Clinical trial NCT05048342
Conditions: Chronic Spontaneous Urticaria
Keywords: Bruton Tyrosine Kinase (BTK) inhibitor Chronic Spontaneous Urticaria (CSU) Urticaria Activity Score (UAS) Weekly Urticaria Activity Score (UAS7) Hives Severity Score (HSS) Weekly Hives Severity Score (HSS7) Itch Severity Score (ISS) Weekly Itch Severity Score (ISS7) Angioedema Activity Score (AAS) Weekly Angioedema Activity Score (AAS7) Dermatology Life Quality Index (DLQI)
Sponsor: Novartis Pharmaceuticals
Start date: 2022-01-15; Completion date: 2023-12-09
Enrollment: 71 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the safety, tolerability and efficacy of remibrutinib (LOU064) in adult Japanese patients chronic spontaneous urticaria (CSU), who remain symptomatic despite treatment by H1-antihistamine (H1-AH) at locally label approved doses, for a duration of 52 weeks of treatment with remibrutinib and a post-treatment follow-up period of up to 4 weeks.

Detailed description:
The study consisted of three periods, the total study duration is up to 60 weeks: screening period of up to 4 weeks, open-label treatment period of 52 weeks (remibrutinib 25 mg b.i.d.), and a treatment free follow-up period of 4 weeks.

It was planned to include approximately 70 patients in the study; 71 patients were enrolled and included in the analyses.

Arms: arm 1: Patients were treated with remibrutinib 25 mg bis in die/twice a day (b.i.d.). LOU064 open-label treatment taken orally for 52 weeks.
Interventions: intervention 1: LOU064
Intervention descriptions: intervention 1: Each patient took one film-coated tablet in the morning and one film-coated tablet in the evening (except the morning dose at the PK sampling visits, which were to be taken on site during the visit).

Protocol documents:
Prot_000.pdf: 


Novartis
Confidential
Page 2 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................22
2
Objectives, endpoints and estimands.................................................................................22
2.1
Primary estimands .................................................................................................24
2.2
Secondary estimands .............................................................................................25
3
Study design ......................................................................................................................27
4
Rationale............................................................................................................................28
4.1
Rationale for study design .....................................................................................28
4.1.1
Rationale for choice of background therapy.........................................29
4.2
Rationale for dose/regimen and duration of treatment ..........................................29
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................32
4.4
Purpose and timing of interim analyses/design adaptations..................................32
4.5
Risks and benefits..................................................................................................33
4.6
Rationale for Public Health Emergency mitigation procedures ............................37
5
Study Population ...............................................................................................................38
5.1
Inclusion criteria ....................................................................................................38
5.2
Exclusion criteria...................................................................................................38
6
Treatment...........................................................................................................................41
6.1
Study treatment......................................................................................................41
6.1.1
Investigational and control drugs..........................................................41
6.1.2
Additional study treatments ..................................................................41
6.1.3
Treatment arms/group ...........................................................................41
6.1.4
Treatment duration................................................................................41
6.2
Other treatments.....................................................................................................42
6.2.1
Concomitant therapy.............................................................................42
6.2.2
Prohibited medication ...........................................................................42
6.2.3
Permitted concomitant therapy requiring caution and/or action...........44
6.2.4
Rescue medication ................................................................................45
 


Novartis
Confidential
Page 3 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
6.3
Preparation and dispensation.................................................................................45
6.3.1
Handling of study treatment and other treatment..................................46
6.3.2
Instruction for prescribing and taking study treatment .........................47
6.4
Participant numbering, treatment assignment, randomization ..............................47
6.4.1
Participant numbering...........................................................................47
6.4.2
Treatment assignment, randomization ..................................................47
6.5
Treatment blinding.................................................................................................47
6.6
Dose escalation and dose modification..................................................................48
6.6.1
Follow-up for toxicities.........................................................................48
6.7
Additional treatment guidance...............................................................................48
6.7.1
Treatment compliance...........................................................................48
6.7.2
Emergency breaking of assigned treatment code..................................48
6.7.3
Treatment of overdose...........................................................................48
7
Informed consent procedures ............................................................................................49
8
Visit schedule and assessments .........................................................................................51
8.1
Screening ...............................................................................................................57
8.1.1
Information to be collected on screening failures.................................57
8.2
Participant demographics/other baseline characteristics .......................................57
8.3
Efficacy..................................................................................................................58
8.3.1
eDiary assessments................................................................................58
8.3.2
Other Patient Reported Outcomes (PRO) assessments.........................61
8.3.3
Appropriateness of efficacy assessments..............................................63
8.3.4
Other assessments: evidence of urticaria ..............................................63
8.4
Safety.....................................................................................................................64
8.4.1
Laboratory evaluations..........................................................................64
8.4.2
Electrocardiogram (ECG) .....................................................................65
8.4.3
Pregnancy and assessments of fertility .................................................66
8.4.4
Appropriateness of safety measurements..............................................67
8.5
Additional assessments..........................................................................................67
8.5.1
Clinical Outcome Assessments (COAs) ...............................................67
9
Discontinuation and completion........................................................................................70
9.1
Discontinuation from study treatment and from study..........................................70
9.1.1
Discontinuation from study treatment...................................................70
 


Novartis
Confidential
Page 4 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
9.1.2
Discontinuation from study...................................................................72
9.1.3
Lost to follow-up...................................................................................72
9.2
Withdrawal of informed consent/Opposition to use data/biological samples .......72
9.3
Study completion and post-study treatment ..........................................................73
9.4
Early study termination by the sponsor .................................................................73
10 Safety monitoring, reporting and committees ...................................................................73
10.1
Definition of adverse events and reporting requirements......................................73
10.1.1
Adverse events ......................................................................................73
10.1.2
Serious adverse events ..........................................................................75
10.1.3
SAE reporting........................................................................................76
10.1.4
Pregnancy reporting ..............................................................................77
10.1.5
Reporting of study treatment errors including misuse/abuse................77
10.2
Additional Safety Monitoring................................................................................78
10.2.1
Liver safety monitoring.........................................................................78
10.2.2
Renal safety monitoring........................................................................79
10.3
Committees............................................................................................................79
10.3.1
Data Monitoring Committee .................................................................79
10.3.2
Steering Committee...............................................................................79
11 Data Collection and Database management......................................................................80
11.1
Data collection.......................................................................................................80
11.2
Database management and quality control............................................................80
11.3
Site monitoring ......................................................................................................80
12 Data analysis and statistical methods ................................................................................81
12.1
Analysis sets ..........................................................................................................81
12.2
Participant demographics and other baseline characteristics.................................82
12.3
Treatments .............................................................................................................82
12.4
Analysis supporting primary objectives ................................................................82
12.4.1
Definition of primary endpoints............................................................82
12.4.2
Statistical model, hypothesis, and method of analysis..........................83
12.4.3
Handling of intercurrent events of primary estimand ...........................84
12.4.4
Handling of missing values not related to intercurrent event ...............84
12.4.5
Sensitivity analyses ...............................................................................84
12.4.6
Supplementary analysis.........................................................................85
12.5
Analysis supporting secondary objectives.............................................................85
12.5.1
Efficacy and/or Pharmacodynamic endpoints.......................................85
12.5.2
Safety endpoints....................................................................................87
 


Novartis
Confidential
Page 5 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
12.7
Interim analyses.....................................................................................................90
12.8
Sample size calculation..........................................................................................90
12.8.1
Primary endpoint...................................................................................91
12.8.2
Secondary endpoints .............................................................................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...............................................................91
13.4
Quality Control and Quality Assurance.................................................................92
13.5
Participant Engagement.........................................................................................92
14 Protocol adherence ............................................................................................................92
14.1
Protocol amendments.............................................................................................92
15 References .........................................................................................................................94
16 Appendices ........................................................................................................................98
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................98
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ..........................................................................................................99
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....102
List of tables
Table 2-1
Objectives and related endpoints ..........................................................22
Table 6-1
Investigational and control drug............................................................41
Table 6-2
Prohibited Medication...........................................................................42
Table 6-3
Permitted concomitant therapy requiring caution and/or action...........45
Table 8-1
Assessment Schedule ............................................................................52
Table 8-2
UPDD....................................................................................................59
Table 8-3
Hives Severity Score.............................................................................59
Table 8-4
Itch Severity Score ................................................................................60
 


Novartis
Confidential
Page 6 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Table 8-7
DLQI score bands and impact on patient's life .....................................61
Table 8-8
Physical assessments.............................................................................64
Table 8-9
Laboratory assessments.........................................................................65
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................78
Table 16-1
Liver event and laboratory trigger definitions ......................................99
Table 16-2
Follow up requirements for liver laboratory triggers: ALT, AST 
and TBL ................................................................................................99
Table 16-3
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia .............................................................................101
Table 16-4
Specific renal alert criteria and actions...............................................102
Table 16-5
Renal event follow-up.........................................................................103
List of figures
Figure 3-1
Study Design .........................................................................................28
Figure 4-1
UAS7 score change from baseline over time estimated with a 
mixed-effect repeated measurement analysis, by treatment group 
(FAS).....................................................................................................31
Figure 4-2
UAS7 = 0 and UAS7 <=6 response rate over time by treatment 
group (as observed) (FAS)....................................................................31
 


Novartis
Confidential
Page 7 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
List of abbreviations
AAS
Angioedema Activity Score
AD
Atopic Dermatitis
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
b.i.d.
bis in die/twice a day
BCR
B cell receptor
BCRP
Breast Cancer Resistance Protein
BP
Blood Pressure
BTK
Bruton's Tyrosine Kinase
BTKi
Bruton's Tyrosine Kinase inhibitor
BUN
Blood Urea Nitrogen
CINDU
Chronic Inducible Urticaria
CIU
Chronic Idiopathic Urticaria
CK
Creatine Kinase
CMO&PS
Chief Medical Office and Patient Safety
COA
Clinical Outcome Assessment
COVID-19
Coronavirus Disease 2019
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical Study Report
CSU
Chronic Spontaneous Urticaria
CU
Chronic Urticaria
CV
Coefficient of Variation
CYP
Cytochrome P
DBP
Diastolic Blood Pressure
DIN
Drug Inducted Nephrotoxicity
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
EDC
Electronic Data Capture
eDiary
Electronic Diary
eGFR
Estimated Glomerular Filtration Rate
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
FAS
Full Analysis Set
FcγR
Fc gamma receptor
FcεR
Fc epsilon Receptor
 


Novartis
Confidential
Page 8 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
FSH
Follicle stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
h
Hour
HBc
Hepatitis B core
HBcAb
Antibodies against hepatitis B core antigen (anti-HBcAg antibodies)
HBsAb
Antibodies against hepatitis B surface antigen (anti-HBsAg antibodies)
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus
HCP
Healthcare Professional
HCV
Hepatitis C Virus
HCVAb
Hepatitis C Virus Antibody
HDL
High-Density Lipoprotein
hERG
Human ether a-go-go related gene
HIV
Human immunodeficiency virus
HRQoL
Health-Related Quality of Life
HSS
Hives Severity Score
HSS7
Weekly Hives Severity Score
i.v.
Intravenous
IA
Interim Analysis
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
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISS
Itch Severity Score
ISS7
Weekly Itch Severity Score
KDIGO
Kidney Disease Improving Global Outcome
LC-
MS/MS
Liquid Chromatography–Mass Spectrometry
LDH
Lactate Dehydrogenase
LDL
Low-Density Lipoprotein
LFT
Liver Function Test
LLOQ
Lower Limit of Quantification
LTRA
Leukotriene Receptor Antagonists
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
 


Novartis
Confidential
Page 9 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities
mg
Milligram(s)
mg/d
Milligram per day
ml
Milliliter(s)
ms
Millisecond
MMRM
Mixed effect Model for Repeated Measurements
NOAC
Novel Oral Anti-Coagulant
NSAID
Nonsteroidal Anti-Inflammatory Drug
PC
Personal Computer
PCR
Protein-creatinine ratio
PD
Pharmacodynamic(s)
PRO
Patient Reported Outcomes
PT
Preferred Term
PT
Prothrombin Time
q.d.
Once a Day
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RDO
Retrieved Drop Out
RNA
Ribonucleic Acid
s.c.
Subcutaneous
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SiS
Sjogren's Syndrome
SMQ
Standardized MedDRA Query
SOC
System Organ Classes
SUSAR
Suspected Unexpected Serious Adverse Reaction
UAS
Urticaria Activity Score
UAS7
Weekly Urticaria Activity Score
ULN
Upper Limit of Normal
UPDD
Urticaria Patient Daily Diary
UV
Ultraviolet
WHO
World Health Organization
WoCBP
Women of Child-Bearing Potential
 


Novartis
Confidential
Page 10 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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
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 or at a 
later point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants.
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate
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.
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
 


Novartis
Confidential
Page 11 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Off-site
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant's home.
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.
Premature participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued, and no further assessments are 
planned
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
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
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or may 
not also be the point/time of study discontinuation 
Tele-visit
Procedures or communications conducted using technology such as telephone or 
video-conference, whereby the participant is not at the investigative site where 
the investigator will conduct the trial.
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
 


Novartis
Confidential
Page 12 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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.
 


Novartis
Confidential
Page 13 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Amendment 1 (06-JUL-2022)
Amendment rationale
This is the first amendment to be released for the CLOU064A1301 BISCUIT study. The main 
purpose of the amendment is to ensure the consistency across the program to reflect the 
recommendations from the US FDA and the feedback received from Health Authorities and 
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) for both pivotal 
Phase 3 trials (CLOU064A2301 and CLOU064A2302, referred to as A2301 and A2302,
respectively) to support remibrutinib for the treatment of CSU in Japan.
The main amendment in the pivotal Phase 3 studies is to implement recommendations from the 
US FDA regarding statistical analysis for covering intercurrent event handling for COVID-19 
related reasons for treatment discontinuation and the use of the same covariates in both primary 
and secondary endpoints. So, in this study, the intercurrent event in statistical analysis was 
updated.
Furthermore, clarifications and corrections were made, and Section 4.5 Risks and benefits has
been amended to include updates from the LOU064 Investigator Brochure Edition 9 (03-May-
2022) as indicated below.
At the time of this amendment (V01) release, enrollment is ongoing with 40 patients screened 
and 28 patients treated.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Title : Study name “BISCUIT” for this study was added.

Section 1.2: Deleted “planned” from the study CLOU064A2301


Section 2.1: Methods for handling of intercurrent events have been updated considering 
US FDA feedback for A2301 and A2302 studies.

Section 2.2: Methods for handling of intercurrent events have been updated considering 
US FDA feedback for A2301 and A2302.

Section 4.5: Risks and benefits has been amended to include updates from the LOU064 
Investigator Brochure Edition 9. No change to risk-benefit assessment of the study.

Section 5.2: Exclusion criteria 5 updated to clarify the disease of angioedema, exclusion 
criteria 13 and 18 updated to reflect the feedback received from Health Authorities, and 
exclusion criteria 19 updated to clarify maximum dose of clopidogrel.

Section 6.2.2: Clarification that immunomodulating biologics are considered prohibited 
medication under immunosuppressive medications; prohibition period for live attenuated 
vaccines updated to reflect feedback from Health Authorities; maximum dose for long-
term clopidogrel use added. Clarification that live attenuated vaccines are prohibited 6 
weeks prior to randomization until at least 4 weeks after last dose of study treatment as 
 


Novartis
Confidential
Page 14 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
consistent with exclusion criteria and Investigator Brochure. Remibrutinib updated with 
study treatment for clarification.

Section 6.6: Clarification that interruptions are permitted related to study treatment.

Section 6.7.3: New section added regarding treatment of overdose, to align with the 
updated Novartis protocol template merged with the TransCelerate Common Protocol 
Template developed with input from industry, regulators, sites, CROs and IRBs

Section 8: Order of assessments clarified.

Table 8-1:Dispense participants' eDiary and Subject's eDiary review removed for Week 
56/Safety FU/Study completion visit, considering eDiary completion ends at Week 
52/Study discontinuation; Weight added at Baseline and Week 24 to allow for eGFR 
calculation; Rescue medication dispensation and usage removed from Week 56/Safety 
FU/Study completion visit, considering eDiary completion ends at Week 52/Study 
discontinuation; Footnotes 1, 3, and 7 updated for additional clarity; Footnote 4 updated to 
reflect feedback from Health Authorities; Footnotes 18, 19 and 20 added for clarity.

Section 8.3.1: Duration of eDiary completion clarified.

Table 8-8: Body temperature added to Physical Examination assessments to reflect 
feedback from Health Authorities in A2301 and A2302.

Table 8-9: Hepatitis screening and Hepatitis re-activation monitoring amended as aligned 
with central laboratory testing procedures.


Section 9.1.1: Clarified that participant can request discontinuation from study treatment 
in writing or verbally; definition of severe/serious infections removed to reflect feedback 
from Health Authorities in A2301 and A2302.

Section 9.1.2: Clarified that participant can request discontinuation from study in writing 
or verbally to reflect feedback from Health Authorities in A2301 and A2302.

Section 9.2: Clarified that participant can request withdrawal of consent in writing or
verbally to reflect feedback from Health Authorities in A2301 and A2302.

Section 10.1.1: “Dose Reduced/increased” removed as dose modifications not permitted

Section 10.1.3: Reporting timelines and follow-up for SAEs clarified to reflect feedback 
from Health Authorities.

Section 10.3.2: Updated with the correct description.

Section 12.4.3: Handling of intercurrent events amended, considering US FDA feedback 
for A2301 and A2302 studies.

Section 12.4.5: AESI which becomes the object of sensitivity analysis clarified

Section 12.5.1: Analysis method for absolute change from baseline in UAS7, ISS7 and 
HSS7 at Week 12 amended, considering US FDA feedback for A2301 and A2302 studies.


Section 15: Additional references added, and one reference removed to align with updated 
Investigator Brochure and Section 4.5.

Section 16.1: QTcF increase ≥60 ms from baseline added to the definition of a notable 
QTc value for ECGs for clarification.
 


Novartis
Confidential
Page 15 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Additional minor changes (e.g., correction of typographical errors) have been incorporated
directly in the protocol with track changes, even if not listed specifically in this section.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
 


Novartis
Confidential
Page 16 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Protocol summary
Protocol number
CLOU064A1301
Full Title
A multicenter, open-label Phase 3 study of remibrutinib (LOU064) to investigate the 
safety, tolerability and efficacy for 52 weeks in adult Japanese chronic spontaneous 
urticaria patients inadequately controlled by H1-antihistamines (BISCUIT)
Brief title
A Phase 3 study of safety and efficacy of remibrutinib in the treatment of chronic 
spontaneous urticaria in Japanese adults inadequately controlled by H1- antihistamines
Sponsor and 
Clinical Phase
Novartis
Phase 3
Investigation type
Drug
Study type
Interventional
Purpose
The purpose of this study is to evaluate the safety and efficacy of remibrutinib (LOU064) 
25 mg b.i.d in adult Japanese chronic spontaneous urticaria 
(CSU) participants inadequately controlled by second generation H1-antihistamines.
Primary Objective 
The primary objective of this study is to evaluate the safety of remibrutinib (25 mg 
b.i.d.) during the 52-week treatment period.
The primary clinical question of interest regarding safety as the primary endpoint is: 
What is the effect of remibrutinib treatment on the incidence of treatment-emergent 
adverse events (i.e., on-treatment 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) in adult participants with CSU who are inadequately controlled by H1-antihistamine 
and receiving a stable locally label approved dose of a second-generation H1-
antihistamine, regardless of treatment discontinuation for any reason, non-compliance 
(interruption) to treatment, switch of background medication or intake of a different 
second-generation H1-antihistamine as rescue medication/concomitant medications?
Secondary 
Objectives
The secondary objective is to evaluate the efficacy of remibrutinib 25 mg b.i.d. by 
evaluation of:

Weekly Urticaria Activity Score (UAS7), Weekly Itch Severity Score (ISS7) and 
Weekly Hive Severity Score (HSS7) change from baseline at Week 12

Proportion of participants who achieve UAS7 ≤ 6, Urticaria Activity Score (UAS) 
= 0 and Dermatology Life Quality Index (DLQI) = 0-1 at Week 12

Proportion of participants who achieve UAS ≤ 6 at Week 2

Proportion of participants who maintain disease activity control assessed as 
cumulative number of weeks with an UAS ≤ 6 response

Angioedema occurrence-free weeks assessed by the cumulative number of 
weeks with a weekly angioedema activity score (AAS7) = 0 response
The secondary clinical question of interest regarding efficacy as secondary endpoint, 
change from baseline in UAS7 score at Week 12 is: What is the effect of remibrutinib 
treatment on the change from baseline in UAS7 score after 12 weeks of treatment in 
adult participants with CSU who are inadequately controlled by H1-antihistamine and 
receiving a stable, locally label approved, dose of a second generation H1-antihistamine, 
regardless of treatment discontinuation for any reason or intake of a different second 
generation H1-antihistamine as rescue medication and considering strongly confounding 
prohibited medication use as an unfavorable outcome?
Study design
This is a Phase 3 multi-center, open-label, single arm study investigating the safety, 
tolerability and efficacy of remibrutinib (25 mg b.i.d.) in participants with CSU 
inadequately controlled by second generation H1-antihistamines. The study consists of 
three periods, the total study duration is up to 60 weeks: screening period of up to 4 
weeks, open-label treatment period of 52 weeks, and a treatment free follow-up period 
of 4 weeks.
Rationale
The Phase 2b clinical trial CLOU064A2201 demonstrated clinical efficacy of remibrutinib 
25 mg b.i.d. in the treatment of CSU patients with a fast onset of action and a favorable 
safety profile. For registration purposes, there is a relatively low number of Japanese 
CSU participants treated with the intended dose or higher during one year in studies 
CLOU064A2201E1 and CLOU064A2301. Therefore, the purpose of this study is to 
 


Novartis
Confidential
Page 17 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
evaluate the safety and efficacy of remibrutinib (LOU064) in adult Japanese 
CSU participants inadequately controlled by second generation H1-antihistamines.
Study population
The study population will consist of approximately 70 Japanese male and female 
participants aged ≥ 18 years with CSU inadequately controlled by second generation 
H1-antihistamines.
Inclusion criteria

Signed informed consent must be obtained prior to participation in the study.

Male and female participants ≥18 years of age at the time of screening.

CSU duration for ≥ 6 months prior to screening (defined as the onset of CSU 
determined by the investigator based on all available supporting 
documentation).

Diagnosis of CSU inadequately controlled by second generation H1-
antihistamines at baseline defined as: 
o
The presence of itch and hives for ≥ 6 consecutive weeks prior to 
screening despite the use of second generation H1-antihistamines 
during this time period
o
UAS7 score (range 0-42) ≥ 16, ISS7 score (range 0-21) ≥ 6 and HSS7 
score (range 0-21) ≥ 6 during the 7 days prior to baseline (Day 1)

Documentation of hives within three months before baseline (either at 
screening and/or at baseline; or documented in the participants' medical 
history).

Willing and able to complete an Urticaria Patient Daily Diary (UPDD) for the 
duration of the study and adhere to the study protocol

Participants must not have had more than one missing UPDD entry (either 
morning or evening) in the 7 days prior to baseline (Day 1).
Key Exclusion 
criteria

Participants having a clearly defined predominant or sole trigger of their chronic 
urticaria (chronic inducible urticaria) including urticaria factitia (symptomatic 
dermographism), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, 
cholinergic-, or contact-urticaria

Other diseases with symptoms of urticaria or angioedema, including but not 
limited to urticaria vasculitis, urticaria pigmentosa, erythema multiforme, 
mastocytosis, hereditary angioedema, or drug-induced urticaria

Any other skin disease associated with chronic itching that might influence in 
the investigator’s opinion the study evaluations and results, e.g., atopic 
dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus or 
psoriasis

Evidence of clinically significant cardiovascular (such as but not limited to 
myocardial infarction, unstable ischemic heart disease, New York heart 
association (NYHA) Class III/IV left ventricular failure, arrhythmia and 
uncontrolled hypertension within 12 months prior to Visit 1), neurological, 
psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, hematological 
disorders, gastrointestinal disease or immunodeficiency that, in the 
investigator's opinion, would compromise the safety of the participant, interfere 
with the interpretation of the study results or otherwise preclude participation or 
protocol adherence of the participant

Significant bleeding risk or coagulation disorders

History of gastrointestinal bleeding, e.g., in association with use of nonsteroidal 
anti-inflammatory drugs (NSAID), that was clinically relevant (e.g., for which
intervention was indicated or requiring hospitalization or blood transfusion)

Requirement for anti-platelet medication, except for acetylsalicylic acid up to 
100 mg/d or clopidogrel up to 75 mg/d. The use of dual anti-platelet therapy 
(e.g., acetylsalicylic acid + clopidogrel) is prohibited.

Requirement for anticoagulant medication (for example, warfarin or Novel Oral 
Anti-Coagulants (NOAC))
 




Novartis
Confidential
Page 19 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
The number and the proportion (%) of participants with the treatment emergent adverse 
events will be summarized in the following ways:

by primary system organ class and preferred term.

by primary system organ class, preferred term and maximum severity.

by Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, 
death, serious adverse events, other significant adverse events leading to 
discontinuation.
In addition, a separate summary for deaths including on- treatment and post-
treatment deaths will be provided.
The number and the proportion (%) of participants with adverse events of special 
interest for remibrutinib (related to identified and potential risks) will be summarized.
One of the secondary (efficacy) endpoints (variables) is the absolute change from 
baseline in UAS7 score at Week 12, which is the UAS7 score at Week 12 minus the 
UAS7 score at baseline. The UAS7 is the sum of the HSS7 score and the ISS7 score, 
and ranges from 0-42. Weekly scores (HSS7 and ISS7 scores) will be derived by adding 
up the average daily scores of the 7 days preceding the visit.
The secondary (efficacy) variables during the study, including absolute change from 
baseline in UAS7 score at Week 12, will be summarized (by visit, if applicable).
Key words
BTK inhibitor; Chronic spontaneous urticaria; Urticaria activity score; Hives severity 
score; Itch severity score
 


Novartis
Confidential
Page 20 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
1
Introduction
1.1
Background
Urticaria is classified into inducible and spontaneous urticaria in Japan. Spontaneous urticaria 
presents with hives occurring spontaneously without a direct cause. The Japanese 
Dermatological Association Guideline for the Treatment of Urticaria 2018 defines chronic 
spontaneous urticaria (CSU) as "urticaria persistent for ≥6 weeks after onset" (Hide et al 2018). 
The Western EAACI/GA2LEN/EDF/WAO Guideline 2018 defines CSU, also known as chronic 
idiopathic urticaria (CIU) as the spontaneous occurrence of itchy wheals (hives), angioedema 
or both, lasting for at least 6 weeks (Zuberbier et al 2014, Zuberbier et al 2018). These Japanese 
and foreign guidelines use different terms, but these differences do not influence the respective 
diagnosis and, thus, describe the same disorder (Hide et al 2018).
The classic description of urticaria is a wheal and flare with a pale elevated lesion and 
surrounding erythema, ranging in size from a few millimeters to a few centimeters across, 
usually occurring in groups and often coalescing to form large confluent lesions. Wheals and 
angioedema in CSU involve the degranulation of mast cells, which release histamine, proteases 
and cytokines. These mediators induce vasodilation, increase vascular permeability, and 
stimulate sensory nerve endings leading to swelling, redness and itch (Kaplan et al 1978, 
Saini and Kaplan 2018).
CSU can be debilitating, is associated with intense itching and has a major impact on patient’s 
quality of life, comparable to that of severe coronary artery disease (Greaves 2003, 
Powell et al 2007). The overall burden of CSU and CSU-associated angioedema for affected 
patients is substantial: CSU and its symptoms have a negative impact on numerous aspects of 
their daily life, including mental health, work productivity, sleep, partnership and family life 
(O'Donnell et al 1997, Maurer et al 2017, Gonçalo et al 2021).
Urticaria treatment aims at fully suppressing the symptoms of both itch and hives and 
occurrence of angioedema. All in all Japan and other countries share the same treatment strategy 
(Hide et al 2012).
Second generation Histamine H1 receptor antagonists (H1-antihistamines) are recommended as 
first-line treatment for patients with CSU but less than 40% of patients respond adequately 
(Guillén-Aguinaga et al 2016). While uptitration of second-generation H1-antihistamines up to 
4-fold the approved dose is recommended by most CSU treatment guidelines as second-line 
therapy (Zuberbier et al 2018), the efficacy of uptitrated H1-antihistamines in CSU has not been 
studied in larger clinical trials and uptitration is considered off-label. The use of H2-
antihistamines and Leukotriene Receptor Antagonists (LTRAs) has in the past been 
recommended by treatment guidelines for patients who remained symptomatic despite 
treatment with H1-antihistamines (Zuberbier et al 2009, Bernstein et al 2014, Hide et al 2018), 
although their use has not been well supported by clinical studies. In the latest version of the 
treatment guidelines (Zuberbier et al 2018), neither H2-antihistamines nor LTRAs are 
perceived to have sufficient evidence to maintain them as recommendable in the algorithm. 
Short courses of systemic corticosteroids are sometimes added to the treatment regimen, 
however they are not recommended in treatment guidelines for long-term use, as this would 
expose patients to the well-known risk of adverse effects associated with chronic systemic 
 




Novartis
Confidential
Page 22 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
1.2
Purpose
The purpose of this study is to investigate the safety, tolerability and efficacy of remibrutinib
(LOU064) in Japanese CSU patients inadequately controlled by H1-antihistamines. This study 
supports the registration of remibrutinib for the treatment of CSU in Japan.
Inadequate control of CSU by H1-antihistamines is defined as:

The presence of itch and hives for ≥6 consecutive weeks prior to screening despite the use 
of second generation H1-antihistamines during this time period

UAS7 score (range 0-42) ≥16, ISS7 score (range 0-21) ≥6 and HSS7 score (range 0-21) 
≥6 during the 7 days prior to baseline (Day 1).
The effect of remibrutinib in patients with CSU inadequately controlled by H1-antihistamines 
was investigated in the Phase 2b dose-range finding study CLOU064A2201 and demonstrated 
efficacy in multiple remibrutinib dose groups compared to placebo. No safety concerns were 
identified in the remibrutinib groups. The long-term safety, tolerability and efficacy in 
participants who have completed the Phase 2b dose range finding study in CSU is investigated 
in the Phase 2b extension study CLOU064A2201E1. No safety concerns have been identified 
in this study either. Two Phase 3 studies CLOU064A2301 and CLOU064A2302 are intended 
to support the registration of remibrutinib for the treatment of patients with CSU in adults 
inadequately controlled by H1-antihistamines.
For the registration purpose, there is a relatively low number of Japanese CSU participants 
treated with the intended dose or higher during one year in studies CLOU064A2201E1 and 
CLOU064A2301. Therefore, the purpose of this CLOU064A1301 study is to evaluate the safety, 
tolerability and efficacy of remibrutinib in adult Japanese subjects with CSU, who remain 
symptomatic despite treatment by H1-antihistamines at locally label approved doses, for a 
duration of 52 weeks of treatment with remibrutinib and a post-treatment follow-up period of 
up to 4 weeks.
2
Objectives, endpoints and estimands
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective

To evaluate the safety of remibrutinib (25 mg 
b.i.d.) in CSU patients

Overall safety data, assessed as treatment emergent 
adverse events during the study
Secondary objectives
Endpoints for secondary objectives

To evaluate the efficacy of remibrutinib (25 mg 
b.i.d.) by evaluation of:

Change from baseline in UAS7 at Week 12

Proportion of participants achieve disease 
activity control (UAS7 ≤ 6) at Week 12

Proportion of participants achieve complete 
absence of hives and itch (UAS7 = 0) at 
Week 12

Change from baseline in ISS7 at Week 12

Absolute change from baseline in UAS7 at Week 12

Achievement of UAS7≤ 6 (yes/no) at Week 12

Achievement of UAS7 = 0 (yes/no) at Week 12

Absolute change from baseline in ISS7 score at 
Week 12
 






Novartis
Confidential
Page 25 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
The primary estimand on safety is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second-
generation H1-antihistamine treatment who have CSU duration ≥6 months, a UAS7 
score ≥16, ISS7 score ≥6 and HSS7 score ≥6 in the last 7 days prior to start of treatment.
2. Endpoint: incidence of treatment-emergent adverse events.
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance (discontinuation/interruption), with background medication of local 
approved second-generation H1-antihistamine, and a different second-generation H1-
antihistamine as rescue medication.
4. Summary Measurement: the number and the proportion of participants with at least one 
treatment-emergent adverse event.
5. Handling of remaining intercurrent events:

Discontinuation of study treatment due to any reason: data collection will be 
maintained in the follow-up period. The data collected after these events will be used 
for analysis.

Treatment non-compliance (interruption), intake of rescue medication, or switch of 
background medication: ignore, i.e., data collection will be maintained and available 
measurements post-intercurrent event will be used as if they had been obtained under 
the treatment: Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment, 
cyclosporine, systemic corticosteroids): Treatment policy strategy

Administration of medications affecting the evaluation of potential risks, including: 
(a) anticoagulant/anti-platelet medications (other than acetylsalicylic acid up to 
100 mg/d or clopidogrel); (b) live attenuated vaccines; (c) strong cytochrome P 
(CYP)3A4 inhibitors; (d) moderate/strong CYP3A4 inducers, (e) Oral breast cancer 
resistance protein (BCRP*) substrates that may have increased exposure when co-
administered with remibrutinib (pitavastatin, rosuvastatin, sulfasalazine and 
ubrogepan): Treatment policy strategy

Intake of other prohibited medication: Treatment policy strategy
* Assessment of confounder BCRP will be specified in the statistical analysis plan (SAP).
2.2
Secondary estimands
Secondary estimand on efficacy as secondary endpoint: change from baseline in UAS7 
score at Week 12 
The secondary clinical question of interest regarding efficacy as secondary endpoint, change 
from baseline in UAS7 score at Week 12 is: What is the effect of remibrutinib treatment on the 
change from baseline in UAS7 score after 12 weeks of treatment in adult participants with CSU 
who are inadequately controlled by H1-antihistamine and receiving a stable locally label 
approved dose of a second generation H1-antihistamine, regardless of treatment discontinuation 
for any reason or intake of a different second generation H1-antihistamine as rescue medication 
and considering strongly confounding prohibited medication use as an unfavorable outcome? 
(see Section 12.5)
 


Novartis
Confidential
Page 26 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
The secondary estimand on efficacy as secondary endpoint, change from baseline in UAS7 
score at Week 12 is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine treatment who have CSU duration ≥6 months, a UAS7 score 
≥16, ISS7 score ≥6 and HSS7 score ≥6 in the last 7 days prior to start of treatment.
2. Endpoint: change in UAS7 from baseline at Week 12.
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance, with background medication of local approved second generation 
H1-antihistamine, and a different second generation H1-antihistamine as rescue 
medication.
4. Summary Measurement: the mean change from baseline.
5. Handling of remaining intercurrent events:

Discontinuation of study treatment due to any reason, treatment non-compliance 
(interruption), intake of rescue medication, or switch of background medication: 
Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporine after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent 
events)

Intake of other prohibited medication: Treatment policy strategy
Secondary estimand on efficacy as secondary endpoint: UAS7 ≤6 response at Week 12 
(Week 2, if applicable)
The secondary clinical question of interest regarding efficacy as secondary endpoint, UAS7 ≤6 
response at Week 12 is: What is the effect of remibrutinib treatment on the UAS7 ≤6 response 
after 12 weeks of treatment in adult participants with CSU who are inadequately controlled by 
H1-antihistamine and receiving a stable locally label approved dose of a second generation H1-
antihistamine, regardless of treatment discontinuation for any reason or intake of a different 
second generation H1-antihistamine as rescue medication and considering strongly 
confounding prohibited medication as an unfavorable outcome?
The secondary estimand on efficacy as secondary endpoint, UAS7 ≤6 response at Week 12 is 
described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine treatment who have CSU duration ≥6 months, a UAS7 
score ≥16, ISS7 score ≥6 and HSS7 score ≥6 in the last 7 days prior to start of treatment.
2. Endpoint: UAS7 ≤6 response at Week 12.
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance, with background medication of locally approved second generation 
H1-antihistamine, and a different second generation H1-antihistamine as rescue 
medication.
4. Summary Measurement: the number and the proportion of participants with UAS7 ≤6 
response at Week 12.
 


Novartis
Confidential
Page 27 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
5. Handling of intercurrent events:

Discontinuation of study treatment due to any reason, treatment non-compliance 
(interruption), intake of rescue medication, or switch of background medication: 
Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporine after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent 
events)

Intake of other prohibited medication: Treatment policy strategy
Secondary estimand on efficacy as secondary endpoint: UAS7=0, DLQI=0-1 and AAS7=0 
response at Week 12
Similar estimand approach will be implemented for these endpoints as for the UAS7 
≤6 response at Week 12.
Secondary estimand on efficacy as other secondary endpoints as defined in Table 2-1.
Similar estimand approach will be implemented for these endpoints as for the change from 
baseline in UAS7 score at Week 12.
3
Study design
This is a single country, multicenter, open-label, single arm Phase 3 study investigating the 
safety, tolerability, and efficacy of remibrutinib (25 mg b.i.d.) in Japanese participants with 
CSU inadequately controlled by second generation H1-antihistamines. The study consists of 
three periods, the total study duration is up to 60 weeks (Figure 3-1):

Screening period: up to 4 weeks

Open-label treatment period: 52 weeks of open-label treatment with remibrutinib 
(25 mg b.i.d.).

Follow-up period: 4 weeks of treatment-free follow-up.
An interim analysis may be conducted after all participants have completed Week 24 or 
discontinued earlier. All participants will be on a stable, local label approved dose of a 
second generation H1-antihistamine (“background therapy”) throughout the entire study 
(starting a minimum of 7 days prior to baseline until the end of the study). To treat unbearable 
symptoms of CSU, participants will be allowed to use another second generation H1-
antihistamine on an as-needed basis (“rescue therapy”).
An extension study is being considered. Eligible participants may roll-over at Week 52 (after 
completing 52 weeks of treatment and all scheduled assessments planned at this visit). The 
details of the study design and procedures of the extension, if implemented, will be described 
in a separate protocol.
 


Novartis
Confidential
Page 28 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Figure 3-1
Study Design
D-1: Day 1, b.i.d.: bis in die/twice a day, IA: interim analysis, mg: milligram(s), Scr: Screening, W: 
Week
4
Rationale
4.1
Rationale for study design
The primary analysis of the Phase 2b dose-range finding study CLOU064A2201 demonstrated 
that treatment with remibrutinib 25 mg b.i.d. substantially improves signs and symptoms of 
CSU compared to placebo, in participants who have not adequately responded to prior treatment 
with H1-antihistamines and other CSU therapies including omalizumab. This Phase 3 study is 
designed to evaluate the safety, tolerability and efficacy of remibrutinib at a dose of 25 mg b.i.d. 
(as determined by the Phase 2b dose-range finding study CLOU064A2201, see also Section 4.2) 
in adult CSU patients. It is an open-label, single arm study that consists of three phases:
1. Screening period: the screening period of up to four weeks will allow the assessment of 
eligibility of participants and the determination of baseline disease activity.
2. Open-label treatment period: during this treatment period of 52 weeks, an open-label 
design without a comparator arm is considered adequate to evaluate long-term safety for 
CSU in Japanese participants and accepted by Japanese Health Authority. The treatment 
period will provide long-term safety and efficacy data to characterize the value of 
remibrutinib in CSU.
3. Follow-up period: a treatment-free follow-up period of four weeks at the end of the study 
will be implemented for all participants who do not enroll into the extension study 
(currently being considered). This allows the assessment of safety after treatment 
discontinuation as well as the dynamics of potential re-occurrence of CSU signs and 
symptoms after treatment discontinuation.
The study population consists of participants with CSU (UAS7 score ≥ 16, with HSS7 score ≥ 
6 and ISS7 score ≥ 6), who have a duration of CSU of ≥6 months and who are inadequately 
controlled despite treatment with second generation H1-antihistamines at least at locally label 
approved dose. Importantly, patients who have inadequately responded to or did not tolerate 
anti-IgE biologic treatments are also eligible for this study. Thus, CSU patients with high unmet 
medical need are the target population for this study.
The primary endpoint of this study is overall safety, assessed as treatment-emergent adverse 
events during the study, as the number of Japanese CSU patients exposed to remibrutinib at the 
intended or higher dose in the global studies (CLOU064A2201, CLOU064A2201E1 and 
 


Novartis
Confidential
Page 29 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
CLOU064A2301) is expected to be limited for registration purpose. Therefore, this study is 
designed to obtain additional safety data of remibrutinib at 25 mg dosed for one year in 
Japanese CSU patients to support for the registration of remibrutinib in Japan.
UAS7, UAS7-based analysis (UAS7≤6 and UAS7=0), the assessment of the impact of 
remibrutinib treatment on itch (ISS7) and hives (HSS7), the assessment of the impact of 
remibrutinib treatment dermatology-related quality of life (DLQI-response of 0/1), and the 
assessment of the impact of remibrutinib treatment on the number of weeks without occurrence 
of angioedema (AAS7=0) were selected as secondary endpoints to further assess the efficacy 
of remibrutinib.
Assessing remibrutinib (25 mg b.i.d.) as add-on to background medication consisting of a 
locally label approved second generation H1-antihistamine follows recommendations of the 
current treatment guidelines (Zuberbier et al 2018).
For the primary safety estimand, applying a treatment policy strategy for all intercurrent events 
aims to collect all treatment-emergent adverse events occurring in the treatment period and 
follow-up period and assess remibrutinib as a CSU therapy (as an add-on to background 
medication) close to a "real-life" situation.
For the secondary efficacy estimand, applying a treatment policy strategy for treatment non-
compliance, the use of rescue medication (a second generation H1-antihistamine that differs 
from the background medication), and most other intercurrent events aims to assess 
remibrutinib as a CSU therapy (as an add-on to background medication) close to a "real-life" 
situation. Only intercurrent events that are likely to impose a strong bias on the efficacy readout 
(such as use of highly effective biologics with a long half-life) will be handled using a composite 
strategy. Taken together, the study design will allow the investigation of long-term safety and 
efficacy of remibrutinib in Japanese CSU participants.
4.1.1
Rationale for choice of background therapy
Second-generation H1-antihistamines are chosen as background medication. Considering the 
add-on remibrutinib therapy, this reflects the current treatment guidelines to add a second- or 
third-line therapy to H1-antihistamine background therapy in CSU patients who are not 
adequately controlled by H1-antihistamines (Zuberbier et al 2018, Hide et al 2018).
4.2
Rationale for dose/regimen and duration of treatment
In this study, remibrutinib will be given at a dosing regimen of 25 mg b.i.d. for a duration of up 
to 52 weeks. A treatment duration of up to 52 weeks is in line with the current treatment 
guidelines (Zuberbier et al 2018) and in line with other current major Phase 3 trials in the CSU 
indication, e.g., with ligelizumab (NCT03580369 and NCT03580356). Therefore, it allows the 
collection of efficacy and safety data for remibrutinib over a treatment duration, which is 
applied in real-world clinical practice and which allows comparison to other Phase 3 trials in 
the same indication. Furthermore, a treatment duration of up to 52 weeks is covered by pre-
clinical toxicity data and is used in the Phase 2b extension study CLOU064A2201E1.
The target population of this trial includes difficult-to-treat patients, such as patients with 
concomitant CINDU, a long disease history, and patients with prior inadequate response to anti-
IgE biologics. In such cases a treatment duration of up to 52 weeks or more can be required. An 
 


Novartis
Confidential
Page 30 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
extension study is being considered and eligible participants will have the opportunity to roll 
over after completing 52 weeks of study treatment in this trial.
Based on the safety data from the completed and ongoing remibrutinib trials, the clinical safety 
profile of remibrutinib is favorable and supports the selected dose of 25 mg b.i.d. In the primary
endpoint analysis of the dose-range finding Phase 2b study CLOU064A2201 (cut-off date at 
14-Jan-2021), most AEs were mild in severity, without patterns of clustering or dose-
dependency. Ongoing clinical safety review of CLOU064A2201E1, a long-term extension 
study of CLOU064A2201, with a 52-week treatment period with 100 mg remibrutinib b.i.d. did 
not reveal any safety signals. In addition, the clinical safety data from the completed Phase 1 
studies, which tested doses of remibrutinib up to 600 mg q.d. and 200 mg b.i.d., was favorable 
and did not raise any concerns. For more detailed information on the safety profile of 
remibrutinib, please see Section 4.5 and the IB.
In the dose-range finding study CLOU064A2201, the efficacy of remibrutinib as an add-on to 
background therapy of second generation H1-antihistamines was assessed versus placebo for 
the following dose regimens: 10 mg q.d., 35 mg q.d., 100 mg q.d., 10 mg b.i.d., 25 mg b.i.d., 
100 mg b.i.d. The treatment duration was 12 weeks and the primary endpoint was change in 
UAS7 score from baseline at Week 4. The key secondary endpoints were defined as change in 
UAS7 score from baseline at Week 12, change in UAS7 score from baseline over time, 
percentage of participants with UAS7 = 0 (complete absence of hives and itch) over time, and 
percentage of participants with UAS7 ≤6 (disease activity control) over time. At the time of the 
primary endpoint analysis, there were 301 participants (40-47 per arm) among 309 under full 
analysis set with a UAS7 score at Week 4, and 233 participants (29-37 per arm) with a UAS7 
score at Week 12. The treatment groups were overall well balanced in terms of demography 
and baseline disease characteristics.
The study demonstrated clinical efficacy of remibrutinib in the treatment of CSU, with all tested 
doses showing superior efficacy over placebo at Week 4. A dose-response relationship was 
established for the q.d. and b.i.d. remibrutinib dosing regimens compared to placebo with 
respect to the change from baseline in UAS7 score at Week 4, with the dose-response plateau 
already achieved at 10 mg for q.d. dosing (=10 mg total daily exposure) and at 25 mg for b.i.d. 
dosing (=50 mg total daily exposure).
 


Novartis
Confidential
Page 31 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Figure 4-1
UAS7 score change from baseline over time estimated with a mixed-
effect repeated measurement analysis, by treatment group (FAS)
Figure 4-2
UAS7 = 0 and UAS7 <=6 response rate over time by treatment group 
(as observed) (FAS)
Assessing the higher hurdle UAS7 ≤ 6 (disease activity control) and UAS7 = 0 (total absence 
of itch and hives) response rates enabled further differentiation between the tested doses (Figure 
4-1 and Figure 4-2): At Week 4, the remibrutinib 25 mg b.i.d dosing regimen achieved 
numerically higher UAS7 ≤ 6 response rates than all other tested doses: 55.8% on25 mg b.i.d. 
compared to 43.2%, 40.9%, 42.6%, 34.1%, 44.4%, 4.8% on 10 mg q.d., 35 mg q.d., 100 mg 
q.d., 10 mg b.i.d., 100 mg b.i.d., placebo (non-responder imputation). In line with that, the 
 


Novartis
Confidential
Page 32 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
25 mg b.i.d. dosing regimen also achieved considerably higher UAS7=0 response rates than all 
other tested doses at Week 4: 41.9% on 25 mg b.i.d compared to 18.2%, 22.7%, 17.0%, 18.2%, 
22.2%, 0.0% on 10 mg q.d., 35 mg q.d., 100 mg q.d., 10 mg b.i.d., 100 mg b.i.d, placebo (non-
responder imputation). The numerically higher efficacy of the 25 mg b.i.d. dosing regimen 
compared to all other doses was observed consistently over time, with higher UAS7 ≤ 6 and 
UAS7 = 0 response rates from Week 2 throughout Week 12 (Figure 4-2). Furthermore, the 
25 mg b.i.d. dosing regimen showed the fastest onset of action, with high response rates already 
achieved at Week 2 (Figure 4-2).
At Week 12, the UAS7 ≤ 6 and UAS7 = 0 response rates for placebo-treated participants were 
relatively high (31.3% and 15.7%), reflecting the fluctuating nature of CSU (Figure 4-2). While 
still showing numerical superiority, the q.d. dosing regimens (10 mg q.d., 35 mg q.d., 100 mg 
q.d.) showed a tendency towards weaker differentiation vs placebo in UAS7 ≤ 6 and UAS7 = 0 
response at Week 12 (UAS7 ≤ 6: 43.2%, 40.9%, 42.6%; UAS7 = 0: 29.4%, 29.4%, 32.4%) (as 
observed), whereas the 25 mg b.i.d. regimen was able to maintain a notable difference (UAS7 
≤ 6: 63.6%, UAS7 = 0: 48.5%). B.i.d. dosing is also supported from a pharmacokinetics, 
pharmacodynamics and mode-of-action perspective, in order to ensure sustained BTK 
inhibition over 24 hours, considering the relatively fast turnover of the covalent BTK-
remibrutinib complex in tissue (see IB for details).
Taken together, all tested remibrutinib dosing regimens demonstrated superior efficacy in 
treating signs and symptoms of CSU compared to placebo, when assessing the mean change 
from baseline in UAS7. However, when analyzing higher hurdle efficacy endpoints with higher 
discriminatory power (UAS7 ≤ 6 or UAS7 = 0) and later time points with higher placebo 
response rates, the 25 mg b.i.d. treatment regimen showed notably higher efficacy than the other 
tested regimens, especially than the q.d. regimens.
A lower b.i.d. dose (10 mg b.i.d.) or once daily dosing (35 mg q.d.) does not enable participants 
to achieve the maximum efficacy which can be achieved with 25 mg b.i.d. dosing, especially 
when considering the UAS7 ≤ 6 and UAS7 = 0 response rates. At the same time, higher dosing 
regimens, such as 100 mg b.i.d., are not required to reach maximum efficacy.
As the safety data also support the 25 mg b.i.d. dosing regimen (see Section 4.5 and the IB) 
with a favorable safety profile and no dose-dependent safety signals, remibrutinib 25 mg b.i.d. 
was selected as the optimal dose for this study.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
One interim analysis may be conducted for the purpose of submission to Health Authorities for 
marketing authorization approval. This interim analysis is planned when all participants have 
completed their Week 24 visit or discontinued early.
Additional interim analyses may be conducted at the discretion of the Sponsor to support 
decision making concerning the current clinical study, the sponsor’s clinical development 
 


Novartis
Confidential
Page 33 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
projects in general, or in case of any safety concerns. These interim analyses are not expected 
to have any impact on the conduct or scientific integrity of the study. Refer to the interim 
analyses Section 12.7 for further details.
4.5
Risks and benefits
Signs and symptoms of CSU are a direct consequence of mast cell degranulation with release 
of inflammatory mediators including histamine (Ferrer 2015, Saini and Kaplan 2018). BTK is 
a cytoplasmic tyrosine kinase that is indispensable for FcεR1 signaling and a central signaling 
kinase in mast cell activation. It has been demonstrated that BTK inhibition can effectively 
inhibit 
mast 
cell 
activation 
and 
reduce 
wheal 
sizes 
in 
skin 
prick 
tests 
(Regan et al 2017; Dispenza et al 2018; Kaul et al 2019). In Phase 1, remibrutinib was well-
tolerated at all doses without any dose-limiting toxicity and showed encouraging blood and skin 
pharmacodynamics with a favorable safety profile, fully supporting further development for 
diseases driven by mast cells, basophils, or B cells, such as CSU. Furthermore, remibrutinib has 
been shown to effectively reduce wheal size in skin prick tests (Kaul et al 2021). The Phase 2b 
clinical trial CLOU064A2201 (primary endpoint analysis) demonstrated clinical efficacy of 
remibrutinib in the treatment of CSU patients with a fast onset of action and a favorable safety 
profile.
Based on this data, 25 mg b.i.d. has been selected as the optimal dosing regimen for the 
treatment of CSU patients. Treatment with remibrutinib 25 mg b.i.d. resulted in a substantial 
reduction of the UAS7 score, which measures frequency/intensity of hives and itch, the two key 
symptoms defining the burden of CSU for affected participants. The benefit for CSU patients 
treated with remibrutinib 25 mg b.i.d. was also reflected by substantial improvements in health-
related quality of life (HRQoL), as measured by the DLQI score (see Investigator’s Brochure 
(IB) for details).
BTK inhibition is a new therapeutic principle for the treatment of CSU that significantly differs 
from currently available treatment options in terms of its mode of action and route of 
administration. Remibrutinib may therefore offer a treatment option for patients with 
contraindications against or inadequate response to approved treatment options for CSU 
including anti-IgE directed biologics. These patients, for whom a high unmet need for new 
treatments exists, are part of the eligible patient population of this study. In the above-
mentioned Phase 2b trial CLOU064A2201, remibrutinib showed a rapid onset of action already 
after the first week of treatment, which is of significant benefit for CSU patients, who often 
have a high current symptom burden. Furthermore, the oral route of administration of 
remibrutinib offers additional convenience compared to injectable biologics.
Taken together, the benefit for study participants is that treatment with remibrutinib could 
substantially improve their CSU signs and symptoms and lead to a better quality of life.
The available clinical safety experience has documented favorable safety and tolerability of 
remibrutinib. As of 10-Mar-2022, approximately 903 participants (healthy volunteers and 
patients suffering from CSU, asthma, Sjogren’s Syndrome, atopic dermatitis (AD), and 
relapsing multiple sclerosis) have been exposed to remibrutinib at doses ranging from 0.5 mg 
to 600 mg, placebo or comparator. A maximum tolerated dose has not been identified.
 


Novartis
Confidential
Page 34 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
In the final analysis of the Phase 2b trial CLOU064A2201 in patients with CSU, 309 
participants (safety set (SAF)) received remibrutinib at doses/regimens up to 100 mg b.i.d. for 
up to 12 weeks. Most adverse events (AEs) were mild in severity, without clustering of specific 
AEs and no apparent dose-related pattern was identified. The most frequent AEs were reported 
in the following System Organ Classes (SOC): Infections and infestations (24.0% in any 
remibrutinib arm vs 21.4% in placebo arm), Skin and subcutaneous tissue disorders (16.9% vs 
4.8%), Nervous system disorders (13.1% vs 16.7%), and Gastrointestinal disorders (11.2% vs 
11.9%). The most frequent AEs (defined by MedDRA Preferred Term (PT)), occurring in ≥ 5% 
of participants in either any remibrutinib or placebo arm) were:

Headache: 9.7% in any remibrutinib arm vs. 14.3% in placebo arm

Nasopharyngitis: 8.6% in any remibrutinib arm vs. 7.1% in placebo arm

Chronic spontaneous urticaria: 6.0% in any remibrutinib arm vs. 2.4% in placebo arm (the 
events of CSU were flares primarily reported by participants during the treatment-free 
follow-up period).
In interim analysis 2 (IA2; cut-off May-2021) of the Phase 2b long-term open-label extension 
trial CLOU064A2201E1, data from 183 CSU participants enrolled with a median exposure to 
remibrutinib 100 mg b.i.d. of 35.14 weeks showed a similar safety profile to that in the core 
CLOU064A2201 study. Most AEs were non-serious, mild in severity, and did not lead to 
treatment discontinuation. The most common SOCs (≥ 10% of subjects) were Infections and 
infestations (23%), Skin and subcutaneous tissue disorders (17.5%), Gastrointestinal disorders 
(14.2%), and Nervous systems disorders (10.4%). The 3 most commonly reported PTs were 
headache (6.6%), COVID-19 (4.9%), and diarrhea (4.9%). Based on the mode of action of 
remibrutinib, pre-clinical safety information, drug-drug-interaction studies, and the review of 
currently available literature as well as safety information of approved BTK inhibitors (e.g., 
ibrutinib, acalabrutinib and zanubrutinib), the following potential risks of remibrutinib have 
been identified (see below). Of note, many safety risks identified for ibrutinib and acalabrutinib, 
two BTK inhibitors approved for the treatment of B cell malignancies (mantle cell lymphoma, 
chronic lymphocytic leukemia, Waldenstroem´s macrogloblinemia), are less likely related to 
the pharmacology of BTK inhibition, but rather to the underlying hemato-oncologic diseases 
being treated and their associated comedications and complications, such as tumor lysis 
syndrome, second primary malignancies, etc. Therefore, when comparing the safety risks 
between the approved BTK inhibitors and remibrutinib, the underlying condition of the treated 
patient population must be taken into consideration. Furthermore, ibrutinib and acalabrutinib 
have a different target selectivity profile compared to remibrutinib (Angst et al 2020).

Infections: BTK is an important signaling kinase downstream of cell surface receptors and 
expressed in a number of cell types of the adaptive and innate immune system, including 
B cells, macrophages, basophils and mast cells. Thus, administration of remibrutinib 
might be associated with an increased risk for infections and participants should be 
monitored for signs and symptoms of infections and be evaluated promptly. In the 
completed and ongoing clinical trials with remibrutinib, infections were well balanced 
between the remibrutinib and placebo arms. Most of the infections observed were mild to 
moderate and did not lead to a change in study treatment. In the final analysis of the Phase
2b study CLOU064A2201, infection rates (defined as MedDRA SOC Infections and 
infestations) were comparable between any remibrutinib arm (24.0%) and the placebo arm 
 


Novartis
Confidential
Page 35 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
(21.4%). Most infections reported in the remibrutinib arms were mild in severity and did 
not lead to treatment discontinuation. All participants in remibrutinib clinical trials are 
monitored closely for signs and symptoms of infections while in the trial. Patients with a 
known history of chronic recurrent or active ongoing infections are excluded from the trial 
(refer to Section 5.2 for details). In addition, the use of live attenuated vaccines should be 
avoided 6 weeks before study treatment and during the study until at least 4 weeks after 
the last dose of the study treatment (see Section 6.2.2).

Response to vaccination: In general, immunomodulatory treatments may diminish vaccine 
efficacy (Farez et al 2019). BTK inhibition is expected to affect the response to 
vaccinations and result in reduced vaccination efficacy. Due to its immunomodulatory 
effects, treatment with remibrutinib might be associated with reduced efficacy of 
vaccinations. There are limited data available on vaccination response in patients treated 
with BTK inhibitors and primarily reported in patients with hematologic malignancies 
(Pleyer et al 2021, Weber et al 2021). In ongoing studies with remibrutinib, participants 
are advised to complete necessary vaccination before starting treatment with remibrutinib. 
If necessary, vaccination with non-live vaccines is allowed during the study.

Effect on platelet function - risk for bleeding: BTK is a signaling molecule in one of 
several platelet activation pathways, and clinically relevant effects of remibrutinib on 
platelet functions were observed in the remibrutinib preclinical toxicology program. The 
mode of action by which remibrutinib could potentially cause bleeding is currently not 
fully understood. In vitro assessments suggest a target-related impact on platelets, similar 
to effects induced by the BTK inhibitor ibrutinib, which has been shown to inhibit clot 
retraction (Bye et al 2015). 

In CSU, in the completed core CLOU064A2201 Phase 2b study, 18 (6.7%) non-serious 
bleeding events were reported in any remibrutinib arm compared to one event on placebo 
(2.4%); none of the AEs was serious or severe. All the bleeding AEs reported were mild, 
except 2 moderate AEs: gingival bleeding and hematuria. Two bleeding events (petechiae 
and hematuria) led to study treatment discontinuation. There were no notable clinically 
relevant abnormalities for coagulation parameters, hemoglobin levels or platelet counts 
noted in these studies. In the interim analysis of the open-label long-term (up to 52 weeks) 
extension trial CLOU064A2201E1, the rate of bleeding events (4.4%) was comparable to 
that seen in the core trial; all events were non-serious, and all but 2 events (purpura and 
heavy menstrual bleeding in the setting of leiomyoma) were mild in severity. Potential 
effects of remibrutinib on hemostasis should be monitored both clinically and by standard, 
validated laboratory measures including complete blood count and standard coagulation 
parameters. Clinical monitoring should focus on skin (bruising, petechiae) and mucosa 
(e.g., gastro-intestinal (GI) tract bleeding including gingival, rectal, and conjunctival
bleeding). Patients with a known history of bleeding disorders, or with a history of 
clinically relevant gastrointestinal bleeding and patients requiring anti-platelet or 
anticoagulant therapy (other than aspirin up to 100 mg/d or clopidogrel up to 75 mg/d) are
excluded from the trial; the use of dual anti-platelet therapy (e.g., acetylsalicylic acid + 
clopidogrel) is prohibited (see details in Section 5.2 and Section 6.2.2). In case of a 
significant bleeding event, study treatment must be discontinued immediately. Please refer 
to the current IB for further details.
 


Novartis
Confidential
Page 36 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301

Effects on QT interval: Remibrutinib is a mild inhibitor of the human ether-a-go-go related 
gene (hERG) channel (IC50 = 1.4 µM; unbound Cmax-based average safety margin of 43-
fold based on 100 mg b.i.d. in humans), without affecting other ion channels in a relevant 
manner. Close ECG monitoring via Holter recordings in the first in human studies 
(CLOU064X2101 and CLOU064X1101) documented a minor exposure-dependent 
increase in QTcF with no outliers (i.e., QT-interval with a frequency correction according 
to Fridericia (QTcF) > 480 ms or increases equal or greater than 60 ms) up to the maximal 
dose of 600 mg. At the projected supratherapeutic exposure calculated based on the 
observed Cmax at 25 mg b.i.d., assuming severe organ impairment and comedication with 
a strong CYP3A4 inhibitors such as ritonavir (“worst case” scenario), the calculated mean 
QTcF effect is 2.580 ms which is well below the threshold of 5 ms to rule out a relevant 
QT-effect. The predicted upper 90% confidence limit of the QTcF changes is well below 
10 ms, the regulatory pharmacologic effect threshold for cardiac repolarization, indicating 
a low probability of clinically significant repolarization effects even at 2-fold higher 
exposure than that of the “worst-case” scenario. In the interim and final analyses of 
ongoing and completed Phase 2 studies in participants with CSU, Sjogren’s Syndrome and 
asthma, no notable trend was observed for the change of ECG over time; no finding in 
ECG recordings or AEs suggestive of pro-arrhythmic events were noted. Patients with a 
history of major cardiovascular events are excluded from the trial. In addition, triplicate 
sequential ECG monitoring is implemented in the study to monitor potential effects of 
remibrutinib on QTc and other ECG parameters.

Myelomodulation: Treatment-emergent grade 3 or 4 cytopenias (neutropenia, 
thrombocytopenia, and anemia) were reported in participants with hematologic 
malignancies treated with ibrutinib and acalabrutinib. Again, the underlying hemato-
oncologic diseases of these participants and their frequent association with such events 
should be taken into consideration here. All cytopenias reported in the final analysis of 
CLOU064A2201 were mild. Participants are closely monitored for signs and symptoms of 
cytopenia while in the trial, and those with a history of hematological disorders or with 
markedly altered hematologic parameters at baseline are excluded from the study (see 
details in Section 5.2).

Drug-drug interactions: Oxidative metabolism is the major clearance pathway of 
remibrutinib and expected to be predominantly mediated by CYP3A4 with minor 
contribution of other CYP450 enzymes (e.g., CYP2C9, CYP1A1). At the dose used in this 
study (25 mg remibrutinib b.i.d.), co-administration of CYP3A4 inhibitors (even of strong 
ones) will not result in exposure levels of remibrutinib that are associated with clinically 
relevant QT prolongation. Likewise, co-administration of even strong CYP3A4 inhibitors 
with 25 mg remibrutinib b.i.d. will not increase exposure levels of remibrutinib beyond 
exposure levels that can be reached with 100 mg remibrutinib b.i.d., a dose that was well-
tolerated in CLOU064A2201 and was not associated with any safety signals, based on the 
interim analysis. Therefore, only co-administration of strong CYP3A4 inhibitors is 
prohibited in this study. Concomitant administration of moderate and strong inducers of 
CYP3A4 is also prohibited during the study (see Table 6-2). Remibrutinib can be co-
administered with oral contraceptives such as ethinylestradiol or levonorgestrel without a 
major impact on their exposure and efficacy. Remibrutinib has been shown to inhibit some 
efflux and uptake transporters (such as P-glycoprotein, OATP1B, Mate1, OAT3, organic 
 


Novartis
Confidential
Page 37 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
cation transporter 1 and BCRP). However at a dose of 25 mg b.i.d. only inhibition of 
BCRP remains as a minor risk which is planned to be investigated in a clinical drug-drug 
interaction study. Therefore, concomitant administration of remibrutinib with respective 
BCRP substrates with a small safety margin may be administered with caution (see Table 
6-3).

Reproductive toxicity: Remibrutinib is not genotoxic or mutagenic in in vitro or in vivo
studies. No effects on fertility or embryo-fetal development were observed in rats up to the 
highest dose, while in rabbits a no-observed-adverse-effect-level at 100 mg/kg/day was 
established. At doses ≥300 mg/kg/day, body weight loss, marked low food consumption, 
and moribundity were noted, as well as a higher incidence of external fetal malformations 
(see details in IB). For the approved BTK inhibitors, embryo-fetal toxicity in animals is 
reported (see national prescribing information). Highly effective methods of contraception 
must be practiced. Women of child-bearing potential will be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during 
the trial and must agree that in order to participate in the trial they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that 
the participant will not reliably comply, they should not be entered or continue in the 
study.
For detailed information on potential risks associated with remibrutinib, please refer to the IB.
In summary, CSU patients with inadequate response to H1-antihistamines (and other available 
treatment options if applicable) participating in this clinical trial may significantly benefit from
treatment with remibrutinib. Additionally, this trial will help to improve the understanding of 
remibrutinib in the management of CSU and potentially enable the development of a novel, 
innovative, oral drug that could improve the quality of life of CSU patients beyond the limited 
treatment modalities currently available. Potential risks are mitigated as far as possible by 
compliance with inclusion/exclusion criteria, study procedures, very close clinical and 
laboratory monitoring, periodic review of safety data by an independent Data Monitoring 
Committee (DMC), and study drug discontinuation rules. As with investigational drugs in 
general, not all safety risks are known. Participants and investigators participating in this trial 
will be informed should important new safety information become available.
Considering all aspects, the risk-benefit assessment fully supports this trial with remibrutinib 
25 mg b.i.d.
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.
 


Novartis
Confidential
Page 38 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
5
Study Population
The study population will consist of approximately 70 eligible female and male adult 
participants with CSU inadequately controlled by second generation H1-antihistamines (at least 
at local label approved dose).
The screen failure rate is estimated to be 30%, meaning approximately 100 participants are 
expected to be screened.
Participants who drop out after they have entered into the treatment period will not be replaced.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Male and female participants ≥18 years of age at the time of screening
3. CSU duration for ≥ 6 months prior to screening (defined as the onset of CSU determined 
by the investigator based on all available supporting documentation)
4. Diagnosis of CSU inadequately controlled by second generation H1-antihistamines at the 
time of baseline (Day 1) defined as:

The presence of itch and hives for ≥6 consecutive weeks prior to screening despite the 
use of second generation H1-antihistamines during this time period

UAS7 score (range 0-42) ≥16, ISS7 score (range 0-21) ≥ 6 and HSS7 score (range 0-
21) ≥ 6 during the 7 days prior to baseline (Day 1)
5. Documentation of hives within three months before baseline (either at screening and/or at 
baseline; or documented in the participants' medical history)
6. Willing and able to complete an UPDD for the duration of the study and adhere to the 
study protocol
7. Participants must not have had more than one missing UPDD entry (either morning or 
evening) in the 7 days prior to baseline (Day 1)
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
Evaluation of participant eligibility for laboratory parameters listed below must be based on 
central laboratory results. In case eligibility criteria are not met for specific laboratory 
parameters, these may be re-tested a maximum of once during the screening period.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible participants.
1. Use of other investigational drugs within 5 half-lives, or within 30 days (for small 
molecules) prior to Screening or until the expected PD effect has returned to baseline (for 
biologics), whichever is longer; or longer if required by local regulations
2. Previous use of remibrutinib or other BTK inhibitors
3. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes
 




Novartis
Confidential
Page 40 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form 
(ICF).
12. Major surgery within 8 weeks prior to screening or planned surgery for the duration of the 
study
13a.History of live attenuated vaccine within 6 weeks prior to baseline or requirement to 
receive these vaccinations at any time during the study
14. Evidence of clinically significant cardiovascular (such as but not limited to myocardial 
infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, 
arrhythmia and uncontrolled hypertension within 12 months prior to Visit 1), neurological, 
psychiatric, pulmonary, renal, hepatic, endocrine, metabolic, hematological disorders, 
gastrointestinal disease or immunodeficiency that, in the investigator's opinion, would 
compromise the safety of the participant, interfere with the interpretation of the study 
results or otherwise preclude participation or protocol adherence of the participant
15. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares 
are commonly treated with oral or parenteral corticosteroids
16. Hematology parameters at screening:

Hemoglobin: < 10 g/dL

Platelets: < 100 000/mm3

Leucocytes: <3 000/mm3

Neutrophils: < 1 500/mm3
17. Significant bleeding risk or coagulation disorders
18a.History of gastrointestinal bleeding, e.g., in association with use of nonsteroidal anti-
inflammatory drugs (NSAIDs), that was clinically relevant (e.g., for which intervention 
was indicated or requiring hospitalization or blood transfusion)
19a.Requirement for anti-platelet medication, except for acetylsalicylic acid up to 100 mg/d 
or clopidogrel up to 75 mg/d. The use of dual anti-platelet therapy (e.g., acetylsalicylic 
acid + clopidogrel) is prohibited.
20. Requirement for anticoagulant medication (e.g., warfarin or Novel Oral Anti-Coagulants 
(NOAC))
21. History or current hepatic disease including but not limited to acute or chronic hepatitis, 
cirrhosis or hepatic failure or Aspartate Aminotransferase (AST)/ Alanine 
Aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) or 
International Normalized Ratio (INR) of more than 1.5 at screening
22. History of renal disease, creatinine level above 1.5x ULN, or estimated Glomerular 
Filtration Rate (eGFR) <45 ml/min (using the Cockcroft-Gault equation) at screening
23. Evidence of an ongoing Hepatitis C infection (e.g., defined by the detection of hepatitis C-
ribonucleic acid (HCV-RNA) at screening) and/or an ongoing Hepatitis B infection 
(defined by the detection of Hepatitis B virus surface antigen (HBsAg) and/or hepatitis B 
virus (HBV)-DNA at screening; participants who are positive for anti-hepatitis B core 
 




Novartis
Confidential
Page 42 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
There are total of 9 dispensing visits per participant in the trial in the open-label period. The 
last dispensing visit occurs at Week 40.
6.2
Other treatments
6.2.1
Concomitant therapy
Throughout the study, participants must take a second generation H1-antihistamine at a locally 
label approved dose (background therapy). Background therapy should not be changed until the 
Week 12 visit and should only be changed thereafter if medically required (i.e., adverse 
reactions that are attributable to background therapy as per investigator judgment). For detailed 
information on the background medication, refer to the corresponding national prescribing 
information.
Prior medication for treatment of CSU will be recorded in the Electronic Case Report Forms 
(eCRF). In addition, all concomitant medication at screening and prior medication that has been 
terminated within 4 weeks prior to screening will be recorded. The investigator should instruct 
the participant to notify the study site about any new medications (including medications that 
are not related to the treatment of CSU) he/she takes after the participant was enrolled into the 
study, ideally before initiating a new treatment.
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 eCRFs.
Each concomitant medication must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis medical 
monitor before treating a participant or allowing a new medication to be started. If the 
participant is already started the study treatment, contact Novartis to determine if the 
participation in the study should be continued.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed during the specified time 
period.
Table 6-2
Prohibited Medication
Medication
Prohibition period
Action taken
Biologics for treatment of CSU 
(including omalizumab and 
ligelizumab)
4 months prior to the first 
administration of study treatment 
until end of treatment1
Discontinue biologic treatment and 
closely monitor for potential 
associated adverse events.
Routine (more than 3 doses over 
5-day period) oral corticosteroids
30 days prior to screening until end 
of treatment
Oral corticosteroids are only 
allowed as an additional rescue 
therapy for CSU AFTER Week 
12, on an as-needed basis for 
unbearable symptoms as per 
Section 6.2.4. Other preparations 
of corticosteroids with limited
systemic exposure for non-CSU 
indications (e.g., intra-nasal or any 
Discontinue routine corticosteroids 
if medically justifiable and closely 
monitor for potential associated 
adverse events. If discontinuation 
of routine corticosteroids is not 
possible, discontinue study 
treatment.
 


Novartis
Confidential
Page 43 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Medication
Prohibition period
Action taken
topical corticosteroids) can be 
used on an as-needed basis.
i.v./IM/IA corticosteroids
30 days prior to screening until end 
of treatment1.
Discontinue i.v./IM/IA 
corticosteroids if medically 
justifiable and closely monitor for 
potential associated adverse 
events. If discontinuation of 
i.v./IM/IA corticosteroids is not 
possible, discontinue study 
treatment.
Leukotriene antagonists (including 
montelukast and zafirlukast)
From screening until end of 
treatment1
Discontinue Leukotriene 
antagonists and closely monitor for 
potential associated adverse 
events.
H2-antihistamines
From screening until end of 
treatment1
Discontinue H2-antihistamines and 
closely monitor for potential 
associated adverse events.
First-generation antihistamines
From screening until end of 
treatment1
Discontinue first-generation 
antihistamines and closely monitor 
for potential associated adverse 
events.
Second generation antihistamines 
other than the participant's 
defined background medication 
and rescue medication
From 7 days prior to the first 
administration of study treatment 
until end of treatment1
Discontinue all second-generation 
H1-antihistamines but the defined 
background and rescue medication 
and closely monitor for potential 
associated adverse events.
Other 
immunosuppressive/immunomodu-
lating medication with or without 
known effect on CSU including but 
not limited to hydroxychloroquine, 
methotrexate, cyclosporine A, 
cyclophosphamide, tacrolimus and 
mycophenolate mofetil
30 days or 5 half-lives (whichever 
is longer) prior to screening until 
end of treatment1
Discontinue immunosuppressive/
immunomodulating medication if 
medically justifiable and closely 
monitor for potential associated 
adverse events. If discontinuation 
not possible, discontinue study 
treatment.
Intravenous (i.v.) immunoglobulins 
or plasmapheresis
30 days prior to screening until end 
of treatment1
Discontinue i.v. immunoglobulins 
or plasmapheresis if medically 
justifiable and closely monitor for 
potential associated adverse 
events. If discontinuation not 
possible, discontinue study 
treatment.
Ultraviolet (UV) therapy
From screening until end of 
treatment1
Discontinue UV therapy and 
closely monitor for potential 
associated adverse events.
Any other therapy intended for the 
treatment of urticaria including but 
not limited to herbal therapies
From 2 weeks prior to the first 
administration of study treatment 
until end of treatment1
Discontinue any therapy intended 
for the treatment of urticaria and 
closely monitor for potential 
associated adverse events.
Live attenuated vaccines
6 weeks prior to baseline until at 
least 4 weeks after last dose of 
study treatment
Discontinue study treatment.
Strong inhibitors of CYP3A4
From 2 weeks prior to the first 
administration of study treatment 
until end of treatment1
Discontinue CYP3A4 inhibitor if 
medically justifiable and closely 
monitor for potential associated 
adverse events. If discontinuation 
 


Novartis
Confidential
Page 44 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Medication
Prohibition period
Action taken
not possible, discontinue study 
treatment
Moderate and strong inducers of 
CYP3A4
From 2 weeks prior to the first 
administration of study treatment 
until end of treatment1
Discontinue CYP3A4 inducers if 
medically justifiable and closely 
monitor for potential associated 
adverse events. If discontinuation 
not possible, discontinue study 
treatment.
Anticoagulant medication (e.g., 
warfarin, or NOAC)
From screening until end of 
treatment1
Only if medically justifiable, 
discontinue anticoagulant 
medication and interrupt study 
medication until anticoagulant 
effects have ended. Otherwise 
discontinue study treatment. 
Closely monitor coagulation 
parameters and associated 
adverse events.
Clinical monitoring should focus on 
skin (bruising, petechiae) and 
mucosa (e.g., gastro-intestinal tract 
bleeding including gingival and 
rectal, or conjunctival bleeding). In 
case of a significant bleeding 
event, study treatment must be 
discontinued immediately.
Anti-platelet medication except for 
acetylsalicylic acid up to 100 mg/d 
or clopidogrel up to 75 mg/d. The 
use of dual anti-platelet therapy 
(e.g., acetylsalicylic acid + 
clopidogrel) is prohibited.
From screening until end of 
treatment1
Only if medically justifiable, 
discontinue anti-platelet medication 
and interrupt study medication until 
anti-platelet effects have ended. 
Otherwise discontinue study 
treatment. Closely monitor 
coagulation parameters and 
associated adverse events. Clinical 
monitoring should focus on skin 
(bruising, petechiae) and mucosa 
(e.g., gastro-intestinal tract 
bleeding including gingival and 
rectal, or conjunctival bleeding). In 
case of a significant bleeding 
event, study treatment must be 
discontinued immediately.
1 The day when patient receives the last study treatment dose (i.e., on Week 52 or in case of early 
treatment discontinuation the day of last dose of study treatment).
6.2.3
Permitted concomitant therapy requiring caution and/or action
Remibrutinib has been shown to inhibit the BCRP transporter at the intestinal level. As a 
consequence, co-administration with remibrutinib can lead to exposure increases are under the 
curve of >1.5-fold. Therefore, concomitant administration of remibrutinib with respective 
BCRP substrates (e.g., pitavastatin, rosuvastatin, sulfasalazine and ubrogepan) may be 
accomplished with caution. BCRP substrates with a small safety margin may be administered 
2 hours before or after remibrutinib (staggered dosing).
 


Novartis
Confidential
Page 45 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Table 6-3
Permitted concomitant therapy requiring caution and/or action
Medication
Period
Guidance
Oral BCRP substrates that may have 
increased exposure when co-administered 
with remibrutinib (pitavastatin, rosuvastatin, 
sulfasalazine and ubrogepan)
1 day prior to dosing with 
remibrutinib until end of 
treatment
Use with caution, replace 
medication or administer 2hr 
before or after remibrutinib 
(staggered dosing)
6.2.4
Rescue medication
H1-antihistamines: In addition to being used as background medication, second generation 
H1-antihistamines are allowed as rescue medication, used on an as needed basis for participants 
with CSU flare-ups of unbearable symptoms during screening, treatment and follow-up periods. 
The selection of the rescue medication H1-antihistamine should be made only once for an 
individual participant and recorded in the source document. For each individual participant, the 
H1-antihistamine used as rescue medication must differ from the H1-antihistamine used 
as background medication. The daily dose of H1-antihistamine rescue medication should not 
exceed 4-fold of the approved dose, as recommended by the current urticaria treatment 
guidelines (Zuberbier et al 2018). For detailed information on the rescue medication, refer to 
the corresponding national prescribing information. A change of the rescue medication for an 
individual participant is only permitted in case of adverse reactions that are, in the judgment of 
the investigator, attributable to rescue medication.
Oral corticosteroids: Prior to Week 12, any corticosteroid use for CSU is prohibited. After 
Week 12, participants will be permitted to use oral corticosteroids such as prednisone or its 
equivalent, as rescue medication if needed for CSU flare-ups of unbearable symptoms. The 
selection of the oral corticosteroid to be used as rescue medication after Week 12, should be 
made only once for an individual participant. A switch of oral corticosteroids as rescue 
medication for an individual is not permitted except due to an AE. Rescue oral corticosteroid 
use will be limited to 3 days in a 30 day period and a maximum of 9 days in total after 
Week 12 to avoid any confounding suppression of signs and symptoms of CSU. The 
recommended dose is 20 - 50 mg prednisone or equivalent per day, which is in line with the 
current urticaria treatment guidelines (Zuberbier et al 2018).
Rescue medication will be sourced locally. Use of H1-antihistamine rescue medication only for 
CSU must be recorded in the eDiary by the participant (number of tablets taken) and the name 
and dose will be captured on the appropriate eCRF. All relevant information for oral 
corticosteroid rescue therapy will be captured in the appropriate eCRF.
6.3
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1).
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 Interactive Response Technology (IRT) and obtaining the medication number(s).
 


Novartis
Confidential
Page 46 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, delivery of IMP directly to a participant’s home may be permitted (if allowed by Local 
or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. The dispatch of IMP from the site to the participant’s 
home remains under the accountability of the Investigator. Each shipment/provisioning will be 
for a maximum of 1-month supply. In this case, phone calls, virtual contacts (e.g., tele consult) 
or visits by site staff/home nursing to the participant's home at the time of a planned on-site 
visit will occur for instructional purposes, safety monitoring, investigation of any adverse 
events, ensuring participants continue to benefit from treatment, and discussion of the 
participant's health status until it is safe for the participant to visit the site again.
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 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 
field monitors during regular monitoring visits, and at the completion of the trial.
Participants will be asked to return all unused study treatment and packaging at each site visit 
during the study and at 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 field monitor 
or to the Novartis address provided in the investigator folder at each site.
6.3.1.2
Handling of other treatment
Not applicable.
 










Novartis
Confidential
Page 51 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and 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.
For participants who discontinue from study treatment refer to Section 9.1.1.
Participants who discontinue from the study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit, if they agree, as soon 
as possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, all dispensed investigational product should be reconciled, and the adverse event 
and concomitant medications not previously reported must be recorded on the CRF.
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.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again.
The preferred sequence of assessments during study visits is PRO completion, ECG collection, 
followed by vital signs, and blood sampling.
 












Novartis
Confidential
Page 57 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
8.1
Screening
Screening and re-screening
Participants will have a screening period of 7 up to a maximum of 28 days to establish eligibility 
for the study.
Once all eligibility criteria have been assessed and the participant is eligible for enrollment in 
the study the baseline visit can be scheduled (this may be prior to the maximum 28 day screening 
period duration).
Evaluation of participant eligibility for laboratory parameters listed in Section 5.2 must be 
based on central laboratory results. In case eligibility criteria are not met for specific laboratory 
parameters, these may be re-tested a maximum of once during the screening period.
If for any reason a participant is a screen failure, the participant may be re-screened. Re-
screening is only allowed once. There is no restriction on how much time must pass from the 
date of screen failure to the date of re-screening.
If a participant re-screens for the study, then they must sign a new ICF and be issued a new 
participant number prior to any screening assessment being conducted for the participant under 
the new screening subject number. The investigator/qualified site staff will record if the 
participant was re-screened on the re-screening eCRF and any applicable screening numbers 
the participant was issued prior to the current screening number.
The date of the new informed consent signature must be entered on the informed consent eCRF 
to correspond to the new screening subject number. For re-screening, all screening assessments 
must be performed per protocol.
8.1.1
Information to be collected on screening failures
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to start the study treatment 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 (SAE) during the 
screening phase (see SAE section for reporting details). If the participant fails to enter the 
treatment phase, the IRT must be notified within 2 days of the screen fail that the participant 
was not enter the treatment phase.
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason 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
Baseline CSU activity will be assessed using the eDiary from Day -7 to Day -1.
 


Novartis
Confidential
Page 58 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF.
Participant demographic and baseline characteristic data to be collected at screening on all 
enrolled participants:

Demography (age, sex, race and ethnicity) information on racial and ethnicity will be 
collected and analyzed to document that the Japanese participants are recruited.

Relevant medical history (including evaluation of inclusion/exclusion criteria, evidence of 
urticaria, CSU history and cardiovascular history) and current medical condition present 
before signing the informed consent. Where possible, diagnoses, and not symptoms, will 
be recorded.

Data on participants’ family history of malignancies will be collected on the respective 
eCRF page, only when a participant has a malignancy event reported during the study, to 
assess possible risk factors related to any malignancies.

Prior urticaria treatment and background therapy

All concomitant medication at screening and prior medication that has been terminated 
within 4 weeks prior to screening

Furthermore, the following assessments will be performed:

Physical examination, height and weight

Vital signs including blood pressure and pulse

12-lead ECG

Laboratory evaluations (e.g., Clinical Chemistry, Hematology, Urinalysis, 
Coagulation Panel)

Pregnancy Test for all pre-menopausal women
8.3
Efficacy
8.3.1
eDiary assessments
All participants will be provided with an electronic device (eDiary) that contains the following 
Patient Reported Outcomes (PRO) assessments: UPDD and AAS.
Site and participants will receive appropriate training and guidance on the use of the eDiary and 
will receive clear instructions on the completion of the assessments. Investigators need to 
review the eDiary at every visit.
Assessments will be completed twice daily (UPDD), once daily (AAS, if triggered by opening 
question within the UPDD) from screening to Week 52/study discontinuation or until early 
treatment discontinuation visit for participants who decline to continue the assessments.
In general, participants complete eDiary questionnaires at home and independent of study visits. 
Participants will be instructed to complete eDiary entries after they took their study medication 
throughout the treatment period.
The DLQI, 
questionnaires will be administered 
during respective visits on site and should be completed prior to any other study specific 
procedure 
. Site personnel must allow participants to complete the questionnaire 
 


Novartis
Confidential
Page 59 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
on their own without any assistance from the site staff. In the case that participants cannot come 
to site (see Section 4.6), the DLQI, 
will be available 
on their electronic device.
8.3.1.1
Urticaria Patient Daily Diary (UPDD)
UPDD includes Urticaria Activity Score (UAS) which assesses twice daily severity of itch and 
number of hives, use of rescue medication, sleep and activity interference, angioedema 
occurrence, its management and records the calls to a healthcare professional (HCP). The 
components are presented in the Table 8-2 and the relevant weekly scores are described below.
Table 8-2
UPDD
Diary component
When assessed
Urticaria Activity Score (UAS)

Itch severity

Number of hives
Morning and evening
Sleep interference
Morning
Daily activity interference
Evening
Rescue medication use
Evening
Angioedema:

Whether patient had an episode

If patient had an episode, how did they manage it
Evening
Contact health care provider
Evening
8.3.1.1.1 Weekly Hives Severity Score (HSS7)
The hives (wheals) severity score, defined by number of hives, will be recorded by the 
participant twice daily in their eDiary, on a scale of 0 (none) to 3 (> 12 hives/12 hours; Table 
8-3). A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days 
preceding the visit. The possible range of the weekly score is therefore 0 - 21.
Table 8-3
Hives Severity Score
Score
Hives (Wheals) (every 12 hours)
0
None
1
1-6 hives/12 hours
2
7-12 hives/12 hours
3
>12 hives/12 hours
8.3.1.1.2 Weekly Itch Severity Score (ISS7)
The severity of the itch will be recorded by the participant twice daily in their eDiary, on a scale 
of 0 (none) to 3 (severe) (Table 8-4). A weekly score (ISS7) is derived by adding up the average 
daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 
0 - 21.
 




Novartis
Confidential
Page 61 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301

Did nothing

Took some prescription or non-prescription medication

Called my doctor, nurse or nurse practitioner

Went to see my doctor, nurse or nurse practitioner

Went to the emergency room at the hospital

Was hospitalized.
8.3.1.1.8 Number of calls to doctor or nurse
The number of calls to doctor, nurse or nurse practitioner because of the participant’s skin 
condition will be recorded once daily in the eDiary by the participant.
8.3.1.2
Angioedema Activity Score (AAS)
AAS is recorded once daily in the evening in the eDiary by the participant. This validated tool 
assesses occurrence of episodes of angioedema. As an opening question, the occurrence of 
angioedema in the UPDD (see Section 8.3.1.1.7) will be used. If participants answer this 
opening question in the UPDD with “no”, AAS score for this day is 0. If “yes” is the answer to 
the opening question in the UPDD, the participant will continue to answer questions about the 
duration, severity and impact on daily functioning and appearance of the angioedema (see 
Appendix 5). A score between 0 and 3 is assigned to every answer field. The AAS score in this 
study will be reported as weekly AAS (AAS7). Minimum and maximum possible AAS7 scores 
are 0−105. A higher score means higher severity.
8.3.2
Other Patient Reported Outcomes (PRO) assessments
8.3.2.1
Dermatology Life Quality Index (DLQI)
The DLQI is a 10-item (grouped in 6 domains) dermatology-specific quality of life (QoL) 
measure (Finlay and Khan 1994). The DLQI was validated for patients aged 16 and above. 
Participants rate their dermatology symptoms as well as the impact of their skin condition on 
various aspects of their lives thinking about the previous 7 days.
An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-
related QoL). Domain scores are calculated for: Symptoms and Feelings (0-6), Daily Activities 
(0-6), Leisure (0-6), Work and School (0-3), Personal Relationships (0-6), Treatment (0-3).
The overall DLQI score range was split into score bands (Hongbo et al 2005) and validated in 
terms of their meaning/relevance to patients as follows:
Table 8-7
DLQI score bands and impact on patient's life
DLQI band
Significance of score
0-1
No effect on patient's life
2-5
Small effect on patient’s life
6-10
Moderate effect on patient’s life
11-20
Very large effect on patient’s life
21-30
Extremely large effect on patient’s life
 






Novartis
Confidential
Page 64 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
record of the participant by a physician trained in the management of urticaria in the past 3 
months.
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 8-8
Physical assessments
Assessment
Specification
Physical 
examination
A complete physical examination (performed at Screening) will include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, neurological and body temperature 
measurement (per local practice). If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
A short physical exam (performed at all visits except Screening) will include the 
examination of general appearance, assessment of the skin for signs of urticaria and 
other skin lesions, body temperature measurement (per local practice) and vital signs 
(blood pressure (BP) [systolic blood pressure (SBP) and diastolic blood (DBP)] and 
pulse).
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed 
consent must be recorded on the appropriate CRF that captures medical history. 
Significant findings made after signing informed consent which meet the definition of an 
Adverse Event must be recorded as an adverse event.
Vital signs
Vital signs include BP and pulse measurements. After the participant has been sitting for 
five minutes, with back supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured three times using an automated validated device, e.g., 
OMRON, with an appropriately sized cuff. The repeat sitting measurements will be made 
at 1 - 2 minute intervals and the mean of the three measurements will be used. 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.
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 as specified in Table 8-1.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section (Table 8-
9) unless noted otherwise. Details on the collections, shipment of samples and reporting of 
results by the central laboratory are provided to investigators in the laboratory manual.
If participants cannot visit the site for protocol specified safety lab assessments (per Section 4.6), 
an alternative lab (local) collection may be used.
Clinically notable laboratory findings are defined in Section 16.1.
 


Novartis
Confidential
Page 65 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Clinically significant abnormalities must be recorded on the relevant section of the eCRF 
capturing medical history/current medical conditions/AEs.
Table 8-9
Laboratory assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, [in the case of clinically significant anemia the following 
parameters will be assessed: Ery. Mean Corpuscular Hemoglobin (MCH), Ery. Mean 
Corpuscular Hemoglobin Concentration (MCHC), Ery. Mean Corpuscular Volume (MCV)], 
Platelets, Erythrocytes, Leukocytes, and Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Bands)
Chemistry
Albumin, Alkaline phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate 
Aminotransferase (AST), Gamma-glutamyl-transferase (GGT), Lactate dehydrogenase 
(LDH), Calcium, Magnesium, Phosphate, Chloride, Sodium, Potassium, Creatinine, 
Creatine Kinase (CK), Direct Bilirubin, Indirect Bilirubin (in case of clinically significant 
elevation), Total Bilirubin, Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, 
High Density Lipoprotein (HDL) Cholesterol, Total Protein, Triglycerides, Urea Nitrogen or 
Urea, Uric Acid, Amylase, Lipase
C-reactive protein (CRP), estimated Glomerular Filtration Rate (eGFR): in all patients at 
screening, baseline, Weeks 12, 24 and 52 and when deemed necessary by the investigator 
at any other visits than those listed. Fasting glucose assessed at baseline, Weeks 2, 12 
and 52.
Urinalysis
Done on site: Macroscopic Panel (Dipstick) (Color, Bilirubin, Occult Blood, 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)
Hepatitis 
screening
Hepatitis B screening: Antibodies against Hepatitis B virus core antigen (HBcAb or anti-
HBc); antibodies against Hepatitis B virus surface antigen (HBsAb or anti-HBs); Hepatitis B 
virus surface antigen (HBsAg).
Hepatitis B virus-Deoxyribonucleic acid (HBV-DNA, only in participants who are positive 
for HBcAb or anti-HBc). The study site may refer to local guidelines for hepatitis B 
monitoring.
Hepatitis C screening: Hepatitis C virus antibodies (anti-HCVAb) and Hepatitis C-
Ribonucleic acid (HCV-RNA, only in participants who are positive for anti-HCVAb)
Hepatitis B re-
activation 
monitoring
Only in participants who are positive for HBcAb (anti-HBc positive) and negative for HBsAb
and HBV-DNA at screening: HBsAg, HBV-DNA. 
The study site may refer to local guidelines for hepatitis B re-activation monitoring.
HIV testing
HIV test performed at screening, only when required by local regulations.
Additional tests
Follicle-stimulating hormone (FSH) (for female participants with unclear fertility status)
Pregnancy Test
Serum / Urine pregnancy test for WoCBP (refer to Section 8.4.3)
8.4.2
Electrocardiogram (ECG)
ECGs must be recorded according to the ECG investigator manual. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital signs, 
and blood sampling. The Fridericia QT correction formula (QTcF) should be used for clinical 
decisions.
Triplicate 12-lead ECGs are to be collected approximately 2 minutes apart for central 
analysis. The mean QTcF value for each visit will be calculated from the triplicate ECGs for 
each participant. At Weeks 2, 12 and 52 pre and post-dose assessments should be collected 
(refer to Table 8-1), post dose assessment should be measured 
 
 


Novartis
Confidential
Page 66 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
and the mean QTcF 
value for each timepoint will be calculated from the triplicate ECGs for each participant.
All ECGs, including unscheduled safety ECGs with clinically relevant findings collected during 
the study needs to be transmitted to the central ECG laboratory for review.
A monitoring or review process should be in place for clinically significant ECG findings 
throughout the study and especially at baseline before administration of study treatment.
In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
arrhythmia, conduction abnormality of QTcF > 450 ms (males)/ 460 ms (females)), a copy of 
the assessment is sent to the core laboratory for expedited review if applicable, and the ECG is 
repeated to confirm the diagnosis. If the participant is hemodynamically compromised, the 
investigator or a medically qualified person must initiate appropriate safety procedures without 
delay (for example cardioversion).
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.
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate.
If participants cannot visit the site for protocol specified safety ECG assessments (per 
Section 4.6), an alternative machine (local) may be used.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing at 
screening (serum), at baseline (Day 1, before administration of study medication (urine)), and 
every 4 weeks thereafter (urine). Where the visit interval is greater than 4 weeks, or in the case 
that the participants cannot visit the site, the participants will be provided with urine pregnancy 
tests kits to be used at home. Results must be provided to the investigator at the next scheduled 
visit. Participants should be 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 positive urine pregnancy test needs to be confirmed with a serum test. Where a home urine 
pregnancy test is positive the participant must contact the investigator and return to site for a 
serum pregnancy test, in the case that participants cannot visit the site an alternative (local lab) 
can be used. If positive the participant must be discontinued from 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).
Additional pregnancy testing might be performed if requested by local requirements.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or bilateral 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:
 










Novartis
Confidential
Page 71 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301

Emergence of the following AEs: 

any adverse events that in the judgement of investigator, taking into consideration the 
participant’s overall status, prevents the participant from continuing participation in 
the study, including: 

hypersensitivity reactions,

severe/serious infections 

clinically significant spontaneous bleeding events

new confirmed diagnosis of malignancy of any organ system (other than 
localized basal cell carcinoma of the skin or in situ cervical cancer)

Platelets < 75 000/mm3

Abnormal renal laboratory results requiring discontinuation (see Section 16.3)

Abnormal liver laboratory results requiring discontinuation (see Section 16.2)

Any other 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

Participant received a live virus vaccination during the study
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.
All participants who discontinue from study treatment prematurely should complete the 
Early treatment discontinuation visit at the time of treatment discontinuation.
For participants who discontinue from study treatment prior to Week 12, where possible they 
should be requested to return for visits after the Early treatment discontinuation visit as per the 
Assessment Schedule (Table 8-1) up to and including the Week 12 timepoint. At the Week 12 
timepoint the study discontinuation visit should be performed 
 If 
the participant declines to continue with assessments as per the visit schedule up to Week 12, 
then they should complete the safety follow-up visit after the Early treatment discontinuation 
visit.
Participants who discontinue from study treatment after Week 12 should complete the safety 
follow-up visit indicated in the Assessment Schedule (Table 8-1) whenever possible.
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.
 


Novartis
Confidential
Page 72 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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, including 
participant’s decision (requested in writing or verbally).
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.
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 or verbally (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
Confidential
Page 73 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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 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, enrolls into the planned extension study following completion 
of the 52 week treatment period or, in the event of an early study termination decision, the date 
of that decision.
Participants who complete participation in the 52 week treatment period of this trial may be 
eligible to receive remibrutinib as part of an extension study (under development) if they meet 
the eligibility criteria defined in the extension study protocol.
The extension study will require endorsement as per local laws and regulations.
9.4
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. Following instruction from Novartis, 
investigators must contact the participant to schedule the study discontinuation and study 
completion visits (as appropriate) and provide instruction regarding study drug intake. 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.
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. 
 


Novartis
Confidential
Page 74 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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.
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
6. Its outcome
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 30 days following the last dose of 
study treatment.
 


Novartis
Confidential
Page 75 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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. See Section 16.1, Section 16.2 and Section 16.3 for alert ranges for 
laboratory and other test abnormalities.
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

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
 


Novartis
Confidential
Page 76 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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 (see Section 10.1.5).
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, then local regulations regarding reporting timelines prevail). 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 electronic 
serious adverse event (eSAE) (with paper backup if required). Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report.
1. Screen Failures (e.g., a participant who is screened but is not treated): SAEs occurring 
after the participant has provided informed consent until the time the participant is deemed 
a Screen Failure must be reported to Novartis with 24 hours of learning of its occurrence.
2. Treated Participants: SAEs collected between time participant signs ICF until 30 days 
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, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, then local regulations 
regarding reporting timelines prevail). 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 IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety (CMO 
& PS) Department associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
 


Novartis
Confidential
Page 77 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment 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 Targeted 
Follow-up pregnancy - Infant status form and should include an assessment of the possible 
relationship to the study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported.
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 
consumer (European Medicines Agency definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
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.
 


Novartis
Confidential
Page 78 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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 10.1.1 and Section 10.1.2).
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 Table 16-1 in 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 Table 16-2 and 
Table 16-3. Repeat liver chemistry tests (i.e., ALT, AST, TBL, PT/INR, ALP and GGT) to 
confirm elevation.
These liver chemistry repeats will be performed using the central laboratory. If results will not 
be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the 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 Section 9.1 and Section 16.2), if 
appropriate

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include, based on investigator's discretion:

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
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
 


Novartis
Confidential
Page 79 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Any one of the following:

Urine protein-creatinine ratio (PCR) ≥1 g/g or ≥100 mg/mmol, OR

New onset dipstick proteinuria ≥ 3+, OR

New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma)
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
as defined in Table 16-4 should be followed up by the investigator or designated personnel at 
the trial site as summarized in Table 16-5.
10.3
Committees
10.3.1
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify, or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
10.3.2
Steering Committee
A steering committee has been established comprising medical and scientific experts who are 
not members of the DMC, and Novartis representatives from the Clinical Trial Team.
The steering committee will ensure transparent management of the study according to the 
protocol through recommending and approving modifications as circumstances require. The 
steering committee will review the initial protocol and protocol amendments as appropriate. 
Together with the clinical trial team, the steering committee will also develop recommendations 
for publications of study results including authorship rules.
 


Novartis
Confidential
Page 80 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Designated investigator staff will enter the data required by the protocol into the 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.
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 (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Dates of screenings, scheduled visit, screen failures and study completion, as well as data about 
all study treatment(s) dispensed to the participant will be tracked using an Interactive Response 
Technology (IRT). The system will be supplied by Novartis, who will also manage the database. 
The data will be sent electronically to Novartis at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis representative will review the protocol and data capture requirements (i.e., eCRFs) 
 


Novartis
Confidential
Page 81 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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/CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
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 analysis will be conducted on all participants' data at the time the trial ends regardless of 
the interim analysis.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The following analysis sets will be used in this study.
Safety Set: The Safety Set includes all participants who received at least one dose of study 
treatment. The safety set will be used in the analysis of all safety variables.
Full Analysis Set (FAS): The FAS comprises all participants to whom study treatment has been 
assigned and received at least one dose of the treatment. The FAS will be used for all efficacy 
variables, unless otherwise stated.
Note that the Safety Set and the FAS are the same except that the Safety Set allows inclusion 
of participants to whom study treatment has not been assigned but received study drug in error.
 


Novartis
Confidential
Page 82 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively 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. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized as 
frequencies and percentage combined by system organ class and preferred term for the Safety 
Set.
Baseline for safety is the last assessment (including unscheduled visits) obtained on or before 
the day of the first dose of study treatment. All assessments obtained after the first dose of study 
treatment are considered as post-baseline unless otherwise specified.
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, 25th and 75th percentiles, minimum, and maximum will be 
presented.
The duration of exposure in weeks to remibrutinib will be summarized.
The duration of exposure to study treatment will be computed without excluding temporary 
treatment interruptions.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the ATC classification system.
Prior medications are defined as drugs taken and stopped prior to first dose of study medication. 
Any medication given at least once between the day of first dose of the study medication and 
the last day of study visit will be a concomitant medication, including those which were started 
pre-baseline and continued into the treatment period. Prior or concomitant medication will be 
identified based on recorded or imputed start and end dates of medication taking.
12.4
Analysis supporting primary objectives
This section will detail the statistical analysis of the primary (safety) estimand.
12.4.1
Definition of primary endpoints
The assessment of safety is based on all safety outcomes including reported adverse events or 
routine assessments such like vital signs, lab parameters or ECG measures. The estimand 
framework cannot be explicitly applied to all parameters. However, it may be useful to apply 
the estimand framework for treatment-emergent AEs.
In the majority of cases the assessments are not performed after permanent treatment 
discontinuation but the data collection are continued until end of safety follow-up period. For 
 


Novartis
Confidential
Page 83 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
the sake of consistency, main estimands defined for treatment-emergent AEs should follow the 
same logic.
The broad clinical question to be addressed is then: what is the safety of LOU064 while 
participant is still on-treatment, i.e., has not yet discontinued for any reasons?
The primary clinical question of interest regarding safety as primary endpoint is: What is the 
effect of remibrutinib treatment on the incidence of 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) in adult participants with CSU who are 
inadequately controlled by H1-antihistamine and receiving a stable locally label approved dose 
of a second-generation H1-antihistamine, regardless of treatment discontinuation for any reason, 
non-compliance (interruption) to treatment, switch of background medication or intake of a 
different second-generation H1-antihistamine as rescue medication/confounding prohibited 
medication? (see Section 2.1)
The primary (safety) endpoint (variable) is the number and the proportion of participants with 
treatment-emergent adverse event. The treatment-emergent adverse event is defined as event 
started during on-treatment period or event present prior to start of treatment but increased in 
severity based on preferred term. The on-treatment period lasts from the date of first 
administration of study treatment to 28 days after the date of the last actual administration of 
the study treatment.
12.4.2
Statistical model, hypothesis, and method of analysis
The number and the proportion (%) of participants with the treatment emergent adverse events 
will be summarized in the following ways:

by primary system organ class and preferred term.

by primary system organ class, preferred term and maximum severity.

by Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
In addition, a separate summary for deaths including on-treatment and post-treatment deaths 
will be provided.
The number and the proportion (%) of participants with adverse events of special interest for 
remibrutinib (related to identified and potential risks) will be summarized.
If a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one adverse 
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable.
All information obtained on adverse events will be displayed by participant.
All analyses for the primary (safety) endpoint will be performed descriptively. No statistical 
hypothesis is set for the primary (safety) endpoint in this study.
For all safety analyses, the Safety Set will be used.
 


Novartis
Confidential
Page 84 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
12.4.3
Handling of intercurrent events of primary estimand
The analysis will account for different intercurrent events as explained in the following:

Discontinuation of study treatment due to any reason:
data collection will be maintained in the follow-up period. The data collected after these 
events will be used for analysis.

Treatment non-compliance (interruption), switch of background medication, or intake of 
rescue medication as per protocol:
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment. Data 
collected after these events will be used for analysis (Treatment policy strategy).

Intake of strongly confounding prohibited medication (e.g., biologics treatment, 
cyclosporine, systemic corticosteroids):
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment: Data 
collected after these events will be used for analysis (Treatment policy strategy).

Administration of medications affecting the evaluation of potential risks, including: (a) 
anticoagulant/anti-platelet medications (other than acetylsalicylic acid up to 100 mg/d or 
clopidogrel); (b) live attenuated vaccines; (c) strong CYP3A4 inhibitors; (d) 
moderate/strong CYP3A4 inducers, (e) Oral BCRP* substrates that may have increased 
exposure when co-administered with remibrutinib (pitavastatin, rosuvastatin, sulfasalazine 
and ubrogepan):
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment: Data 
collected after these events will be used for analysis (Treatment policy strategy).

Intake of other prohibited medication:
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment: Data 
collected after these events will be used for analysis (Treatment policy strategy).
* Assessment of confounder BCRP will be specified in the SAP.
12.4.4
Handling of missing values not related to intercurrent event
No imputation will be done for missing data. All available data will be used for the analyses.
12.4.5
Sensitivity analyses
If unexpectedly high incidence of adverse events of special interest (AESI) is observed, then
sensitivity analysis may be performed for the AESI.
The following sensitivity analysis may be performed on AESI, to assess the causality between
the occurrence of AESI and medications. The sensitivity analysis will be implemented with the 
same target population, on AESI variable and the summary measure as for the primary estimand, 
but using the different assumptions or handling of intercurrent events.
 


Novartis
Confidential
Page 85 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301

Intake of strongly confounding prohibited medication (e.g., biologics treatment, 
cyclosporine, systemic corticosteroids): only measurements prior to intake of these 
prohibited medications will be used for analysis (While on treatment strategy).

Intake of medications affecting the evaluation of potential risks, including: (a) 
anticoagulant/anti-platelet medications (other than acetylsalicylic acid up to 100 mg/d or 
clopidogrel); (b) live attenuated vaccines; (c) strong CYP3A4 inhibitors; (d) 
moderate/strong CYP3A4 inducers, (e) Oral BCRP* substrates that may have increased 
exposure when co-administered with remibrutinib (pitavastatin, rosuvastatin, sulfasalazine 
and ubrogepan): only measurements prior to intake of these medications will be used for 
analysis (While on treatment strategy).
* Assessment of confounder BCRP will be specified in the SAP.
12.4.6
Supplementary analysis
No supplementary analysis is planned for the primary (safety) endpoints.
12.5
Analysis supporting secondary objectives
This section will detail the statistical analysis of the secondary (efficacy) estimands (see
Section 2.2).
12.5.1
Efficacy and/or Pharmacodynamic endpoints
Definition of secondary endpoints
The secondary clinical question of interest regarding efficacy as secondary endpoint, change 
from baseline in UAS7 score at Week 12 is: What is the effect of remibrutinib treatment on the 
change from baseline in UAS7 score at Week 12 after treatment in adult participants with CSU 
who are inadequately controlled by H1-antihistamine and receiving a stable locally label 
approved dose of a second-generation H1-antihistamine, regardless of treatment 
discontinuation for any reason or intake of a different second-generation H1-antihistamine as 
rescue medication and considering strongly confounding prohibited medication use as an 
unfavorable outcome?
One of the secondary (efficacy) endpoints (variables) is the absolute change from baseline in
UAS7 score at Week 12, which is the UAS7 score at Week 12 minus the UAS7 score at baseline. 
The UAS7 is the sum of the HSS7 score and the ISS7 score, and ranges from 0-42. Weekly 
scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 
days preceding the visit.
Other secondary endpoints are listed in the Table 2-1.
Statistical model, hypothesis, and method of analysis
The secondary (efficacy) variables during the study, including absolute change from baseline 
in UAS7 score at Week 12, will be summarized (by visit, if applicable).
Baseline for efficacy is comprised of the 7 days prior to Day 1 (Enrollment in treatment period 
day) for UAS7 and other assessment on or prior enrollment in treatment period day.
 


Novartis
Confidential
Page 86 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
All analyses for the secondary (efficacy) endpoints will be performed descriptively. No 
statistical hypothesis is set for the secondary (efficacy) endpoints in this study.
For all efficacy analyses, the FAS will be used.
The analyses will be performed based on the data after the missing data imputation for the 
intercurrent events have been performed.
Handling of intercurrent events of secondary estimand
Participants who discontinue from study treatment early due to any reason will be encouraged 
to stay in the study following the procedures. Every effort will be made to continue to follow 
participants who discontinued from study treatment up to Week 12. These are considered as 
Retrieved drop-out (RDO) participants.
The analysis will account for different intercurrent events as explained in the following:

Discontinuation of study treatment prior to Week 12 due to any reason: ignore, i.e., data 
collection will be maintained and available measurements post-treatment discontinuation 
will be used as if they had been obtained under the treatment: RDO data collected after 
study treatment discontinuation will be used for analysis (Treatment policy strategy).

Treatment non-compliance (interruption), switch of background medication, or intake of 
rescue medication as per protocol prior to Week 12: ignore, i.e., data collected after these 
events will be used for analysis (Treatment policy strategy).Intake of strongly 
confounding prohibited medication (e.g., biologics treatment at any time before Week 12, 
cyclosporine after Week 8, systemic corticosteroids after Week 8): measurements after 
this event will be excluded from the analysis and will be imputed using the worst value of 
the endpoint (e.g., 42 for UAS7 score at Week 12, or non-response for binary endpoints) 
(Composite strategy (irrespective of potential occurrence of other intercurrent events)).

Intake of other prohibited medication prior to Week 12: ignore, i.e., data collected after 
these events will be used for analysis (Treatment policy strategy).
Handling of missing values not related to intercurrent event
The UAS7 score is derived from the sum of the HSS7 score and the ISS7 score. The HSS7 and 
ISS7 score will be derived by adding up the daily HSS and ISS scores of the 7 days preceding 
the visit, respectively. The daily score (HSS and ISS) will be calculated by averaging the 
morning and evening HSS and ISS score, respectively. If one of the morning or evening scores 
is missing, the non-missing score for that day (morning or evening) will then be used as the 
daily score.
For each weekly score from the UPDD (i.e., HSS7, ISS7), if one or more of the daily scores are 
missing, the following principles will be applied to handle the missing data:

The weekly UAS7 is the sum of both the HSS7 score and the ISS7 score and will be 
missing if at least one of them is missing.

If a patient has at least 4 non-missing daily (morning or evening) scores within the 7 days 
prior to the study visit, the weekly score for HSS or ISS will be calculated as the sum of 
the available eDiary scores of that week, divided by the number of non-missing days, 
multiplied by 7.
 










Novartis
Confidential
Page 91 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
screened in order to collect approximately 70 participants who enter the treatment period and 
to collect a total of approximately 60 completed participants.
12.8.1
Primary endpoint
Not applicable.
12.8.2
Secondary endpoints
Not applicable.
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.
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.
 


Novartis
Confidential
Page 92 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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 Standard Operating Procedures, 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

Individual study results - after CSR publication

Trial Feedback Questionnaires - 3 timepoints: at the start, during and at the end of the 
trial.
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.
 


Novartis
Confidential
Page 93 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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.
 










Novartis
Confidential
Page 98 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The following specific criteria have been identified for this study. Should these criteria be met, 
a re-test must be done within 5 days after the first assessment. Discontinuation of the study 
treatment should be considered if the abnormal hematology parameter is confirmed:

Hemoglobin: < 10 g/dl

Platelets: < 75 000/mm3

Leukocytes: < 3 000/mm3

Neutrophils: < 1 500/mm3
For all other laboratory assessments, the central laboratory will flag laboratory values falling 
outside of the normal ranges on the central laboratory report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the eCRF.
Refer to Section 16.2 for clinically notable laboratory values for hepatotoxicity.
Refer to Section 16.3 for clinically notable laboratory values for nephrotoxicity.
Notable values for vital signs and change from baseline will be summarized.
Notable values are defined as follows:

heart rate of < 50 or > 100 bpm

systolic blood pressure of < 90 and ≥ 140 mmHg

diastolic blood pressure of < 60 and ≥ 90 mmHg.
For ECGs, a notable QTc value is defined as an absolute QTc (Fridericia’s) interval of greater 
than 450 ms for males or greater than 460 ms for females QTcF increase of ≥60 ms compared 
to baseline QTcF value – all such ECGs will be flagged by the central CRO’s cardiologist and 
require assessment for clinical relevance by the investigator.
 


Novartis
Confidential
Page 99 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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
ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ULN:
upper limit of normal
Table 16-2
Follow up requirements for liver laboratory triggers: ALT, AST and 
TBL
Trigger
Liver Symptoms
Action Taken
Monitoring
Follow-up 
Monitoring
Study Medication
ALT
ALT > 3 ULN
TBL normal, or no 
change for 
participants with 
Gilbert’s syndrome
None
Measure ALT, AST, 
ALP, GGT, TBL, 
INR, albumin, CK, 
and GLDH in 48-72 
hours
Follow up for 
symptoms
Continue dosing
ALT > 5 x ULN for 
more than two 
weeks
TBL normal, or no 
change for 
participants with 
Gilbert’s syndrome
None
Measure ALT, AST, 
ALP, GGT, TBL, 
INR, albumin, CK, 
and GLDH in 48-72 
hours
Follow-up for 
symptoms
Initiate close 
monitoring and 
workup for 
competing 
etiologies
Interrupt
Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline
ALT > 8 x ULN
TBL normal, or no 
change for 
participants with 
Gilbert’s syndrome
None
Measure ALT, AST, 
ALP, GGT, TBL, 
INR, albumin, CK, 
and GLDH in 48-72 
hours
Follow-up for 
symptoms
Initiate close 
monitoring and 
workup for 
competing 
etiologies
Interrupt
Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline
ALT > 3 x ULN
TBL > 2 x ULN (or 
INR > 1.5)
For patients with 
None
Measure ALT, AST, 
ALP, GGT, TBL, 
INR, albumin, CK, 
Follow-up for 
symptoms
Initiate close 
monitoring and 
Interrupt
Study drug can be 
restarted only if 
another etiology is 
 


Novartis
Confidential
Page 100 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Trigger
Liver Symptoms
Action Taken
Monitoring
Follow-up 
Monitoring
Study Medication
Gilbert’s syndrome: 
Doubling of direct 
bilirubin
and GLDH in 48-72 
hours
workup for 
competing 
etiologies
identiﬁed and liver 
enzymes return to 
baseline
ALT > 3 x ULN
TBL normal or 
elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
Measure ALT, AST, 
ALP, GGT, TBL, 
INR, albumin, CK, 
and GLDH in 48-72 
hours
Follow-up for 
symptoms
Initiate close 
monitoring and 
workup for 
competing 
etiologies
Interrupt
Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline
Total Bilirubin (isolated)
>1.5 – 3.0 ULN
Repeat LFTs within 
48-72 hours
Monitor LFTs 
weekly until 
resolution1 to ≤ 
Grade 1 or to 
baseline
Continue dosing
> 3 - 10 × ULN (in 
the absence of 
known Gilbert 
syndrome)
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 
resolution1 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)
Interrupt
> 10 x ULN
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 
resolution1 (frequen
cy at investigator 
discretion)
Discontinue 
treatment 
immediately
General Clinical Symptoms
Any AE potentially indicative of a liver 
toxicity including: (General) malaise, 
fatigue, abdominal pain, nausea, or 
vomiting, or rash with eosinophilia
Establish causality
Record the AE and 
contributing 
factors(e.g., 
conmeds, med hx, 
lab) in the 
appropriate CRF
Investigator 
discretion
Consider study 
treatment 
interruption or 
discontinuation
1 Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death
Alb: Albumin, ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, AST: Aspartate 
aminotransferase, CK: Creatinine kinase, CRF: Case report form, GGT: Gamma-glutamyl transferase, 
GLDH: glutamate dehydrogenase, INR: International Normalized Ratio, LFTs: Liver function tests, Med 
Hx: medical history, PT: Prothrombin time, TBL: Total bilirubin, ULN: upper limit of normal
 


Novartis
Confidential
Page 101 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
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 (≤ 1.5 
ULN)
or to baseline
> 3 - 10 x 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 (≤ 1.5 ULN) 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 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.
 


Novartis
Confidential
Page 102 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific renal alert criteria and actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow -up within 2-5 days; increase fluid intake before 
assessment if appropriate

Repeat follow-up (every 2-5 days) until creatinine is 
<125% of baseline value
Serum creatinine increase ³ 50 % 1

Consider causes and possible interventions and initiate 
renal investigation

Repeat assessment within 24-48 h if possible

Interruption of study drug

Close follow-up (every 24-48 h), consider participant 
hospitalization and specialized treatment until creatinine 
is <125% of baseline value
New onset dipstick proteinuria ≥ 31
When urine proteins are measured as a follow-
up of positive urine dipstick 
measurements:Protein-creatinine ratio (PCR) ≥ 
1 g/g Cr (or mg/mmol equivalent as converted 
by the measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected
New onset hematuria ≥ 31 on urine dipstick

Assess and document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the distal urinary 
tract/bladder, menstruation

Consider bleeding disorder
1 Corresponds to KDIGO criteria for Acute Kidney Injury
Whenever a renal event is identified, a detailed participant history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, eg, dehydration due to delirium, tumor lysis
 


Novartis
Confidential
Page 103 of 103
Amended Protocol Version No. 01 (Clean)
Protocol No. CLOU064A1301
Table 16-5
Renal event follow-up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in the CRF:

Urine dipstick and sediment microscopy evidence of Drug-Induced Nephrotoxicity (DIN): crystals, red blood 
cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) in the CRF
Monitor participant regularly (frequency at investigator's discretion) until:

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization 
at a new level with ±50% variability over last 6 months.
Analysis of urine markers in samples collected over the course of the DIN event
 

SAP_001.pdf: 
Clinical Development
LOU064/remibrutinib
CLOU064A1301
A multicenter, open-label Phase 3 study of remibrutinib (LOU064) to 
investigate the safety, tolerability and efficacy for 52 weeks in adult 
Japanese chronic spontaneous urticaria patients inadequately 
controlled by H1-antihistamines
Statistical Analysis Plan (SAP)  
Document type:
SAP Documentation
Document status:
Amendment 4
Release date:
9-Jan-2024
Number of pages:
54
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










Novartis
Confidential
Page 6 of 54
SAP
Study No. CLOU064A1301
Date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted (Current)
Section 2.7.3 add lab parameters with 
CTCAE grades
Clarify the criteria of potential Hy’s 
Law case
Update the notable criteria of Serum 
creatinine
Section 2.7.4 update the condition of 
clinically notable changes of ECG and 
vital sign tables
9-
Jan-
2024
Prior to 
final 
DBL
In general the 
SAP was 
amended to 
align with 
LOU064A2301 
and 
LOU064A2302 
studie
Remove the 
word 
“EudraCT”
SAP 
Amendment 
4
Section 1 update the version of 
reference document
Section 2.7.3 update the definition of 
the combination criteria of parameters
Section 2.7.3 update CTCAE grade for 
neutrophil 
count 
decrease 
and 
lymphocyte count decreased according 
to updated internal CTCAE guidance.”
Section 2.7.1.2 remove the word 
“EudraCT” because this study does not 
register for EudraCT 
 


Novartis
Confidential
Page 7 of 54
SAP
Study No. CLOU064A1301
Table of contents
Table of contents..................................................................................................................7
List of abbreviations ............................................................................................................9
1
Introduction........................................................................................................................12
1.1
Study design...........................................................................................................12
1.2
Study objectives, endpoints and estimands............................................................13
1.2.1
Primary estimand(s)...............................................................................15
1.2.2
Secondary estimand(s)...........................................................................16
2
Statistical methods .............................................................................................................18
2.1
Data analysis general information..........................................................................18
2.1.1
General definitions ................................................................................18
2.2
Analysis sets...........................................................................................................27
2.2.1
Subgroup of interest ..............................................................................28
2.3
Patient disposition, demographics and other baseline characteristics....................28
2.3.1
Patient disposition .................................................................................28
2.3.2
Demographics and other baseline characteristics..................................29
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................30
2.4.1
Study treatment / compliance................................................................30
2.4.2
Prior, concomitant and post therapies ...................................................31
2.5
Analysis supporting primary objective(s)..............................................................31
2.5.1
Primary endpoint(s)...............................................................................31
2.5.2
Statistical hypothesis, model, and method of analysis ..........................32
2.5.3
Handling of intercurrent events.............................................................33
2.5.4
Handling of missing values not related to intercurrent event................33
2.5.5
Sensitivity analyses ...............................................................................34
2.5.6
Supplementary analyses ........................................................................34
2.6
Analysis supporting secondary objectives.............................................................34
2.6.1
Secondary endpoint(s)...........................................................................34
2.6.2
Statistical hypothesis, model, and method of analysis ..........................37
2.6.3
Handling of intercurrent events.............................................................37
2.6.4
Handling of missing values ...................................................................38
2.6.5
Sensitivity analyses ...............................................................................38
2.6.6
Supplementary analyses ........................................................................38
2.7
Safety analyses.......................................................................................................38
2.7.1
Adverse events (AEs)............................................................................38


Novartis
Confidential
Page 8 of 54
SAP
Study No. CLOU064A1301
2.7.2
Deaths....................................................................................................39
2.7.3
Laboratory data......................................................................................39
2.7.4
Other safety data....................................................................................42
2.10
Patient-reported outcomes (PROs).........................................................................44
2.13
Interim analysis......................................................................................................48
3
Sample size calculation......................................................................................................48
4
Change to protocol specified analyses...............................................................................48
5
Appendix............................................................................................................................49
5.1
Imputation rules .....................................................................................................49
5.1.1
Study drug .............................................................................................49
5.1.2
AE date imputation................................................................................49
5.1.3
Concomitant medication date imputation..............................................50
5.1.4
Concomitant therapy date imputation ...................................................51
5.1.5
Other imputations..................................................................................51
5.2
AEs coding/grading................................................................................................52
5.3
Laboratory parameters derivations.........................................................................52
5.4
Statistical models ...................................................................................................52
5.4.1
Analysis supporting primary objective(s) .............................................52
5.4.2
Analysis supporting secondary objective(s)..........................................53
5.5
Rule of exclusion criteria of analysis sets..............................................................53
6
Reference ...........................................................................................................................54


Novartis
Confidential
Page 9 of 54
SAP
Study No. CLOU064A1301
List of abbreviations
AAS
Angioedema Activity Score
AAS7
Weekly Angioedema Activity Score
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
b.i.d.
bis in die/twice a day
BCRP
Breast Cancer Resistance Protein
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
BSL
Baseline
CI
Confidential Interval
cm
Centimeter(s)
CM
Concomitant Medication
COVID-19
Coronavirus Disease 2019
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical Study Report
CSU
Chronic Spontaneous Urticaria
CTCAE
Common Terminology Criteria for Adverse Event
CU
Chronic Urticaria
CV
Coefficient of Variation
CYP
Cytochrome P
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRS
Electronic Case Retrieval Strategy
eDiary
Electronic Diary
ETD
Early Treatment Discontinuation
FAS
Full Analysis Set
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HSS
Hives Severity Score
HSS7
Weekly Hives Severity Score
hrs
Hours


Novartis
Confidential
Page 10 of 54
SAP
Study No. CLOU064A1301
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
Ig
Immunoglobulin
INR
International Normalized Ratio
ISS
Itch Severity Score
ISS7
Weekly Itch Severity Score
IU
International Unit
kg
Kilogram(s)
LLN
Lower Limit of Normal-range
LLOQ
Lower Limit of Quantification
MAP
Master Analysis Plan
MAR
Missing At Random
MedDRA
Medical dictionary for regulatory activities
m
Meter(s)
mg
Milligram(s)
mL
Milliliter(s)
PD
Protocol Deviation
PRO
Patient Reported Outcomes
PT
Preferred Term
QTcF
QT interval corrected by Fridericia’s formula
RDO
Retrieved Drop Out
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard Deviation
SD
Study Discontinuation
SMQ
Standardized MedDRA Query
SOC 
System Organ Class
TBL
Total Bilirubin
TFLs
Tables, Figures, Listings Shells document
UAS
Urticaria Activity Score
UAS7
Weekly Urticaria Activity Score
ULN
Upper Limit of Normal-range


Novartis
Confidential
Page 11 of 54
SAP
Study No. CLOU064A1301
ULOQ
Upper Limit of Quantification
UPDD
Urticaria Patient Daily Diary




Novartis
Confidential
Page 13 of 54
SAP
Study No. CLOU064A1301
additional optional interim analyses and the timing/data to be reviewed will be documented in 
the SAP prior to the conduct of any additional optional interim analysis.
The final analysis will be conducted on all participants' data at the time the trial ends regardless 
of the interim analysis.
All participants will be on a stable, local label approved dose of a second-generation H1-
antihistamine (“background therapy”) throughout the entire study (starting a minimum of 7 days 
prior to baseline until the end of the study). To treat unbearable symptoms of CSU, participants 
will be allowed to use another second-generation H1-antihistamine on an as-needed basis 
(“rescue therapy”).
Figure 1-1
Study Design
 
D-1: Day 1, b.i.d.: bis in die/twice a day, IA: interim analysis, mg: milligram(s), Scr: Screening, W: 
Week
1.2
Study objectives, endpoints and estimands  
Table 1-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective
•
To evaluate the safety of remibrutinib (25 mg 
b.i.d.) in CSU patients
•
Overall safety data, assessed as treatment 
emergent adverse events during the study
Secondary objectives
Endpoints for secondary objectives
•
To evaluate the efficacy of remibrutinib (25 mg 
b.i.d.) by evaluation of:
•
Change from baseline in UAS7 at Week 
12
•
Proportion of participants achieve disease 
activity control (UAS7 ≤ 6) at Week 12 
•
Proportion of participants achieve 
complete absence of hives and itch (UAS7 
= 0) at Week 12
•
Change from baseline in ISS7 at Week 12
•
Change from baseline in HSS7 at Week 
12 
•
Proportion of participants achieve disease 
activity control (UAS7 ≤ 6) at Week 2
•
Absolute change from baseline in UAS7 at Week 
12
•
Achievement of UAS7≤ 6 (yes/no) at Week 12
•
Achievement of UAS7 = 0 (yes/no) at Week 12
•
Absolute change from baseline in ISS7 score at 
Week 12
•
Absolute change from baseline in HSS7 score at 
Week 12
•
Achieving early onset of disease activity control, as 
defined as achievement of UAS7≤ 6 (yes/no) at 
Week 2






Novartis
Confidential
Page 16 of 54
SAP
Study No. CLOU064A1301
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance (discontinuation/interruption), with background medication of local 
approved second-generation H1-antihistamine, and a different second-generation H1-
antihistamine as rescue medication.
4. Summary Measurement: the number and the proportion of participants with at least one 
treatment-emergent adverse event.
5. Handling of remaining intercurrent events: 
•
Discontinuation of study treatment due to any reason: data collection will be maintained 
in the follow-up period. The data collected after these events will be used for analysis.
•
Treatment non-compliance (interruption), intake of rescue medication, or switch of 
background medication: ignore, i.e., data collection will be maintained and available 
measurements post-intercurrent event will be used as if they had been obtained under 
the treatment: Treatment policy strategy
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment, 
cyclosporine, systemic corticosteroids): Treatment policy strategy
•
Administration of medications affecting the evaluation of potential risks, including: (a) 
anticoagulant/anti-platelet medications (other than acetylsalicylic acid up to 100mg/day 
or clopidogrel); (b) live attenuated vaccines; (c) strong cytochrome P (CYP) 3A4 
inhibitors; (d) moderate/strong CYP3A4 inducers, (e) Oral breast cancer resistance 
protein (BCRP) substrates that may have increased exposure when co-administered 
with remibrutinib (defined as pitavastatin, rosuvastatin, sulfasalazine and ubrogepan): 
Treatment policy strategy
•
Intake of other prohibited medication: Treatment policy strategy
1.2.2
Secondary estimand(s) 
Secondary estimand on efficacy as secondary endpoint: change from baseline in UAS7 
score at Week 12 
The secondary clinical question of interest regarding efficacy as secondary endpoint, change 
from baseline in UAS7 score at Week 12 is: What is the effect of remibrutinib treatment on the 
change from baseline in UAS7 score after 12 weeks of treatment in adult participants with CSU 
who are inadequately controlled by H1-antihistamine and receiving a stable locally label 
approved dose of a second-generation H1-antihistamine, regardless of treatment 
discontinuation for any reason or intake of a different second-generation H1-antihistamine as 
rescue medication and considering strongly confounding prohibited medication use as an 
unfavorable outcome? 
The secondary estimand on efficacy as secondary endpoint, change from baseline in UAS7 
score at Week 12 is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second- 
generation H1-antihistamine treatment who have CSU duration ≥6 months, a UAS7 score 
≥16, ISS7 score ≥6 and HSS7 score ≥6 in the last 7 days prior to start of treatment.
2. Endpoint: change in UAS7 from baseline at Week 12.


Novartis
Confidential
Page 17 of 54
SAP
Study No. CLOU064A1301
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance, with background medication of local approved second-generation 
H1-antihistamine, and a different second-generation H1-antihistamine as rescue medication.
4. Summary Measurement: the mean change from baseline.
5. Handling of remaining intercurrent events:
•
Discontinuation of study treatment due to any reason: Treatment policy strategy
•
Treatment non-compliance (interruption), switch of background medication, or intake 
of rescue medication as per protocol prior to Week 12: Treatment policy strategy 
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporine after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent events)
•
Intake of other prohibited medication prior to Week 12: Treatment policy strategy
Secondary estimand on efficacy as secondary endpoint: UAS7 ≤6 response at Week 12 
(Week 2, if applicable)
The secondary clinical question of interest regarding efficacy as secondary endpoint, UAS7 ≤6 
response at Week 12 is: What is the effect of remibrutinib treatment on the UAS7 ≤6 response 
after 12 weeks of treatment in adult participants with CSU who are inadequately controlled by 
H1-antihistamine and receiving a stable locally label approved dose of a second-generation H1-
antihistamine, regardless of treatment discontinuation for any reason or intake of a different 
second-generation H1-antihistamine as rescue medication and considering strongly 
confounding prohibited medication as an unfavorable outcome?
The secondary estimand on efficacy as secondary endpoint, UAS7 ≤6 response at Week 12 is 
described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second- 
generation H1-antihistamine treatment who have CSU duration ≥6 months, a UAS7 
score ≥16, ISS7 score ≥6 and HSS7 score ≥6 in the last 7 days prior to start of treatment.
2. Endpoint: UAS7 ≤6 response at Week 12.
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance, with background medication of locally approved second-generation 
H1-antihistamine, and a different second-generation H1-antihistamine as rescue medication.
4. Summary Measurement: the number and the proportion of participants with UAS7 ≤6 
response at Week 12.
5. Handling of intercurrent events:
•
Discontinuation of study treatment due to any reason: Treatment policy strategy
•
Treatment non-compliance (interruption), switch of background medication, or intake 
of rescue medication as per protocol prior to Week 12: Treatment policy strategy
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporine after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent events)
•
Intake of other prohibited medication before Week 12: Treatment policy strategy




Novartis
Confidential
Page 19 of 54
SAP
Study No. CLOU064A1301
2.1.1.2
Study Day 1 and Study Day
For safety analysis, the day of first dose of study treatment is defined as Day 1.
For efficacy analysis, the day of enrollment in treatment period is defined as Day 1.
All other study days will be labeled relative to Day 1. 
• For event dates on or after Day 1, study day for a particular event date is calculated as [Date 
of event] – [Date of first dose (for safety)/day of the enrollment in the treatment period (for 
efficacy)] + 1, i.e., Day 2, Day 3, etc., will be one day, two days, etc., after Day 1, 
respectively. 
• For the dates before Day 1, study day for an event date is calculated as [Date of event] – 
[Date of first dose (for safety)/enrollment in the treatment period (for efficacy)], i.e., Day -
1, Day -2, etc., will be one day, two days, etc., before Day 1, respectively. Duration of an 
event will be calculated as (Event end date – Event start date + 1). 
The descriptor “Day 0” will not be used.
2.1.1.3
On-treatment period for safety assessment
The on-treatment period is defined as the period from the first date of dose intake of treatment 
to the last date of dose intake + a period of time accounting for remaining exposure to drug in 
relation to the potential pharmacodynamic effects of remibrutinib. It is the reference period for 
safety analyses on adverse events, laboratory, vital signs, etc. 
Remibrutinib has a short half-life (5hrs). Due to the covalent-binding mode, pharmacodynamic 
effects, including target inhibition in tissues and cells is to be taken into account for determining 
the follow-up time after the last study drug dose, which is beyond 5 half-lives’. As a 
conservative measure, 28 days was selected.
The on-treatment period lasts from the date of first administration of study treatment to 28 days 
after the date of the last actual administration of the study treatment or the end of study where 
the end of study is either of the date of study discontinuation, or study completion, or safety 
follow-up completion or cut-off date, depending on participant’s status.
2.1.1.4
Assessment window
Assessment window for weekly scores (e.g., UAS7, ISS7, HSS7, etc.) from 
eDiary data
For completers (i.e., participants completed Week 52 study treatment), the study weeks for 
assessment completed on eDiary up to Week 52 are defined based on the study days starting 
with Day 1 (day of the enrollment in treatment period). The study day for the eDiary date will 
be calculated as [Date of Diary] – [Date of day of the enrollment in treatment period] + 1 for 
post-baseline assessment and [Date of Diary] – [Date of day of  the enrollment in treatment 
period] for baseline assessment. 


Novartis
Confidential
Page 20 of 54
SAP
Study No. CLOU064A1301
The analysis Week 1 through Week 51 of the treatment period will be derived based on 
scheduled visit day as defined in Table 2-1. eDiary data on or before Day -1 of actual Week 52 
study visit will be used for weekly score calculation up to Week 51. 
The analysis Week 52 score will be derived as Day -7 to Day -1 of actual Week 52 study visit 
day.
The analysis follow-up Week 1 to Week 4 will be derived based on the actual Week 52 study 
visit day as defined in Table 2-1. 
Table 2-1
Assessment window for weekly scores based on eDiary (for 
completers) 
Study period
Analysis visit
Scheduled visit day
eDiary assessment window
Treatment
Baseline
1
Day -7 to Day -1
Week 1
-
Day 1 to Day 7
Week 2
15
Day 8 to Day 14
Week 3
-
Day 15 to Day 21
Week 4
29
Day 22 to Day 28
Week 5
-
Day 29 to Day 35
Week 6
-
Day 36 to Day 42
Week 7
-
Day 43 to Day 49
Week 8
57
Day 50 to Day 56
Week 9
-
Day 57 to Day 63
Week 10
-
Day 64 to Day 70
Week 11
-
Day 71 to Day 77
Week 12
85
Day 78 to Day 84 
Week 13
-
Day 85 to Day 91
Week 14
-
Day 92 to Day 98 
Week 15
-
Day 99 to Day 105 
Week 16
113
Day 106 to Day 112 
Week 17
-
Day 113 to Day 119 
Week 18
-
Day 120 to Day 126
Week 19
-
Day 127 to Day 133


Novartis
Confidential
Page 21 of 54
SAP
Study No. CLOU064A1301
Week 20
141
Day 134 to Day 140
Week 21
-
Day 141 to Day 147
Week 22
-
Day 148 to Day 154
Week 23
-
Day 155 to Day 161
Week 24
169
Day 162 to Day 168
Week 25
-
Day 169 to Day 175
Week 26
-
Day 176 to Day 182
Week 27
-
Day 183 to Day 189
Week 28
-
Day 190 to Day 196
Week 29
-
Day 197 to Day 203
Week 30
-
Day 204 to Day 210
Week 31
-
Day 211 to Day 217
Week 32
225
Day 218 to Day 224
Week 33
-
Day 225 to Day 231
Week 34
-
Day 232 to Day 238
Week 35
-
Day 239 to Day 245
Week 36
-
Day 246 to Day 252
Week 37
-
Day 253 to Day 259
Week 38
-
Day 260 to Day 266
Week 39
-
Day 267 to Day 273
Week 40
281
Day 274 to Day 280
Week 41
-
Day 281 to Day 287
Week 42
-
Day 288 to Day 294
Week 43
-
Day 295 to Day 301
Week 44
-
Day 302 to Day 308
Week 45
-
Day 309 to Day 315


Novartis
Confidential
Page 22 of 54
SAP
Study No. CLOU064A1301
Week 46
-
Day 316 to Day 322
Week 47
-
Day 323 to Day 329
Week 48
-
Day 330 to Day 336
Week 49
-
Day 337 to Day 343
Week 50
-
Day 344 to Day 350
Week 51
-
Day 351 to Day 357
Week 52
365
Day -7 to Day -1 of Week 52 
study visit
Note: Week 52 study visit is during treatment epoch. eDiary data on this day will not be taken 
in the analysis.   
For participants early discontinued study treatment prior to Week 12, it is suggested to collect 
the eDiary data even after the participant discontinued from treatment per “Treatment policy 
strategy” (this part of data is named as “retrieved drop-out data”). The retrieved drop-out (RDO) 
data will be included in the weekly score derivation until Week 12, when treatment policy 
strategy is used for estimands. 
For participants who discontinued the study treatment earlier than Week 52, assessment 
will follow rules as defined in Table 2-2 up to Week 52. After Week 52, weekly scores will 
not be derived even when the eDiary data are collected. 
Table 2-2
Assessment window for weekly scores based on eDiary (for early 
treatment discontinued participants earlier than Week 52)
Study period
Analysis visit
Scheduled visit day
eDiary assessment window
Treatment
Baseline
1
Day -7 to Day -1
Week 1
-
Day 1 to Day 7
Week 2
15
Day 8 to Day 14
Week 3
-
Day 15 to Day 21
Week 4
29
Day 22 to Day 28
Week 5
-
Day 29 to Day 35
Week 6
-
Day 36 to Day 42
Week 7
-
Day 43 to Day 49
Week 8
57
Day 50 to Day 56
Week 9
-
Day 57 to Day 63
Week 10
-
Day 64 to Day 70


Novartis
Confidential
Page 23 of 54
SAP
Study No. CLOU064A1301
Week 11
-
Day 71 to Day 77
Week 12
85
Day 78 to Day 84 
Week 13
-
Day 85 to Day 91
Week 14
-
Day 92 to Day 98 
Week 15
-
Day 99 to Day 105 
Week 16
113
Day 106 to Day 112 
Week 17
-
Day 113 to Day 119 
Week 18
-
Day 120 to Day 126
Week 19
-
Day 127 to Day 133
Week 20
141
Day 134 to Day 140
Week 21
-
Day 141 to Day 147
Week 22
-
Day 148 to Day 154
Week 23
-
Day 155 to Day 161
Week 24
169
Day 162 to Day 168
Week 25
-
Day 169 to Day 175
Week 26
-
Day 176 to Day 182
Week 27
-
Day 183 to Day 189
Week 28
-
Day 190 to Day 196
Week 29
-
Day 197 to Day 203
Week 30
-
Day 204 to Day 210
Week 31
-
Day 211 to Day 217
Week 32
225
Day 218 to Day 224
Week 33
-
Day 225 to Day 231
Week 34
-
Day 232 to Day 238
Week 35
-
Day 239 to Day 245
Week 36
-
Day 246 to Day 252
Week 37
-
Day 253 to Day 259


Novartis
Confidential
Page 24 of 54
SAP
Study No. CLOU064A1301
Week 38
-
Day 260 to Day 266
Week 39
-
Day 267 to Day 273
Week 40
281
Day 274 to Day 280
Week 41
-
Day 281 to Day 287
Week 42
-
Day 288 to Day 294
Week 43
-
Day 295 to Day 301
Week 44
-
Day 302 to Day 308
Week 45
-
Day 309 to Day 315
Week 46
-
Day 316 to Day 322
Week 47
-
Day 323 to Day 329
Week 48
-
Day 330 to Day 336
Week 49
-
Day 337 to Day 343
Week 50
-
Day 344 to Day 350
Week 51
-
Day 351 to Day 357
Week 52
365
Day 358 to Day 364
No further analysis visit
Assessment window for the assessments performed at study visit (e.g., DLQI, 
safety assessment except AEs, etc.) until Week 52
When the assessments are summarized by visit, they are based on the visit numbers as recorded 
in eDiary or eCRF except for early treatment discontinuation (ETD) visit, and study 
discontinuation (SD) visit. ETD visit, SD visit will be remapped to the scheduled visit. Safety 
follow-up visit or unscheduled visits will NOT be remapped (except for the unscheduled visit 
to be consider as baseline).
The assessment window is based on the study assessment schedule. The assessment schedule 
defined in the protocol is shown in Table 2-3. Note for Electrocardiogram (ECG), at Week 2, 
12, 52 and SD visit pre and post dose assessments will be performed. ETD visit can be remapped 
to Week 24 only, and SD visit can be remapped to Week 2, 12 and 52.


Novartis
Confidential
Page 25 of 54
SAP
Study No. CLOU064A1301
Table 2-3
Assessment schedule
Visit name
BSL
Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 40
Week 52
ETD
SD
Scheduled visit 
day
1
15
29
57
85
113
141
169
225
281
365
-
-
Vital signs
Clinical 
chemistry*
Hematology
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
Panel
X
X
X
X
X
X
X
X
Weight
 
 
 
 
X
 
 
 
 
 
X
X
X
Electrocardiogram 
(ECG)
X
X2
 
 
X2
 
 
X
 
 
X2
X
X2
DLQI
X
 
X
 
X
 
 
X
 
 
X
X
X
X: to be recorded, BSL: Baseline, ETD: Early treatment discontinuation, SD: Study discontinuation
1 only post baseline
2 pre and post dose
* C-reactive protein (CRP), estimated Glomerular Filtration Rate (eGFR): assessed at screening, baseline, 
weeks 12, 24 and 52. Fasting glucose assessed at baseline, weeks 2, 12 and 52.
The Table 2-4 shows the assessment window for the assessments performed at every visits (i.e., 
vital signs, clinical chemistry, hematology, urinalysis).
If more than one assessment fall into the interval, 
• Then if there is the scheduled visit recorded in eDiary or eCRF, this visit will be chosen.
• If no, the earliest visit day will be chosen.


Novartis
Confidential
Page 26 of 54
SAP
Study No. CLOU064A1301
For example, when a participant discontinued study treatment after completing Week 2 and 
Week 4, and ETD visit occurred on Day 35 and SD visit occurred on Day 80, the ETD visit will 
be mapped to Week 8 and SD visit will be remapped to Week 12.
If a participant visited the site earlier than scheduled visit day, e.g., Week 4 on Day 25 and ETD 
visit on Day 29, ETD visit will be remapped to Week 4. As the participant already performed 
Week 4 scheduled visit, the remapped Week 4 (ETD visit) will not be used.
If a participant visited the site late than scheduled visit day, e.g., Week 4 on Day 25, ETD visit 
on Day 58 and SD visit on Day 85, both ETD visit and SD visit will be remapped to Week 12. 
In this case, ETD visit will be used as Week 12, and Week 8 will be missing.
Table 2-4
Assessment window for vital signs, clinical chemistry, hematology, 
urinalysis until Week 52
Assessment visit
Scheduled 
visit Day
Assessment window
Week 2
15
Day 2 to Day 15
Week 4
29
Day 16 to Day 29
Week 8
57
Day 30 to Day 57
Week 12
85
Day 58 to Day 85 
Week 16
113
Day 86 to Day 113
Week 20
141
Day 114 to Day 141
Week 24
169
Day 142 to Day 169
Week 32
225
Day 170 to Day 225
Week 40
281
Day 226 to Day 281
Week 52
365
Day 282 to Day 365
For the assessments which are not collected at every visit (e.g., DLQI etc.), assessment window 
will be combined. For example, DLQI is collected at Week 4, Week 12, Week 24 and Week 
52. The assessment window will be combined as Table 2-5.
Table 2-5
Assessment window for DLQI until Week 52
Assessment visit
Scheduled 
visit day
Assessment window
Week 4
29
Day 2 to Day 29


Novartis
Confidential
Page 27 of 54
SAP
Study No. CLOU064A1301
Week 12
85
Day 30 to Day 85 
Week 24
169
Day 86 to Day 169
Week 52
365
Day 170 to Day 365
Table 2-6 show the assessment windows of days for each assessment.
Table 2-6
Assessment windows by assessment
Assessment visit
Week 2
Week 4
Week 8
Week 12
Week 16
Week 20
Week 24
Week 32
Week 40
Week 52
Scheduled visit 
day
15
29
57
85
113
141
169
225
281
365
Vital signs
Clinical chemistry
Hematology
Urinalysis
2-15
16-29
30-57
58-85
86-113 114-
141
142-
169
170-
225
226-
281
282-
365
Coagulation
Panel
2-29
30-85
86-169
170-281
282-
365
Electrocardiogram 
(ECG)
2-15
16-85
86-169
170-365
DLQI
2-29
30-85
86-169
170-365
2.2
Analysis sets 
The following analysis sets will be used in this study.


Novartis
Confidential
Page 28 of 54
SAP
Study No. CLOU064A1301
Screened Set: The Screened Set includes all participants who had signed an informed 
consent form and had a screening visit.
Safety Set (SAF): The Safety Set includes all participants who received at least one dose of 
study treatment. The safety set will be used in the analysis of all safety variables. 
Full Analysis Set (FAS): The FAS comprises all participants to whom study treatment has been 
assigned and received at least one dose of the treatment. The FAS will be used for all efficacy 
variables, unless otherwise stated.
Note that the Safety Set and the FAS are the same except that the Safety Set allows inclusion 
of participants to whom study treatment has not been assigned but received study drug in error.
For the rule of exclusion criteria of analysis sets, see Appendix 5.5.
2.2.1
Subgroup of interest
To explore the impact of disease characteristics at baseline on the efficacy, subgroup analysis 
will be provided on:
•
UAS7 change from baseline over time
•
Achievement of UAS7 ≤ 6 over time
•
Achievement of UAS7 = 0 over time
The definition of subgroups are following, 
•
Duration of CSU defined as Time since diagnosis of urticaria, informed consent date – 
diagnosis date + 1 (≤ 1 year, > 1 to 3 years, > 3 to 5 years, > 5 years)*
* The subgroup categorization may be re-assessed and re-defined in the TFLs (Tables, 
Figures, Listings Shells document) if one subgroup has 5 or less participants.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number of participants screened will be presented. The number and percentage of 
participants who completed screening phase, and who discontinued screening phase will be 
presented for all screened participants. The reasons of screen failure will also be summarized if 
available. For participants screened more than once, the data from the last screening visit will 
be used in the summaries.
The number and percentage of participants in the Safety Set who completed the study treatment 
period, who discontinued the study treatment and the reason for treatment discontinuation will 
be presented. 


Novartis
Confidential
Page 29 of 54
SAP
Study No. CLOU064A1301
The number and percentage of participants in the Safety Set who completed the study (including 
follow-up period), who discontinued the study and the reason for discontinuation will be 
presented as well.
The number of participants in each analysis set (FAS and Safety Set) will be presented. The 
reason for exclusion from any analysis set will be listed.
The number and percentage of participants who have experienced protocol deviations (PD) will 
be tabulated by deviation category. The summary of overall important PDs (including COVID-
19 related PDs), important COVID-19 related PDs will be provided by study period for the 
enrolled participants.
2.3.2
Demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively on the Safety Set.
The following common background, demographic and disease characteristics variables will be 
analyzed:
Continuous variables:
• Screening Age (years)   
• Screening Height (cm)
• Screening Weight (kg)
• Body mass index (BMI) calculated as (body weight at screening in kilograms) / (height at 
screening in meters)2
• Baseline UAS7 score
• Baseline ISS7 score
• Baseline HSS7 score
• Baseline AAS7 score
• Baseline DLQI score
• Duration of CSU defined as Time since diagnosis of urticaria (years) = (informed consent 
date – diagnosis date + 1) / 365.25
Categorical variables:
•
Age categories (≥ 18 - < 65, ≥ 65 - < 85, ≥ 85 years)
•
Gender 
•
Race
•
Ethnicity
•
BMI groups (< 25, 25 -< 30, ≥ 30 kg/m2)


Novartis
Confidential
Page 30 of 54
SAP
Study No. CLOU064A1301
•
Baseline UAS7 categories (Mild disease: 6 < UAS7 < 16, Moderate disease: 16 ≤ UAS7 
< 28, Severe disease: 28 ≤ UAS7 ≤ 42)
•
Baseline AAS7 = 0 response (Yes, No)
•
Previous exposure to anti-IgE biologics for CSU (Yes, No)
•
Previous experience of Angioedema (Yes, No)
 
•
Duration of CSU defined as Time since diagnosis of urticaria, informed consent date – 
diagnosis date + 1 (≤ 1 year, > 1 to 3 years, > 3 to 5 years, > 5 years)
The following relevant medical histories and current medical conditions at baseline will be 
summarized combined by system organ class and preferred term on the Safety Set.
•
CSU related history (CSU, Urticaria related history, 
)
•
Non-CSU related history (general medical history)
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The analysis of study treatment data and the analysis of duration of study will be based on the 
Safety Set.
Duration of exposure (days) will be defined as last dose of study treatment – first dose of 
study treatment + 1.
Duration of study (days) will be defined as last study visit – first dose of study treatment + 1. 
The duration of exposure and the duration of study in weeks will be derived as follows: 
• Duration of exposure (weeks) = duration of exposure (days) / 7
• Duration of study (weeks) = duration of study (days) / 7
• Duration of exposure (years) = duration of exposure (days) / 365.25
• Duration of study (years) = duration of study (days) / 365.25
The duration of exposure to study treatment will be computed without excluding temporary 
treatment interruptions.
The duration of exposure and duration of study in weeks to LOU064 25mg will be summarized. 
The number of participants with the duration of exposure and the duration of study of at least 
certain thresholds (e.g., any exposure, >0 - <2 weeks, ≥2 weeks - <4 weeks, ≥4 weeks - <8 
weeks, ≥8 weeks - <12 weeks, ≥12 weeks - <16 weeks, ≥16 weeks - <20 weeks, ≥20 weeks -


Novartis
Confidential
Page 31 of 54
SAP
Study No. CLOU064A1301
<24 weeks, ≥24 weeks - <32 weeks, ≥32 weeks - <40 weeks, ≥40 weeks - <52 weeks and ≥52 
weeks) will be displayed.
2.4.2
Prior, concomitant and post therapies
Medications will be identified using the WHODrug including Anatomical Therapeutic 
Chemical (ATC) code. In the summary tables, medications (including background or rescue 
medications) will be presented in alphabetical order, by ATC codes and preferred term. Tables 
will show the overall number and percentage of participants receiving at least one drug of a 
particular ATC code and at least one drug in a particular preferred term. 
Prior medications are defined as drugs taken and stopped prior to first dose of study medication.  
Any medication given at least once between the day of first dose of study treatment and the last 
day of study visit will be a concomitant medication, including those which were started pre- 
baseline and continued into the treatment period. Prior or concomitant medication will be 
identified based on recorded or imputed start and end dates of medication taking. 
The Safety Set will be used for the analyses described in this section.
Prior urticaria medications and prior non-urticaria medications will be summarized 
separately by ATC code and preferred term. 
Concomitant medications (excluding background or rescue medications) will be 
summarized by ATC code and preferred term. 
Background medications will be summarized by ATC code, preferred term, and dose per 
administration.
Rescue medication: H1-antihistamines will be summarized by ATC code, preferred term, and 
dose per tablet.
Rescue medication: oral corticosteroids will be summarized by ATC code and preferred term.
In addition, prior/concomitant significant non-drug therapies/procedures will be summarized 
separately by primary system organ class and preferred term of MedDRA dictionary. 
2.5
Analysis supporting primary objective(s)
2.5.1
Primary endpoint(s)
The primary clinical question of interest regarding safety as primary endpoint is: What is the 
effect of remibrutinib treatment on the incidence of 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) in adult participants with CSU who are 
inadequately controlled by H1-antihistamine and receiving a stable locally label approved dose 
of a second-generation H1-antihistamine, regardless of treatment discontinuation for any reason, 
non-compliance (interruption) to treatment, switch of background medication or intake of a 
different second-generation H1-antihistamine as rescue medication/ confounding prohibited 
medication? 


Novartis
Confidential
Page 32 of 54
SAP
Study No. CLOU064A1301
The primary (safety) endpoint (variable) is the number and the proportion of participants with 
treatment-emergent adverse event. The treatment-emergent adverse event is defined as event 
started during on-treatment period or event present prior to start of treatment but increased in 
severity based on preferred term. The on-treatment period lasts from the date of first 
administration of study treatment to 28 days after the date of the last actual administration of 
the study treatment or the end of study where the end of study is either of the date of study 
discontinuation, or study completion, or safety follow-up completion or cut-off date, depending 
on participant’s status.
2.5.2
Statistical hypothesis, model, and method of analysis 
The number and the proportion (%) of participants with the treatment-emergent adverse events 
will be summarized in the following ways:
•
by primary system organ class and preferred term
•
by primary system organ class, preferred term and maximum severity
•
by Standardized MedDRA Query (SMQ, narrow) and preferred term
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
The most common adverse events reported (5% for each preferred term or 5% for each SMQ) 
will be presented in descending frequency according to its incidence starting from the most 
common event. The cut-off of 5% can be re-evaluated based on number of participants with 
events.
In these summary tables, 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. 
In the summary by severity table, if a participant reported more than one adverse event with the 
same preferred term, the adverse event with the greatest severity will be presented. If a 
participant reported more than one adverse event within the same primary system organ class, 
the participant will be counted only once with the greatest severity at the system organ class 
level.
Adverse events of special interest (AESI) for remibrutinib (such as risks defined in the Safety 
Profiling Plan, Risk Management Plan or topics of interest regarding signal detection or routine 
analysis) will be defined based on the latest Case Retrieval Strategy (eCRS). The 
comprehensive search of AESI will be performed for all treatment-emergent adverse events.
The number and the proportion (%) of participants with AESI will be summarized by safety 
topic of interest (i.e., risk name) and preferred term. 
In addition, for adverse events, serious adverse events and AESI exposure adjusted incidence 
rates will be estimated for the entire study period.
The rate estimates will be reported with exact Poisson 95% CIs (Garwood 1936, Sahai and
Khurshid 1993). Please see Section 5.4.1 for details.


Novartis
Confidential
Page 33 of 54
SAP
Study No. CLOU064A1301
For infections and infestations (SOC), the number (and percentage) of participants with this 
event will be summarized by treatment group, SOC, HLGT, HLT and PT.
All information obtained on adverse events will be displayed by participant.
All analyses for the primary (safety) endpoint will be performed descriptively. No statistical 
hypothesis is set for the primary (safety) endpoint in this study.
For all safety analyses, the Safety Set will be used. 
2.5.3
Handling of intercurrent events 
The analysis will account for different intercurrent events as explained in the following:
•
Discontinuation of study treatment due to any reasons:
data collection will be maintained in the follow-up period. Participants with these 
events will be encouraged to stay in the study following the procedures. Every effort 
will be made to continue to follow participants with these events up to study end. The 
data collected after these events will be used for analysis.
•
Treatment non-compliance (interruption), switch of background medication, or intake of 
rescue medication as per protocol:
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment  
(Treatment policy strategy).
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment, 
cyclosporine, systemic corticosteroids):
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment  
(Treatment policy strategy).
•
Administration of medications affecting the evaluation of potential risks, including: (a) 
anticoagulant/anti-platelet medications (other than acetylsalicylic acid up to 100 mg/day or 
clopidogrel); (b) live attenuated vaccines; (c) strong CYP3A4 inhibitors; (d) 
moderate/strong CYP3A4 inducers, (e) Oral BCRP substrates that may have increased 
exposure when co-administered with remibrutinib (defined as pitavastatin, rosuvastatin, 
sulfasalazine and ubrogepan):
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment  
(Treatment policy strategy).
•
Intake of other prohibited medication:
ignore, i.e., data collection will be maintained and available measurements post-
intercurrent event will be used as if they had been obtained under the treatment  
(Treatment policy strategy).
2.5.4
Handling of missing values not related to intercurrent event
No imputation will be done for missing data. All available data will be used for the analyses.


Novartis
Confidential
Page 34 of 54
SAP
Study No. CLOU064A1301
2.5.5
Sensitivity analyses 
If unexpectedly high incidence of adverse events of special interest (AESI) is observed, i.e., if 
incidence of AESI is greater than the one reported in the final analysis of A2201E1 study +20%, 
then sensitivity analysis will be performed for the AESI.
The following sensitivity analysis maybe performed on AESI, to assess the causality between 
the occurrence of AESI and medications. The sensitivity analysis will be implemented with the 
same target population, on AESI variable and the summary measure as for the primary estimand, 
but using the different assumptions or handling of intercurrent events.
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment (as 
identified by PD M-COMD03 and/or M-COMD03B), cyclosporine (as identified by PD 
M-COMD04 and/or M-COMD04B), systemic corticosteroids (as identified by PD M-
COMD02B and/or M-COMD04 and/or M-COMD05)) : only measurements prior to 
intake of these prohibited medications will be used for analysis (While on treatment 
strategy).
•
Intake of medications affecting the evaluation of potential risks, including: (a) 
anticoagulant/anti-platelet medications (other than acetylsalicylic acid up to 100 mg/day or 
clopidogrel) (as identified by PD M-COMD07); (b) live attenuated vaccines (as identified 
by PD M-COMD07); (c) strong CYP3A4 inhibitors (as identified by PD M-COMD07); (d) 
moderate/strong CYP3A4 inducers (as identified by PD M-COMD07), (e) Oral BCRP 
substrates that may have increased exposure when co-administered with remibrutinib 
(defined as pitavastatin, rosuvastatin, sulfasalazine and ubrogepan) (as identified by the 
name of concomitant medications entered in CRFs): only measurements prior to intake of 
these medications will be used for analysis (While on treatment strategy).
2.5.6
Supplementary analyses
No supplementary analysis is planned for the primary (safety) endpoints.
2.6
Analysis supporting secondary objectives 
2.6.1
Secondary endpoint(s)
The secondary clinical question of interest regarding efficacy as secondary endpoints is: What 
is the effect of remibrutinib treatment on secondary efficacy endpoints after treatment in adult 
participants with CSU who are inadequately controlled by H1-antihistamine and receiving a 
stable locally label approved dose of a second-generation H1-antihistamine, regardless of 
treatment discontinuation for any reason or intake of a different second-generation H1-
antihistamine as rescue medication and considering strongly confounding prohibited 
medication use as an unfavorable outcome?
The secondary estimand on efficacy as secondary endpoints is described by the following 
attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second- 
generation H1-antihistamine treatment who have CSU duration ≥6 months, a UAS7 score 
≥16, ISS7 score ≥6 and HSS7 score ≥6 in the last 7 days prior to start of treatment.


Novartis
Confidential
Page 35 of 54
SAP
Study No. CLOU064A1301
2. Endpoint: see below.
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.) regardless of 
treatment compliance, with background medication of local approved second-generation 
H1-antihistamine, and a different second-generation H1-antihistamine as rescue medication.
4. Summary Measurement: see Table 2-7 below.
5. Handling of remaining intercurrent events: see Section 2.6.3.
One of the secondary (efficacy) endpoints (variables) is the absolute change from baseline in 
UAS7 score at Week 12, which is the UAS7 score at Week 12 minus the UAS7 score at baseline. 
The UAS7 is the sum of the HSS7 score and the ISS7 score, and ranges from 0-42. Weekly 
scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 
days preceding the visit.
Derivation of UAS7
HSS and ISS are recorded by the participant twice daily (morning, evening) in their eDiary, on 
scale of 0 to 3.  
The daily score of HSS and ISS will be calculated by averaging the morning and evening HSS 
and ISS score, respectively (possible range 0-3). If one of the morning or evening scores is 
missing, the non-missing score for that day (morning or evening) will then be used as the daily 
score. If both of the morning and evening scores are missing, the daily score for that day will 
be missing.
If the questionnaires in eDiary are completed more than once per session (morning, evening) 
on the same day, then the worst score will be used for that day.
HSS7 and ISS7
The weekly score of HSS and ISS (HSS7 and ISS7) will be derived by adding up the daily HSS 
and ISS scores of the 7 days preceding the visit, respectively (please refer to the assessment 
window in Section 2.1.1.4). If one or more of the daily scores are missing, the following 
principles will be applied to handle the missing data:
If a participant has at least 4 non-missing daily scores within the 7 days, HSS7 or ISS7 will be 
calculated as the sum of the available scores of that week, divided by the number of non-missing 
days, multiplied by 7.
If there are less than 4 non-missing daily scores within the 7 days, HSS7 or ISS7 will be 
considered as missing for that week. 
UAS7
The UAS7 score will be derived from the sum of the HSS7 score and the ISS7 score when both 
HSS7 and ISS7 are non-missing. If at least one of them is missing, the UAS7 will be missing.
Other secondary endpoints are as follows:


Novartis
Confidential
Page 36 of 54
SAP
Study No. CLOU064A1301
•
Disease activity control at Week 12, assessed as proportion of participants achieving 
UAS7 ≤6
•
Complete absence of hives and itch at Week 12, assessed as proportion of participants 
achieving UAS7 =0
•
Improvement of severity of itch at Week 12, assessed as absolute change from baseline in 
ISS7 score 
•
Improvement of severity of hives at Week 12, assessed as absolute change from baseline 
in HSS7 score
•
Disease activity control at Week 2, assessed as proportion of participants achieving 
UAS7 ≤6
For derivation of UAS7, HSS7 and ISS7 scores, see just above. The response variables (e.g., 
UAS7 ≤6) will be derived using the corresponding weekly score. 
•
No impact on participants’ dermatology-quality of life at Week 12, assessed as proportion 
of participants achieving DLQI =0-1
Seven scores will be derived from the DLQI: the score of each of the six dimensions as well as 
the total score of the DLQI will be calculated based on the developers' rules. 
For the DLQI subscale and total score derivation, if there is only one missing score per visit, 
then it will be imputed to 0 and then the subscale including this item and the total score will be 
calculated accordingly. If there are two or more missing scores per visit, then the score will be 
missing.
•
Cumulative number of weeks that participants achieving UAS7 ≤6 response between 
baseline and Week 12
The cumulative number of weeks achieving UAS7 ≤6 response between baseline and Week 12 
will be derived based on the eDiary (possible range 0-12). If the UAS7 score for a week is 
missing, it will be considered as a non-response for that week for the cumulative number of 
weeks that participants achieve UAS7 ≤6 response calculation.
•
Cumulative number of weeks that participants achieving AAS7 =0 response between 
baseline and Week 12.
The cumulative number of weeks achieving AAS7 =0 response between baseline and Week 12 
will be derived based on the AAS eDiary (possible range 0-12). The AAS7 =0 response will be 
derived using the weekly score as described below.
Derivation of AAS7
A weekly AAS7 score will be derived by adding up the daily scores (possible range 0-15) of 
the 7 days preceding the visit, and ranges from 0 to 105 (please refer to the assessment window 
in Section 2.1.1.4). If one or more of the daily scores are missing, the following principles will 
be applied to handle the missing data: If a participant has at least 4 non-missing daily scores 


Novartis
Confidential
Page 37 of 54
SAP
Study No. CLOU064A1301
within the 7 days, AAS7 will be calculated as the sum of the available scores of that week, 
divided by the number of non-missing days, multiplied by 7. If there are less than 4 non-missing 
daily scores within the 7 days, AAS7 will be considered as missing for that week. If the AAS7 
score for a week is missing, it will be considered as a non-response for that week for the 
cumulative number of weeks that participants achieve AAS7 =0 response calculation.
Table 2-7
Estimand attributes for secondary endpoints
Endpoint
Summary measurement
UAS7 score change from baseline to 
Week 12
Mean change from baseline
UAS7 ≤6 at Week 12
Number and proportion of participants with UAS7 ≤6 
response at Week 12
UAS7 =0 at Week 12
Number and proportion of participants with UAS7 =0 
response at Week 12
ISS7 score change from baseline to 
Week 12
Mean change from baseline
HSS7 score change from baseline to 
Week 12
Mean change from baseline
UAS7 ≤6 at Week 2
Number and proportion of participants with UAS7 ≤6 
response at Week 2
DLQI =0-1 at Week 12
Number and proportion of participants with DLQI =0-1 
response at Week 12
Cumulative number of weeks with an 
UAS7 ≤6 response between baseline 
and Week 12
Mean of cumulative number of weeks with an UAS ≤6 
response between baseline and Week 12
Cumulative number of weeks with an 
AAS7 =0 response between baseline 
and Week 12
Mean of cumulative number of weeks with an AAS7 =0 
response between baseline and Week 12
2.6.2
Statistical hypothesis, model, and method of analysis
The secondary (efficacy) variables during the study, listed in Table 2-7, will be summarized. 
All analyses for the secondary (efficacy) endpoints will be performed descriptively. No 
statistical hypothesis is set for the secondary (efficacy) endpoints in this study.
For all efficacy analyses, the FAS will be used.
2.6.3
Handling of intercurrent events 
Participants who discontinue from study treatment early due to any reason will be encouraged 
to stay in the study following the procedures. Every effort will be made to continue to follow 
participants who discontinued from study treatment up to Week 12. These are considered as 
RDO participants. If no RDO data was collected after study treatment permanent 
discontinuation, missing data will be handled without imputation and all available data will be 
used for the analysis.


Novartis
Confidential
Page 38 of 54
SAP
Study No. CLOU064A1301
The analysis will account for different intercurrent events as explained in the following:
•
Discontinuation of study treatment prior to Week 12 due to any reason: ignore, i.e., data 
collection will be maintained and available measurements post-treatment discontinuation 
will be used as if they had been obtained under the treatment: RDO data collected after 
study treatment discontinuation will be used for analysis (Treatment policy strategy).
•
Treatment non-compliance (interruption), switch of background medication, or intake of 
rescue medication as per protocol prior to Week 12: ignore, i.e., data collected after these 
events will be used for analysis (Treatment policy strategy). 
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment at any time 
before Week 12 (as identified by PD M-COMD03), cyclosporine after Week 8 to Week 12  
(as identified by PD M-COMD04), systemic corticosteroids after Week 8 to Week 12 (as 
identified by PD M-COMD04)): measurements after this event will be excluded from the 
analysis and will be imputed using the worst value of the endpoint (e.g., 42 for UAS7 score 
at Week 12, 21 for ISS7 or HSS7 score) (Composite strategy (irrespective of potential 
occurrence of other intercurrent events)). Note: for the endpoint of UAS7 ≤6 at Week 2, 
intake of cyclosporine or systemic corticosteroids will not be considered.
•
Intake of other prohibited medication prior to Week 12: ignore, i.e., Data collected after 
these events will be used for analysis (Treatment policy strategy).
2.6.4
Handling of missing values 
See Section 2.6.1 for the derivation of the each variable.
If there is any intermittent missing data not due to any of the intercurrent events as we defined 
above, the missing data will be handled without imputation and all available data will be used 
for the analysis.
2.6.5
Sensitivity analyses
No sensitivity analysis is planned for the secondary (efficacy) estimands.
2.6.6
Supplementary analyses
No supplementary analysis is planned for the secondary (efficacy) estimands.
2.7
Safety analyses
For all safety analyses, the Safety Set will be used.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries).
For details of the on-treatment period, please see Section 2.1.1.3.
2.7.1
Adverse events (AEs)
See Section 2.5.


Novartis
Confidential
Page 39 of 54
SAP
Study No. CLOU064A1301
2.7.1.1
Adverse events of special interest / grouping of AEs
See Section 2.5.2.
2.7.1.2
Requirements of ClinicalTrials.gov
For the legal requirements of ClinicalTrials.gov, two required tables on treatment emergent 
adverse events (AEs): non-serious AEs with an incidence greater than 5% , and deaths and 
serious AEs (SAEs) including the events suspected to be related to study treatment, will be 
provided by system organ class (SOC) and preferred term (PT) on the Safety Set. The cut-off 
of 5% can be re-evaluated based on number of participants with events.
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.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
These tables will be provided at the final analysis after completion of the study.
2.7.2
Deaths
Death including on-treatment and post-treatment deaths will be listed.
2.7.3
Laboratory data
All laboratory data will be listed by participant and visit and if normal ranges are available 
abnormalities will be flagged. 
For Hematology and Serum chemistry, central laboratory data will be included in the summary 
tables. Local laboratory data will only be listed but not be included in the summary tables.
For Urinalysis, local laboratory data will be included in the summary tables. For participants 
who have only central laboratory data, central data will be used in the summary tables. Both of 
local and central data will be listed. For by-visit summary tables, scheduled visits (including 
remapped visits following the assessment window in Section 2.1.1.4) will be considered in the 
analysis. Unscheduled visits will not be included.
For notable summary tables, all post-baseline visits including unscheduled visits will be 
considered in the analysis.
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(Hematology, Serum chemistry and Urinalysis).


Novartis
Confidential
Page 40 of 54
SAP
Study No. CLOU064A1301
For continuous variables, descriptive summary statistics for the change from baseline to each 
study visit will be presented. These descriptive summaries will be presented by laboratory test. 
Change from baseline will only be summarized for participants with both baseline and post 
baseline values and will be calculated as:
change from baseline = post baseline value – baseline value.
For categorical variables, descriptive statistics will be presented in contingency tables including 
the number and percentage of participants for each category.
For Hematology and Serum chemistry, the maximum change from baseline (maximum decrease 
and maximum increase) will be summarized during the treatment period.
In addition, for laboratory parameters where normal ranges are available, shift tables will be 
provided for all parameters to compare a participant’s baseline laboratory evaluation relative to 
the worst on-treatment value. For the shift tables, the normal laboratory ranges will be used to 
evaluate whether a particular laboratory test value was normal, low, or high for each visit value 
relative to whether or not the baseline value was normal, low, or high. These summaries will be 
presented by laboratory test.
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Event (CTCAE) grades (version 5.0), given in Table 2-8: 
hemoglobin, platelets, white blood cells, neutrophils, lymphocytes, prothrombin time-
international normalized ratio (INR), creatinine, creatinine kinase, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total cholesterol, triglycerides, amylase, 
and lipase.
CTCAE grades based on lab results alone will be applied programmatically, and clinical 
assessments (in italic below) will not be considered. In case of missing baseline laboratory 
assessment, it will be assumed as normal. The number and percentage of participants with 
CTCAE grade newly occurring or worsening after baseline will be presented. A case is 
considered as newly occurring abnormality if the value is not notable or missing at baseline but 
is notable thereafter. A case is considered as worsening abnormality if the value is notable at 
baseline and at least one post-baseline value is worse than baseline.
Shift tables will be provided on CTCAE grades to compare baseline relative to the worst grade. 
These summaries will be split into hematology and chemistry, and will be presented. 
Table 2-8
CTCAE grades for laboratory parameters to be analyzed
CTCAE 
term
Laboratory 
assessment
Grade 1
Grade 2
Grade 3
Grade 4
Anemia 
Hemoglobin 
(Hgb) 
<LLN-10.0 
g/dL
<10.0-8.0 g/dL
<8.0 g/dL
Life-threatening 
consequences
Platelet count 
decreased 
Platelets
<LLN-
75,000/mm3
<75,000- 
50,000/mm3
<50,000- 
25,000/mm3
<25,000/mm3


Novartis
Confidential
Page 41 of 54
SAP
Study No. CLOU064A1301
White blood 
cell count 
decreased 
White blood 
cells
<LLN- 
3000/mm3
<3000- 
2000/mm3
<2000- 
1000/mm3
<1000/mm3
Neutrophil 
count 
decreased 
Neutrophils
<2000- 
1500/mm3
<1500- 
1000/mm3
<1000-500/mm3
<500/mm3
Lymphocyte 
count 
decreased 
Lymphocytes 
<1500-800/mm3
<800-500/mm3
<500-200/mm3
<200/mm3
INR increased 
INR
>1.2-1.5
>1.5-2.5
>2.5
-
Creatinine 
increased 
Serum 
creatinine
>ULN-1.5 x 
ULN 
>1.5-3.0 x ULN 
>3.0-6.0 x ULN 
>6.0 x ULN 
Creatinine 
kinase 
increased
Serum 
creatinine 
kinase
>ULN-2.5 x 
ULN
>2.5 - 5.0 x 
ULN
>5.0 - 10.0 x 
ULN 
>10.0 x ULN
Blood 
bilirubin 
increased
Total bilirubin 
(TBL)
>ULN-1.5 x 
ULN 
>1.5-3.0 x ULN 
>3.0-10.0 x 
ULN 
>10.0 x ULN 
GGT 
increased
Gamma-
glutamyl 
transferase 
(GGT)
>ULN-2.5 x 
ULN 
>2.5-5.0 x ULN 
>5.0-20.0 x 
ULN 
>20.0 x ULN 
ALT increased 
Alanine 
aminotransfera
se (ALT)
>ULN-3.0 x 
ULN 
>3.0-5.0 x ULN 
>5.0-20.0 x 
ULN 
>20.0 x ULN 
AST increased 
Aspartate 
aminotransfera
se (AST)
>ULN-3.0 x 
ULN 
>3.0-5.0 x ULN 
>5.0-20.0 x 
ULN 
>20.0 x ULN 
ALP increased 
Alkaline 
phosphatase 
(ALP)
>ULN-2.5 x 
ULN 
>2.5-5.0 x ULN 
>5.0-20.0 x 
ULN 
>20.0 x ULN 
Total 
cholesterol 
increased
Total 
Cholesterol
>ULN-7.75 
mmol/L
>7.75-10.34 
mmol/L
>10.34-12.92 
mmol/L
>12.92 mmol/L
Triglyceride 
increased
Triglyceride
>=1.71-3.42 
mmol/L
>3.42-5.7 
mmol/L
>5.7-11.4 
mmol/L
>11.4 mmol/L
Amylase 
increased
Amylase
>ULN-1.5 x 
ULN 
>1.5-2.0 x ULN
>2.0-5.0 x ULN
>5.0 x ULN
Lipase 
increased
Lipase
>ULN-1.5 x 
ULN 
>1.5-2.0 x ULN
>2.0-5.0 x ULN
>5.0 x ULN
ULN: Upper limit of normal range; LLN: Lower limit of normal range.
Note: The comparison with baseline is not considered for derivation of LAB CTC grade due to Novartis CTCAE V5 implementation guide.


Novartis
Confidential
Page 42 of 54
SAP
Study No. CLOU064A1301
To evaluate potential drug-induced liver injury, newly occurring liver enzyme abnormalities 
will also be summarized based on the event criteria given in Table 2-9. For the combination 
criteria of parameters, except potential Hy’s Law case, all the elevations must occur at the same 
post-baseline timepoint. A case will be considered as newly occurring if a criterion is not met 
or missing at baseline but is met thereafter.  A case is considered as worsening abnormality if 
the value is notable at baseline and at least one post-baseline value is worse than baseline.
Similarly, participants meeting specific renal alert criteria at any post-baseline will be 
summarized according to Table 2-10.
In addition to liver enzyme test abnormalities, for participants meeting the criteria [ALT or 
AST >5x ULN] or [ALT or AST>3xULN & TBL >2xULN & ALP <2xULN], graphical case 
(per participant) representation to include graph of liver enzymes over time (ALT, AST, TBL, 
ALP, based on xULN) with treatment exposure and concomitant medications, will be provided 
if any case.
Table 2-9
Liver enzyme abnormalities
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
(ALT or AST) & TBL
>3xULN & (TBL>1.5xULN; >2xULN)
(ALT or AST) & INR
>3xULN & INR>1.5
TBL
>1xULN; >1.5xULN; >2xULN
ALP
>1.5xULN; >2xULN; >5xULN
ALP & TBL
>3xULN; >5xULN & TBL>2xULN
(ALT or AST) & TBL & ALP
ALT or AST>3xULN & TBL>2xULN & ALP<2xULN (Potential Hy’s 
Law) 
Table 2-10
Specific renal alert criteria
Parameter
Notable criteria
Serum creatinine
Increase 25% - <50% (%change from baseline)
Increase ≥ 50%
Dipstick proteinuria
≥ 3 + (Newly occurring)
Dipstick hematuria (occult blood)
≥ 3 + (Newly occurring)
2.7.4
Other safety data
2.7.4.1
ECG and cardiac imaging data
PR, QRS, QT, QTcF, RR intervals, and mean heart rate will be obtained from triplicate 12-lead 
ECGs for each participant during the study. ECG data will be read and interpreted centrally.
All ECG data will be listed by participant and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by visit/time.


Novartis
Confidential
Page 43 of 54
SAP
Study No. CLOU064A1301
In case multiple measurements on ECG are done for some visits, for numeric measurements, 
the mean of the scheduled measurements will be used. For ECG overall interpretation, most 
common interpretation (normal/abnormal) of the three assessments taken will be used. At visits 
with pre and post dose assessments, they will be presented separately.
A shift table from baseline to the worst post-baseline value will be presented based on the 
overall ECG interpretation.
The number and percentage of participants with newly occurring of the following criteria after 
baseline will be summarized:
• QT interval > 500 msec
• QTc (Fridericia’s) interval > 450 msec (males), QTc (Fridericia’s) interval > 460 msec 
(females)
• QTc (Fridericia’s) interval change from baseline > 30 - <60 msec, >= 60 msec
• PR interval > 250 msec
• PR interval > 250 msec and PR interval increase from baseline > 25%
• QRS duration >110 - <=120 msec, >120 msec
• QRS duration > 120 msec and QRS duration increase from baseline > 25%
For notable summary tables, all post-baseline visits including unscheduled visits will be 
considered in the analysis.
2.7.4.2
Vital signs
All vital signs data will be listed by participant, and visit/time and if ranges are available, 
abnormalities (and relevant changes) will be flagged. Summary statistics will be provided by 
visit.
For by-visit summary tables, scheduled visits (including remapped visits following the 
assessment window in Section 2.1.1.4) will be considered in the analysis. Unscheduled visits 
will not be included.
For notable summary tables, all post-baseline visits including unscheduled visits will be 
considered in the analysis.
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post baseline visit will be performed. Change from baseline will only be 
summarized for participants with both baseline and post baseline values and will be calculated 
as:
change from baseline = post baseline value – baseline value
The number and percentage of participants with newly occurring clinically notable vital signs 
changes from baseline will be presented. Clinically notable vital sign results are provided in 
Table 2-11 below.












Novartis
Confidential
Page 49 of 54
SAP
Study No. CLOU064A1301
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Partial dose date is not allowed in data collection.
5.1.2
AE date imputation
Imputation for AE end date:
1. If the AE end date ‘month’ is missing, the imputed end date should be set to the earliest of 
the (last visit 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 
(last visit date, last day of the month, date of death). 
3. If the AE end date ‘year’ is missing or the AE is ongoing, the end date will not be imputed. 
Imputation for AE start date: 
Before imputing AE start date, find the AE start reference date as below:
•
If the (imputed) AE end date is complete and the (imputed) AE end date < the treatment 
start date then AE start reference date = min (informed consent date, earliest visit date)
•
Else AE start reference date = the treatment start date
1. If the AE start date ‘year’ is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the AE start date ‘year’ is missing, the imputed AE start date is set to 
NULL. 
2. If the AE start date ‘year’ is less than the treatment start date ‘year’, the AE started before 
treatment. Therefore: 
•
If the AE start date ‘month’ is missing, the imputed AE start date is set to the mid-year 
point (01JulYYYY)
•
Else if the AE start date ‘month’ is not missing, the imputed AE start date is set to the 
mid-month point (15MONYYYY)
3. If the AE start date ‘year’ is greater than the treatment start date ‘year’, the AE started after 
treatment. Therefore: 
•
If the AE start date ‘month’ is missing, the imputed AE start date is set to the year start 
point (01JanYYYY)


Novartis
Confidential
Page 50 of 54
SAP
Study No. CLOU064A1301
•
Else if the AE start date ‘month’ is not missing, the imputed AE start date is set to the 
later of the (month start point (01MONYYYY), AE start reference date + 1 day)
4. If the AE start date ‘year’ is equal to the treatment start date ‘year’: 
•
And the AE start date ‘month’ is missing, the imputed AE start date is set to the AE 
reference start date + 1 day
•
Else if the AE start date ‘month’ is less than the treatment start date ‘month’, the imputed 
AE start date is set to the mid-month point (15MONYYYY)
•
Else if the AE start date ‘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 the 
(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 the imputed AE start date should be set to the (imputed) AE 
end date. 
5.1.3
Concomitant medication date imputation
Imputation for concomitant medication (CM) end date: 
1. If the CM end date ‘day’ is missing and the CM end date ‘month’ and ’year’ are not 
missing, the imputed CM end date is set to the earlier of the (treatment end date and last day 
of the month).
2. If the CM end date ‘day’ and ‘month’ are missing and the CM end date ‘year’ is not 
missing, the imputed CM end date is set to the earlier of the (treatment end date and end of the 
year (31DECYYYY)). 
3. If the imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 
Imputation for CM start date: 
1. If the CM start date ‘year’ is missing, the imputed CM start date is set to one day prior to 
the treatment start date. 
2. If the CM start date ‘year’ is less than the treatment start date ‘year’, the CM started before 
treatment. Therefore: 
•
If the CM start date ‘month’ is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY)
•
Else if the CM start date ‘month’ is not missing, the imputed CM start date is set to the 
mid-month point (15MONYYYY)


Novartis
Confidential
Page 51 of 54
SAP
Study No. CLOU064A1301
3. If the CM start date ‘year’ is greater than the treatment start date ‘year’, the CM started 
after treatment. Therefore: 
•
If the CM start date ‘month’ is missing, the imputed CM start date is set to the year start 
point (01JanYYYY)
•
Else if the CM start date ‘month’ is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY)
4. If the CM start date ‘year’ is equal to the treatment start date ‘year’: 
•
And the CM start date ‘month’ is missing or the CM start date ‘month’ is equal to the 
treatment start date ‘month’, the imputed CM start date is set to one day prior to the 
treatment start date. 
•
Else if the CM start date ‘month’ is less than the treatment start date ‘month’, the imputed 
CM start date is set to the mid-month point (15MONYYYY)
•
Else if the CM start date ‘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 the imputed CM start date should be set to the (imputed) CM 
end date. 
5.1.4
Concomitant therapy date imputation
Same rule as for concomitant medication in Section 5.1.3.
5.1.5
Other imputations
First diagnosis date imputation
1. If the first diagnosis date ‘day’ and ‘month’ are missing and ‘year’ is not missing:
•
If the first diagnosis date ‘year’ is equal to the inform consent date ‘year’, the imputed 
first diagnosis date is set to the year start point (01JanYYYY)
•
Else the imputed first diagnosis date is set to the mid-year point (01JulYYYY)
2. If the first diagnosis date ‘day’ is missing and ‘month’ and ‘year’ are not missing:
•
If the first diagnosis date ‘month’ and ‘year’ are equal to the inform consent date ‘year’ 
and ‘month’, then the imputed first diagnosis date is set to the month start point 
(01MONYYYY)
•
Else the imputed first diagnosis date is set to the mid-month point (15MONYYYY)


Novartis
Confidential
Page 52 of 54
SAP
Study No. CLOU064A1301
5.2
AEs coding/grading
AEs are coded using the MedDRA terminology with the latest version at the analysis.
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
5.4.1
Analysis supporting primary objective(s) 
5.4.1.1
Exposure adjusted incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n participants in a clinical trial the time tj (j=1,...,n) to the 
first occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 𝑇= ∑𝑛
𝑗=1 𝑡𝑗 and D is the number of participants 
with at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a 
Poisson variable with parameter θT and observed value D can be obtained based on (Garwood, 
1936), from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows 
(Sahai, 1993; Ulm, 1990):
Lower confidence limit  𝐿=
0.5𝑐𝛼/2,2𝐷
𝑇
 for D>0, 0 otherwise,
Upper confidence limit  𝑈=
0.5𝑐1―𝛼
2,2𝐷+2
𝑇
where 𝑐𝛼, 𝑘 is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.4.1.2
Confidence interval for proportion of binary data
Confidence intervals for proportion of binary data including response rate and adverse event 
incidence rate will be derived as well based on the score method including continuity correction 
(Newcombe, 1998):
With 𝑧 as (1-α/2)-quantile of the standard normal distribution (SAS: z = PROBIT(1-α/2), 𝑛 as 
total number of subjects (i.e. number of subjects in the denominator), and 𝑝 as estimated crude 
incidence (number of subjects with event / 𝑛) it is 𝑞= 1 ― 𝑝
Then the lower limit is for 𝑝> 0, (𝐿= 0 𝑓𝑜𝑟 𝑝= 0),
𝐿= 𝑚𝑎𝑥0,
2𝑛𝑝+ 𝑧2 ― 1 ― 𝑧𝑧2 ― 2 ― 1 𝑛+ 4𝑝(𝑛𝑞+ 1)
2(𝑛+ 𝑧2)
and the upper limit is for 𝑝< 1, (𝑈= 1 𝑓𝑜𝑟 𝑝= 1),