for 24 weeks. Double-blind supply will be used. arm 3: MCTD participants randomized in the MHV370 arm will be treated with MHV370 for 24 weeks. Double-blind supply will be used. arm 4: MCTD participants randomized in the placebo arm will be treated with placebo for 24 weeks. Double-blind supply will be used.

Interventions: intervention 1: MHV370 intervention 2: Placebo
Intervention descriptions: intervention 1: MHV370 for 24 weeks intervention 2: Placebo for 24 weeks

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
MHV370
Clinical Trial Protocol CMHV370A12201
A multi-center, randomized, participant- and investigator-
blinded, placebo-controlled, parallel group basket study to 
evaluate the safety, tolerability and efficacy of MHV370 in 
participants with Sjögren’s Syndrome or Mixed Connective 
Tissue Disease
Document type:
Amended Protocol Version
EUDRACT number:
2020-004937-19
Version number:
v03 (Clean)
Clinical Trial Phase:
II
Release date:
09-May-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021


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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................19
1
Introduction........................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose...................................................................................................................25
2
Objectives, endpoints and estimands.................................................................................25
2.1
Primary estimands..................................................................................................27
2.2
Secondary estimands..............................................................................................28
3
Study design.......................................................................................................................29
4
Rationale ............................................................................................................................31
4.1
Rationale for study design......................................................................................31
4.1.1
Rationale for choice of background therapy .........................................32
4.2
Rationale for dose/regimen and duration of treatment...........................................33
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................33
4.4
Purpose and timing of interim analyses/design adaptations ..................................33
4.5
Risks and benefits ..................................................................................................33
4.5.1
Potential benefit.....................................................................................34
4.5.2
Potential risks ........................................................................................34
4.5.3
Blood sample volume............................................................................37
4.6
Rationale for Public Health Emergency mitigation procedures.............................37
5
Study Population................................................................................................................38
5.1
Inclusion criteria ....................................................................................................38
5.2
Exclusion criteria ...................................................................................................39
6
Treatment...........................................................................................................................42
6.1
Study treatment ......................................................................................................42
6.1.1
Additional study treatments...................................................................42
6.1.2
Treatment arms/group ...........................................................................42
6.2
Other treatment(s) ..................................................................................................43
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6.2.1
Concomitant therapy .............................................................................43
6.2.2
Prohibited medication............................................................................44
6.2.3
Rescue medication.................................................................................45
6.2.4
Restriction for study participants...........................................................45
6.3
Preparation and dispensation .................................................................................46
6.3.1
Handling of study treatment and other treatment..................................46
6.3.2
Instructions for prescribing and taking study treatment........................47
6.4
Participant numbering, treatment assignment, randomization...............................48
6.4.1
Participant numbering ...........................................................................48
6.4.2
Treatment assignment, randomization...................................................48
6.5
Treatment blinding.................................................................................................49
6.6
Dose escalation and dose modification..................................................................50
6.7
Additional treatment guidance...............................................................................51
6.7.1
Treatment compliance ...........................................................................51
6.7.2
Recommended treatment of adverse events ..........................................51
6.7.3
Emergency breaking of assigned treatment code ..................................51
7
Informed consent procedures.............................................................................................52
8
Visit schedule and assessments..........................................................................................54
8.1
Screening................................................................................................................59
8.1.1
Eligibility screening...............................................................................59
8.1.2
Information to be collected on screening failures .................................60
8.2
Participant demographics/other baseline characteristics........................................61
8.3
Efficacy..................................................................................................................61
8.3.1
EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) 
(SjS and MCTD participants)................................................................61
8.3.2
Physician’s global assessment scale (PhGA) (SjS and MCTD 
participants)...........................................................................................62
8.3.3
FACIT-Fatigue (SjS and MCTD participants)......................................62
8.3.4
EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) 
(SjS participants only)...........................................................................62
8.3.5
Schirmer's test (SjS participants only)...................................................63
8.3.6
Salivary flow rate (unstimulated) (SjS participants only) .....................63
8.3.7
Forced Vital Capacity (FVC) and Forced Expiratory Volume 
(FEV) (MCTD participants only)..........................................................63
8.3.8
Diffusing capacity of the lungs for carbon monoxide (DLCO) 
(MCTD participants only).....................................................................63
8.3.9
Raynaud’s Condition Score (RCS) (MCTD participants only).............64


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8.3.10
King’s Brief Interstitial Lung Disease (K-BILD) (MCTD 
participants only)...................................................................................64
8.3.11
Sjögren’s Tool for Assessing Response (STAR) ..................................64
8.3.12
Appropriateness of efficacy assessments ..............................................65
8.4
Safety .....................................................................................................................65
8.4.1
Laboratory evaluations..........................................................................66
8.4.2
Electrocardiogram (ECG)......................................................................68
8.4.3
Pregnancy and assessments of fertility..................................................68
8.4.4
Appropriateness of safety measurements ..............................................69
8.5
Additional assessments ..........................................................................................69
8.5.1
Pharmacokinetics...................................................................................69
8.5.3
Other Assessments.................................................................................72
9
Discontinuation and completion ........................................................................................73
9.1
Discontinuation from study treatment and from study ..........................................73
9.1.1
Discontinuation from study treatment...................................................73
9.1.2
Discontinuation from study...................................................................74
9.1.3
Lost to follow-up...................................................................................74
9.2
Withdrawal of informed consent/Opposition to use data/biological samples........75
9.3
Study stopping rules...............................................................................................75
9.4
Study completion and post-study treatment...........................................................76
9.5
Early study termination by the sponsor..................................................................76
10 Safety monitoring, reporting and committees....................................................................77
10.1
Definition of adverse events and reporting requirements......................................77
10.1.1
Adverse events.......................................................................................77
10.1.2
Serious adverse events...........................................................................78
10.1.3
SAE reporting........................................................................................79
10.1.4
Pregnancy reporting...............................................................................80
10.1.5
Reporting of study treatment errors including misuse/abuse ................80
10.2
Additional Safety Monitoring................................................................................81
10.2.1
Liver safety monitoring.........................................................................81
10.2.2
Renal safety monitoring ........................................................................82
10.3
Committees ............................................................................................................82
11 Data Collection and Database management ......................................................................82
11.1
Data collection .......................................................................................................82
11.2
Database management and quality control ............................................................83
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11.3
Site monitoring.......................................................................................................83
12 Data analysis and statistical methods.................................................................................84
12.1
Analysis sets...........................................................................................................84
12.2
Participant demographics and other baseline characteristics.................................84
12.3
Treatments..............................................................................................................84
12.4
Analysis supporting primary objectives.................................................................85
12.4.1
Definition of primary endpoint(s) .........................................................85
12.4.2
Statistical model, hypothesis, and method of analysis ..........................85
12.4.3
Handling of intercurrent events of primary estimand............................86
12.4.4
Handling of missing values not related to intercurrent event................87
12.4.5
Sensitivity analyses ...............................................................................87
12.4.6
Supplementary analyses ........................................................................87
12.5
Analysis supporting secondary objectives.............................................................87
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s) ....................................88
12.5.2
Safety endpoints ....................................................................................88
12.5.3
Pharmacokinetics...................................................................................89
12.5.4
PK/PD relationships ..............................................................................89
12.6
Analysis of exploratory endpoints .........................................................................89
12.7
Interim analyses .....................................................................................................90
12.8
Sample size calculation..........................................................................................91
12.8.1
Primary endpoint(s)...............................................................................91
13 Ethical considerations and administrative procedures.......................................................91
13.1
Regulatory and ethical compliance........................................................................91
13.2
Responsibilities of the investigator and IRB/IEC..................................................91
13.3
Publication of study protocol and results...............................................................92
13.4
Quality Control and Quality Assurance.................................................................92
13.5
Participant Engagement .........................................................................................92
14 Protocol adherence.............................................................................................................93
14.1
Protocol amendments.............................................................................................93
15 References..........................................................................................................................94
16 Appendices.........................................................................................................................97
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................97
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16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements...........................................................................................................98
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....101
16.4
Appendix 4: Prohibited Co-Medication...............................................................103
16.5
Appendix 5: Permitted concomitant therapy requiring caution and/or action.....105
List of tables
Table 2-1
Objectives and related endpoints...........................................................25
Table 4-1
Rationale for study design.....................................................................31
Table 6-1
Investigational and control drug............................................................42
Table 6-2
Treatments against dryness of eyes/mouth............................................43
Table 6-3
Prohibited Medication ...........................................................................44
Table 6-4
Dose and treatment schedule.................................................................47
Table 6-5
Blinding and unblinding plan................................................................50
Table 8-1
Assessment Schedule.............................................................................55
Table 8-2
Hepatitis screening ................................................................................60
Table 8-3
STAR response criteria used in the study..............................................64
Table 8-4
Assessments & Specifications...............................................................65
Table 8-5
Laboratory evaluations..........................................................................66
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................81
Table 12-1
Non-compartmental pharmacokinetic parameters.................................89
Table 16-1
Liver event and laboratory trigger definitions.......................................98
Table 16-2
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL........................................................................................................99
Table 16-3
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia..............................................................................100
Table 16-4
Specific Renal Alert Criteria and Actions...........................................101
Table 16-5
Follow up of renal events ....................................................................102
Table 16-6
Narrow therapeutic index CYP substrates...........................................103
Table 16-7
Strong and moderate inhibitors of CYP3A .........................................103
Table 16-8
Strong and moderate inducers of CYP3A ...........................................104
Table 16-9
Substrates of MATE1/2.......................................................................104
Table 16-10
Sensitive CYP substrates.....................................................................105
List of figures
Figure 3-1
Study design ..........................................................................................29


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List of abbreviations
ACR
American College of Rheumatology
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANAs
Antinuclear Antibodies
Anti-dsDNA
Anti-double stranded DNA
Anti-HBc
Hepatitis B core antibody
Anti-SSA
Anti-Sjögren’s Syndrome A
Anti-SSB
Anti-Sjögren’s Syndrome B
Anti-U1-RNP
Anti-Uridylate 1-Ribonucleoprotein
aPTT
activated partial thromboplastin time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
b.i.d.
bis in die/twice a day
BP
Blood Pressure
bpm
Beats per minute
°C
Degree Celsius
CBC
Complete blood count
CD
Cluster of differentiation
CFR
Code of Federal Regulations (United States)
CK
Creatine Kinase
cm
Centimeter(s)
Cmax
Maximal concentration
CMO&PS 
Chief Medical Office and Patient Safety
CNS
Central Nervous System
CO
Country Organization
CO
Carbon monoxide
COA
Clinical Outcome Assessment
COVID-19
Corona-virus disease (2019)
CQ
Chloroquine
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical study report
CT
Computer tomography
CTLA4
cytotoxic T-lymphocyte-associated protein 4
CTT
Clinical Trial Team
CV
Coefficient of variation
CXCL10
C-X-C motif chemokine ligand 10
CYP
Cytochrome P450 (enzyme)
CysC
Cystatin C
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DDI
Drug-drug interaction
dL
deciliter(s)
DLCO
Diffusing Capacity of Lungs for Carbon Monoxide
DMARDs
disease-modifying antirheumatic drugs
DNA
Desoxyribonucleic Acid
dsDNA
Double-stranded DNA (desoxyribonucleic acid)
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
e.g.
For example (“exempli gratia”)
EMA
European Medical Agency
EMG
Electromyography
ENA
extractable nuclear antigen
EOS
End of Study
eSource
Electronic Source
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren's Syndrome Patient Reported Index
EU
European Union 
EudraCT
European Union Drug Regulating Authorities Clinical Trials
EULAR
European League against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
Fc
fragment crystallizable region (of an antibody)
FEV
Forced Expiratory Volume
FFPRHC
Faculty of Family Planning and Reproductive Health Care
FIH
First in Human
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
g
gram(s)
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GFR 
(eGRF/mGFR)
Glomerular Filtration Rate (estimated/measured)
GGT
Gamma-glutamyl transferase
GLDH
Glutamate Dehydrogenase
GU
Guanosine-uridine
h
Hour
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus
HCQ
Hydroxychloroquine
HCV
Hepatitis C Virus
HDPE
High Density Poly Ethylene 
HIV
Human immunodeficiency virus


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HRCT
High Resolution Computer Tomography 
i.e.
that is (“id est”)
Ig
Immunoglobulin
i.v.
intravenous
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFN
Interferon
IFNAR
Type I interferon receptor
IL
Interleukin
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISG
Interferon Stimulated Genes
IUD
Intrauterine Device
IUS
Intrauterine System
IVIG
Intravenous Immunoglobulin
K-BILD
King’s Brief Interstitial Lung Disease
kg
kilogram(s)
LC-MS/MS
Liquid chromatography mass spectrometry
LDH
lactate dehydrogenase
LFT
Liver function test 
LLOQ
lower limit of quantification
LMW
Low molecular weight
mAb
monoclonal antibody
MATE
Multidrug and toxic compound extrusion (transporter enzyme)
MCTD
Mixed Connective Tissue Disease
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
µL
microliter(s)
mm
millimeter(s)
mmol
millimole(s)
MMRM
mixed effect model for repeated measurements
MRI
Magnetic resonance imaging
mRNA
messenger RNA (ribonucleic acid)
ng
nanogram(s)


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No.
Number
NOAC
Novel Oral Anti-Coagulant
NSAIDs
nonsteroidal anti-inflammatory drugs
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PhGA
Physician global assessment scale
PK
Pharmacokinetic(s)
PNS
Peripheral Nervous System
PPD
Purified Protein Derivative
PRO
Patient Reported Outcomes
PT
Prothrombin time
PTT
Partial thromboplastin time
QMS 
Quality Management System
RCS
Raynaud’s Condition Score
RNA
Ribonucleic Acid
RNP
Ribonucleoprotein
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
sCr
Serum creatinine
SD
standard deviation
sec
second
SjS
Sjögren’s Syndrome
SOC
System organ class
SOP
Standard operating procedure
SSRI
Selective serotonin re-uptake inhibitor
ssRNA
Single-strand RNA
STAR
Sjögren’s Tool for Assessing Response
SUSAR
Suspected, Unexpected, Serious Adverse Reaction
TB
Tuberculosis
TBL
Total bilirubin time
TEARS
Tolerance and Efficacy of Rituximab in Sjögren's Disease (Clinical Study)
TLR
Toll Like Receptor
Tmax
Time to reach maximum concentration
TNF
Tumor necrosis factor
ULN
upper limit of normal
ULOQ
Upper limit of quantification
VAS
Visual Analog Scale
WHO
World Health Organization 
WoC
Withdrawal of Consent
WOCBP
Women of child-bearing potential


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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 participant 
Clinical Outcome 
Assessment (COA)
A measure that describes or reflects how a participant feels, functions, 
or survives
Clinical Trial Team
A group of people responsible for the planning, execution and reporting 
of all clinical trial activities. Examples of team members include the 
Study Lead, Medical Monitor, Trial Statistician etc.
Coded Data
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code.
Cohort
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time
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
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of their 
samples or data.
Discontinuation from 
study treatment
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop 
the use of their samples or data.
Dosage
Dose of the study treatment given to the participant 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 source 
data/documents used at the point of care
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last 
participant 
Enrollment
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise 
description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same participants under different treatment 
conditions being compared. Attributes of an estimand include the 
population, variable (or endpoint) and treatment of interest, as well as 
the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable.


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Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Intercurrent events
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest.
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 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study or the participant allocated to 
an invalid stratification factor
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 participants with 
established disease and in those with newly diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in 
data collection
Participant number
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc.
Patient-Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else
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
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples.
Randomization
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias.
Randomization number
A unique identifier assigned to each randomized participant
Re-screening
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol
Remote
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location
Screen Failure
A participant who did not meet one or more criteria that were required 
for participation in the study


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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 participant
Study treatment
Any drug or combination of drugs or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the 
combination and may consist of 1 or more cohorts.
Treatment of interest
The treatment of interest and, as appropriate, the alternative treatment 
to which comparison will be made. These might be individual 
interventions, combinations of interventions administered concurrently, 
e.g. as add-on to standard of care, or might consist of an overall 
regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event.
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation.
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
different legal reason than consent.


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Protocol No. CMHV370A12201
Protocol summary
Protocol number
CMHV370A12201
Full Title
A multi-center, randomized, participant- and investigator-blinded, placebo-
controlled, parallel group basket study to evaluate the safety, tolerability and 
efficacy of MHV370 in participants with Sjögren’s Syndrome or Mixed 
Connective Tissue Disease
Brief title
A study to evaluate the safety, tolerability and efficacy of MHV370 in 
participants with Sjögren’s Syndrome (SjS) or Mixed Connective Tissue 
Disease (MCTD)
Sponsor and 
Clinical Phase
Novartis. Phase II
Investigation type
Drug
Study type
Interventional
Purpose
This study is designed to establish safety, tolerability and efficacy of 
MHV370 in Sjögren’s Syndrome (SjS) and Mixed Connective Tissue 
Disease (MCTD).
Primary 
Objective(s) 
SjS:
•
To evaluate the efficacy of MHV370 compared to placebo based on 
change from baseline in ESSDAI at Week 24.
MCTD:
•
To evaluate the efficacy of MHV370 compared to placebo based on 
change from baseline in Physician Global Assessment (PhGA) at 
Week 24.
Secondary 
Objectives
SjS and MCTD:
•
To evaluate the efficacy of MHV370 compared to placebo based on 
change from baseline on patient and physician-reported outcomes 
over time up to Week 24.
•
To evaluate the safety and tolerability of MHV370.
•
To assess PK parameters of MHV370 (Cmax, AUC, Tmax and 
others) at steady state.
SjS:
•
To explore the effect of MHV370 on quantitative salivary flow 
(unstimulated) over 24 weeks.
•
To explore the effect of MHV370 on quantitative tear production 
over 24 weeks.
•
To explore the effect of MHV370 on the rate of STAR responders 
MCTD:
•
To evaluate the efficacy of MHV370 based on change from 
baseline in Forced Vital Capacity (FVC) and Forced Expiratory 
Volume (FEV1, FEV2, FEV3) over time up to Week 24.
•
To evaluate the efficacy of MHV370 based on change from 
baseline in the diffusing capacity of lungs for carbon monoxide 
(DLCO) over time up to Week 24.
•
To evaluate the efficacy of MHV370 based on change from 
baseline in the patient reported outcome on lung function.


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•
To evaluate the efficacy of MHV370 compared to placebo based on 
change from baseline in Raynaud's Condition Score (RCS) over 
time up to Week 24.
Study design
This is a randomized, participant- and investigator-blinded, placebo-
controlled, multi center parallel group basket study to evaluate the safety, 
tolerability and efficacy of 200 mg twice daily (b.i.d) of MHV370 in 
participants with Sjögren's Syndrome (SjS) or with Mixed Connective Tissue 
Disease (MCTD) over 24 weeks of treatment, followed by 4 weeks of follow-
up. Total study duration for each participant will be up to 34 weeks.
Rationale
Ribonucleoproteins (RNPs), in complex with disease-associated RNP-
specific antinuclear autoantibodies (ANAs) are a key driver of TLR7 and 
TLR8 activation. TLR7 and TLR8 are thought to play a role in several 
systemic autoimmune diseases, including SjS and MCTD. MHV370 is an 
orally bioavailable antagonist of human TLR7 and TLR8 and is intended for 
the treatment of diseases where pathology is thought to be driven by 
excessive activation of TLR7/8. SjS and MCTD are phenotypically different 
but in terms of presence of anti-RNP and TLR7/8 signaling, molecularly 
homogeneous autoimmune diseases, hence we investigate them in one 
study (i.e. a basket study)
Study population
Female and male participants aged 18 to 75 years with moderate to severe 
SjS or diagnosis of MCTD; a total of approximately 60 participants will be 
enrolled in this study: approximately 48 participants with SjS and 
approximately 12 participants with MCTD.
Key Inclusion 
criteria
SjS and MCTD:
•
Male or female participants aged 18 to 75 years at screening
•
Fully vaccinated with any locally approved COVID-19 vaccination, 
including booster vaccination, if required by local guidelines
SjS:
•
Unstimulated whole salivary flow rate of > 0 mL/min at screening
•
Positive anti-Ro/SSA results 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). Participants 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
MCTD:
•
Diagnosis of MCTD based on modified Kahn’s criteria 
(John et al 2020)
o
Serological criteria: seropositive for anti-U1-RNP antibodies 
at central lab
o
Raynaud’s phenomenon
o
At least two of the four following signs: i) synovitis, ii) 
myositis, iii) swollen fingers and vi) interstitial lung disease


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•
Patients with overlap syndromes, i.e. patients meeting diagnostic
criteria for systemic autoimmune disease other than MCTD (e.g.
SLE, scleroderma, dermato- or polymyositis, rheumatoid arthritis or
Sjögren’s syndrome) may be included unless they have major
organ involvement (e.g. lupus nephritis) as judged by the
investigator
Key Exclusion 
criteria
SjS and MCTD:
•
Prior use of B-cell depleting therapy within 6 months of baseline. For
participants who received B-cell depleting therapy within 6 -12 months
of baseline visit, B-cell count should be within normal range
•
Prior treatment with any of the following within 3 months of baseline
•
CTLA4-Fc Ig (abatacept)
•
Anti-TNF mAb
•
Intravenous Ig
•
Plasmapheresis
•
i.v. or oral cyclophosphamide
•
i.v. or oral cyclosporine A
•
Screening CBC laboratory values as follows:
•
Hemoglobin levels < 8 g/dL (< 5 mmol/L)
•
Total leukocyte count < 2,000/µL (2 x 109/L)
•
Platelets < 50,000/µL (50 x 109/L)
•
Neutrophil count < 1,000/µL (1 x 109/L)
•
Cardiovascular disease or ECG abnormalities indicating significant
safety risk for the participants
•
Pregnant or nursing (lactating) women
•
Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they use a highly effective
method of contraception
SjS:
•
Sjögren’s Syndrome overlap syndromes where another autoimmune
disease constitutes the primary illness
•
Required regular use of medications known to cause, as a major side
effect, dry mouth / eyes
Study treatment
Two capsules of blinded study medication are to be taken in the morning 
and two capsules in the evening (see Section 6.1). One capsule of blinded 
study medication contains 100 mg of MHV370 or placebo.
Treatment of 
interest
Further details about the investigational treatment are provided in Section 6
Efficacy 
assessments
SjS:
•
ESSDAI, ESSPRI, FACIT-F, PhGA, salivary flow test, Schirmer’s test
MCTD:
•
PhGA, ESSDAI (articular and pulmonary domains only), FACIT-F, RCS,
K-BILD, FVC, FEV, DLCO
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Pharmacokinetic 
assessments 
•
Serial blood samples for analysis of MHV370 concentrations and
calculation of PK parameters (AUC, Cmax, Tmax and others as defined
in Section 12.5.3)
Key safety 
assessments
•
Adverse event monitoring
•
Physical examinations
•
Vital Signs
•
Monitoring of laboratory markers in blood and urine
•
ECG assessment
•
Additional liver and renal safety monitoring
•
Assessment of pregnancy and fertility
Other assessments 
Data analysis
SjS
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 with 
the treatment group, visit as category variable and treatment group by visit 
interaction as fixed effects and baseline ESSDAI as a continuous covariate. 
An unstructured variance-covariance matrix will be fitted to model the 
dependency between repeated observations.
The difference between MHV370 and placebo in change from baseline at 
each visit will be estimated from the model and presented with 95% 
confidence intervals.
The following two criteria will be used to assess treatment efficacy
•
a statistically significant reduction in ESSDAI at Week 24 in
MHV370 group compared to placebo, at the one-sided 10%
significance level, and
•
an estimated mean reduction in ESSDAI at Week 24 in the
MHV370 group to be at least 2 points greater than in placebo.
A positive sign of efficacy will be considered if both criteria are met.
MCTD
A MMRM will be fitted to the changes from baseline in PhGA for all time 
points until Week 24 with the treatment group, visit as category variable, 
treatment group by visit interaction 
 as fixed effects and baseline PhGA as a 
continuous covariate. A random intercepts model will be used.
The difference between MHV370 and placebo in change from baseline at 
each visit will be estimated from the model and presented with 95% 
confidence intervals.
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Key words
Sjögren's Syndrome, Mixed Connective Tissue Disease, ESSDAI, Toll Like 
Receptor 7/8 inhibitor, MHV370


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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 characterized by 
exocrinopathy of salivary and lacrimal glands presenting with dryness of the mouth and eyes. 
However, symptoms can be systemic and may include musculoskeletal pain and fatigue, 
affecting nearly all patients, or 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). 
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 an early stage of the 
disease suggests that autoreactive B-cells participate in the pathomechanism of SjS 
(Nocturne and Mariette 2018). Sjögren’s syndrome is also linked with increased risk for 
malignancy, with a 10-fold elevation of lifetime-risk for B-cell lymphomas in SjS patients 
(Baldini et al 2014). SjS is observed in 0.3 to 1 per 1,000 persons, and its prevalence is second 
only to rheumatoid arthritis among systemic autoimmune disease. The disease affects mainly 
women with a female/male ratio of 9:1 and can occur at any age (Qin et al 2015). SjS has a 
severe impact on quality of life and productivity, often caused by disabling fatigue associated 
with the disease (Mariette and Criswell 2018).
Mixed connective tissue disease (MCTD) was first described in 1972 as a disease syndrome 
with overlapping features of other systemic autoimmune diseases, associated with antibodies to 
RNA sensitive extractable nuclear antigen (Sharp et al 1972). Patients with MCTD often have 
Sjögren's syndrome; notably, 42 % of patients with MCTD are reported to have sicca features 
(Ramos-Casals et al 2007). Clinical manifestations include a high frequency of Raynaud’s 
syndrome, swollen hands, sclerodactyly, arthritis, polymyositis and interstitial lung disease 
(Venables 2006). The female to male ratio is around three, and the mean age at diagnosis of 
adult-onset MCTD is between 35 and 40 years. MCTD is rare, the point prevalence below 4 per 
100,000 adults (Gunnarsson et al 2011). There is currently no cure for either SjS or MCTD.
Toll like receptors (TLRs) are part of the innate immune system and recognize conserved 
microbial structures. TLR7 and TLR8 are expressed intracellularly in endosomes and recognize 
the same ligand, guanosine-uridine (GU) rich single-strand RNA (ssRNA) (Heil et al 2004). 
In several autoimmune diseases, including both SjS and MCTD, TLR7/8 are activated by 
self-RNA after shuttling of ribonucleoprotein (RNP) autoantigens such as Ro60 to endosomes, 
in the form of immune complexes with autoantibodies (Båve et al 2005; Junt and Barchet 2015). 
Presence of autoantibodies against another RNP, U1-RNP, is a diagnostic criterion for MCTD 
(Tani et al 2014), and immune complexes of autoantibodies with U1-RNP lead to activation of 
TLR7 (Savarese et al 2006), and likely also TLR8.


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MHV370 is an orally bioavailable low-molecular weight (LMW) antagonist of human TLR7 
and TLR8 and is intended for the treatment of systemic autoimmune diseases, such as SjS or 
MCTD, where pathology is thought to be driven by excessive activation of TLR7/8 through 
RNP autoantigen containing immune complexes.
 
 
1.2
Purpose
This study is designed to establish safety, tolerability and efficacy of MHV370 in Sjögren’s 
Syndrome (SjS) and Mixed Connective Tissue Disease (MCTD).
2
Objectives, endpoints and estimands
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
SjS: To evaluate the efficacy of MHV370 compared 
to placebo based on change from baseline in 
ESSDAI at Week 24
•
SjS: Change from baseline in 
ESSDAI at Week 24
•
MCTD: To evaluate the efficacy of MHV370 
compared to placebo based on change from 
baseline in Physician Global Assessment (PhGA) at 
Week 24
•
MCTD: Change from baseline in 
PhGA at Week 24
Secondary objective(s)
Endpoint(s) for secondary 
objective(s)
•
SjS/MCTD: To evaluate the efficacy of MHV370 
compared to placebo based on change from 
baseline on patient and physician-reported outcomes 
over time up to Week 24
•
SjS: Change from baseline in 
ESSDAI, ESSPRI, FACIT-F and 
PhGA over time up to Week 24
•
MCTD: Change from baseline in 
FACIT-F, PhGA and ESSDAI 
(articular and pulmonary domains 
only) over time up to Week 24
•
SjS/MCTD: To evaluate the safety and tolerability of 
MHV370
•
SjS/MCTD: 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 values 
during the study
•
SjS/MCTD: To assess PK parameters of MHV370
•
SjS/MCTD: PK parameters AUC, 
Cmax, Tmax and others as needed 
at steady state
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Objective(s)
Endpoint(s)
•
SjS: To explore the effect of MHV370 on quantitative
salivary flow (unstimulated) over 24 weeks
•
SjS: Changes from baseline to the
salivary flow rate over time up to 24
weeks of treatment
•
SjS: To explore the effect of MHV370 on quantitative
tear production over 24 weeks
•
SjS: Changes from baseline to the
Schirmer’s test over time up to 24
weeks of treatment
•
SjS: To explore the effect of MHV370 on the rate of
STAR responders
•
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in Forced Vital Capacity
(FVC) and Forced Expiratory Volume (FEV1, FEV2,
FEV3) over time up to Week 24
•
SjS: STAR response over time up to
week 24
•
MCTD: Change from baseline in
FVC, FEV1, FEV2 and FEV3 over
time up to Week 24
•
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in the diffusing capacity of
lungs for carbon monoxide (DLCO) over time up to
Week 24
•
MCTD: Change from baseline in the
diffusing DLCO over time up to
Week 24
•
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in the patient reported
outcome on lung function.
•
MCTD: Change from baseline in
King’s Brief Interstitial Lung Disease
(K-BILD) over time up to week 24
•
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in Raynaud's Condition
Score (RCS) over time up to Week 24
•
MCTD: Change from baseline in
RCS over time up to Week 24
Exploratory objective(s)
Endpoint(s) for exploratory 
objective(s)
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Objective(s)
Endpoint(s)
2.1
Primary estimands
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment).
SjS
The primary clinical question of interest is: What is the effect of MHV370 on change in 
ESSDAI total score after 24 weeks of treatment in patients with moderate to severe Sjögren’s 
Syndrome who are receiving a stable dose of certain concomitant medication (systemic 
corticosteroid treatment, azathioprine, methotrexate, leflunomide, hydroxychloroquine (HCQ) 
and chloroquine (CQ)), had treatment continued for the entire 24 week duration, had no dose 
change in certain allowed concomitant medication occurred and had no prohibited medication 
been taken?
The justification for the primary estimand is that wish to estimate the effect of the study drug 
for the full treatment duration when administered without dose changes in certain allowed 
concomitant medication (systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ) and without intake of prohibited medication.
The primary estimand is described by the following attributes:
1. Population: Patients with moderate to severe Sjögren's Syndrome receiving a stable dose 
of certain concomitant medication (systemic corticosteroid treatment, azathioprine, 
methotrexate, leflunomide, HCQ and CQ). Further details about the population are 
provided in Section 5.
2. Endpoint: Change from baseline in ESSDAI total score at Week 24.
3. Treatment of interest: the randomized treatment (investigational treatment MHV370 or 
placebo) with or without the allowed concomitant medication.
4. Handling of remaining intercurrent events:
•
Treatment discontinuations for any reason: had participants taken the assigned 
treatment for the entire study duration (hypothetical strategy).
•
Unforeseen change in the dose of certain allowed concomitant medication: had no 
change in the dose of systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ occurred (hypothetical strategy).
•
Intake of prohibited medication: had no prohibited medication been taken 
(hypothetical strategy).
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5. The summary measure: Difference in mean change from baseline in ESSDAI total score at 
Week 24 between treatments.
MCTD
The primary clinical question of interest is: What is the effect of MHV370 on change in PhGA 
after 24 weeks of treatment in patients with MCTD who are receiving a stable dose of certain 
concomitant medication (systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ), had treatment continued for the entire 24 week duration, had no 
dose change in certain allowed concomitant medication occurred and had no prohibited 
medication been taken?
The justification for the primary estimand is that wish to estimate the effect of the study drug 
for the full treatment duration when administered without dose changes in certain allowed 
concomitant medication (systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ) and without intake of prohibited medication.
The primary estimand is described by the following attributes:
1. Population: Patients with MCTD receiving a stable dose of certain concomitant 
medication (systemic corticosteroid treatment, azathioprine, methotrexate, leflunomide, 
HCQ and CQ). Further details about the population are provided in Section 5.
2. Endpoint: Change from baseline in PhGA at Week 24.
3. Treatment of interest: the randomized treatment (investigational treatment MHV370 or 
placebo) with or without the allowed concomitant medication.
4. Handling of remaining intercurrent events:
•
Treatment discontinuations for any reason: had participants taken the assigned 
treatment for the entire study duration (hypothetical strategy).
•
Unforeseen change in the dose of certain allowed concomitant medication: had no 
change in the dose of systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ occurred (hypothetical strategy).
•
Intake of prohibited medication: had no prohibited medication been taken 
(hypothetical strategy).
5. The summary measure: Difference in mean change from baseline in PhGA at Week 24 
between treatments.
2.2
Secondary estimands
Not applicable.


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3
Study design
This is a phase 2 randomized, participant- and investigator-blinded, placebo-controlled, 
multi-center, parallel group basket study to evaluate the safety, tolerability and efficacy of 
MHV370 in patients with moderate to severe Sjögren's Syndrome (SjS) or patients with 
diagnosis of Mixed Connective Tissue Disease (MCTD). In case study participants receive 
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).
A total of approximately 48 participants with SjS will be randomized in a 1:1 ratio to MHV370 
or placebo. A total of approximately 12 participants with MCTD will be randomized in a 1:1 
ratio to MHV370 or placebo.
Figure 3-1
Study design
Study Conduct
Participants will first undergo a screening period of up to 6 weeks, followed by a treatment 
duration of 24 weeks and a follow-up period of 4 weeks. The total duration for each participant 
in the study will be up to 34 weeks.
Participants will receive 200 mg b.i.d. (200 mg twice per day) doses of MHV370 or placebo.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, biochemistry and urinalysis), pregnancy and fertility 
assessments, as well as adverse event and serious adverse event monitoring.
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Screening
After signing informed consent, participants will be assessed for ESSDAI (SjS participants) and 
RCS and K-BILD (MCTD participants) as well as completing safety and other assessments to 
confirm RNP positivity and evaluate eligibility. For logistical reasons, assessments may be 
performed on different days during the 6-week screening period if deemed appropriate by the 
Investigator. Participants that fail screening may be re-screened for one further occasion.
Baseline
Eligible participants will return for the Baseline visit on Day 1. Participants 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 day prior to Day 1.
Treatment
Treatment period lasts for 24 weeks, from Day 1 to Week 24 (Day 169). On Day 1, participants 
will be randomized to the respective SjS or MCTD treatment arms. 
Participants will return to the site at approximately 4-weekly intervals. As MHV370 is 
administered for the first time in patients with SjS and MCTD, an additional visit will be 
performed at Week 2 (Day 15) for safety and compliance purposes.
 
 
The PK assessments will be performed pre dose and at various time points post dose (until 4 h 
after dosing) at Week 4, Week 12 and Week 24. At Week 4, an additional PK sample will be 
taken at 6 hours post dose, at selected sites.
Additionally, as per the Assessment Schedule (Table 8-1), participants with SjS will:
•
undergo ESSDAI, salivary flow rate and Schirmer’s test assessments
•
complete ESSPRI assessments
and participants with MCTD will:
•
undergo ESSDAI (articular and pulmonary domains only), local spirometry, DLCO test 
•
complete RCS and K-BILD assessments
On the visit days, participants will be asked to take their morning dose of the study drug at the 
site. Participants 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.
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Each week, participants will be asked to complete diaries to record the administration of 
treatment.
All study visits will be ambulatory, however, for logistical reasons, it may be necessary for 
participants to come to the site the evening before their scheduled assessment visit. In these 
instances, the participants may stay overnight at the site, but this would not be considered a 
hospital admission.
Participants 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.
The primary endpoint of the study will be assessed after the completion of 24-week treatment 
(Day 169; Week 24 visit).
Follow up and End of Study visit (EoS)
After the last day of dosing, participants will enter a 4-week follow-up period without study 
drug treatment. Participants will be asked to return to the site at Week 28 for the End of Study 
visit. At this visit, participants will undergo final assessments as indicated in the Assessment 
schedule (Table 8-1).
Upon completion of this visit, participants will be discharged from the study.
4
Rationale
4.1
Rationale for study design
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Randomization (strata, allocation ratio)
Randomization decreases the chance of 
imbalance of subject characteristics between 
groups, thereby facilitating an unbiased 
assessment of safety, tolerability and efficacy. In 
addition, randomization prevents selection bias.
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Study Design Aspect
Rationale
Allocation ratio of 1:1 to placebo and MHV370 is 
used to ensure maximum statistical power given 
a fixed total sample size.
Blinding
The study is participant- and investigator-blinded 
until final database lock (except where indicated 
in Section 6.5) to reduce potential bias in the 
assessment of subjective readouts.
Duration of study periods
Treatment groups
The control group is placebo on top of standard 
of care because there is no approved systemic 
treatment for SjS or MCTD.
However, all participants can continue with their 
current immunomodulatory therapy, if on a 
stable dose and as described in Section 6.2.1.
4.1.1
Rationale for choice of background therapy
There is no approved systemic treatment for SjS and MCTD, though some immunomodulatory 
treatments, such as antimalarials (i.e. CQ, HCQ) or steroids are often used empirically. 
All participants can continue with their current immunomodulatory therapy, if on a stable dose, 
and as described in Section 6.2.1.
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4.2
Rationale for dose/regimen and duration of treatment
The dose planned for this study is 200 mg b.i.d. (200 mg twice per day). This dose is expected 
to be safe and efficacious based on data from the FIH clinical trial:
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The comparator treatment in the study will be placebo, in order to provide objective control for 
the evaluation of safety, clinical efficacy and PD during the 24-week treatment with MHV370.
Since there is no approved systemic treatment for SjS and MCTD, the use of placebo as 
comparator is considered justified. Current standard of care for SjS and MCTD patients is often 
limited to symptomatic care (e.g. dryness or Raynaud’s phenomenon). 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
An interim analysis is planned after approximately 50% of SjS participants have completed 
24 weeks of treatment to evaluate the efficacy of MHV370.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general, or in case of any 
safety concerns.
4.5
Risks and benefits
Please refer to the Investigator’s Brochure (Section 7.1) for a full review of potential risks.
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4.5.1
Potential benefit
4.5.2
Potential risks
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. Participants and investigators participating in this study 
will be informed should important new safety information become available.
Please refer to the Investigator’s Brochure (Section 7.1) for a full review of potential risks. 
Below is a summary of risks included in the IB.
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4.5.3
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of 
34 weeks, from each participant 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 laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual. 
See the Section 8.5.2.5 on the potential use of residual samples.
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.
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5
Study Population
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria at 
screening unless specified otherwise below:
All participants
1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female participants aged 18 to 75 years.
3. Fully vaccinated with any locally approved COVID-19 vaccine including booster
vaccinations, as required by local guidance, and allowing sufficient time for the vaccine to be
protective prior to baseline.
4. Able to communicate well with the Investigator to understand and comply with the
requirements of the study.
SjS participants
5. Unstimulated whole salivary flow rate of > 0 mL/min at screening.
7. Classification of Sjögren's Syndrome according to the 2016 ACR/EULAR Classification
Criteria (Shiboski et al 2017).
8. Screening ESSDAI value (based on weighted score) ≥ 5 from 8 defined specific domains
(biologic, hematologic, articular, cutaneous, glandular, lymphadenopathy, renal,
constitutional). Participants 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 the efficacy assessment.
MCTD participants
9. Diagnosis of MCTD based on modified Kahn's criteria (John et al 2020)
10. Patients with overlap syndromes, i.e. patients meeting diagnostic criteria for systemic
autoimmune disease other than MCTD (e.g. SLE, scleroderma, dermato- or polymyositis,
rheumatoid arthritis or Sjögren’s syndrome) may be included unless they have major
organ involvement (e.g. lupus nephritis), as judged by the investigator.
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5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
All participants
1. Use of other investigational drugs within 5 half-lives of baseline or within 30 days, 
whichever is longer; or longer if required by local regulations.
2. Prior use of B-cell depleting therapy (e.g. rituximab or other anti-CD20 mAb, anti-CD22 
mAb, anti-CD52 mAb) within 6 months of baseline. For participants who received B-cell 
depleting therapy within 6-12 months of baseline visit, B-cell count should be within 
normal range.
4. Prior treatment with any of the following within 3 months of baseline:
•
CTLA4-Fc Ig (abatacept)
•
Anti-TNF mAb
•
Intravenous Ig
•
Plasmapheresis
•
i.v. or oral cyclophosphamide
•
i.v. or oral cyclosporine A
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14. Screening central laboratory complete blood count values as follows:
•
Hemoglobin levels < 8 g/dL (< 5 mmol/L)
•
Total leukocyte count < 2,000/µL (2 x 109/L)
•
Platelets < 50,000/µL (50 x 109/L)
•
Neutrophil count < 1,000/µL (1 x 109/L)
19. Pregnant or nursing (lactating) women.
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for at least 5 days after stopping of investigational drug. Highly 
effective contraception methods include:
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SjS participants
22. Sjögren’s Syndrome overlap syndromes where another autoimmune rheumatic disease
constitutes the primary illness, specifically:
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6
Treatment
6.1
Study treatment
The investigational drug will be provided by Novartis as appropriately blinded labeled HDPE 
(High Density Poly Ethylene) bottles. The bottles will contain capsules with either 100 mg 
active substance (MHV370) or matching Placebo.
Each dose (2 capsules) has to be swallowed with water. Between morning and evening doses, 
a dosing interval of approximately 12 hours (between 10 and 14 hours) should be kept.
Novartis Global Clinical Supply (GCS) will provide IMP supplies as detailed in the table 
(Table 6-1) below.
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug 
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Sponsor (global 
or local)
MHV370
100 mg
Hard Gelatin 
Capsule
Oral use
Novartis
Placebo
Hard Gelatin 
Capsule
Oral use
Novartis
6.1.1
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.2
Treatment arms/group
Participants will be assigned at visit Day 1 to one of the following 2 treatment arms/groups in 
a ratio of 1:1 MHV370:Placebo.
CCI
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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 participant 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 participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
Concomitant treatment may include standard of care for dry eye and dry mouth symptoms, such 
as the use of artificial tears and artificial saliva/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
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Additionally, herbal treatments should be used with caution.
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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
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Medication
Prohibition period
Action to be taken
anticholinergics, sedatives, antipsychotic 
drugs, anti-Parkinson agents, diuretics)
Live attenuated vaccine (locally 
approved mRNA vaccines, protein 
subunit vaccines, viral vector vaccines 
and inactivated vaccines are not “live 
attenuated” vaccines and are therefore 
not prohibited) (see also Section 4.5.2)
8 weeks prior to 
baseline and for at least 
7 days after the last 
dose of MHV370 
Study drug discontinuation 
may be required on a case-
by-case basis
Strong and moderate inhibitors of 
CYP3A (see Table 16-7)
From screening until 
end of study
Study drug discontinuation 
may be required on a case-
by-case basis
Strong and moderate inducers of 
CYP3A (see Table 16-8)
From screening until 
end of study
Study drug discontinuation 
may be required on a case-
by-case basis
Narrow therapeutic index substrates of 
CYP 2B6, 2C8, 2C9, 2C19 and 3A4 
(see Table 16-6)
From screening until 
end of study
Study drug discontinuation 
may be required on a case-
by-case basis
Substrates of MATE1/2 (see Table 16-9)
From screening until 
end of study
Study drug discontinuation 
may be required on a case-
by-case basis
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)
From screening until 
end of study
Study drug discontinuation 
may be required on a case-
by-case basis
6.2.3
Rescue medication
There is no established, approved immunosuppressive treatment for SjS or MCTD, however, in 
case of acute, severe systemic manifestations, high dose steroid or other systemic 
immunosuppressant may be administered as rescue. Participants 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 participant 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. Participants should be encouraged to come for the remaining visits and end-of-study 
visit even when discontinued permanently from study medication.
6.2.4
Restriction for study participants
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section.
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6.2.4.1
Dietary restrictions and smoking
Study participants should not eat or drink for 90 minutes before the assessment of salivary flow. 
It is recommended that participants do not smoke for 90 minutes before the pre-dose PK 
assessment and until all the PK study assessments are performed on the study visits of Day 29 
(Week 4), Day 85 (Week 12) and Day 169 (Week 24). Study participants should not eat 
grapefruit or drink grapefruit juice on Day 29 (Week 4), Day 85 (Week 12) and Day 169 
(Week 24) due to potential interference with PK assessments. It is also recommended that 
participants avoid ingestion of cruciferous vegetables (e.g. broccoli, brussel sprouts, cabbage, 
cauliflower) on these days.
6.2.4.2
Other restrictions
On the study days when PK assessments are performed, any permitted concomitant medication 
(see Section 6.2.1.1 and Section 6.2.1) should be separated by at least 3 hours of study drug 
intake. Moreover, on the study days when PK assessments are performed, participants have to 
avoid strenuous movements for 4 hours after dosing.
6.3
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document.
6.3.1
Handling of study treatment and other treatment
6.3.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
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If study treatment is administered at home, participants will be asked to return all used and 
unused study treatment and packaging at every study visit and the end of the study or at the time 
of discontinuation of study treatment.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site.
6.3.1.2
Handling of other treatment
Not applicable.
6.3.2
 Instructions for prescribing and taking study treatment
Table 6-4
Dose and treatment schedule
Investigational / Control Drug 
(Name and Strength)
Dose
Frequency and/or Regimen
MHV370 100 mg 
Placebo 
200 mg (2 capsules x 100 mg)
2 matching placebo capsules
b.i.d. (twice daily)
b.i.d. (twice daily)
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
•
Participants should be instructed to take MHV370 twice daily at approximately the same 
time each day, around 12 hours apart.
•
Participants should be instructed not to make up missed doses, i.e. when the full dose is 
not taken within 4 hours after the time of the usual dosing.
•
The first dose of MHV370 should be taken in the morning of Day 1 and the last dose of 
MHV370 should be taken in the morning of Day 169.
•
On study visits, the participant should take their morning dose of MHV370 at the clinic.
•
Participants should take MHV370 without regard to food. Each dose may be taken with a 
glass of water.
•
Participants should be instructed to swallow whole capsules and not to chew or open them.
•
If vomiting occurs during the course of treatment, participants should not take the study 
treatment MHV370 again before the next scheduled dose.
•
Participants will be provided with individual diaries to record each administration of study 
treatment. These will be checked regularly by site staff.


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6.4
Participant numbering, treatment assignment, randomization
6.4.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at the 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed.
6.4.2
Treatment assignment, randomization
At Day 1, all eligible participants will be randomized via IRT to one of the treatment arms. 
The investigator or his/her delegate will contact the IRT after confirming that the participant 
fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization number to the 
participant, which will be used to link the participant to a treatment arm and will specify a 
unique medication number for the first package of study treatment to be dispensed to the 
participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. 
A participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment.
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4.2.1
Replacement policy
Participants will not be replaced on this study.
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6.5
Treatment blinding
Participants, investigator staff and the persons performing the assessments will remain blinded 
to the study treatment from the time of randomization until database lock, except where 
indicated below.
Site staff
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. As a result, the participant should be 
discontinued from the study treatment.
Sponsor staff
The following unblinded sponsor roles are required for this study:
•
Unblinded clinical staff managing drug re-supply to site
•
Unblinded sample analysts (PK)
The following methods will be used to maintain the blind:
1. all unblinded personnel will keep randomization list and data or information that could 
unblind other study team members confidential and secure except as described below
2. the identity of the treatments will be concealed by the use of study drug that are all 
identical in packaging, labeling, schedule of administration and appearance.
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes. For example, unblinded summaries and unblinded individual data 
can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g. 
decision boards) as required for internal decision making on the study or the project at the time 
of interim analyses while the study is ongoing.
Following final database lock all roles may be considered unblinded.


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Table 6-5
Blinding and unblinding plan
6.6
Dose escalation and dose modification
Investigational treatment dose adjustments and/or interruptions are not permitted, with the 
exception of interruption in case of confirmed SARS-CoV2 infection, as described under 
Section 4.5.
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6.7
Additional treatment guidance
6.7.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts (if applicable) and information provided by the participant in the study medication diary. 
This information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with MHV370, as detailed in the pharmacokinetics section.
6.7.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs).
In case of serious adverse events suspected by the investigator to be related to the study 
medication, a temporary or permanent discontinuation of the study drug needs to be considered.
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
6.7.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely.
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant 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 participant, he/she must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for 
the participant. The investigator will then receive details of the investigational drug treatment 
for the specified participant and a fax or email confirming this information. The system will 
automatically inform Novartis monitor for the site and the study team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a 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
•
participant number
In addition, oral and written information to the participant 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.


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After emergency unblinding a permanent discontinuation of the study drug needs to be 
considered.
7
Informed consent procedures
Eligible participants may only be included in the study after providing IRB/IEC-approved 
informed consent.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 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 treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant 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 (IN) or an aggregate safety finding. New information might require an update to 
the informed consent and then must be discussed with the participant.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
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Declining to participate in these optional assessments will in no way affect the participant’s 
ability to join the main research study.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
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 may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).


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8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. Participants should be seen for all visits/assessments as outlined in the 
assessment schedule (Table 8-1) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation.
Participants who discontinue from study treatment should continue to attend the remaining 
study visits and perform the assessments as indicated in the Assessment Schedule.
 
 
 
 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database.
Every effort will be made to take the pharmacokinetic samples at the protocol specified time.
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 allowable by a 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
Follow up
Visit Name Screening
Baseline 
/ Day 1 Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
EOS
Days
-42
1
15
29
57
85
113
141
169
199
Weeks
-6
0
2
4
8
12
16
20
24
28
Time (post-dose)
-
-
-
0h
0.5h
1h
2h
4h
6h
-
0h
4h
-
-
0h
4h
-
Informed consent
X
Inclusion / 
Exclusion criteria
X
Demography
X
Medical 
history/current 
medical conditions
X
Contact IRT / 
Randomization
S
Drug dispensation
S
S
S
S
S
S
S
Dose 
administration
X
X
X
X
X
X
X
HIV screen
S
Hepatitis screen
S
Hepatitis monitor-
ing (HBsAg)1
S
S
S
S
S
S
S
S
TB screen 
S
Physical 
Examination
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
Body Temperature
X
X
X
X
X
X
X
X
X
X
Body Height
X
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Period Screening
Treatment
Follow up
Visit Name Screening
Baseline 
/ Day 1 Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
EOS
Days
-42
1
15
29
57
85
113
141
169
199
Weeks
-6
0
2
4
8
12
16
20
24
28
Time (post-dose)
-
-
-
0h
0.5h
1h
2h
4h
6h
-
0h
4h
-
-
0h
4h
-
Body Weight
X
X
X
X
X
X
X
X
X
PhGA - VAS
X
X
X
X
X
X
FACIT-Fatigue
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
Coagulation Panel
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
PK blood collection
X2
X
X
X
X
X3
X2
X
X2
X
Electrocardiogram 
(ECG)
X
X
X
X
X
X
X
X
X
X
Patient diary 
(paper)
S
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Period Screening
Treatment
Follow up
Visit Name Screening
Baseline 
/ Day 1 Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
EOS
Days
-42
1
15
29
57
85
113
141
169
199
Weeks
-6
0
2
4
8
12
16
20
24
28
Time (post-dose)
-
-
-
0h
0.5h
1h
2h
4h
6h
-
0h
4h
-
-
0h
4h
-
Pregnancy and 
assessments of 
fertility6,7
X
S
S
S
S
S
S
S
X
Study completion 
information
X
Concomitant 
medications
X
Adverse Events
X
Assessments specific to SjS
ESSDAI
X
X
X
X
X
X
X
ESSPRI
X
X
X
X
X
X
Anti-Ro/SSA 
(screening test)
X
Schirmer's test
X
X
X
X
X
Salivary flow rate 
(unstimulated)
X
X
X
X
X
Assessments specific to MCTD
Anti-U1-RNP 
(screening test)
X
Local spirometry 
(FVC/FEV)
X
X
X
DLCO
X
X
X
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Period Screening
Treatment
Follow up
Visit Name Screening
Baseline 
/ Day 1 Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
EOS
Days
-42
1
15
29
57
85
113
141
169
199
Weeks
-6
0
2
4
8
12
16
20
24
28
Time (post-dose)
-
-
-
0h
0.5h
1h
2h
4h
6h
-
0h
4h
-
-
0h
4h
-
ESSDAI8
X
X
X
X
X
X
Raynaud's 
Condition score
X
X
X
X
X
K-BILD
questionnaire
X
X
X
X
X
X
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 HBsAg and HBV DNA monitoring: only required for anti-HBc positive patients
2 Pre-dose
3 Only at selected sites
6 Serum pregnancy test will be done at Screening and EOS. For remaining visits urine pregnancy test will be performed. 
7 Assessment of fertility at Screening only
8 Articular and pulmonary domains only
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8.1
Screening
Screening
It is permissible to re-screen a participant if she/he fails the initial screening; however, each 
case must be discussed and agreed with the Sponsor on a case-by-case basis. Participants can 
be re-screened only once, and no study-related re-screening procedure should be performed 
prior to written re-consent by the participant.
•
Tests for HIV, Hepatitis B and C 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 or anti-U1 RNP, results do not need to be 
repeated in re-screening.
In case where a safety laboratory assessment at screening is outside of the range specified in 
the eligibility criteria, the assessment may be repeated once prior to randomization, i.e. without 
repeating the screening visit. If the repeat value remains outside of the specified ranges, the 
participant must be excluded from the study.
8.1.1
Eligibility screening 
8.1.1.1
Hepatitis screen, HIV screen, TB test
Hepatitis
All participants will be screened for hepatitis B surface antigen (HBsAg) and hepatitis B core 
antibody (anti-HBc). HBV DNA testing will be performed if needed.
•
If HBsAg is positive then the participant is not eligible, regardless of other test results, and 
HBV DNA test is not required.
•
If HBsAg and anti-HBc are both negative, then the participant is eligible and HBV DNA 
test is not required.
•
If HBsAg is negative and anti-HBc is positive, then HBV DNA test has to be performed to 
confirm eligibility: the participant is only eligible if HBV DNA is negative.
•
For such participants, an expert in hepatitis must be consulted and recommendations 
followed. If enrolled, hepatitis B monitoring must be implemented: HBsAg and HBV 
DNA tested every 4 weeks until the end of study.
•
In case of sero-conversion (i.e., if either HBsAg or HBV DNA turn positive) during 
the study, an expert in hepatitis must be consulted and recommendations observed. 
Immediate initiation of preemptive anti-viral treatment (e.g., lamivudine or entecavir) 
should be considered.


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Table 8-2
Hepatitis screening
HBsAg
Anti-HBc
HBV DNA
Eligible
Comment
-
-
Not required
Yes
-
+
-
Yes
Monitoring required
-
+
+
No
Consider treatment
+
+ or -
Not required
No
Consider treatment
Screening for hepatitis C will be based on Hepatitis C Virus Antibody (HCV) and Hepatitis C 
Virus RNA (HCV RNA).
HIV
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site e.g. Western blot. Appropriate counseling will be made 
available by the Investigator in the event of a positive confirmatory test. Notification of state 
and federal authorities, as required by law, will be the responsibility of the Investigator.
TB
Tuberculosis (TB) test (i.e. QuantiFERON® TB Gold Plus [QFT Plus] or T-SPOT® TB test 
[T-Spot], but not PPD test) performed by the local or central lab must be negative within 
8 weeks prior to baseline. If a negative test result is not available for any reason or the result is 
‘indeterminate’, then a second negative QuantiFERON® or T-SPOT® TB test (but not PPD) 
from the local or central lab can be accepted for eligibility if performed within 8 weeks prior to 
baseline.
If a patient is included based on a negative local QuantiFERON® or T-SPOT® TB test (but not 
PPD), local test results have to be documented in the patient's source file.
If the QuantiFERON® or T-SPOT® screening test is positive and active TB can be excluded as 
per the investigator's judgement (i.e. the patient has latent TB), the patient may be eligible if 
prophylactic treatment according to local guidelines is initiated prior to baseline. The exclusion 
of active TB has to be documented in the patient's source file.
8.1.1.2
Anti-Ro/SSA and Anti-U1-RNP antibodies
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see SAE 
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section for reporting details). If the participant fails to be randomized, the IRT must be notified 
within 2 days of the screen fail that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Participant demographics: year of birth, sex, race/predominant ethnicity (if permitted) and 
relevant medical history/current medical conditions (until date of signature of informed consent) 
will be recorded in the eCRF. Where possible, the diagnosis and not symptoms should be 
recorded. Participant race/ethnicity data are collected and analyzed to identify any differences 
in the safety and/or efficacy profile of the treatment due to these characteristics, as well as to 
assess the diversity of the study population as required by Health Authorities.
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See Section 6.2.1 Concomitant Therapy for further 
details on what information must be recorded on the appropriate page of the eCRF.
8.3
Efficacy
Clinical efficacy measurements related to primary and secondary objectives are outlined below.
Patient reported outcome assessments must be completed before any clinical assessments are 
performed at any given visit. The resulting scores will be entered in the eCRF.
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) (SjS and 
MCTD participants)
ESSDAI is a validated disease outcome measure for Sjögren’s Syndrome that will be applied 
to the study participants. 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.


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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 by the 
site in the eCRF. At screening, the ESSDAI subscore from 8 pre-selected domains listed in the 
inclusion criterion #8 will be calculated to determine participant'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 participant so to provide correct ESSDAI readout.
Participants with MCTD will complete the articular (from 0 “no activity” to 3 “high activity”) 
and pulmonary (from 0 “no activity to 3 “high activity”) domains of the ESSDAI only. These 
domains will be assessed separately over the treatment period.
8.3.2
Physician’s global assessment scale (PhGA) (SjS and MCTD 
participants)
The physician’s global assessment scale is used for the Investigator to rate the disease activity 
of their patient using 100 mm VAS (Visual Analog Scale) 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
FACIT-Fatigue (SjS and MCTD participants)
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).
FACIT-F will be completed by all study participants at the study site as per study assessment 
schedule (Table 8-1).
8.3.4
EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) (SjS 
participants only)
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 participant 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 completed by the study participants at the study site as per study 
assessment schedule (Table 8-1).


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8.3.5
Schirmer's test (SjS participants only)
Schirmer’s test is used to measure the quantity of tear secretion especially for those who suffer 
from dry eye syndrome. Materials required will be provided by the central laboratory. Schirmer 
testing will be done in an exploratory manner at screening, baseline, and following treatment at 
time points as specified in the assessment schedule (Table 8-1).
The participant is seated in the examining chair with the room lights dimmed and their head 
against a headrest for comfort. Both eyes will be assessed simultaneously.
The procedure is briefly outlined below:
•
The eye is gently dried of excess tears
•
The Schirmer strip is folded 5 mm from one end and kept in the lower fornix at the 
junction of lateral 1/3 and medial 2/3 (do not touch cornea or lashes)
•
The participant is asked to close the eyes
•
Tears in the conjunctival sac will cause progressive wetting of the paper strip
•
After 5 minutes, the filter paper is removed and the distance between the leading edge of 
wetness and the initial fold is measured, using a millimeter ruler
8.3.6
Salivary flow rate (unstimulated) (SjS participants only)
Unstimulated whole salivary fluid is obtained from participants at Screening, Baseline, Week 4, 
Week 12 and Week 24.
Unstimulated salivary secretions are collected over 5 minutes. All assessments are to be 
performed at a fixed time of the day to minimize fluctuations related to the circadian rhythm of 
salivary flow and composition. Participants are instructed not to eat, drink or smoke for 
90 minutes before the assessment. The start time and end time of saliva collection will be 
recorded to calculate the salivary flow rate per minute.
8.3.7
Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV) 
(MCTD participants only)
Forced expiratory volume (FEV) measures how much air a person can exhale during a forced 
breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), 
and/or third seconds (FEV3) of the forced breath. Forced vital capacity (FVC) is the total 
amount of air exhaled during the FEV test. Forced expiratory volume and forced vital capacity 
are lung function tests that are measured during spirometry and are important measures of lung 
function. 
8.3.8
Diffusing capacity of the lungs for carbon monoxide (DLCO) (MCTD 
participants only)
DLCO is a measurement to assess the ability of the lungs to transfer gas from inspired air to the 
bloodstream. Inhaled carbon monoxide (CO) is used for this test due to its high affinity for 
hemoglobin. In brief, during a ten-second breath-hold, DLCO measures uptake of CO per time 
per CO pressure (cc of CO/sec/mm of Hg; (Ogilvie et al 1957; Cotes et al 1993; 
Modi et al 2020).


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8.3.9
Raynaud’s Condition Score (RCS) (MCTD participants only)
The Raynaud's Condition score (RCS) is participant's rating of difficulty considering number 
of attacks, duration, amount of pain, numbness, or other symptoms caused in the fingers 
(including painful sores) due to the Raynaud's phenomenon and impact of Raynaud's alone on 
use of hands every day. An 11 point Likert scale is used to rate the difficulty caused by the 
condition with 0 = no difficulty and 10 = extreme difficulty. Participants are asked to select the 
number that best describes their difficulty, with higher score indicating worse condition.
RCS will be completed by the study participants with MCTD at the study site as per study 
assessment schedule (Table 8-1).
8.3.10
King’s Brief Interstitial Lung Disease (K-BILD) (MCTD participants 
only)
The K-BILD questionnaire is a self-administered health-status questionnaire that has been 
developed in patients with interstitial lung diseases. It consists of 15 items in three domains: i) 
breathlessness and activities, ii) psychological factors, and iii) chest symptoms. Domain and 
total scores range from 0 to 100, with higher scores representing better health status 
(Patel et al 2013; Sinha et al 2019; Nolan et al 2019; Flaherty et al 2019).
K-BILD will be completed by the study participants with MCTD at the study site as per study 
assessment schedule (Table 8-1).
8.3.11
Sjögren’s Tool for Assessing Response (STAR)
STAR is a composite responder index, including in a single tool all main disease features, and 
designed for use as a key efficacy endpoint in SjS randomized clinical trials (Seror et al 2022).
In this study lacrimal gland function will be assessed using the Schirmer’s test, while ocular 
staining score will not be used to calculate STAR response. Further, the biological domain will 
be assessed using IgG, while rheumatoid factor (RF) will not be used to assess STAR response. 
Table 8-3
STAR response criteria used in the study
Domain
Point
Definition of response
Systemic activity
3
Decrease in clin ESSDAI ≥ 3 points
Patient reported outcome
3
Decrease in ESSPRI ≥ 1 point or 15% 
Lacrimal gland function 
(assessed by Schirmer’s 
test)
1
If abnormal score at baseline: increase ≥ 5 mm from baseline
If normal score at baseline: no change to abnormal
Salivary gland function 
(assessed by unstimulated 
salivary flow)
1
increase ≥ 25% from baseline
Biological (assessed by 
serum IgG levels)
1
Decrease ≥ 10%
STAR responder ≥ 5 points


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8.3.12
Appropriateness of efficacy assessments
Efficacy measures in this study are primarily based on ESSDAI measuring organ-specific 
disease criteria, and on ESSPRI 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.
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 2015a). 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 2015b).
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
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.
Table 8-4
Assessments & 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 participant 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.


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Assessment
Specification
Vital signs
Vital signs will include the collection of otic or oral body temperature (recorded 
in °C), blood pressure (BP) and pulse measurements. 
After the participant has been sitting for 3 minutes, with back supported and 
both feet placed on the floor, systolic and diastolic BP will be measured using 
an automated validated device, e.g. OMRON with an appropriately sized cuff. 
In case the cuff sizes available are not large enough for the participant's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be 
used.
In case of repeated vital assessments, the eCRF should contain all the results.
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.
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.
Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and to allow proper assessments.
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. 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 8-5
Laboratory evaluations
Test Category
Test Name
Hematology
Hematocrit,
Hemoglobin,
Ery. Mean Corpuscular Hemoglobin,
Ery. Mean Corpuscular HGB Concentration,
Ery. Mean Corpuscular Volume,
Platelets,
Erythrocytes,
Leukocytes,
Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Bands),
Immunoglobulins quantitative (IgG, IgA, IgM, IgE),
Ccomplement (C3, C4, CH50)


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Test Category
Test Name
Chemistry
Albumin,
Alkaline phosphatase,
ALT,
AST, 
Gamma-glutamyl-transferase (GGT),
Lactate dehydrogenase (LDH),
Bicarbonate,
Calcium,
Chloride, 
Sodium,
Potassium,
Creatinine,
eGFR,
Cystatin C,
Creatine kinase,
Total Bilirubin (if elevated above 1.5x, Direct Bilirubin 
and Indirect Bilirubin will be differentiated),
Total Cholesterol,
Total Protein,
Triglycerides,
Urea Nitrogen or Urea,
Uric Acid,
Amylase,
Lipase,
Glucose (non-fasting),
CRP,
Urinalysis
Microscopic Panel (Erythrocytes, Leukocytes, Casts, 
Crystals, Bacteria, Epithelial cells)
Macroscopic Panel (Dipstick) (Color, Bilirubin, 
Macroscopic Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen)
Coagulation
Prothrombin time (PT),
International normalized ratio [INR]),
Activated partial thromboplastin time (APTT) 
Serology (Hepatitis and HIV) 
Hepatitis B Virus Surface Antigen (HBsAg),
Hepatitis B Virus core antibody (Anti-HBcAb),
Hepatitis B Virus DNA (HBV DNA),
Hepatitis C Virus Antibody (HCV),
Hepatitis C Virus RNA (HCV RNA),
HIV Ab
Pregnancy Test
Serum / Urine pregnancy test
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8.4.2
Electrocardiogram (ECG)
ECGs will be collected at the site and evaluated centrally.
Single 12-lead ECGs will be recorded at each study visit.
Full details of all procedures relating to the ECG collection and reporting are contained in the 
technical manual provided by the core laboratory.
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The Fridericia QT correction formula (QTcF) will be used for clinical 
decisions.
All ECGs, including unscheduled safety ECGs with clinically relevant findings collected during 
the study need to be transmitted to the central ECG laboratory for review.
Additional, unscheduled safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings before 
administration of study treatment and during the study.
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. Serum 
pregnancy testing is required at screening and the follow up visit. During the study, urine 
pregnancy testing should be done at monthly intervals. The positive urine test needs to be 
confirmed with serum test. If positive, the participant must be discontinued from study 
treatment.
Local pregnancy test and associated results will not be collected on CRF.
If participants cannot visit the site to have serum pregnancy tests 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, 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 proceed with the 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).


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Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH (Follicle Stimulating Hormone) 
testing is required of any female participant regardless of reported reproductive/menopausal 
status at screening.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.5
Additional assessments
8.5.1
Pharmacokinetics
PK blood samples will be collected at the visits and time points defined in the assessment 
schedule (Table 8-1). Instructions outlined in the laboratory manual regarding sample collection, 
numbering, processing and shipment should be followed. 
 
PK samples will be obtained in all participants. They will be evaluated in all participants, except 
the placebo group. From those blood samples, plasma will be prepared and plasma 
concentrations over time of MHV370 will be determined by a validated LC-MS/MS method 
with an anticipated Lower Limit of Quantification (LLOQ) of 1.0 ng/mL. Concentrations will 
be expressed in mass per volume units (ng/mL) and will refer to the free base. Concentrations 
below the LLOQ will be reported as “zero” and missing data will be labeled as such in the 
Bioanalytical Data Report.
In the optional case of further exploratory assessment (e.g. investigation of metabolites), a 
non-validated method will be used and results will be provided in a separate standalone report.
For standard PK abbreviations and definitions see the list provided in Section 12.5.3.
The following PK parameters at steady-state after 4 weeks of b.i.d. treatment will be determined 
from the plasma concentration time data using the actual recorded sampling times and 
non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or higher): Cmax, Tmax, 
AUClast. Additional PK parameters may be added to further characterize the dose/exposure 
relationship or refine PK/PD analysis. In addition, concentrations of MHV370 at selected time 
points will be characterized at Week 12 and Week 24.
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8.5.3
Other Assessments
8.5.3.1
Patient Diary
Participants will receive a medication diary where they have to record the intake of study 
medication daily.
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9
Discontinuation and completion
9.1
Discontinuation from study treatment and from study
9.1.1
Discontinuation from study treatment
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. Discontinuation from study 
treatment is required under the following circumstances:
•
Participant/guardian decision
•
Pregnancy
•
Use of prohibited treatment as per recommendations in the prohibited treatment section 
(see Table 6-3)
•
Any situation in which continued study participation might result in a safety risk to the 
participant
•
Emergency unblinding
•
Emergence of the following adverse events:
a. Laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study (see also Section 16.1)
b. ECG abnormalities, if the investigator considers that continued study participation 
might result in a safety risk to the participant
c. Severe treatment related hypersensitivity reaction requiring treatment
d. Severe systemic infection or severe opportunistic infection requiring treatment
e. Severe, treatment related and persisting changes in heart rate or blood pressure (see 
Section 16.1 for clinically notable vital sign values)
f.
Pancreatitis, as confirmed by clinical symptoms, elevated levels of pancreatic 
enzymes and/or imaging techniques (CT, MRI, ultrasound)
g. Myofiber toxicity, as attested by acute muscle weakness, myalgia, muscle swelling, 
dark (tea/cola) colored urine, creatine kinase (CK) elevation (> x 5 ULN) and/or 
myoglobinuria, in the absence of exercise (Stahl et al 2020).
•
For liver events, please see Section 10.2.1 and consult the Hepatotoxicity Clinical Safety 
Standard Guideline. For renal events, please see Section 10.2.2 and consult the Drug 
Induced Nephrotoxicity Guidelines at the Renal Safety Group site, [http://go/rsg or CSSG].
•
If a liver- or renal event occurs, follow guidelines outlined in Section 16.2 and Section 16.3 
regarding discontinuation of study treatment.
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information.


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Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8).
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After discontinuation from study treatment, 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 participant’s discontinuation from 
study treatment.
9.1.2
Discontinuation from study
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason.
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8).
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant 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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9.2
Withdrawal of informed consent/Opposition to use 
data/biological samples
Withdrawal of consent/opposition to use data/biological samples occurs when a participant:
•
Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples)
and
•
No longer wishes to receive study treatment
and
•
Does not want any further visits or assessments (including further study-related contacts)
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information.
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their 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 participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
9.3
Study stopping rules
The study will be placed on hold if any of the following occurs, unless clearly unrelated to 
treatment:
•
One patient with treatment related death
•
Two or more treatment related SAEs within one system organ class (SOC)
•
Two or more participants presenting with the following AEs
a. severe treatment related hypersensitivity reaction requiring treatment
b. severe systemic infection or severe opportunistic infection requiring treatment
c. severe, treatment related and persisting changes in heart rate or blood pressure 
(see Section 16.1 for clinically notable vital sign values)


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d. pancreatitis, as confirmed by clinical symptoms, elevated levels of pancreatic 
enzymes and/or imaging techniques (CT, MRI, ultrasound)
e. myofiber toxicity, as attested by acute muscle weakness, myalgia, muscle swelling, 
dark (tea/cola) colored urine, creatine kinase (CK) elevation (> x 5 ULN) and/or 
myoglobinuria, in the absence of exercise (Stahl et al 2020).
•
The Sponsor and Investigator considers that based on available safety data (including 
number and/or severity of AEs, laboratory tests, vital signs, etc.) putting the study on hold 
is justified.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed. Any restart of the study following a full safety review will require notification 
to health authorities or submission and approval of a substantial amendment, whichever is 
appropriate based on local requirements.
9.4
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them. All randomized and/or 
treated participants should have a safety follow-up call conducted 4 weeks 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. Documentation of 
attempts to contact the participant should be recorded in the source documentation.
9.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination
•
Unexpected, significant, or unacceptable safety risk to participants enrolled in the study
•
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data
•
Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. 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 participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.


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10
Safety monitoring, reporting and committees
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 clinical 
investigation participant 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 participant 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 participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant 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 participant
3. Its duration (start and end dates or ongoing) and the outcome 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
•
Drug interrupted/permanently discontinued
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Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 4 weeks 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 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 participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 16.1.
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 participant 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: 
•
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


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•
social reasons and respite care in the absence of any deterioration in the participant’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 participant 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 participant 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 participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 4 weeks following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, under no 
circumstances later than 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. Information about all SAEs is collected and recorded on the Serious 
Adverse Event Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report.
No pre-specified study endpoints are considered to be exempted from SAE reporting.
SAE reporting timeframes: 
•
Screen Failures (e.g. a participant who is screened but is not treated or randomized): SAEs 
occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis within 24 hours of learning of its 
occurrence.
•
Randomized OR Treated Participants: SAEs collected between time participant signs ICF 
until 4 weeks after the participant has discontinued from study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, and under no circumstances later than within 24 hours of 


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the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS (Chief Medical 
Office and Patient Safety) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification 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 4 weeks period following the last study visit should only be 
reported to Novartis Safety if the investigator suspects a causal relationship to study treatment, 
unless otherwise specified by local law/regulations.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant 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.
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 of MHV370 to any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
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, participant or 
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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be 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 the 
respective sections (Section 10.1).
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant 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 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 16-1 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 (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) 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 participant. 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 CRF.
•
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.
•
Discontinuation of the investigational drug (refer to the Discontinuation of study 
treatment, Section 9.1.1), if appropriate
•
Hospitalization of the participant if appropriate


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•
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.
•
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
•
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
•
Imaging such as abdominal US, CT or MRI, as appropriate
•
Obtaining a history of exposure to environmental chemical agents. 
•
Considering gastroenterology or hepatology consultations. 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF.
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff as summarized 
in Section 16.3.
10.3
Committees
There are no Committees applicable for this trial.
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 participant 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.


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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 will be processed centrally, and the results will be sent electronically to 
Novartis.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant 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.
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 (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 participant 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 organization, in compliance with local regulations. 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 participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 


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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 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
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 
participants will be disclosed.
12
Data analysis and statistical methods
The analyses will be provided separately for SjS and MCTD unless otherwise specified.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
The safety analysis set will include all participants that received any study drug.
The PK analysis set will include all participants with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received MHV370 and with no protocol 
deviations with impact on PK data.
The PD analysis set will include all participants who received any study drug and have no 
protocol deviations with relevant impact on PD/efficacy data.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data will be summarized descriptively by treatment group for 
the safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, and by treatment group.
12.3
Treatments
The safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented.
The duration of exposure in weeks to MHV370 and placebo will be summarized by means of 
descriptive statistics using the safety set.


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis supporting primary objectives
The PD analysis set will be used.
SjS
The primary objective is to assess the efficacy of MHV370 based on change from baseline in 
ESSDAI at Week 24. The statistical analysis model will include data on the ESSDAI from all 
time points at which it was recorded (Baseline, Week 4, Week 8, Week 12, Week 20, Week 24) 
but the primary comparison is made for Week 24.
MCTD
The primary objective is to assess the efficacy of MHV370 based on change from baseline in 
Physician Global Assessment (PhGA) at Week 24. The statistical analysis model will include 
data on the PhGA from all time points at which it was recorded (baseline, Week 4, Week 8, 
Week 12, Week 20, Week 24) but the primary comparison is made for Week 24.
12.4.1
Definition of primary endpoint(s)
SjS
The primary endpoint is the change from baseline in ESSDAI total score at Week 24, defined 
as the Week 24 visit ESSDAI total score minus the baseline ESSDAI total score. A negative 
change indicates an improvement of disease activity.
MCTD
The primary endpoint is the change from baseline in PhGA after 24 weeks of treatment. It is 
defined as the Week 24 visit PhGA value minus the baseline PhGA value. A negative change 
indicates an improvement in disease activity.
12.4.2
Statistical model, hypothesis, and method of analysis
SjS
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 with the following fixed effects 
•
treatment group
•
visit as categorical variable
•
treatment group by visit interaction


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and baseline ESSDAI as a continuous covariate. An unstructured variance-covariance matrix 
will be fitted to model the dependency between repeated observations.
The difference between MHV370 and placebo in change from baseline at each visit will be 
estimated from the model and presented with 95% confidence intervals.
The following two criteria will be used to assess treatment efficacy:
•
a statistically significant reduction in ESSDAI at Week 24 in the MHV370 group 
compared to placebo, at the one-sided 10% significance level, and
•
an estimated mean reduction in ESSDAI at Week 24 in the MHV370 group to be at least 2 
points greater than in placebo.
A positive sign of efficacy will be considered if both criteria are met.
MCTD
The change from baseline in PhGA is assumed to be normally distributed.
A MMRM will be fitted to the changes from baseline in PhGA for all time points until Week 24 
with the following fixed effects
•
treatment group
•
visit as categorical variable
•
treatment group by visit interaction
•
stratification factor pulmonary involvement at baseline (yes/no)
and baseline PhGA as a continuous covariate. A random intercepts model will be used.
The difference between MHV370 and placebo in change from baseline at each visit will be 
estimated from the model and presented with 95% confidence intervals.
12.4.3
Handling of intercurrent events of primary estimand
SjS and MCTD
The primary analysis will account for different intercurrent events as explained in the following:
1. Treatment discontinuation: Data from participants who have discontinued treatment early 
will be regarded as missing after the treatment discontinuation. Data from participants 
who have temporarily discontinued treatment will be regarded as missing during the 
temporary treatment discontinuation.
2. Change in the dose of certain allowed concomitant mediation (systemic corticosteroid 
treatment, azathioprine, methotrexate, leflunomide, HCQ and CQ): Data after change in 
the dose of allowed concomitant medication will be regarded as missing. 
3. Intake of prohibited medication: Data after intake of prohibited medication will be regarded 
as missing.


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12.4.4
Handling of missing values not related to intercurrent event
SjS
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.
SjS and MCTD
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 and, if necessary, 
further methods may be applied.
12.4.5
Sensitivity analyses
Other models that the one specified in Section 12.4.2 may be considered. For SjS, simpler 
covariance structures than the unstructured one may also be considered.
12.4.6
Supplementary analyses
SjS
The target population, the primary variable and the summary measure of the supplementary 
estimand are the same as for the primary estimand. Differently from the primary estimand, the 
intercurrent events will be ignored. Data from participants who have discontinued treatment 
early (permanently or temporarily), had a dose change in the concomitant medications or had 
prohibited medication during the study will be included in the analyses.
12.5
Analysis supporting secondary objectives
SjS
For the analysis of the secondary endpoints of change from baseline in ESSPRI, FACIT-F 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 participants in 
the PD analysis set.
Responder status in STAR will be assessed at weeks 4, 12 and 24. Missing responses will be 
treated as non-responders. The percentage of responders together with the 95% confidence 
interval (Clopper-Pearson method) will be presented by treatment.


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For the Schirmer’s test and salivary flow data descriptive summary statistics will be provided 
for all participants in the PD analysis set.
MCTD
For the secondary endpoints change from baseline in FVC, FEV1, FEV2, FEV3, RCS, 
FACIT-F, DLCO, K-BILD, RCS, PhGA and ESSDAI (articular and pulmonary domains only) 
descriptive summary statistics will be provided for all participants in the PD analysis set.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
SjS
The change from baseline over time for secondary efficacy endpoints (ESSPRI, FACIT-F 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 similar MMRM as the one used for the 
primary efficacy variable. Differences in change from baseline between MHV370 treatment 
group and placebo, along with associated 95% confidence intervals, will be presented by visit.
For the Schirmer’s test and salivary flow data descriptive summary statistics will be presented 
by treatment group and visit.
MCTD
The change from baseline over time for secondary efficacy endpoints FVC, FEV1, FEV2, FEV3, 
RCS, FACIT-F, DLCO, K-BILD, RCS, PhGA and ESSDAI (articular and pulmonary domains 
only) will be presented by treatment group and visit.
12.5.2
Safety endpoints
All safety endpoints will be summarized by treatment group for all participants in the safety set.
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized in the following ways:
•
by treatment, primary system organ class
•
by treatment, preferred term
•
by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.


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Vital signs
Summary statistics will be provided by treatment group and visit/time.
12-lead ECG
Summary statistics will be provided by treatment group and visit/time.
Clinical laboratory evaluations
Summary statistics will be provided by treatment group and visit/time.
12.5.3
Pharmacokinetics
Descriptive summary statistics for MHV370 PK plasma concentration data will be provided by 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero. Summary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum, and maximum.  Concentrations below LLOQ 
will be treated as zero in summary statistics and for PK parameter calculations.
Descriptive summary statistics for pharmacokinetic parameters will be provided. Summary 
statistics include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), 
median, minimum, and maximum. An exception to this is Tmax where only median, minimum, 
and maximum will be presented.
Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(ng x h / mL)
AUC0-t
The AUC from time zero to specified time t (ng x h / mL)
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)
The PK profile of MHV370 will be characterized but not limited to the PK parameters listed 
above.
12.5.4
PK/PD relationships
The relationship between PK and PD endpoints may be explored graphically. Modelling of the 
PK and PD data using a population approach may be performed, as appropriate, and may be 
reported in a separate, standalone modelling and simulation report.
12.6
Analysis of exploratory endpoints 
Details of the statistical analyses of exploratory endpoints will be described in the Statistical 
Analysis Plan (SAP).


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12.7
Interim analyses
 
 
 
 
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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.
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13.3
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13.5
Participant Engagement
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis.
•
Thank You letter
•
Plain language trial summary - after CSR publication
•
Treatment Sharing Information


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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 participants 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 participant 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 participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
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.
Båve U, Nordmark G, Lövgren T, et al (2005) Activation of the type I interferon system in 
primary Sjögren's syndrome: a possible etiopathogenic mechanism. Arthritis and rheumatism, 
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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
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Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al (2014) Treatment of primary 
Sjögren syndrome with rituximab: a randomized trial. Ann. Intern. Med. p. 233-42.
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Flaherty KR, Wells AU, Cottin V, et al (2019) Nintedanib in progressive fibrosing interstitial 
lung diseases. New England Journal of Medicine, 381(18), pp.1718-1727.
Gunnarsson R, Molberg O, Gilboe, et al (2011) The prevalence and incidence of mixed 
connective tissue disease: a national multicentre survey of Norwegian patients. Annals of the 
rheumatic diseases, 70(6), pp.1047-1051.
Heil F, Hemmi H, Hochrein H, et al (2004) Species-specific recognition of single-stranded 
RNA via toll-like receptor 7 and 8. Science. 303(5663), p. 1526-1529.
John JK, Sadiq M, George T, et al (2020) Clinical and Immunological Profile of Mixed 
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Li Y, Chen M, Cao H, et al (2013) Extraordinary GU-rich single-strand RNA identified from 
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Modi P and Cascella M (2020) Diffusing Capacity Of The Lungs For Carbon Monoxide 
(DLCO). (Internet) Available from: https://www.ncbi.nlm.nih.gov/books/NBK556149/ 
(Accessed 01-May-2021).
Nocturne G, Mariette X (2018) B cells in the pathogenesis of primary Sjögren syndrome. Nat 
Rev Rheumatol p. 133-145.
Nolan CM, Birring SS, Maddocks M, et al (2019) Kings Brief Interstitial Lung Disease 
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Patel AS, Siegert RJ, Keir GJ, et al (2013) The minimal important difference of the King’s 
Brief Interstitial Lung Disease questionnaire (K-BILD) and forced vital capacity in interstitial 
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Ramos-Casals M, Brito-Zerón P, Font J (2007) The overlap of Sjögren’s syndrome with other 
systemic autoimmune diseases. Seminars in arthritis and rheumatism, 36(4), pp. 246-255. 
Savarese E, Chae O, Trowitzsch S, et al (2006) U1 small nuclear ribonucleoprotein immune 
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Seror R, Baron G, Camus M, et al (2022) Development and preliminary validation of the 
Sjögren’s Tool for Assessing Response (STAR): a consensual composite score for assessing 
treatment effect in primary Sjögren’s syndrome. Annals of the Rheumatic Diseases. Published 
online at http://dx.doi.org/10.1136/annrheumdis-2021-222054
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Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome. 
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Sharp GC, Irvin WS, Tan EM, et al (1972) Mixed connective tissue disease-an apparently 
distinct rheumatic disease syndrome associated with a specific antibody to an extractable 
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(KBILD) questionnaire: an updated minimal clinically important difference. BMJ Open 
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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Central laboratory assessments:
The central laboratory will flag on the central laboratory report
i)
all values falling outside of the central laboratory normal ranges 
ii)
all values falling in the below alert range:
a.
Hemoglobin levels < 8 g/dL (< 5 mmol/L)
b. Total leukocyte count < 2,000/µL (2 x 109/L)
c.
Platelets < 50,000/µL (50 x 109/L)
d. Neutrophil count < 1,000/ µL (1 x 109/L)
Vital signs:
Clinically notable values for vital signs are defined as:
•
heart rate of < 50 and > 100 bpm
•
systolic blood pressure of < 90 and ≥ 140 mmHg
•
diastolic blood pressure of < 60 and ≥ 90 mmHg 
The investigator will report an adverse event for clinically significant vital-sign or laboratory 
abnormalities.


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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at 
baseline: 
•
ALT or AST > 5 × ULN
•
ALP > 2 × ULN (in the absence of known 
bone pathology)
•
Total bilirubin > 3 × 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 Total bilirubin > 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
If ALT or AST abnormal at baseline:
•
ALT or AST > 3x baseline or > 300 U/L 
(whichever occurs first)


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Table 16-2
Follow up requirements for liver laboratory triggers - ALT, AST, TBL
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
 
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
Normal
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL
None
•
No change 
to study 
treatment
•
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.
•
Follow-up for 
symptoms.
If normal at 
baseline:
ALT > 5 x ULN 
for more than two 
weeks
 
If elevated at 
baseline:
ALT > 3 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst) for 
more than two 
weeks
Normal
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL
None
 
If normal at 
baseline:
ALT > 8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
TBL > 2 x ULN 
(or INR > 1.5)
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin
None
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
Normal or 
elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
•
Interrupt 
study drug
•
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.
•
Follow-up for 
symptoms.
•
Initiate close 
monitoring 
and workup 
for competing 
etiologies.
•
Study drug 
can be 
restarted only 
if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline.


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Protocol No. CMHV370A12201
ALT
TBL
Liver Symptoms
Action
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
Table 16-3
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
 
 
>1.5 – 3.0 ULN
•
Maintain treatment
•
Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)
•
Interrupt treatment 
•
Repeat LFT within 48-72 
hours
•
Hospitalize if clinically 
appropriate
•
Establish causality
•
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 10 x ULN
•
Discontinue the study 
treatment immediately 
•
Hospitalize the participant
•
Establish causality
•
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution (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’s discretion
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 16-4
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum cystatin C increase 25 – 49% 
compared to baseline
•
Consider causes and possible interventions
•
Follow up within 2-5 days
Serum cystatin C increase ≥ 50%
•
Consider causes and possible interventions
•
Repeat assessment within 24-48h if possible
•
Consider drug interruption or discontinuation 
•
Consider hospitalization and specialized treatment
New onset dipstick proteinuria ≥ 1+
•
Consider causes and possible interventions
•
Assess serum albumin & serum protein
•
Repeat assessment to confirm
•
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected
New onset glycosuria on urine dipstick 
(unless related to treatment, diabetes)
Assess & document:
•
Blood glucose (fasting)
•
Serum cystatin C
New hematuria on dipstick concomitant
Assess & document:
•
Urine sediment microscopy
•
Assess serum cystatin C 
•
Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation
•
Consider bleeding disorder
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 strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:
•
Blood pressure assessment (after 5 min rest, with an appropriate cuff size)
•
Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, 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 potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-5
Follow up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data load. 
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.
•
Urine dipstick and sediment microscopy
•
Blood pressure and body weight
•
Serum cystatin C, electrolytes (sodium, 
potassium, phosphate, calcium), bicarbonate 
and uric acid
•
Urine output
Monitor subject regularly (frequency at 
investigator’s discretion) until:
•
Event resolution: (serum cystatin C within 
10% of baseline or protein-creatinine ratio 
within 50% of baseline)
or
•
Event stabilization: serum cystatin C level with 
±10% variability over last 6 months or protein-
creatinine ratio stabilization at a new level with 
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive 
metric for integrated kidney function that requires excellent tubular function. A high urinary osmolality 
in the setting of an increase in CysC will point toward a “pre-renal” cause rather than tubular toxicity.


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16.4
Appendix 4: Prohibited Co-Medication
Table 16-6
Narrow therapeutic index CYP substrates
Category
Drug Names
Narrow therapeutic index substrates of CYP2B6
None reported to date
Narrow therapeutic index substrates of CYP2C8
paclitaxel
Narrow therapeutic index substrates of CYP2C9
phenytoin, (S)-warfarin (also sensitive)
Narrow therapeutic index substrates of 
CYP2C19
(S)-mephenytoin (also sensitive)
Narrow therapeutic index substrates of CYP3A
abemaciclib, acalabrutinib, astemizole, 
cyclosporine, dihydroergotamine, entrectinib, 
ergotamine, pimozide, quinidine, sirolimus, 
tacrolimus, zanubrutinib
Table 16-7
Strong and moderate inhibitors of CYP3A
Category
Drug Names
Strong inhibitors of CYP3A
boceprevir, ceritinib, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, 
indinavir, indinavir/ritonavir, itraconazole, 
josamycin, ketoconazole, lopinavir/ritonavir, 
mibefradil, mifepristone, nefazodone, nelfinavir, 
ombitasvir/paritaprevir/dasabuvir/ritonavir 
(Viekira Pak), posaconazole, ribociclib, ritonavir, 
saquinavir, saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, 
troleandomycin, tucatinib, voriconazole 
Moderate inhibitors of CYP3A
ACT-178882, ACT-539313, aprepitant, 
amprenavir, atazanavir, atazanavir/ritonavir, 
casopitant, cimetidine, ciprofloxacin, crizotinib, 
darunavir, darunavir/ritonavir, diltiazem, 
dronedarone, duvelisib, erythromycin, 
faldaprevir, fedratinib, FK1706, fluconazole, 
grapefruit juice, GSK2647544, imatinib, 
isavuconazole, istradefylline, lefamulin, 
letermovir, Magnolia vine (Schisandra 
sphenanthera), netupitant, nilotinib, 
ravuconazole, tofisopam, verapamil, voxelotor


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Table 16-8
Strong and moderate inducers of CYP3A
Category
Drug Names
Strong inducers of CYP3A
apalutamide, avasimibe, carbamazepine, 
enzalutamide, ivosidenib, lumacaftor, mitotane, 
phenobarbital, phenytoin, rifampicin, rifapentine, 
St. John’s wort (Hypericum perforatum)
Moderate inducers of CYP3A
asunaprevir / beclabuvir / daclatasvir, bosentan, 
cenobamate, dabrafenib, elagolix, efavirenz, 
etravirine,  lesinurad, lersivirine, lopinavir, 
nafcillin, PF-06282999, phenobarbital, 
primidone, rifabutin,  talviraline, telotristat ethyl, 
thioridazine, tipranavir/ritonavir
Table 16-9
Substrates of MATE1/2
Category
Drug Names
Substrates of MATE 1/2
acyclovir, cephalexin, cimetidine, ganciclovir, 
fexofenadine, glycopyrronium, metformin, 
pindolol, pilsicainide, procainamide, ranitidine, 
topotecan, varenicline


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16.5
Appendix 5: Permitted concomitant therapy requiring caution 
and/or action
Table 16-10
Sensitive CYP substrates
Category
Drug Names
Sensitive substrates of CYP2B6
bupropion
Sensitive substrates of CYP2C8
daprodustat, repaglinide
Sensitive substrates of CYP2C9
benzbromarone, celecoxib, glimepiride, glipizide, 
ibuprofen, lornoxicam, meloxicam, piroxicam, 
tolbutamide
Sensitive substrates of CYP2C19
(R)-(-)-hexobarbital, clobazam, (R)-lansoprazole 
(dexlansoprazole), diazepam, gliclazide, (S)-
lansoprazole, (R)-mephobarbital, (R)-
omeprazole, omeprazole, pantoprazole, 
proguanil, rabeprazole, tilidine
Sensitive substrates of CYP3A
alisporivir, almorexant, alfentanil, alpha-
dihydroergocryptine, aplaviroc, atorvastatin, 
avanafil, avapritinib, blonanserin, bosutinib, 
brecanavir, brigatinib, brotizolam, budesonide, 
buspirone, cabazitaxel, capravirine, cobimetinib, 
darifenacin, dasatinib, ebastine, eletriptan, 
eliglustat, eplerenone, everolimus, felodipine, 
fluticasone, grazoprevir, ibrutinib, itacitinib, 
ivabradine, ivacaftor, levomethadyl (LAAM), 
lomitapide, lovastatin, lumefantrine, lurasidone, 
maraviroc, midazolam, midostaurin, 
morphothiadin, naloxegol, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, sildenafil, 
simeprevir, simvastatin, ticagrelor, tilidine, 
tolvaptan, triazolam, ubrogepant, ulipristal, 
vardenafil, venetoclax, vicriviroc, vilaprisan, 
voclosporin

SAP_001.pdf: 
Clinical Development
MHV370
CMHV370A12201
A multi-center, randomized, participant- and investigator-
blinded, placebo-controlled, parallel group basket study to 
evaluate the safety, tolerability and efficacy of MHV370 in 
participants with Sjögren’s Syndrome or Mixed Connective 
Tissue Disease
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation
Document status:
Final Amendment v02
Release date:
22-Mar-2023
Number of pages:
34
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 4.0, Effective from 23-Apr-2021


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SAP
Study No. CMHV370A12201
Commercially Confidential Information (CCI)


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SAP
Study No. CMHV370A12201
Table of contents
Table of contents..................................................................................................................3
List of tables.........................................................................................................................4
List of figures.......................................................................................................................4
List of abbreviations ............................................................................................................5
1
Introduction..........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives, endpoints and estimands..............................................................7
1.2.1
Primary estimands ...................................................................................8
2
Statistical methods .............................................................................................................10
2.1
Data analysis general information..........................................................................10
2.1.1
General definitions ................................................................................11
2.2
Analysis sets...........................................................................................................12
2.2.1
Subgroup of interest ..............................................................................12
2.3
Participant disposition, demographics and other baseline characteristics .............12
2.3.1
Participant disposition ...........................................................................12
2.3.2
Demographics and other baseline characteristics..................................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................13
2.4.2
Prior, concomitant and post therapies ...................................................13
2.5
Analysis supporting primary objective(s)..............................................................13
2.5.1
Primary endpoint(s)...............................................................................13
2.5.2
Statistical hypothesis, model, and method of analysis ..........................13
2.5.3
Handling of intercurrent events.............................................................14
2.5.4
Handling of missing values not related to intercurrent event................14
2.5.5
Sensitivity analyses ...............................................................................15
2.5.6
Supplementary analyses ........................................................................15
2.6
Analysis supporting secondary objectives.............................................................15
2.6.1
Secondary endpoint(s)...........................................................................15
2.6.2
Statistical hypothesis, model, and method of analysis ..........................16
2.6.3
Handling of intercurrent events.............................................................16
2.6.4
Handling of missing values not related to intercurrent event................16
2.7
Safety analyses.......................................................................................................16
2.7.1
Adverse events (AEs)............................................................................16
2.7.2
Deaths....................................................................................................17
2.7.3
Laboratory data......................................................................................17


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2.7.4
Other safety data....................................................................................17
2.8
Pharmacokinetic endpoints ....................................................................................18
2.9
PD and PK/PD analyses.........................................................................................18
2.10
Participant-reported outcomes ...............................................................................18
2.12
Other Exploratory analyses....................................................................................22
2.13
Interim analysis......................................................................................................22
3
Sample size calculation......................................................................................................22
3.1
Primary endpoint(s)................................................................................................22
4
Change to protocol specified analyses...............................................................................22
5
Appendix............................................................................................................................22
5.1
Imputation rules .....................................................................................................22
5.1.1
Study drug .............................................................................................22
5.1.2
AE date imputation................................................................................23
5.1.3
Concomitant medication date imputation..............................................24
5.2
AEs coding/grading................................................................................................25
5.3
Laboratory parameters derivations.........................................................................25
5.4
Statistical models ...................................................................................................26
5.4.1
Analysis supporting primary objective(s) .............................................26
5.4.2
Analysis supporting secondary objective(s)..........................................33
5.5
Considerations due to COVID-19..........................................................................33
5.6
Rule of exclusion criteria of analysis sets..............................................................33
6
Reference ...........................................................................................................................34
List of tables
Table 2-1
PK Parameters .......................................................................................18
Table 5-1
FACIT-F questions................................................................................28
Table 5-2
K-BILD Response Option Weightings..................................................29
Table 5-3
Criteria leading to exclusion..................................................................33
List of figures
Figure 1-1
Study design ............................................................................................6
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List of abbreviations
AE
Adverse Event
AUC
Area Under the Curve
b.i.d.
bis in die/twice a day
BMI
Body Mass Index
Cmax
Maximal concentration
CSR
Clinical study report
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiography
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren's Syndrome Participant Reported Index
EudraCT
European Union Drug Regulating Authorities Clinical Trials
EULAR
European League against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
Full Analysis Set
FEV
Forced Expiratory Volume
FVC
Forced Vital Capacity
K-BILD
King’s Brief Interstitial Lung Disease
LLOQ
lower limit of quantification
MCTD
Mixed Connective Tissue Disease
MedDRA
Medical dictionary for regulatory activities 
MMRM
mixed effect model for repeated measurements
MRI
Magnetic resonance imaging
mRNA
messenger RNA (ribonucleic acid)
PD
Pharmacodynamic(s)
PhGA
Physician global assessment scale
PK
Pharmacokinetic(s)
PRO
Participant Reported Outcomes
PT
Prothrombin time
QTcF
Fridericia QT correction formula
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SjS
Sjögren’s Syndrome
SOC
System organ class
Tmax
Time to reach maximum concentration
ULOQ
Upper limit of quantification
WHO
World Health Organization 
WoC
Withdrawal of Consent


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1
Introduction
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CMHV370A12201”.
The Statistical Analysis Plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.1
Study design
This is a phase 2 randomized, participant- and investigator-blinded, placebo-controlled, multi-
center, parallel group basket study to evaluate the safety, tolerability and efficacy of MHV370 
in participants with moderate to severe Sjögren’s Syndrome (SjS) or participants with diagnosis 
of Mixed Connective Tissue Disease (MCTD). In case study participants receive 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.
A total of approximately 48 participants with SjS will be randomized in a 1:1 ratio to MHV370 
(200 mg b.i.d.) or placebo. A total of approximately 12 participants with MCTD will be 
randomized in a 1:1 ratio to MHV370 (200 mg b.i.d.) or placebo. 
As shown in Figure 1-1, participants will first undergo a screening period of up to 6 weeks, 
followed by a treatment duration of 24 weeks and a follow-up period of 4 weeks. The total 
duration for each participant in the study will be up to 34 weeks.
Figure 1-1
Study design
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Screening and Baseline
Participants will be assessed for ESSDAI (SjS participants) and RCS, and K-BILD (MCTD 
participants) as well as completing safety and other assessments to confirm RNP positivity and 
evaluate eligibility. Eligible participants will return for the Baseline visit on Day 1, to complete 
baseline assessments prior to dosing on Day 1. Some baseline assessments may be carried out 
on the day prior to Day 1.
Treatment
As shown from Figure 1-1, treatment period lasts for 24 weeks, from Day 1 to Week 24 (Day 
169). On Day 1,
Follow-up and End of Study visit (EoS)
After the last day of dosing, participants will enter a 4-week follow-up period without study 
drug treatment. Participants will be asked to return to the site at Week 28 for the End of Study 
visit. Upon competition of this visit, participants will be discharged from the study.
1.2
Study objectives, endpoints and estimands
Primary Objective(s)
●
SjS: To evaluate the efficacy of MHV370
compared to placebo based on change from baseline
in ESSDAI at Week 24
●
SjS: Change from baseline in ESSDAI at Week 24
●
MCTD: To evaluate the efficacy of MHV370
compared to placebo based on change from baseline
in Physician Global Assessment (PhGA) at Week 24
●
MCTD: Change from baseline in PhGA at Week
24
Secondary Objective(s)
●
SjS/MCTD: To evaluate the efficacy of MHV370
compared to placebo based on change from baseline
on patient and physician-reported outcomes over time
up to Week 24
●
SjS: Change from baseline in ESSDAI, ESSPRI,
FACIT-F and PhGA over time up to Week 24
●
MCTD: Change from baseline in FACIT-F, PhGA
and ESSDAI (articular and pulmonary domains only)
over time up to Week 24
●
SjS/MCTD: To evaluate the safety and tolerability
of MHV370
●
SjS/MCTD: 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 values during the
study
●
SjS/MCTD: To assess PK parameters of MHV370
●
SjS/MCTD: PK parameters AUC, Cmax, Tmax
and others as needed at steady state.
●
SjS: To explore the effect of MHV370 on
quantitative salivary flow (unstimulated) over 24
weeks
●
SjS: Changes from baseline to the salivary flow
rate over time up to 24 weeks of treatment
●
SjS: To explore the effect of MHV370 on
quantitative tear production over 24 weeks
●
SjS: Changes from baseline to the Schirmer’s test
over time up to 24 weeks of treatment
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SAP
Study No. CMHV370A12201
●
SjS: To explore the effect of MHV370 on the rate
of STAR responders
●
SjS: STAR response over time up to Week 24
●
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in Forced Vital Capacity
(FVC) and Forced Expiratory Volume (FEV1, FEV2,
FEV3) over time up to Week 24
●
MCTD: Change from baseline in FVC, FEV1,
FEV2 and FEV3 over time up to Week 24
●
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in the diffusing capacity of
lungs for carbon monoxide (DLCO) over time up to
Week 24
●
MCTD: Change from baseline in the diffusing
DLCO over time up to Week 24
●
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in the patient reported
outcome on lung function
●
MCTD: Change from baseline in King’s Brief
Interstitial Lung Disease (K-BILD) over time up to
Week 24
●
MCTD: To evaluate the efficacy of MHV370 based
on change from baseline in Raynaud’s Condition
Score (RCS) over time up to Week 24
●
MCTD: Change from baseline in RCS over time
up to Week 24
Exploratory objective(s)
1.2.1
Primary estimands
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment).
SjS
The primary clinical question of interest is: What is the effect of MHV370 on change in 
ESSDAI total score after 24 weeks of treatment in participants with moderate to severe 
Sjögren’s Syndrome who are receiving a stable dose of a certain concomitant medication 
(systemic 
corticosteroid 
treatment, 
azathioprine, 
methotrexate, 
leflunomide, 
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Study No. CMHV370A12201
hydroxychloroquine (HCQ) and chloroquine (CQ)), had treatment continued for the entire 24 
week duration, had no dose change in certain allowed concomitant medication occurred and 
had no prohibited medication been taken?
The justification for the primary estimand is that wish to estimate the effect of the study drug 
for the full treatment duration when administered without dose changes in certain allowed 
concomitant medication (systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ) and without intake of prohibited medication.
The primary estimand is described by the following attributes:
1. Population: Participants with moderate to severe Sjögren's Syndrome receiving a stable
dose of a certain concomitant medication (systemic corticosteroid treatment, azathioprine,
methotrexate, leflunomide, HCQ and CQ).
2. Endpoint: Change from baseline in ESSDAI total score at Week 24.
3. Treatment of interest: the randomized treatment (investigational treatment MHV370 or
placebo) with or without the allowed concomitant medication.
4. Handling of remaining intercurrent events:
•
Treatment discontinuations for any reason: had participants taken the assigned
treatment for the entire study duration (hypothetical strategy).
•
Unforeseen change in the dose of certain allowed concomitant medication: had no
change in the dose of systemic corticosteroid treatment, azathioprine, methotrexate,
leflunomide, HCQ and CQ occurred (hypothetical strategy).
•
Intake of prohibited medication: had no prohibited medication been taken
(hypothetical strategy).
5. The summary measure: Difference in mean change from baseline in ESSDAI total score at
Week 24 between treatments.
MCTD
The primary clinical question of interest is: What is the effect of MHV370 on change in PhGA 
after 24 weeks of treatment in participants with MCTD who are receiving a stable dose of a 
certain concomitant medication (systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ), had treatment continued for the entire 24 week duration, had no 
dose change in certain allowed concomitant medication occurred and had no prohibited 
medication been taken?
The justification for the primary estimand is that wish to estimate the effect of the study drug 
for the full treatment duration when administered without dose changes in certain allowed 
concomitant medication (systemic corticosteroid treatment, azathioprine, methotrexate, 
leflunomide, HCQ and CQ) and without intake of prohibited medication.
The primary estimand is described by the following attributes:
1. Population: Participants with MCTD receiving a stable dose of certain concomitant
medication (systemic corticosteroid treatment, azathioprine, methotrexate, leflunomide,
HCQ and CQ).
2. Endpoint: Change from baseline in PhGA at Week 24.


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3. Treatment of interest: the randomized treatment (investigational treatment MHV370 or
placebo) with or without the allowed concomitant medication.
4. Handling of remaining intercurrent events:
•
Treatment discontinuations for any reason: had participants taken the assigned
treatment for the entire study duration (hypothetical strategy).
•
Unforeseen change in the dose of certain allowed concomitant medication: had no
change in the dose of systemic corticosteroid treatment, azathioprine, methotrexate,
leflunomide, HCQ and CQ occurred (hypothetical strategy).
•
Intake of prohibited medication: had no prohibited medication been taken
(hypothetical strategy).
5. The summary measure: Difference in mean change from baseline in PhGA at Week 24
between treatments.
2
Statistical methods
2.1
Data analysis general information
Blinded analyses using dummy treatment codes will be produced by 
 statisticians and 
programmers according to this SAP, using SAS version 9.4 or later (SAS Institute, Cary NC). 
Programs and datasets will then be provided to and run by 
Statistician and 
Programmer using the true treatment codes to provide the unblinded TLFs in electronic format 
for discussion.  
Interim analyses
One interim analysis is planned for this study, as described in Section 2.13.
Data collected up to the cut-off date will be included in the analysis. The data will include the 
subjects at various stages of the study. Some subjects may have full data while some may only 
have partial data available.
CCI
CCI


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Descriptive statistics
Descriptive statistics on continuous data will include mean, standard deviation, median, 
minimum and maximum, while categorical data will be summarized as frequencies and 
percentages. 
Analyses will be provided separately for SjS and MCTD, unless otherwise specified.
In shift tables and tables of abnormal values all unscheduled assessments are included.
2.1.1
General definitions 
Study treatment refers to MHV370 200 mg b.i.d or placebo.
The term ‘date of first administration of study drug/treatment’ refers to the date on which the 
study drug/treatment was given for the first time in the CMHV370A12201 study.
The term ‘date of last administration of study drug/treatment’ refers to the date on which the 
study drug/treatment was given for the last time in the CMHV370A12201 study.
The term ‘study day’ refers to the Analysis Relative Day, Relative Start Day or Relative End 
Day, as applicable. Day 1 is defined as the date of first dose of study drug (MHV370 or placebo). 
Study day is defined as the number of days since the date of first dose of study treatment (Day 
1). 
Therefore, for a particular date, study day will be calculated as follows:
•
for dates on or after the first administration of study treatment,
Study day = Assessment date – Date of first dose of study treatment +1
•
for dates prior to the date of first administration of study treatment,
Study day = Assessment date – Date of first dose of study treatment.
The term ‘baseline’ refers to the last assessment performed prior to administration of the first 
dose of study treatment. In case the scheduled baseline assessment value is missing, the 
scheduled screening value if available will be used instead.
The term ‘Treatment period’ refers to the 24 weeks period from Day 1 to Week 24 (Day 169). 
The term ‘treatment-emergent adverse event’ refers to any adverse event (AE) started after the 
first dose of study treatment, or events present prior to the first dose of study treatment but 
increased in severity (based on preferred term (PT)).
The term ‘concomitant medication’ refers to any medication (except study medication) given 
after the first dose of the randomized study treatment.
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2.2
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
The safety analysis set will include all participants that received any study drug.
The PK analysis set will include all participants with at least one available valid (i.e. not 
flagged for exclusion) PK concentration measurement, who received any study drug and with 
no protocol deviations with impact on PK data.
The PD analysis set will include all participants who received study drug and have no protocol 
deviations with relevant impact on PD/efficacy data.
2.2.1
Subgroup of interest
No subgroup analysis is planned.
2.3
Participant disposition, demographics and other baseline 
characteristics
Safety analysis set will be used for the below analyses.
2.3.1
Participant disposition
The participant disposition will be summarized by treatment group.
The number and percent of participants screened, randomized, completed and discontinued 
from the study will be summarized with reasons of discontinuation.
2.3.2
Demographics and other baseline characteristics
Demographics (age, sex, race, ethnicity, weight, height, BMI, disease duration) and other 
baseline data including disease characteristics (ESSDAI and number of participants per 
ESSDAI stratum, ESSPRI, PhGA, FACIT-F, Salivary flow rate and Schirmer’s test for SjS 
participants and ESSDAI [articular and pulmonary domains only], baseline pulmonary 
involvement factor, PhGA, FACIT-F, FVC, FEV1, FEV2, FEV3, DLCO, K-BILD and RCS for 
MCTD participants) will be summarized descriptively by treatment group. 
Relevant medical history and current medical conditions at baseline will be summarized 
combined by SOC, PT and treatment group and listed by treatment group and participant.
Protocol deviations will be summarized by treatment, deviation category and protocol deviation 
term. A participant with deviations within a protocol deviation coded term is only counted once 
towards the total. 
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The safety analysis set will be used for the analyses below.


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2.4.1
Study treatment / compliance
The duration (in days) of exposure to study treatment will be summarized by means of 
descriptive statistics for all participants, and by treatment group. The duration of treatment (in 
days) is defined as the last known date the participant took the study drug – the first day the 
participant took the study drug + 1, regardless of any temporary treatment interruption.
2.4.2
Prior, concomitant and post therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, and by treatment group.
2.5
Analysis supporting primary objective(s)
All participants within the PD analysis set will be included for the primary analyses.
2.5.1
Primary endpoint(s)
SjS
The primary endpoint is the change from baseline in ESSDAI total score at Week 24, defined 
as the Week 24 visit ESSDAI total score minus the baseline ESSDAI total score. A negative 
change indicates an improvement of disease activity. Details for the derivation of ESSDAI total 
score can be found in Appendix 5.4.1.1.
The ESSDAI score for SjS participants will be listed by treatment group, participant and 
visit/time. Descriptive statistics (raw and change from baseline) will be provided by treatment 
group and visit/time. Graphical methods, such as spaghetti plots up to Week 24, may be 
employed by treatment and visit/time. In addition, bar plots will be used to visualize (1) the 
contribution of the individual ESSDAI domains to the estimated change from baseline in the 
total ESSDAI score by treatment group and visit/time and (2) the difference in the contribution 
of the individual ESSDAI domains to the estimated change from baseline in the total ESSDAI 
score between the treatment groups by visit/time.
MCTD
The primary endpoint is the change from baseline in PhGA (ranging from “no disease activity” 
(0) to “maximal disease activity” (100)) after 24 weeks of treatment. It is defined as the Week 
24 visit PhGA value minus the baseline PhGA value. A negative change indicates an 
improvement in disease activity. The PhGA score for MCTD participants, will be listed by 
treatment group, participant and visit/time. Descriptive statistics (raw and change from baseline) 
will be provided by treatment group and visit/time. Graphical methods, such as spaghetti plots 
up to Week 24, may be employed by treatment and visit/time.
2.5.2
Statistical hypothesis, model, and method of analysis 
SjS
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, with the following fixed effects: 


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•
treatment group
•
visit as categorical variable
•
treatment group by visit interaction
and baseline ESSDAI as continuous covariate. An unstructured variance-covariance matrix will 
be fitted to model the dependency between repeated observations. If not possible, other 
appropriate covariance structures will be explored. 
The difference between MHV370 and placebo in change from baseline at each visit will be 
estimated from the model and presented with 95% confidence intervals and one-sided p-value.
The following two criteria will be used to assess treatment efficacy:
•
a statistically significant reduction in ESSDAI at Week 24 in the MHV370 group 
compared to placebo, at the one-sided 10% significance level, and
•
an estimated mean reduction in ESSDAI at Week 24 in the MHV370 group to be at least 
2 points greater than in placebo.
A positive sign of efficacy will be considered if both criteria are met.
2.5.3
Handling of intercurrent events 
SjS and MCTD 
The primary analysis will account for different intercurrent events as explained in the following:
1. Treatment discontinuation: Data from participants who have discontinued treatment early 
will be regarded as missing after the treatment discontinuation. Data from participants 
who have temporarily discontinued treatment (defined as missing more than two 
consecutive doses) will be regarded as missing during the temporary treatment 
discontinuation.
2. Any change in the dose of certain allowed concomitant mediation (systemic corticosteroid 
treatment [bethamethasone, prednisone, prednisolone, triamcinolone, methylprednisolone, 
dexamethasone, hydrocortisone, cortisone, ethamethasoneb], azathioprine, methotrexate, 
leflunomide, HCQ and CQ). Data after change in the dose of allowed concomitant 
medication will be regarded as missing (identified with OTH12 protocol deviation code). 
3. Intake of prohibited medication: Data after intake of prohibited medication will be 
regarded as missing (identified with COMD01 protocol deviation code).
2.5.4
Handling of missing values not related to intercurrent event
SjS
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.


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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.
SjS 
The MMRM utilized for the primary analysis implicitly imputes missing data under a missing 
at random assumption. 
2.5.5
Sensitivity analyses 
2.5.6
Supplementary analyses
2.6
Analysis supporting secondary objectives 
All participants within the PD analysis set will be included for the primary analyses.
2.6.1
Secondary endpoint(s)
SjS
For the analysis of the secondary endpoints ESSPRI, FACIT-F, PhGA, Schirmer’s test and 
salivary flow rate, descriptive summary statistics (raw and change from baseline) will be 
provided by endpoint, treatment group and visit/time. Graphical methods, such as spaghetti 
plots, may be employed by endpoint, treatment group and visit/time. 
For the secondary endpoint STAR, responder status in STAR will be assessed at Weeks 4, 12 
and 24. Descriptive frequency table will be provided by treatment group and visit/time. Missing 
responses will be treated as non-responders. The percentage of responders together with the 95% 
confidence interval (Clopper-Pearson method) will be presented along with p-values from 
Fisher’s exact test for the difference between treatment groups will be presented. Graphical 
methods, such as bar plots, may be employed by treatment group and visit/time.
Details for the derivation of secondary endpoints total scores can be found in Appendix 5.4.1.2, 
Appendix 5.4.1.3 and Appendix 5.4.1.4.
MCTD
For the secondary endpoints FVC, FEV1, FEV2, FEV3, RCS, FACIT-F, DLCO, K-BILD, 
PhGA and ESSDAI (articular and pulmonary domains only) descriptive summary statistics (raw 
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and change from baseline) will be provided by endpoint, treatment group and visit/time. 
Graphical methods, such as arithmetic mean or spaghetti plots, may be employed for each 
endpoint. 
Details for the derivation of secondary endpoints total scores can be found in Appendix 5.4.1.5.
2.6.2
Statistical hypothesis, model, and method of analysis
SjS
The change from baseline in ESSPRI, FACIT-F total score, PhGA, Schirmer’s test and salivary 
flow rate is assumed to be normally distributed. A mixed effect model for repeated 
measurements (MMRM) will be fitted to the changes from baseline in each secondary endpoint, 
for all time points until Week 24, with the following fixed effects: 
•
treatment group
•
visit as categorical variable
•
treatment group by visit interaction
and baseline of corresponding endpoint analyzed as a continuous covariate. An unstructured 
variance-covariance matrix will be fitted to model the dependency between repeated 
observations. If not possible, other appropriate covariance structures will be explored. 
The difference between MHV370 and placebo in change from baseline at each visit will be 
estimated from the model and presented with 95% confidence intervals and one-sided p-value.
2.6.3
Handling of intercurrent events 
Same as in Section 2.5.3.
2.6.4
Handling of missing values not related to intercurrent event
Same as in Section 2.5.4.
2.7
Safety analyses
All safety endpoints will be summarized by treatment group for all participants in the safety set.
2.7.1
Adverse events (AEs)
All information obtained on adverse events will be displayed by treatment group and participant.
The number and percentage of participants with treatment emergent adverse events (TEAEs) 
will be summarized in the following ways:
•
by treatment, primary system organ class
•
by treatment, preferred term
•
by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related TEAEs, death, serious 
TEAEs, other significant TEAEs leading to discontinuation.
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A participant with multiple adverse events within a primary SOC or PT, is only counted once 
towards the total of the primary SOC or PT.
ClinicalTrials.gov and EudraCT
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 5% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same participant, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
2.7.2
Deaths
All information obtained on deaths will be listed by treatment group and participant. 
2.7.3
Laboratory data
Laboratory data with any abnormal values will be listed by treatment group and participant; in 
case of any value outside the normal range in a parameter in a participant, all records of this 
parameter will be presented. Summary statistics will be provided by treatment and visit/time.
Graphical methods for laboratory data, such as spaghetti plots, may be employed over time by 
treatment group. 
2.7.4
Other safety data
2.7.4.1
ECG and cardiac imaging data
ECG 
parameters 
will 
be 
obtained 
from 
12-lead 
ECGs 
for 
each 
participant
during the study. ECG values with any abnormal values will be listed by treatment group and 
participant. Summary statistics will be provided by treatment and visit/time.
2.7.4.2
Vital signs
Vital signs values outside normal range will be listed by treatment group and participant. 
Summary statistics will be provided by treatment and visit/time.
Graphical methods for vital sings data, such as spaghetti plots, may be employed over time by 
treatment group.


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2.8
Pharmacokinetic endpoints  
All participants within the PK analysis set will be included for the PK analyses.
MHV370 PK plasma concentration data will be listed by treatment group, participant and 
visit/sampling time point. Descriptive summary statistics for PK concentration data will be 
provided by treatment group and sampling time point, including the frequency (n, %) of 
concentrations below the lower limit of quantification (LLOQ) and reported as zero. Summary 
statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum and maximum. Concentrations below LLOQ will be treated as zero in 
summary statistics and for PK parameter calculations. 
PK parameters will be listed by treatment group, visit/time and participant. Descriptive 
summary statistics for pharmacokinetic parameters will be provided by treatment separately 
and combined for SjS and MCTD subjects. 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 2-1
PK Parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (ng x h / 
mL)
AUC0-t
The AUC from time zero to specified time t (ng x h / mL)
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)
The PK profile of MHV370 will be characterized but not limited to the PK parameters listed 
above.
Arithmetic mean (SD) and geometric mean (95% CI) plasma concentration data will be plotted 
across time, with separate line types for treatment.
2.9
PD and PK/PD analyses
The relationship between PK and PD endpoints may be explored graphically. Modelling of the 
PK and PD data using a population approach may be performed, as appropriate, and may be 
reported in a separate, standalone modelling and simulation report. 
2.10
Participant-reported outcomes
N/A.
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2.12
Other Exploratory analyses
2.13
Interim analysis
An interim analysis is planned after approximately 50% of SjS participants have completed 
24 weeks of treatment to evaluate the efficacy of MHV370. 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns.
3
Sample size calculation
3.1
Primary endpoint(s)
SjS
A total of approximately 48 participants with SjS will be randomized in a 1:1 ratio to MHV370 
or placebo, with the aim to have at least 40 participants completing Week 24 assessment.
With 40 participants in the analysis of the primary efficacy variable (20 in MHV370 and 20 in 
placebo), the study would have approximately 80% chance of meeting both efficacy criteria, 
when the true difference between MHV370 and placebo is 3.5 points. In case the difference 
between MHV370 and placebo is zero points, the study would have approximately 10 % chance 
of meeting both efficacy criteria.
These calculations are based on assumed standard deviation of 5.1 in change from baseline in 
ESSDAI, based on data from TEARS study with rituximab (Devauchelle-Pensec et al 2014).
MCTD
A total of approximately 12 participants with MCTD will be randomized in a 1:1 ratio to 
MHV370 or placebo. The sample size was chosen for logistical reasons and no sample size 
calculations were made.
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
No imputation will be made to the start date and end date of study treatment.
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5.1.2
AE date imputation
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
As per Novartis standard AE date imputation rules, the following matrix explains the logic 
behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( a )
Before 
Treatment Start
( b )
Before Treatment 
Start
( b )
Before Treatment 
Start
( b )
Before Treatment Start
YYYY = TRTY
( a )
Uncertain
( b )
Before Treatment 
Start
( c )
Uncertain
( c )
After Treatment Start
YYYY > TRTY
( a )
After Treatment 
Start
( b )
After Treatment 
Start
( b )
After Treatment 
Start
( b )
After Treatment Start
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min(informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Rules for imputing the AE start date:
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore:
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).


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4. If the AE start date year value is equal to the treatment start date year value:
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.
b. Else if the AE month is less than the treatment start month, the imputed AE start date 
is set to the mid-month point (15MONYYYY).
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
Rules for imputing the AE end date: 
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed
5.1.3
Concomitant medication date imputation
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
 ( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( a ) 
Before Treatment 
Start
( b )
Before Treatment 
Start
( b )
Before Treatment 
Start
( b )
Before Treatment 
Start
YYYY = TRTY
( a )
Uncertain
( b )
Before Treatment 
Start
( a )
Uncertain
( c )
After Treatment Start
YYYY > TRTY
( a )
After Treatment Start
( b )
After Treatment Start
( b )
After Treatment Start
( b )
After Treatment Start
Rules for imputing the CM start date:
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 


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2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore:
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
Rules for imputing the CM end date:
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY).
3. If CM day/month/year is missing then use the treatment end date + 1 day as the imputed 
CM end date. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
The above imputation rules apply to both prior therapies and post therapies. 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. AEs will be categorized as mild, moderate, or severe. 
5.3
Laboratory parameters derivations
Central laboratory assessments:
The central laboratory will flag on the central laboratory report all values falling outside of the 
central laboratory normal ranges 


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Vital and ECG signs:
Clinically notable values for vital signs are defined as:
•
heart rate of < 50 and > 100 bpm
•
systolic blood pressure of < 90 and ≥ 140 mmHg
•
diastolic blood pressure of < 60 and ≥ 90 mmHg 
•
history of long QT syndrome or resting QTcF (Fridericia) prolonged (>450 ms for males 
or >460 ms for females)
•
QT increase from baseline ≥ 60msec
5.4
Statistical models
The mean responses at treatment group will be obtained through covariate-adjusted treatment 
effects by using a MMRM as specified in Section 2.5.2 and Section 2.6.2. The model will be 
fitted using the SAS procedure “PROC MIXED”. For SjS MMRM related model, the 
unstructured covariance matrix will be used  (TYPE = UN), thus allowing adjustment for 
correlations between time points within participants. In order to get the variance covariance 
matrix of treatment effects to be full rank matrix, no intercept option will be used (NOINT 
option in MODEL statement). 
Adjusted means and the corresponding variance covariance matrix will be estimated. The 
estimated treatment differences for treatment comparisons will be tabulated along with the 
associated 95% confidence intervals (two-sided ALPHA = 0.05) and one-sided p-value. No 
adjustment for multiplicity will be made. For calculation of denominator degrees of freedom 
Kenwood-Rogers method would be used (DDFM=KR).
In case the MMRM model does not converge the following sequential steps will be used:
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2.
2. change type=un to type=cs. If still no convergence, perform step 3. This is for SjS analysis
3. remove covariates in the following order until convergence: stratification factor, treatment 
group by visit interaction.
5.4.1
Analysis supporting primary objective(s) 
5.4.1.1
ESSDAI
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 by the 
site in the eCRF. At screening, the ESSDAI sub-score from 8 pre-selected domains listed in the 
inclusion criterion #8 will be calculated to determine participant's eligibility.


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Participants with MCTD will complete the articular (from 0 “no activity” to 3 “high activity”) 
and pulmonary (from 0 “no activity to 3 “high activity”) domains of the ESSDAI only. 
These domains will be assessed separately over the treatment period.
5.4.1.2
ESSPRI
The total score of ESSPRI is defined as the mean of the three domains (pain, fatigue and 
dryness). If at least one of the domains is missing, then the total score of ESSPRI will not be 
derived for the corresponding participant.
5.4.1.3
Sjögren Tool for Assessing Response (STAR)
STAR is a composite responder index, including in a single tool all main disease feature. In this 
study lacrimal gland function will be assessed using the Schirmer’s test, while ocular staining 
score will not be used to calculate STAR response. Further, the biological domain will be 
assessed using IgG, while rheumatoid factor (RF) will not be used to assess STAR response.
*For ocular tests, Schirmer’s test should be performed without anaesthesia and is considered 
abnormal if <5 mm. The mean of both eyes was used for calculation.
5.4.1.4
FACIT-F
The total score of FACIT-F will be used to assess the impact on fatigue. The FACIT-F contains 
13 questions, where each has a scale from 0 to 4, where 0 is for “Not at all”, 1 is for “A little 
bit”, 2 is for “Somewhat”, 3 is for “Quite a bit” and 4 is for “Very much”.
The total score is derived as the sum of all item scores. Theoretical values of the total score 
range from 0 to 52. A high (low) total score corresponds to a high (low) quality of life.


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Table 5-1
FACIT-F questions
Question no
Question
1
I feel fatigued
2
I feel weak all over
3
I feel listless (“washed out”)
4
I feel tired
5
I have trouble starting things because I am tired
6
I have trouble finishing things because I am tired
7
I have energy
8
I am able to do my usual activities
9
I need to sleep during the day
10
I am too tired to eat
11
I need help to do my usual activities
12
I am frustrated by being too tried to do the things I want to do
13
I have to limit my social activity because I am tired
Each item score, except for questions 7 and 8, is calculated as 4 minus the corresponding item 
response, since questions have negative directions, and it is necessary to reverse the responses 
for all questions except 7 and 8. The item score for questions 7 and 8 is calculated as 0 plus the 
corresponding item response. 
When there are missing item scores, the total score will be computed by summing the non-
missing item scores, multiplying by 13 (the total number of items) and dividing by the number 
of non-missing items (i.e. normalizing the result). The latter rule is applied only when at least 
half of the items (seven or more) are non-missing.
5.4.1.5
FVC and FEV
Forced expiratory volume (FEV) measures how much air a person can exhale during a forced 
breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), 
and/or third seconds (FEV3) of the forced breath. Forced vital capacity (FVC) is the total 
amount of air exhaled during the FEV test. Forced expiratory volume and forced vital capacity 
are lung function tests that are measured during spirometry and are important measures of lung 
function.
5.4.1.6
K-BILD
The K-BILD is comprised of 15 items in three distinct health status domains, including:
•
breathlessness and activities (items 1,4,11 and 13)
•
chest symptoms (items 2,7 and 9) 
•
psychological (items 3,5,6,8,10,12 and 14) domains 
A final item (15) is used to assess the impact of the respondent’s lung condition on their 
financial state. 
The 15 items could be combined into a total score (12). The domain and total scores each range 
from 0-100 and higher scores indicate a better health status. Response options for all 15 items 
are on a 7-point Likert scale, ranging from 1 to 7. For each of the items, the response options 


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vary, including: item 1 (1=’Every time’, 7=’Never’); items 2-4 and 6-14 (1=’All of the time’, 
7=’None of the time’); item 5 (1=’None of the time’, 7=’all of the time’) and item 15 (1=’A 
significant amount’, 7=’Not at all’). 
To score the K-BILD, the Likert response scale weightings for individual items are combined, 
to ensure they detect progressive change in health status. Table 5-2 shows the recoded scale 
weightings associated with each raw, item-level score value. Raw domain and total scores are 
then calculated by summing the recoded scale values provided in that table. 
Table 5-2
K-BILD Response Option Weightings
 
1. Domain scores should be generated first. 
•
If there is more than 50% of missing items per domain, then the domain score is set to 
missing. 
•
In case of missing data in each domain, missing item scale scores will be imputed 
based on the average of the non-missing item scores within that domain, rounded to 
the nearest integer (up or down as appropriated).
2. Then re-score all individual items by transforming each 1-7 score to the new scoring 
system as per scoring in Table 5-2.
3. Calculate the sum of all the transformed scores in the domain and then total score. 
4. The raw domain and total scores will be transformed to a range of 0-100 by using logit 
values as provided by the transformation tables for each domain below.
5. If item 15 is missing, it will be replaced by the average of all available items 1-14. If any 
of the domain scores are missing, the total score is set to missing. 


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Breathlessness and Activities
Scale 0-21 Breathlessness and Activities domain score
Scale 0-100 score
0
0
1
10
2
18
3
23
4
27
5
30
6
33
7
36
8
38
9
40
10
42
11
44
12
46
13
48
14
50
15
53
16
55
17
58
18
63
19
69
20
80
21
100
Chest symptoms
Scale 0-8 Chest symptoms domain score
Scale 0-100 score
0
0
1
17
2
32
3
44
4
54
5
64
6
73
7
85
8
100
Psychological
Scale 0-34 Psychological domain  score
Scale 0-100 score
0
0
1
11


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Scale 0-34 Psychological domain  score
Scale 0-100 score
2
17
3
22
4
25
5
28
6
30
7
32
8
34
9
36
10
37
11
38
12
40
13
41
14
42
15
44
16
45
17
46
18
48
19
49
20
51
21
52
22
54
23
55
24
57
25
59
26
61
27
63
28
65
29
68
30
72
31
76
32
81
33
89
34
100
Total Score
Scale 0-65 Total score
Scale 0-100 score
0
0 
1
9
2
15
3
19


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Scale 0-65 Total score
Scale 0-100 score
4
23
5
25
6
27
7
29
8
31
9
32
10
33
11
34
12
36
13
37
14
38
15
38
16
39
17
40
18
41
19
42
20
42
21
43
22
44
23
45
24
45
25
46
26
47
27
47
28
48
29
48
30
49
31
50
32
50
33
51
34
52
35
52
36
53
37
53
38
54
39
55
40
55
41
56
42
57


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Scale 0-65 Total score
Scale 0-100 score
43
57
44
58
45
59
46
59
47
60
48
61
49
62
50
63
51
63
52
64
53
65
54
66
55
67
56
69
57
70
58
71
59
73
60
75
61
78
62
81
63
85
64
91
65
100
5.4.2
Analysis supporting secondary objective(s)
N/A.
5.5
Considerations due to COVID-19
Due to the COVID-19 pandemic, it might not be possible to perform some procedures as per 
protocol. All deviations due to COVID-19 may be listed separately to other deviations and may 
be also tabulated. 
5.6
Rule of exclusion criteria of analysis sets
Table 5-3
Criteria leading to exclusion
Analysis Set
Criteria that cause 
participants to be excluded


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6
Reference
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al (2014) Treatment of primary 
Sjögren syndrome with rituximab: a randomized trial. Ann. Intern. Med. p. 233-42.