Clinical trial NCT05030311
Conditions: Chronic Spontaneous Urticaria
Keywords: BTK inhibitor Chronic spontaneous urticaria Urticaria activity score Hives severity score Itch severity score CSU
Sponsor: Novartis Pharmaceuticals
Start date: 2021-11-30; Completion date: 2024-01-19
Enrollment: 470 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to establish the efficacy, safety, and tolerability of remibrutinib (LOU064) in adult participants suffering from chronic spontaneous urticaria (CSU) inadequately controlled by H1-antihistamines in comparison to placebo.

Detailed description:
This was a global Phase III multi-centered, randomized,double-blind, parallel-group, placebo-controlled study investigating the safety, tolerability, and efficacy of remibrutinib (25 mg b.i.d.) in adult patients with CSU inadequately controlled by second generation H1-antihistamines (H1-AHs). The study consisted of four periods, the total study duration was up to 60 weeks: Screening period of up to 4 weeks, Double-blind placebo-controlled treatment period of 24 weeks, Open-label treatment period with remibrutinib period of 28 weeks, and treatment-free follow-up period of 4 weeks. The planned sample size was approximately 450 patients randomized in 2:1 ratio to remibrutinib or placebo arm (300 in the remibrutinib arm and 150 in placebo arm).

Arms: arm 1: Patients initially randomized to Remibrutinib during the Double-blind treatment period and continued Remibrutinib during the Open-label treatment period (Up to Week 52) arm 2: Patients initially randomized to Placebo (Up to Week 24)
Interventions: intervention 1: LOU064 25 mg (b.i.d) intervention 2: Placebo intervention 3: LOU064 25 mg (b.i.d) as a tablet.
Intervention descriptions: intervention 1: LOU064 25 mg was administered by oral route twice a day (b.i.d) as a tablet. intervention 2: Placebo intervention 3: LOU064 25 mg was administered by oral route twice a day (b.i.d) as a tablet in open label phase.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
LOU064/remibrutinib
Clinical Trial Protocol CLOU064A2301 / NCT05030311
A multicenter, randomized, double-blind, 
placebo-controlled Phase 3 study of remibrutinib (LOU064) 
to investigate the efficacy, safety and tolerability for 52 
weeks in adult chronic spontaneous urticaria patients 
inadequately controlled by H1-antihistamines
Document type:
Global Amended Protocol Version
EUDRACT number:
2021-000471-37
Version number:
01 (Clean)
Clinical Trial Phase:
III
Release date:
23-May-2022 (content final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................17
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.2
Purpose ..................................................................................................................24
2
Objectives, endpoints and estimands.................................................................................24
2.1
Primary estimands .................................................................................................29
2.2
Secondary estimands .............................................................................................30
3
Study design ......................................................................................................................31
4
Rationale............................................................................................................................32
4.1
Rationale for study design .....................................................................................32
4.1.1
Rationale for choice of background therapy.........................................34
4.2
Rationale for dose/regimen and duration of treatment ..........................................34
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................37
4.4
Purpose and timing of interim analyses/design adaptations..................................38
4.5
Risks and benefits..................................................................................................39
4.6
Rationale for Public Health Emergency mitigation procedures ............................43
5
Study Population ...............................................................................................................43
5.1
Inclusion criteria ....................................................................................................44
5.2
Exclusion criteria...................................................................................................44
6
Treatment...........................................................................................................................47
6.1
Study treatment......................................................................................................47
6.1.1
Investigational and control drugs..........................................................48
6.1.2
Additional study treatments ..................................................................48
6.1.3
Treatment arms/group ...........................................................................48
6.1.4
Treatment duration................................................................................48
6.2
Other treatment(s)..................................................................................................48
6.2.1
Concomitant therapy.............................................................................48
6.2.2
Permitted concomitant therapy requiring caution and/or action...........49
6.2.3
Prohibited medication ...........................................................................49
6.2.4
Rescue medication ................................................................................52


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6.3
Preparation and dispensation.................................................................................53
6.3.1
Handling of study treatment and other treatment..................................53
6.3.2
Instruction for prescribing and taking study treatment .........................54
6.4
Participant numbering, treatment assignment, randomization ..............................54
6.4.1
Participant numbering...........................................................................54
6.4.2
Treatment assignment, randomization ..................................................55
6.5
Treatment blinding.................................................................................................55
6.6
Dose escalation and dose modification..................................................................56
6.6.1
Follow-up for toxicities.........................................................................56
6.7
Additional treatment guidance...............................................................................56
6.7.1
Treatment compliance...........................................................................56
6.7.2
Emergency breaking of assigned treatment code..................................57
6.7.3
Treatment of overdose...........................................................................57
7
Informed consent procedures ............................................................................................58
8
Visit schedule and assessments .........................................................................................59
8.1
Screening ...............................................................................................................66
8.1.1
Information to be collected on screening failures.................................66
8.2
Participant demographics/other baseline characteristics .......................................66
8.3
Efficacy..................................................................................................................67
8.3.1
eDiary assessments................................................................................67
8.3.2
Other Patient Reported Outcomes (PRO) assessments.........................70
8.3.3
Appropriateness of efficacy assessments..............................................72
8.3.4
Other assessments: evidence of urticaria ..............................................72
73
8.4
Safety.....................................................................................................................73
8.4.1
Laboratory evaluations..........................................................................75
8.4.2
Electrocardiogram (ECG) .....................................................................76
8.4.3
Pregnancy and assessments of fertility .................................................77
8.4.4
Appropriateness of safety measurements..............................................78
8.5
Additional assessments..........................................................................................78
8.5.1
Clinical Outcome Assessments (COAs) ...............................................78
78
79
9
Discontinuation and completion........................................................................................80
9.1
Discontinuation from study treatment and from study..........................................80
9.1.1
Discontinuation from study treatment...................................................80


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9.1.2
Discontinuation from study...................................................................82
9.1.3
Lost to follow-up...................................................................................82
9.2
Withdrawal of informed consent/Opposition to use data/biological samples .......82
9.3
Study completion and post-study treatment ..........................................................83
9.4
Early study termination by the sponsor .................................................................83
10 Safety monitoring, reporting and committees ...................................................................84
10.1
Definition of adverse events and reporting requirements......................................84
10.1.1
Adverse events ......................................................................................84
10.1.2
Serious adverse events ..........................................................................85
10.1.3
SAE reporting........................................................................................86
10.1.4
Pregnancy reporting ..............................................................................87
10.1.5
Reporting of study treatment errors including misuse/abuse................88
10.2
Additional Safety Monitoring................................................................................88
10.2.1
Liver safety monitoring.........................................................................88
10.2.2
Renal safety monitoring........................................................................89
10.3
Committees............................................................................................................89
10.3.1
Data Monitoring Committee .................................................................89
10.3.2
Steering Committee...............................................................................90
11 Data Collection and Database management......................................................................90
11.1
Data collection.......................................................................................................90
11.2
Database management and quality control............................................................90
11.3
Site monitoring ......................................................................................................91
12 Data analysis and statistical methods ................................................................................91
12.1
Analysis sets ..........................................................................................................92
12.2
Participant demographics and other baseline characteristics.................................92
12.3
Treatments .............................................................................................................92
12.4
Analysis supporting primary objectives ................................................................93
12.4.1
Definition of primary endpoint(s).........................................................93
12.4.2
Statistical model, hypothesis, and method of analysis..........................93
12.4.3
Handling of intercurrent events of primary estimand ...........................94
12.4.4
Handling of missing values not related to intercurrent event ...............95
12.4.5
Sensitivity analyses ...............................................................................96
12.4.6
Supplementary analysis.........................................................................96
12.5
Analysis supporting secondary objectives.............................................................97
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................97
12.5.2
Safety endpoints..................................................................................101


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102
102
103
103
103
104
12.7
Interim analyses...................................................................................................105
12.8
Sample size calculation........................................................................................105
12.8.1
Primary endpoint(s).............................................................................105
12.8.2
Secondary endpoint(s).........................................................................106
13 Ethical considerations and administrative procedures ....................................................107
13.1
Regulatory and ethical compliance......................................................................107
13.2
Responsibilities of the investigator and IRB/IEC................................................107
13.3
Publication of study protocol and results.............................................................107
13.4
Quality Control and Quality Assurance...............................................................107
13.5
Participant Engagement.......................................................................................108
14 Protocol adherence ..........................................................................................................108
14.1
Protocol amendments...........................................................................................108
15 References .......................................................................................................................109
16 Appendices ......................................................................................................................113
16.1
Appendix 1: Clinically notable laboratory values and vital signs .......................113
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................114
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....118
16.4
Appendix 4: PRO Tools.......................................................................................120
List of tables
Table 2-1
Objectives and related endpoints – Scenario with UAS7 as the 
primary efficacy endpoint .....................................................................25
Table 2-2
Objectives and related endpoints - Scenario with ISS7 and HSS7 as 
the co-primary efficacy endpoints.........................................................28
Table 6-1
Investigational and control drug............................................................48
Table 6-2
Permitted concomitant therapy requiring caution and/or action...........49
Table 6-3
Prohibited medication ...........................................................................49
Table 8-1
Assessment Schedule ............................................................................61
Table 8-2
UPDD....................................................................................................67
Table 8-3
Hives Severity Score.............................................................................68


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Table 8-4
Itch Severity Score ................................................................................68
69
.69
Table 8-7
DLQI score bands and impact on patient's life .....................................70
Table 8-8
Physical assessments.............................................................................74
Table 8-9
Laboratory assessments.........................................................................75
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................88
Table 16-1
Liver event and laboratory trigger definitions ....................................114
Table 16-2
Follow up requirements for liver laboratory triggers: ALT, AST 
and TBL ..............................................................................................114
Table 16-3
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia .............................................................................116
Table 16-4
Specific renal alert criteria and actions...............................................118
Table 16-5
Renal event follow-up.........................................................................119
List of figures
Figure 3-1
Study Design .........................................................................................32
Figure 4-1
UAS7 score change from baseline over time estimated with a 
mixed-effect repeated measurement analysis, by treatment group 
(FAS).....................................................................................................36
Figure 4-2
UAS7 = 0 and UAS7 <= 6 response rate over time by treatment 
group (as observed) (FAS)....................................................................36
73
Figure 12-1
Testing strategy with UAS7 as the primary endpoint...........................99
Figure 12-2
Testing strategy with ISS7/HSS7 as the co-primary endpoints ..........101


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List of abbreviations
AAS
Angioedema Activity Score
AD
Atopic Dermatitis
AE
Adverse Event
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


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FAS
Full Analysis Set
FcγR
Fc gamma receptor
FcεR
Fc epsilon Receptor
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
Intra-articular
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
J2R
Jump to Reference
KDIGO
Kidney Disease Improving Global Outcome


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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
MAR
Missing At Random
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities 
mg
Milligram(s)
MI
Multiple Imputation
ml
Milliliter(s)
MMRM
Mixed effect Model for Repeated Measurements
NOAC
Novel Oral Anti Coagulant
NSAID
Nonsteroidal Anti-Inflammatory Drug
PA
Primary analysis
Pbo
Placebo
PCR
Protein-creatinine ratio
PD
Pharmacodynamic(s)
PE
Primary endpoint
PK
Pharmacokinetic(s)
PRO
Patient Reported Outcomes
PT
Prothrombin Time
q.d.
Once a Day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RAS
Randomized Set
RDO
Retrieved Drop Out
RNA
Ribonucleic Acid
s.c.
Subcutaneous
SAE
Serious Adverse Event
SAF
Safety Set
SBP
Systolic Blood Pressure
SD
Standard Deviation
SjS
Sjoegren’s Syndrome
SMQ
Standardized MedDRA Query
SUSAR
Suspected Unexpected Serious Adverse Reaction


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TBL
Total Bilirubin
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


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g., any background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant 
Clinical Outcome 
Assessment (COA)
A measure that describes or reflects how a participant feels, functions, 
or survives
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 


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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
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
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
Randomization
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias.
Randomization number
A unique identifier assigned to each randomized participant


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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 of interventions administered concurrently, 
e.g., as add-on to standard of care, or might consist of an overall 
regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment.
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event.
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation.
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal 
reason than consent.


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Amendment 1 (23-May-2022) 
Amendment rationale 
Amendment 1 implements 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. In 
addition, feedback received from Health Authorities and Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) for both pivotal Phase 3 trials (CLOU064A2301 
and CLOU064A2302) was considered to ensure consistency across the program and the 
protocol amended as indicated below.
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 205 patients screened 
and 114 patients randomized. 
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.
 

Section 2.1: Methods for handling of intercurrent events have been updated considering US 
FDA feedback.

Section 2.2: Methods for handling of intercurrent events have been updated considering US 
FDA feedback.

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 13 and 18 updated to reflect the feedback received from 
Health Authorities, exclusion criteria 19 updated to clarify maximum dose of clopidogrel.

Section 6.2.3: 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 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


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
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 Randomization/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 17 and 18 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.

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.

Section 9.1.2: Clarified that participant can request discontinuation from study in writing or 
verbally to reflect feedback from Health Authorities.

Section 9.2: Clarified that participant can request withdrawal of consent in writing or 
verbally to reflect feedback from Health Authorities.

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 12.4.3: Handling of intercurrent events amended considering US FDA feedback.

Section 12.4.5: Tipping point analysis removed from sensitivity analysis methods 
considering US FDA feedback.

Section 12.4.6: Handling of intercurrent events amended considering US FDA feedback.

Section 12.5.1: Analysis method for absolute change from baseline in ISS7 and HSS7 at 
Week 12 amended considering US FDA feedback.


Section 15: Additional references added and two references removed to align with updated 
Investigator Brochure and Section 4.5.

Section 16.1: QTcF increase ≥60 msec from baseline added to the definition of a notable 
QTc value for ECGs for clarification.


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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.


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Protocol summary
Protocol number
CLOU064A2301
Full Title
A multicenter, randomized, double-blind, placebo-controlled Phase 3 study of 
remibrutinib (LOU064) to investigate the efficacy, safety and tolerability for 
52 weeks in adult chronic spontaneous urticaria patients inadequately 
controlled by H1-antihistamines
Brief title
A Phase 3 study of efficacy and safety of remibrutinib in the treatment of 
chronic spontaneous urticaria in 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 establish the efficacy, safety, and tolerability 
of remibrutinib (LOU064) 25 mg b.i.d. in adult participants suffering from 
chronic spontaneous urticaria (CSU) inadequately controlled by 
H1-antihistamines in comparison to placebo.
Primary 
Objective(s) 
The primary objective of this study is to demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with respect to change from baseline in 
Weekly Urticaria Activity Score (UAS7) in Weekly Itch Severity Score (ISS7) 
and Weekly Hive Severity Score (HSS7) for the second primary endpoint 
scenario) at Week 12.
The primary clinical question of interest is: What is the effect of remibrutinib 
treatment versus placebo on the change from baseline in UAS7 score (in 
HSS7 and ISS7 for the second primary endpoint scenario) 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 discontinuation from study 
treatment for any reason and regardless of intake of a different second 
generation H1-antihistamine as rescue medication and considering strongly 
confounding prohibited medication as an unfavourable outcome?
Secondary 
Objectives
Scenario #1 with UAS7 as the primary endpoint
To demonstrate that a greater proportion of participants achieve disease 
activity control (UAS7 ≤ 6) at Week 12 when treated with remibrutinib (25 mg 
b.i.d.) compared to placebo-treated participants.

The secondary clinical question of interest is: What is the effect of 
remibrutinib treatment versus placebo on the UAS7 ≤ 6 response after 12 
weeks 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 and regardless of intake of a 
different second generation H1-antihistamine as rescue medication and 
considering 
strongly 
confounding 
prohibited 
medication 
as 
an 
unfavourable outcome?


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To demonstrate that a greater proportion of participants achieve complete 
absence of hives and itch (UAS7 = 0) at Week 12 when treated with 
remibrutinib (25 mg b.i.d.) compared to placebo-treated participants 

The secondary clinical question of interest is: What is the effect of 
remibrutinib treatment versus placebo on the UAS7 = 0 response after 12 
weeks 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 and regardless of intake of a 
different second generation H1-antihistamine as rescue medication and 
considering 
strongly 
confounding 
prohibited 
medication 
as 
an 
unfavourable outcome?
To demonstrate the superiority of remibrutinib (25 mg b.i.d.) versus placebo 
with respect to a reduction from baseline in the weekly itch severity score 
(ISS7) at Week 12
To demonstrate the superiority of remibrutinib (25 mg b.i.d.) versus placebo 
with respect to a reduction from baseline in the weekly hive severity score 
(HSS7) at Week 12
To demonstrate that a greater proportion of participants achieve UAS7 ≤ 6 at 
Week 2 when treated with remibrutinib (25 mg b.i.d.) compared to placebo-
treated participants
To demonstrate that a greater proportion of participants who are treated with 
remibrutinib (25 mg b.i.d.) achieve dermatology life quality index (DLQI) = 0-1 
at Week 12 compared to placebo-treated participants
To demonstrate that remibrutinib (25 mg b.i.d.) treated participants maintain 
disease activity control (defined as UAS7 ≤ 6) for more weeks compared to 
placebo treated participants over a total of 12 weeks
To demonstrate that remibrutinib (25 mg b.i.d.) treated participants have more 
angioedema occurrence-free weeks over a total of 12 weeks compared with 
placebo-treated participants
To demonstrate the safety and tolerability of remibrutinib (25 mg b.i.d.)
Scenario #2 with ISS7 and HSS7 as the co-primary endpoints
To demonstrate that remibrutinib (25 mg b.i.d.) is superior to placebo in CSU 
with respect to change from baseline in UAS7 at Week 12
To demonstrate that a greater proportion of participants achieve disease 
activity control (UAS7 ≤ 6) at Week 12 who are treated with remibrutinib (25 
mg b.i.d.) compared to placebo-treated participants

The secondary clinical question of interest is: What is the effect of 
remibrutinib treatment versus placebo on the UAS7 ≤ 6 response after 12 
weeks 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 and regardless of intake of a 
different second generation H1-antihistamine as rescue medication and 
considering 
strongly 
confounding 
prohibited 
medication 
as 
an 
unfavourable outcome?


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To demonstrate that a greater proportion of participants achieve complete 
absence of hives and itch (UAS7 = 0) at Week 12 who are treated with 
remibrutinib (25 mg b.i.d.) compared to placebo-treated participants

The secondary clinical question of interest is: What is the effect of 
remibrutinib treatment versus placebo on the UAS7=0 response after 12 
weeks 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 and regardless of intake of a 
different second generation H1-antihistamine as rescue medication and 
considering 
strongly 
confounding 
prohibited 
medication 
as 
an 
unfavourable outcome?
To demonstrate that a greater proportion of participants achieve UAS7 ≤ 6 at 
Week 2 who are treated with remibrutinib (25 mg b.i.d.) compared to placebo-
treated participants
To demonstrate that a greater proportion of participants who are treated with 
remibrutinib (25 mg b.i.d.) achieve DLQI = 0-1 at Week 12 compared to 
placebo-treated participants
To demonstrate that remibrutinib (25 mg b.i.d.) treated participants maintain 
disease activity control (defined as UAS7 ≤ 6) for more weeks compared to 
placebo treated participants over 12 weeks
To demonstrate that remibrutinib (25 mg b.i.d.) treated participants have more 
angioedema occurrence-free weeks over 12 weeks compared with placebo-
treated participants
To demonstrate the safety and tolerability of remibrutinib (25 mg b.i.d.)
Study design
This is a global Phase 3 multicenter, randomized, double-blind, parallel-group, 
placebo-controlled 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 four periods, the 
total study duration is up to 60 weeks: screening period of up to 4 weeks, 
double-blind placebo controlled treatment period of 24 weeks, open-label 
treatment with remibrutinib period of 28 weeks, treatment free follow-up period 
of 4 weeks.
Rationale
Signs and symptoms of CSU are a direct consequence of mast cell 
degranulation with release of inflammatory mediators including histamine. 
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase which is 
indispensable for Fc epsilon receptor (FcεR1), Fc gamma receptor (FcγR) as 
well as B cell receptor (BCR) signaling and a central signaling kinase in mast 
cell activation. It has been demonstrated that BTK inhibition can effectively 
inhibit mast cell activation. Remibrutinib (LOU064) is a low molecular weight 
compound for oral administration that covalently binds and inhibits BTK with 
high selectivity. In Phase 1, remibrutinib was well tolerated at all doses without 
any dose-limiting toxicity and showed encouraging blood and skin 
pharmacodynamics (PD) with a favorable safety profile, fully supporting further 
development. 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. This Phase 3 study is 
designed to confirm and further evaluate the efficacy and safety of remibrutinib 
in adult CSU patients at a dose of 25 mg b.i.d. A second, nearly identical 
Phase 3 study will be conducted in parallel.


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Study population
The study population will consist of approximately 450 randomized female and 
male adult participants (300 in the active arm and 150 in placebo arm) with 
CSU inadequately controlled by second generation H1-antihistamines.
The screen failure rate is estimated to be 30%, meaning approximately 645 
participants are expected to be screened.
Participants will be stratified based on prior exposure to anti-immunoglobulin 
(Ig) E biologics and geographic region. Maximum number of participants with 
prior exposure to anti-IgE biologics will be limited to approximately 30% of the 
total study population.
Key Inclusion 
criteria

Signed informed consent must be obtained prior to participation in the 
study.

Male and female adult 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 the time of randomization 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 
randomization (Day 1)

Documentation of hives within three months before randomization (either 
at screening and/or at randomization; 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 randomization (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 urticaria, 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 


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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., where 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))

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
Study treatment

LOU064 25mg film-coated tablets (blinded)

LOU064 25mg placebo film-coated tablets (blinded)

LOU064 25mg film-coated tablets (open-label)
Efficacy 
assessments
All efficacy measures are Patient Reported Outcomes (PROs):
Electronic Diary (eDiary) assessments

Urticaria Patients Daily Diary (UPDD), which assesses: 

Hives Severity Score (HSS)

Itch Severity Score (ISS)

Urticaria Activity Score (UAS)

angioedema occurrence

number of calls to doctor, nurse or nurse practitioner

Angioedema Activity Score (AAS)
 
 
Key safety 
assessments
Adverse event (AE) monitoring
Physical examinations
Vital signs
Monitoring of laboratory markers in blood and urine
Central electrocardiogram (ECG) monitoring
Other 
assessments 
Other PROs assessments

Dermatology Life Quality Index (DLQI)


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Data analysis
The main purpose of this study is to demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with respect to change from baseline in 
UAS7 at Week 12 (for second scenario, in ISS7 and HSS7). A linear mixed 
model with repeated measures (MMRM) will be used to estimate treatment 
differences for change from baseline in UAS7 score (ISS7 and HSS7 for 
second scenario) at Week 12, based on the full analysis set (FAS).
For secondary endpoints, a logistic regression model will be used to estimate 
treatment differences for disease activity control at weeks 2 and 12, complete 
response and DLQI = 0/1 endpoints at week 12. Negative binomial regression 
model will be used to estimate treatment differences for the cumulative 
number of weeks achieving AAS7 = 0 response and UAS7<= 6 between 
baseline and Week 12.
The primary and secondary endpoints analyses are planned to use the 
multiple testing strategy to control the family-wise error at α = 0.025 (one-
sided).
Summary tables will be presented by treatment group and visit (as 
applicable) using descriptive statistics, which include absolute and relative 
frequencies for categorical variables and arithmetic mean, standard deviation, 
minimum, maximum, median and 25th and 75th percentiles for continuous 
variables.
Key words
BTK inhibitor; Chronic spontaneous urticaria; Urticaria activity score; Hives 
severity score; Itch severity score


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1
Introduction
1.1
Background
Chronic Spontaneous Urticaria (CSU), also known as Chronic Idiopathic Urticaria (CIU), is 
defined 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). 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 
vasodilatation, 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).
Second generation 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), 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 corticosteroid use. Omalizumab is an effective third-line therapy for CSU patients. 
However, less than 50% of patients treated with omalizumab reach complete control of signs 
and symptoms (Kaplan et al 2016). Therefore, there is a high unmet medical need for new 
treatment options for CSU patients inadequately controlled by H1-antihistamines.
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and member of the TEC kinase 
family. BTK is expressed in selected cells of the adaptive and innate immune system including 
B cells, macrophages and mast cells/basophils. BTK is indispensable for signaling through the 
Fc epsilon receptor (FcεR1 for IgE), the activating Fc gamma receptors (FcγR for IgG), as well 
as the B cell antigen receptor (BCR) and therefore an important signaling node in the 
activation/degranulation of B cells, macrophages, mast cells or basophils (Rip et al 2018).


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BTK inhibitors (BTKi) like ibrutinib have been first approved for the treatment of B cell 
malignancies (Hendriks et al 2014). Due to the above described role of BTK in adaptive as well 
as innate immune signaling and associated with that, its role in immune-mediated diseases, 
targeting BTK is regarded as a promising new approach for the treatment of various immune-
mediated conditions. 
 
Mast cells and basophils play a key role in the pathophysiology of CSU, and it has been 
demonstrated that BTK inhibition leads to blockade of mast cell and basophil 
activation/degranulation in vitro and to reduced wheal sizes in skin prick tests with patients 
suffering 
from 
IgE-mediated 
allergies 
(Smiljkovic et al 2017, 
Regan et al 2017, 
Dispenza et al 2017). Thus, BTK inhibition is a promising therapeutic concept for the treatment 
of CSU.
Remibrutinib (LOU064) is a low molecular weight compound for oral administration that 
covalently 
binds 
and 
inhibits 
BTK 
with 
high 
selectivity 
(Angst et al 2020, 
Gabizon and London 2020). 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, and B cells, such as chronic spontaneous urticaria (Kaul et al 2021). The Phase 2b 
clinical trial CLOU064A2201 primary endpoint analysis demonstrated clinical efficacy and a 
fast onset of action of remibrutinib in the treatment of CSU patients as well as a favorable safety 
profile (for detailed information please refer to the Investigator`s Brochure (IB)).
Taken together, remibrutinib may offer a novel therapeutic approach for patients with CSU and 
is advanced to Phase 3 clinical development.
1.2
Purpose
The purpose of this study is to establish the efficacy, safety, and tolerability of remibrutinib 
(LOU064) 25 mg b.i.d. in adult participants suffering from chronic spontaneous urticaria (CSU) 
inadequately controlled by H1-antihistamines in comparison to placebo.
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 randomization (Day 1).
2
Objectives, endpoints and estimands
There are two primary objective scenarios based on regional regulatory precedent and Health 
Authorities’ feedback. These two primary objective scenarios will be tested in two distinct 
testing strategies (Table 2-1and Table 2-2). Distinctions in the secondary objectives reflect the 
corresponding scenario: the primary objective in one scenario is presented as secondary 
objective(-s) in another. The other secondary 
 objectives are identical in both 
scenarios.


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Table 2-1
Objectives and related endpoints – Scenario with UAS7 as the primary 
efficacy endpoint
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with 
respect to change from baseline in UAS7 
at Week 12

Absolute change from baseline in UAS7 at 
Week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To demonstrate that a greater proportion 
of participants achieve disease activity 
control (UAS7 ≤ 6) at Week 12 who are 
treated with remibrutinib (25 mg b.i.d.) 
compared to placebo-treated participants

Achievement of UAS7 ≤ 6 (yes/no) at Week 12

To demonstrate that a greater proportion 
of participants achieve complete absence 
of hives and itch (UAS7 = 0) at Week 12 
who are treated with remibrutinib (25 mg 
b.i.d.) compared to placebo-treated 
participants

Achievement of UAS7 = 0 (yes/no) at Week 12

To demonstrate the superiority of 
remibrutinib (25 mg b.i.d.) treated 
participants with respect to a reduction 
from baseline in the weekly itch severity 
score at Week 12 compared to placebo-
treated participants

Improvement of severity of itch, assessed as 
absolute change from baseline in ISS7 score at 
Week 12

To demonstrate the superiority of 
remibrutinib (25 mg b.i.d.) treated 
participants with respect to a reduction 
from baseline in the weekly hive severity 
score at Week 12 compared to placebo-
treated participants

Improvement of severity of hives, assessed as 
absolute change from baseline in HSS7 score 
at Week 12

To demonstrate that a greater proportion 
of participants achieve UAS7 ≤ 6 at Week 
2 who are treated with remibrutinib (25 
mg b.i.d.) compared to placebo-treated 
participants

Achieving early onset of disease activity 
control, as defined as achievement of UAS7≤ 6 
(yes/no) at Week 2

To demonstrate that a greater proportion 
of participants who are treated with 
remibrutinib (25 mg b.i.d.) achieve DLQI 
= 0-1 at Week 12 compared to placebo-
treated participants

No impact on participants' dermatology-quality 
of life, as defined by achievement of DLQI = 0-1 
(yes/no) at Week 12

To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants maintain 
disease activity control (defined as UAS7
≤6) for more weeks compared to placebo 
treated participants over 12 weeks

Achieving sustained disease activity control, 
assessed as cumulative number of weeks with 
an UAS7 ≤6 response between baseline and 
Week 12

To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants have more 

Number of weeks without angioedema, 
assessed by the cumulative number of weeks 


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Objective(s)
Endpoint(s)
angioedema occurrence-free weeks over 
12 weeks compared with placebo-treated 
participants
with an AAS7 = 0 response between baseline 
and Week 12

To demonstrate the safety and tolerability 
of remibrutinib (25 mg b.i.d.)

Occurrence of treatment emergent adverse 
events and serious adverse events during the 
study


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Objective(s)
Endpoint(s)


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Table 2-2
Objectives and related endpoints - Scenario with ISS7 and HSS7 as 
the co-primary efficacy endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with 
respect to change from baseline in ISS7 and 
HSS7 at Week 12

Absolute change from baseline in ISS7 at 
Week 12

Absolute change from baseline in HSS7 at 
Week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with 
respect to change from baseline in UAS7 at 
Week 12

Absolute change from baseline in UAS7 at 
Week 12

To demonstrate that a greater proportion of 
participants achieve disease activity control 
(UAS7 ≤ 6) at Week 12 who are treated with 
remibrutinib (25 mg b.i.d.) compared to 
placebo-treated participants

Achievement of UAS7≤ 6 (yes/no) at Week 
12

To demonstrate that a greater proportion of 
participants achieve complete absence of 
hives and itch (UAS7 = 0) at Week 12 who 
are treated with remibrutinib (25 mg b.i.d.) 
compared to placebo-treated participants

Achievement of UAS7 = 0 (yes/no) at Week 
12

To demonstrate that a greater proportion of 
participants achieve UAS7 ≤ 6 at Week 2 
who are treated with remibrutinib (25 mg 
b.i.d.) compared to placebo-treated 
participants

Achieving early onset of disease activity 
control, as defined as achievement of UAS7
≤ 6 (yes/no) at Week 2

To demonstrate that a greater proportion of 
participants who are treated with 
remibrutinib (25 mg b.i.d.) achieve DLQI = 0-
1 at Week 12 compared to placebo-treated 
participants

No impact on participants' dermatology 
quality of life as defined by achievement of 
DLQI = 0-1 (yes/no) at Week 12.

To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants maintain disease 
activity control (defined as UAS7 ≤6) for 
more weeks compared to placebo treated 
participants over 12 weeks

Achieving sustained disease activity control, 
assessed as cumulative number of weeks 
with an UAS7 ≤6 response between 
baseline and Week 12

To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants have more 
angioedema occurrence-free weeks over 12 
weeks compared with placebo-treated 
participants

Number of weeks without angioedema, 
assessed by the cumulative number of 
weeks with an AAS7 = 0 response between 
baseline and Week 12

To demonstrate the safety and tolerability of 
remibrutinib (25 mg b.i.d.)

Occurrence of treatment emergent adverse 
events and serious adverse events (SAEs)
during the study


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Objective(s)
Endpoint(s)
2.1
Primary estimands
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment).
Primary estimand for scenario with UAS7 as primary efficacy endpoint
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the change from baseline in UAS7 score after 12 weeks 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 
discontinuation from study treatment for any reason and regardless of intake of a different 
second generation H1-antihistamine as rescue medication and considering strongly 
confounding prohibited medication as an unfavourable outcome?
The primary estimand is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥ 6 months, a UAS7 score ≥ 16, 
ISS7 ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint: Change in UAS7 from baseline at Week 12.
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: the mean difference between treatment groups.
5. Handling of intercurrent events:

Discontinuation of study treatment due to any: Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 8): 
Composite strategy (irrespective of potential occurrence of other intercurrent events)

Intake of rescue medication, switch of background medication, intake of other prohibited 
medication: Treatment policy strategy


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Primary estimand for scenario with ISS7/HSS7 as co-primary efficacy endpoints
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the co-primary endpoints change from baseline in ISS7 score and change from 
baseline in HSS7 score 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 discontinuation from study treatment for any reason 
and regardless of intake of a different second generation H1-antihistamine as rescue medication 
and considering strongly confounding prohibited medication as an unfavourable outcome?
The primary estimand is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥ 6 months, a UAS7 score ≥ 16, 
ISS7 ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint (co-primary): Change in ISS7 from baseline at Week 12 and change in HSS7 
from baseline at Week 12.
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: the mean difference between treatment groups.
5. Handling of intercurrent events:

Discontinuation of study treatment due to any reason: Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent 
events)

Intake of rescue medication, switch of background medication, intake of other 
prohibited medication: Treatment policy strategy
2.2
Secondary estimands
Secondary estimand on the secondary endpoint UAS7 ≤ 6 response at week 12
The secondary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the UAS7 ≤ 6 response after 12 weeks 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 and regardless of intake of a different second generation H1-antihistamine as rescue 
medication and considering strongly confounding prohibited medication as an unfavourable 
outcome?
The secondary estimand is described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥6 months, a UAS7 score ≥ 16, 
ISS7 score ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint: UAS7 ≤ 6 response at Week 12.


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3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: the odds ratio between treatment groups.
5. Handling of intercurrent events:

Discontinuation of study treatment due to any reason non-compliance (dose 
interruption): Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent 
events)

Intake of rescue medication, switch of background medication, intake of other 
prohibited medication: Treatment policy strategy
Secondary estimand on the secondary endpoint UAS7 = 0 response at week 12
Similar Estimand approach will be implemented for UAS7= 0 as for UAS7 ≤ 6.
Other secondary estimand on the other secondary endpoints as defined in Table 2-1 and 
Table 2-2.
Similar Estimand approach will be implemented for these endpoints as the primary Estimand 
or co-primary Estimand.
3
Study design
This is a global, multicenter, randomized, double-blind, parallel-group, placebo-controlled 
Phase 3 study investigating the safety, tolerability, and efficacy of remibrutinib (25 mg b.i.d.) 
in adult participants with CSU inadequately controlled by second generation H1-antihistamines. 
The study consists of four periods, the total study duration is up to 60 weeks (Figure 3-1):

Screening period: up to 4 weeks.

Double-blind treatment period: 24 weeks of double-blind treatment with remibrutinib 
(25 mg b.i.d.) or placebo.

Open-label treatment period: 28 weeks of open-label treatment with remibrutinib (25 
mg b.i.d.).

Follow-up period: 4 weeks of treatment-free follow-up.
The primary analysis may be conducted after all participants have completed Week 24 or 
discontinued earlier and when a minimum of 150 participants across both Phase 3 pivotal 
studies (a second, nearly identical Phase 3 study will be conducted in parallel) have completed 
the treatment period at Week 52 (see Section 4.4). All participants will be on a stable, locally 
label approved dose of a second generation H1-antihistamine (“background therapy”) 
throughout the entire study (starting a minimum of 7 days prior to randomization 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”). 
Eligible participants will be randomly assigned to the treatment arms in a 2:1 ratio. The study 


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population will consist of approximately 450 female and male adult participants (300 in the 
active arm and 150 in the placebo arm) with CSU inadequately controlled by second generation 
H1-antihistamines at least at locally label approved dose. Participants will be stratified based 
on prior exposure to anti-IgE biologics and geographic region.
An extension study is in development. 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.
Figure 3-1
Study Design
D-1: Day 1, b.i.d.: bis in die/twice a day, mg: milligram(s), Pbo: placebo, PA: Primary Analysis, PE: 
Primary Endpoint, 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 confirm and further evaluate the efficacy and safety 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 Section 4.2) in adult CSU patients. It is a randomized, double-blind, parallel-group, and 
placebo-controlled study that consists of four periods:
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.


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2. Double-blind treatment period: a placebo-controlled, double-blind treatment period until 
Week 24. The placebo-controlled, double-blind design is mandatory to enable a robust 
assessment of the efficacy of remibrutinib without bias by the fluctuating nature of CSU 
(and the resulting significant placebo effect). Furthermore, it is required for a robust 
assessment of the safety profile of remibrutinib in comparison to placebo over an adequate 
period of time (for further details please see Section 4.3). This design is in line with other 
major Phase 3 trials in the field of CSU, e.g., with ligelizumab (NCT03580369 and 
NCT03580356), which ensures comparability. In order to limit the number of participants 
exposed to placebo while maintaining the scientific validity of the study, the randomization 
ratio will be 2:1 of active vs. placebo treatment. A placebo comparison up to Week 24 
(which is beyond the primary endpoint at Week 12) will provide a background incidence in 
the study population for possible safety findings and will ensure a valid assessment of the 
durability of the treatment response. It will support a more robust characterization of the 
safety profile of remibrutinib, i.e., if safety events are observed in both the placebo and 
remibrutinib arms, it may be inferred that the events are not necessarily related to the study 
treatment. To limit the duration of placebo treatment, the placebo-controlled treatment 
period will stop at Week 24, since a period of 24 weeks allows a reliable and valid 
assessment of efficacy and safety in patients with CSU.
3. Open-label treatment period: during this treatment period of 28 weeks, all participants 
will receive open-label remibrutinib (25 mg b.i.d.). Together with the preceding double-
blind, placebo-controlled period, a total of up to 52 weeks of remibrutinib (25 mg b.i.d.) 
treatment will be studied within this trial. This is in line with current CSU treatment 
guidelines (Zuberbier et al 2018) and will provide adequate long-term efficacy and safety 
data to fully characterize the value of remibrutinib (25 mg b.i.d.) in CSU treatment. 
Switching placebo treated participants to active treatment with remibrutinib at Week 24 
gives all participants the opportunity to receive active treatment with remibrutinib within 
the course of this study.
4. 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 
in planning stage). This allows the assessment of safety of 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 a high 
unmet medical need are the target population for this study.
Historically, the treatment paradigm for CSU focused primarily on the key symptom itch, as 
assessed by the weekly Itch Severity Score (ISS7). Over the past several years, the emphasis 
and target of therapy, as described in the current CSU treatment guidelines 
(Zuberbier et al 2018), have evolved to also integrate the second key symptom of CSU, which 
is hives. Therefore, UAS7, which is a composite of ISS7 and the weekly Hives Severity Score 
(HSS7), is now recommended, rather than using ISS7 alone. Thus, the primary endpoint of this 


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study is change in UAS7 from baseline at Week 12 or a co-primary endpoint of change from 
baseline in ISS7 and HSS7 at Week 12. Two separate statistical analyses will be used to enable
the two different primary and consecutive secondary endpoints, in order to fulfill regional health 
authority requests. They will be assessed in independent testing strategies for all participants. 
Furthermore, a primary endpoint at Week 12 ensures adequate comparability of the efficacy 
outcomes with other major Phase 3 trials in the field of CSU, e.g., with omalizumab 
(Maurer et al 2013) or ligelizumab (NCT03580369 and NCT03580356). UAS7-based 
responder analyses (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 on 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) have been 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 approved second generation H1-antihistamine follows the recommendations of the 
current treatment guidelines (Zuberbier et al 2018).
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 the efficacy and safety of 
remibrutinib in CSU as per current scientific, medical, ethical and regulatory standards, while 
limiting the burden for participants as much as possible.
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, which recommend 
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). Furthermore, it 
allows active treatment of participants in the placebo arm, including the use of additional rescue 
medication. Thus, participants in the placebo arm are not left without CSU treatment.
4.2
Rationale for dose/regimen and duration of treatment
In this study, remibrutinib will be given in 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.


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The target population of this trial includes difficult-to-treat patients, such as patients with 
concomitant CINDU, long disease history and patients with prior inadequate response to anti-
IgE biologics. In such cases a treatment duration of up to 52 weeks and more can be required. 
An extension study is under development 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 adverse events (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 Investigator's Brochure.
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).


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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% under 25 mg 
b.i.d. compared to 43.2%, 40.9%, 42.6%, 34.1%, 44.4%, 4.8% under 10 mg q.d., 35 mg q.d., 


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100 mg q.d., 10 mg b.i.d., 100 mg b.i.d., placebo (non-responder imputation). In line with that, 
the 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% under 25 mg b.i.d. compared to 18.2%, 22.7%, 17.0%, 
18.2%, 22.2%, 0.0% under 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 turn-over of the covalent BTK-
remibrutinib complex in tissue (see Investigator´s Brochure 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 
Investigator's Brochure) 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 Phase 3 study.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Placebo was chosen as a comparator for this trial to adjust for the fluctuating nature of CSU, 
which can result in a pronounced placebo effect. Therefore, comparison to placebo allows a 
robust and scientifically valid efficacy assessment. Furthermore, comparison to placebo allows 
a meaningful safety assessment. The use of placebo in this study population is considered to be 
appropriate 
since 
participants 
will 
additionally 
receive 
background 
therapy 
of 
H1-antihistamines (see Section 6.1.2) and will have access to additional rescue medication (see 
Section 6.2.4). Although it is an inclusion criterion of the study to be inadequately controlled 
by H1-antihistamines, this does not mean that participants do not benefit from 


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H1-antihistamines at all. The allowed H1-antihistamine background treatment still alleviates 
participants´ symptoms to a certain degree. Thus, participants in the placebo arm are not left 
without treatment during the placebo-controlled period. Furthermore, participants in the 
placebo arm will be switched to active treatment with remibrutinib at Week 24, giving all 
participants the opportunity to receive treatment with remibrutinib during the course of the trial.
As the target patient population is hard-to-treat CSU patients with a prior inadequate response 
to second generation H1-antihistamines, the only potential active comparator according to the 
current treatment guidelines would be omalizumab (Zuberbier et al 2018). CSU patients, who 
have already been treated with, and potentially failed to respond to, omalizumab, have a high 
unmet medical need, since they are currently left without approved treatment options. Adding 
omalizumab as an active comparator to the study would significantly restrict the study 
population, as these omalizumab (or any other anti-IgE biologics) pretreated patients would 
need to be excluded from the study in order to prevent a potential prior treatment bias and allow 
a fair comparison, thus preventing the collection of efficacy and safety data for this population. 
Additionally, the burden for enrolled participants would increase as the administration routes
of remibrutinib (oral) and omalizumab (subcutaneous (s.c.)) would mandate a double-dummy 
design with placebo injections for participants in the remibrutinib arm and 4-weekly visits 
throughout the entire study duration (instead of extended periods between visits after Week 24 
as per the current study design). Furthermore, the long half-life of omalizumab (approximately 
4 weeks vs a half-life of approximately 1 hour for remibrutinib) would mandate a significantly 
longer treatment-free follow-up period after the end of the treatment period. Due to differences 
in the route of administration (s.c. vs. oral), different PK-PD profiles and speed of onset kinetics, 
omalizumab is not considered an ideal comparator for remibrutinib. Lastly, historical 
comparisons of the data from the confirmatory omalizumab trials to the current remibrutinib 
trial will be possible, given their similarities with regard to patient population, background 
medication, endpoints and the use of placebo as the control arm in the omalizumab studies.
Taken together, a placebo comparison over 24 weeks is appropriate and justified for this trial, 
allowing a robust and scientifically valid assessment of the safety and efficacy of remibrutinib. 
The additional comparative information which could be gained by adding the active comparator 
omalizumab does not outweigh the restrictions in study population and the additional 
participant burden this would entail.
4.4
Purpose and timing of interim analyses/design adaptations
A primary analysis may be conducted when all participants have completed their Week 24 visit 
or discontinued early and when a minimum of 150 participants across both Phase 3 pivotal 
studies have completed the treatment period (a second, nearly identical Phase 3 study will be 
conducted in parallel). The minimum of 150 participants reaching week 52 should enable 
analysis on a minimum of 100 participants exposed to remibrutinib for 52 weeks considering 
the initial randomization to either the remibrutinib or the placebo arm (2:1). The results of the 
primary analysis will further inform decision making for the remibrutinib development 
program.
After the primary analysis and/or after all participants have entered the open label treatment 
period, additional optional interim analyses may be conducted to support potential Health 


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Authority interactions and requests (these interim analyses are not expected to have any impact 
on the conduct or scientific integrity of the study).
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). Bruton’s 
tyrosine kinase (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 
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 (HVs) 
and patients suffering from CSU, asthma, Sjoegren’s Syndrome (SjS), atopic dermatitis (AD), 
and relapsing multiple sclerosis (RMS)) 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 
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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 adverse events were 
reported in the following System Organ Classes (SOC): Infections and infestations (24.0% any 
remibrutinib dose 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 chronic spontaneous urticaria 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 macroglobulinemia), 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 (21.4%). Most infections 


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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 and during the study 
until at least 4 weeks after the last dose of the study treatment (see Section 6.2.3).

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 events 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 and 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, all but 2 events (the 
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 Table 6-3). In case of a significant 
bleeding event, study treatment must be discontinued immediately. Please, refer to the 
current IB for further details.


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
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 FIH 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 
msec or increases equal or greater than 60 msec) 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, SjS 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 cytochrome P450 (CYP) 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 6-3). 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 cation transporter 1 and breast cancer resistance protein (BCRP)). However,
at a dose of 25 mg b.i.d., only inhibition of BCRP remains as a minor risk which is planned 


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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 6-2)

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 Investigator's Brochure). 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 
Investigator’s Brochure.
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.
5
Study Population
The study population will consist of approximately 450 randomized female and male adult 
participants (300 in the active arm and 150 in the placebo arm) with CSU inadequately 
controlled by second generation H1-antihistamines (at least at locally label approved dose).


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The screen failure rate is estimated to be 30%, meaning approximately 645 participants are 
expected to be screened.
Participants will be stratified based on prior exposure to anti-IgE biologics and geographic 
region; maximum number of participants with prior exposure to anti-IgE biologics will be 
limited to approximately 30% of the total study population.
Participants who drop out after they have been randomized 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 adult 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 randomization 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 randomization (Day 1)
5. Documentation of hives within three months before randomization (either at screening 
and/or at randomization; or documented in the participants` medical history)
6. Willing and able to complete an Urticaria Patient Daily Diary (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 randomization (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 pharmacodynamic (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 
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4. 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
5. Other diseases with symptoms of urticaria or angioedema, including but not limited to 
urticaria vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary 
urticaria, or drug-induced urticaria
6. 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
7. Participants taking medications prohibited by the protocol (see Table 6-3)
8. Known history or evidence of ongoing alcohol or drug abuse within the last 6 months 
before randomization
9. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases
10. Pregnant or nursing (lactating) women
11. Women of child-bearing potential (WoCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and for 7 days after stopping of study treatment. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before 
taking investigational drug. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment 

Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception 
 
 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, 
history of vasomotor symptoms). Women are considered not of child-bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the 


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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
13.a
History of live attenuated vaccine within 6 weeks prior to randomization 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
18.a
History of gastrointestinal bleeding, e.g., in association with use of nonsteroidal anti-
inflammatory drugs (NSAID), that was clinically relevant (e.g., where intervention was 
indicated or requiring hospitalization or blood transfusion)
19.a
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 (for example, 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) <45ml/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 


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(HBc) antibodies but who are negative for antibodies against HBsAg and HBV-DNA can 
be included into the study if they agree to monitoring for HBsAg and HBV-DNA re-
activation)
24. Known or suspected ongoing, chronic or recurrent infectious disease including but not 
limited to opportunistic infections (e.g., tuberculosis, atypical mycobacterioses, listeriosis 
or aspergillosis) and/or known positivity for Human Immunodeficiency Virus (HIV) 
infection. HIV antigen/antibody tests will be performed to determine HIV status if 
required according to local regulations.
6
Treatment
6.1
Study treatment
Novartis Global Clinical Supply (GCS) will supply the following IMPs in the trial in 
appropriately labeled bottles:
-
LOU064 25mg (blinded)
-
LOU064 25mg placebo (blinded)
-
LOU064 25mg (open-label)
No other supplies apart from these would be provided by Global Clinical Supply (GCS).


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6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor (global 
or local)
LOU064 25 mg
Film coated tablet
Oral use
Double blind
Novartis Pharma 
AG
LOU064 25 mg 
matching Placebo
Film coated tablet
Oral use
Double blind
Novartis Pharma 
AG
LOU064 25 mg
Film coated tablet
Oral use
Open label
Novartis Pharma 
AG
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug (remibrutinib and placebo) are 
included in this trial.
Participants will take background medication (second generation H1-antihistamines at locally 
label approved doses) with a stable regimen during the study (Section 6.2.1). For rescue 
medication, see Section 6.2.4.
6.1.3
Treatment arms/group
Participants will be assigned at Day 1 to either remibrutinib 25 mg b.i.d. or matching placebo 
in a ratio of 2:1. At week 24 participants in the placebo arm will be switched to active treatment. 
Each participant will take one film-coated tablet in the morning and one film-coated tablet in 
the evening 
 
.
6.1.4
Treatment duration
The planned duration of treatment is 52 weeks. Participants may discontinue from study 
treatment earlier at the discretion of the investigator or the participant, e.g., due to adverse 
events (see Section 9.1) or lack/loss of efficacy. Eligible participants may roll over into the 
planned extension study at Week 52 (after completing all scheduled assessments planned at 
these visits). The details of the study design and procedures of the extension, if implemented, 
will be described in a separate protocol.
There are a total of 9 dispensing visits per participant in the trial, 6 in the double-blind period 
and 3 in the open-label period. The last dispensing visit occurs at Week 40.
6.2
Other treatment(s)
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 


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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 randomizing a participant or allowing a new medication to be started. If the 
participant is already enrolled, contact Novartis to determine if the participation in the study 
should be continued.
6.2.2
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 area under the 
curve of >1.5-fold. Therefore, concomitant administration of remibrutinib with respective 
BCRP substrates may be accomplished with caution. BCRP substrates with a small safety 
margin may be administered 2 hours before or after remibrutinib (staggered dosing).
Table 6-2
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)
6.2.3
Prohibited medication
Use of the treatments displayed in the below table are not allowed during the specified time 
period.
Table 6-3
Prohibited medication
Medication
Prohibition period
Action taken
Biologics for treatment of CSU 
(including omalizumab and 
ligelizumab)
4 months prior to 
randomization until end of 
treatment
Discontinue biologic treatment 
and closely monitor for 
potential associated adverse 
events.


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Medication
Prohibition period
Action taken
Routine (more than 3 doses 
over a 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 (CS) with limited 
systemic exposure for non-
CSU indications (e.g., intra-
nasal or any topical CS) can be 
used on an as-needed basis.
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.
i.v./IM/IA corticosteroids
30 days prior to screening until 
end of treatment
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 
treatment
Discontinue Leukotriene 
antagonists and closely monitor 
for potential associated 
adverse events.
H2-antihistamines
From screening until end of 
treatment
Discontinue H2-antihistamines 
and closely monitor for 
potential associated adverse 
events.
First generation antihistamines
From screening until end of 
treatment
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 
randomization until end of 
treatment
Discontinue all second 
generation H1-antihistamines 
but the defined background 
and rescue medication and 
closely monitor for potential 
associated adverse events.
Other 
immunosuppressive/immunom
odulating 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 treatment
Discontinue immunosuppressiv
e/immunomodulating 
medication if medically 
justifiable and closely monitor 
for potential associated 
adverse events. If 
discontinuation not possible, 
discontinue study treatment.


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Medication
Prohibition period
Action taken
Intravenous (i.v.) 
immunoglobulins or 
plasmapheresis
30 days prior to screening until 
end of treatment
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 
treatment
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 
randomization until end of 
treatment
Discontinue any therapy 
intended for the treatment of 
urticaria and closely monitor for 
potential associated adverse 
events.
Live attenuated vaccines
6 weeks prior to randomization 
until at least 4 weeks after last 
dose of study treatment
Discontinue study treatment.
Strong inhibitors of CYP3A4
From 2 weeks prior 
randomization until end of 
treatment
Discontinue CYP3A4 inhibitor if 
medically justifiable and closely 
monitor for potential associated 
adverse events. If 
discontinuation not possible, 
discontinue study treatment
Moderate and strong inducers 
of CYP3A4
From 2 weeks prior 
randomization until end of 
treatment
Discontinue CYP3A4 inducers 
if medically justifiable and 
closely monitor for potential 
associated adverse events. If 
discontinuation not possible, 
discontinue study treatment.
Anticoagulant medication (for 
example, warfarin, or Novel 
Oral Anti-Coagulants (NOAC))
From screening until end of 
treatment
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.


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Medication
Prohibition period
Action taken
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 
treatment
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.
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 
the Week 12 primary endpoint, 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 electronic Case Report Form (eCRF). All relevant 
information for oral corticosteroid rescue therapy will be captured in the appropriate eCRF.


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6.3
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the Interactive Response Technology (IRT) and obtaining the medication number(s). 
The study medication has a 2-part label (base plus tear-off label), immediately before dispensing 
the medication kit to the participant, site personnel will detach the outer part of the label from 
the packaging and affix it to the source document.
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 Investigational Medicinal Product (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-months 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 
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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.
6.3.2
Instruction for prescribing and taking study treatment
Every participant should take one film-coated tablet of remibrutinib 25 mg or placebo in the 
morning and in the evening, respectively, with a 12 hour interval at approximately the same 
time every day. The study medication may be taken with or without a meal but participants 
should adhere to their choice throughout the study. If taken without food, the study medication 
should be taken with a glass of water (250 milliliters (ml)) at least 2 hours after the last meal 
and 1 hour before the next meal. Participants should be instructed to swallow whole tablets and 
not to chew or break them.
 
 
If vomiting occurs during the course of treatment, participants should not take the study 
treatment again before the next scheduled dose.
Participants should be instructed not to make up missed doses. A missed dose is defined as a 
case when the full dose is not taken within 6 hours after the approximate time of the usually 
morning/evening dosing. That dose should be omitted and the participant should continue 
treatment with the next scheduled dose.
H1-antihistamines taken as either as background medication or rescue medication, respectively, 
should be taken according to the local treatment instructions.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
6.4
Participant numbering, treatment assignment, randomization
6.4.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.


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A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.4.2
Treatment assignment, randomization
At the randomization visit, all eligible participants will be randomized via IRT to one of the 
treatment arms. The investigator or his/her delegate will contact the IRT after confirming that 
the participant fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization 
number to the participant, which will be used to link the participant to a treatment arm and will 
specify a unique medication number for the first package of study treatment to be dispensed to 
the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by Novartis Global Clinical 
Supply (GCS) using a validated system that automates the random assignment of medication 
numbers to packs containing the study treatment.
Randomization will be stratified by prior anti-IgE biologic use and geographic 
region; maximum number of participants with prior exposure to anti-IgE biologics will be 
limited to approximately 30% of the total study population.
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.5
Treatment blinding
Participants, investigator staff, persons performing the assessments, and the study team directly 
involved with the conduct of the trial will remain blinded to the identity of the treatment during 
the double-blind treatment period (i.e., up to week 24) from the time of randomization until the 
final database lock.
The following methods will be used to maintain the blind:
(1) Randomization data will be kept strictly confidential until the time of final database lock, 
and will not be accessible by anyone else involved in the study with the following exceptions:

The designated Novartis study team members involved in the primary analysis

The bioanalyst 
 (to avoid the unnecessary analysis of placebo samples)

An independent analysis team who need to prepare DMC reports.
(2) The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor.
At the time of the primary analysis, a selected Novartis Team will create and review unblinded 
interim reports. No access will be given to the study team conducting the ongoing trial until 
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Unblinding a single participant at the study site for safety reasons (necessary for participant 
management) will occur via an emergency system in place at the site. As a result, the participant 
should be discontinued from the study treatment.
The DMC will review semi-blinded interim reports created by an independent analysis team. 
More details will be provided in the DMC charter.
6.6
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted.
Study treatment interruptions are permitted in order to manage the following events:

Management of bleeding events: in case of planned surgery with clinical significant 
bleeding risk, interruption of study treatment 7 days before the surgery is required; after 
recovery, participant may re-start study treatment after 7 days.

Management of participants in case of Hepatitis B re-activation (new appearance of 
detectable HBV-DNA or positive HBsAg): participants should start antiviral treatment 
according to local clinical practice and interrupt study treatment until HBV-DNA and 
HBsAg reach an undetectable level, and then re-start study treatment.
Study treatment interruption for other than the above reasons is only permitted if, in the opinion 
of the investigator, a participant is deemed to be at a significant safety risk unless administration 
of investigational treatment is temporarily interrupted. In such cases study treatment should be 
interrupted only during the time that this risk is present and ongoing. Study treatment can be re-
started at the next scheduled visit after resolution of the safety risk.
6.6.1
Follow-up for toxicities
Not applicable.
6.7
Additional treatment guidance
6.7.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as 
prescribed. Compliance will be assessed by the investigator and/or study personnel at each visit 
using tablet counts (if applicable) and information provided by the participant. This information 
should be captured in the source document at each visit. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log.
 


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6.7.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely.
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a participant, he/she must provide the requested 
participant identifying information and confirm the necessity to break the treatment code for 
the participant. The investigator will then receive details of the investigational drug treatment 
for the specified participant and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. If the IRT system is not available for technical reasons, the IRT help desk can facilitate 
emergency code break requests.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any participant whose treatment code has been broken inadvertently 
for any reason.
Study treatment must be discontinued after emergency unblinding and the participant will be 
withdrawn from the trial and would not be eligible for enrollment into the planned open-label 
extension study.
6.7.3
Treatment of overdose
No clinical data are available to assess the risk of overdose. Based on preclinical data it is 
concluded that remibrutinib has a low potential to cause acute toxicity, e.g., in case of accidental 
overdosing. Single and multiple ascending doses of remibrutinib up to 600 mg were studied in 
healthy volunteers with no dose-limiting toxicities identified. With the 25 mg b.i.d. dose used 
in this study, the potential of remibrutinib to cause acute toxicity is assessed as low.
There is no specific antidote to remibrutinib; therefore, adverse events will be managed 
symptomatically according to standard of care and applicable clinical guidelines.
In the event of an overdose, the Investigator should:

Contact the medical monitor immediately.

Closely monitor the participant for any AE/SAE and laboratory abnormalities.

Document the quantity of the excess dose as well as the duration of the overdose.


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7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6 good clinical practice (GCP) guidelines and 
regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed by Novartis before 
submission to the IRB/IEC.
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant.
The following informed consents are included in this study:

Main study consent, which also includes: 

 
 

As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment


Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
 
 
 


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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
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.


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The preferred sequence of assessments during study visits is PRO completion, ECG collection, 
followed by vital signs, and blood sampling.


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Table 8-1
Assessment Schedule
Period Screening
Treatment
Follow-up
Unscheduled visit
Visit Name Screening
Baseline/ 
Randomization1
week 21
week 4
week 8
week 121
week 16
week 20
week 24
week 32
week 40
Early 
treatment 
discontinu-
ation
week 
52/Study 
discontinu-
ation1
week 
56/Safety 
FU/Study 
completion
Unscheduled visit
Days
-28 to -1
1
15
29
57
85 113 141
169
225
281
-
365
394
-
Informed consent
X
IRT transaction
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion / 
Exclusion criteria
X
X
Randomization
X
Demography
X
Pregnancy and 
assessments of 
fertility2
XS
S
S
S
S
S
S
S
S
S
S
S
S
S
Evidence of 
urticaria
S
S
Hepatitis screen
X
Relevant medical 
history
X
Dispense 
participants' 
eDiary3
S
S
S
CSU History and 
prior urticaria 
treatment
X
Cardiovascular 
history
X


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Period Screening
Treatment
Follow-up
Unscheduled visit
Visit Name Screening
Baseline/ 
Randomization1
week 21
week 4
week 8
week 121
week 16
week 20
week 24
week 32
week 40
Early 
treatment 
discontinu-
ation
week 
52/Study 
discontinu-
ation1
week 
56/Safety 
FU/Study 
completion
Unscheduled visit
Days
-28 to -1
1
15
29
57
85 113 141
169
225
281
-
365
394
-
Physical 
Examination4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Height and 
Weight5
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
X
X6
X6
X
X
X6
X
X
Subject's eDiary 
review7
S
S
S
S
S
S
S
S
S
S
S
S
S
DLQI8
X
X
X
X
X
X
X
Study drug 
dispensation
X
X
X
X
X
X
X
X
X
Background 
medication 
dispensation and 
compliance 
assessment17
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue 
medication 
X
X
X
X
X
X
X
X
X
X
X
X


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Period Screening
Treatment
Follow-up
Unscheduled visit
Visit Name Screening
Baseline/ 
Randomization1
week 21
week 4
week 8
week 121
week 16
week 20
week 24
week 32
week 40
Early 
treatment 
discontinu-
ation
week 
52/Study 
discontinu-
ation1
week 
56/Safety 
FU/Study 
completion
Unscheduled visit
Days
-28 to -1
1
15
29
57
85 113 141
169
225
281
-
365
394
-
dispensation and 
usage10
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel
X
X
X
X
X
X
X
X
X
X
Hepatitis B re-
activation 
monitoring15
X
X
X
X
X
X
X
X
X
X
X
X


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Period Screening
Treatment
Follow-up
Unscheduled visit
Visit Name Screening
Baseline/ 
Randomization1
week 21
week 4
week 8
week 121
week 16
week 20
week 24
week 32
week 40
Early 
treatment 
discontinu-
ation
week 
52/Study 
discontinu-
ation1
week 
56/Safety 
FU/Study 
completion
Unscheduled visit
Days
-28 to -1
1
15
29
57
85 113 141
169
225
281
-
365
394
-
Eligibility 
assessment for 
extension study18
X
Prior and 
concomitant 
medication
X
Adverse Events
X
Study completion 
information
X
1 Participant to come fasting for ≥8 h (ideally overnight) to visits: Baseline/Randomization, week 2, week 12 and week 52
2 Serum pregnancy test and fertility assessment will be done at Screening. Urine pregnancy test to be completed every 4 weeks by WoCBP from Randomization through 
to Study completion visit. At Weeks 28, 36, 44 and 48 test may be performed at home - sites must contact participants to obtain test results. Any positive or 
undetermined test result must be confirmed by a serum pregnancy test done by central lab and results received electronically. Urine pregnancy results are reported as 
source. 
3 Participants eDiary will be returned to site at either Week 52/study discontinuation
4 Complete physical exam at screening, short physical exam at all subsequent visits including body temperature monitoring (per local practice)
5 Height collected at screening visit only
6 pre and post dose
7 eDiary includes UPDD (Urticaria Patient Daily Diary) with UAS (Urticaria Activity Score, part of UPDD) and AAS (Angioedema Activity Score), eDiary to be completed 
from screening to week 52/study discontinuation
8 Completed in the patient’s eDiary during site visit. Order of completion: DLQI 
. All questionnaires should be completed prior to 
any other physician assessment.
  
14 At selected sites only


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Period Screening
Treatment
Follow-up
Unscheduled visit
Visit Name Screening
Baseline/ 
Randomization1
week 21
week 4
week 8
week 121
week 16
week 20
week 24
week 32
week 40
Early 
treatment 
discontinu-
ation
week 
52/Study 
discontinu-
ation1
week 
56/Safety 
FU/Study 
completion
Unscheduled visit
Days
-28 to -1
1
15
29
57
85 113 141
169
225
281
-
365
394
-
15 Hepatitis B re-activation monitoring only for participants who were HBsAg negative and HBcAb (anti-HBc) positive with a negative HBV DNA test at Screening.
17Dispensation for background medication covers prescription, dispensation and/or instruction of the participant on dosing and use of background medication and 
protocol requirements, considering different procedures for the provision of background medication at investigational sites. At Week 56/Safety FU/Study completion visit 
only compliance to be checked 
18 Only for participants who have completed Week 52 visit, not applicable at Study discontinuation visit


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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 randomization will be considered a screen failure. The reason for screen failure should 
be recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event (SAE) during the screening phase 
(see SAE section for reporting details). If the participant fails to be randomized, the IRT must 
be notified within 2 days of the screen fail that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form.
8.2
Participant demographics/other baseline characteristics
Baseline CSU activity will be assessed using the eDiary from Day -7 to Day -1. Participant 
demographic and baseline characteristic data to be collected on all participants include age, sex, 
race and ethnicity. Participant race and ethnicity, as required by some Health Authorities, are 
collected to assess the diversity of the study population and to evaluate their impact on the 


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safety and efficacy parameters in the study. Relevant medical history (including evaluation of 
inclusion/exclusion criteria, CSU history and cardiovascular history) and current medical 
condition present before signing the informed consent will be captured. 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.
Country-specific regulations should be considered for the collection of demographic and
baseline characteristics in alignment with CRF.
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: Urticaria Patient Daily Diary (UPDD) and 
Angioedema Activity Score (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.
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.
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 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) (see 
Section 16.4). 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


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Diary component
When assessed
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.
Table 8-4
Itch Severity Score
Score
Pruritus (Itch) (every 12 hours)
0
None
1
Mild (minimal awareness, easily tolerated)
2
Moderate (definite awareness, bothersome but 
tolerable)
3
Severe (difficult to tolerate)
8.3.1.1.3 Weekly Urticaria Activity Score (UAS7)
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly 
UAS7 score is 0 – 42 (highest activity).


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8.3.1.1.7 Angioedema occurrence
Angioedema occurrence is recorded once daily in the evening in the eDiary by the participant. 
Reporting the occurrence of angioedema will be used as opening question for the assessment of 
the AAS (see Section 8.3.1.2). Actions and/or treatments related to those angioedema 
occurrences will be also recorded in the eDiary as follows (multiple answers possible):

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


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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 
Section 16.4). 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 Dermatology Life Quality Index (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
A DLQI score of > 10 is relevant for a very large impact on patients’ life and justification for a 
biologic prescription for example in psoriasis (Finlay 2005). The DLQI questionnaires are 
completed at visits detailed in Table 8-1 in the eDiary. The DLQI should be completed prior to 
any other assessment and prior to administration of investigational medication.


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1.
8.3.3
Appropriateness of efficacy assessments
UAS7: The UAS7 score is a unified, simple, well-established and validated tool, recommended 
by the current urticaria guidelines for the assessment of disease activity and treatment response 
in real-world clinical practice as well as in clinical trials with urticaria patients 
(Młynek et al 2008, Hawro et al 2018, Zuberbier et al 2018). It is based on the assessment of 
the two key urticaria signs and symptoms, wheals and pruritus, which are documented by the 
patient, making this score especially valuable. The use of the UAS7 facilitates comparison of 
study results across different trials, since it is used in other major Phase 3 trials in the CSU 
indication as well (e.g., with ligelizumab).
AAS7: The AAS7 score is a unified, simple and validated tool, recommended by the current 
urticaria guidelines for the assessment of disease activity and treatment response in patients 
with angioedema (Weller et al 2013, Zuberbier et al 2018). The use of the AAS7 facilitates 
comparison of study results across different trials, since it is used in other major Phase 3 trials 
in the CSU indication as well (e.g., with ligelizumab).
 
 
8.3.4
Other assessments: evidence of urticaria
The investigator must confirm the presence of urticaria (i.e., the presence of hives) in each 
participant before randomization by direct physical examination. In the absence of active 
disease at the screening and/or randomization visit, the following will be acceptable: (a) a 
clearly identifiable photograph of the participant that is no older than 3 months showing the 
presence of urticaria, (b) the investigator must have seen the participant with active CSU in the 
past 3 months, or (c) the presence of hives/wheals must have been documented in the medical 
record of the participant by a physician trained in the management of urticaria in the past 3 
months.


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8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.


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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 
pressure (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.


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Assessment
Specification
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.
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 
later visits.


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Test Category
Test Name
Fasting glucose assessed at randomization, 
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 (anti-HBs or HBs-Ab); Hepatitis 
B virus surface antigen (HBsAg).
Hepatitis B-Deoxyribonucleic acid (HBV-
DNA, only in participants who are positive 
for anti-Hepatitis B virus Core HBc-Ab or anti-
HBc).
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 HBc-Ab 
(anti-HBc positive) and negative for anti-HBsAg 
and HBV-DNA at screening: HBsAg, HBV- DNA
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)
Electrocardiograms (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 
with ECG machines supplied by the core laboratory. 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 
 


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 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.
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 randomization (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:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.


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In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Appropriateness of safety measurements
The selected safety monitoring assessments (including laboratory assessments covering clinical 
chemistry, hematology, coagulation status 
, as well as clinical and 
physical assessments, triplicate ECG monitoring and general AE assessments) are reliable and 
well-established standard measures which allow valid and close safety monitoring of the trial´s 
patient population, with regards to their disease, to the compound they are treated with, 
remibrutinib, and also to their overall medical safety.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Trial Feedback
This study includes an optional anonymized questionnaire, the ‘Trial Feedback Questionnaire’ 
for trial participants to provide feedback on their clinical trial experience at 3 timepoints: at the 
start, during and at the end of the trial. Individual trial participant responses will not be reviewed 
by investigators. Responses may be used by the sponsor to understand where improvements can 
be made in the clinical trial process. This questionnaire does not ask questions about the trial 
participant’s disease, symptoms, treatment effect or adverse events and therefore is not 
considered as trial data.


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9
Discontinuation and completion
9.1
Discontinuation from study treatment and from study
9.1.1
Discontinuation from study treatment
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the protocol planned completion of study drug administration) 
and can be initiated by either the participant or the investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Discontinuation from study treatment is required under the following circumstances:

Participant decision (requested in writing or verbally)

Pregnancy

Use of prohibited treatment requiring study treatment discontinuation as detailed in 
Table 6-3 or discontinuation of highly effective methods of contraception as detailed 
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
Any situation in which continued study participation might result in a safety risk to the 
participant

Following emergency unblinding

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


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The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.
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.


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Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
9.3
Study 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 open-label 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 open-label extension study (under development) if 
they meet the eligibility criteria defined in the extension study protocol.
The open-label extension will require endorsement in participating countries and sites as per 
local laws and regulations.
For participants not willing or ineligible to roll over into the extension study and who want to 
continue receiving remibrutinib every effort will be made to continue provision of study 
treatment prior to the investigational treatment becoming available in the respective country, if 
in the opinion of the investigator, they are still deriving clinical benefit from remibrutinib.
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 
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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. 
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:


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
Dose not changed

Drug interrupted/permanently discontinued
6. Its outcome (i.e., recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the 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.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in 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 
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
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred (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 or randomized): 
SAEs occurring after the participant has provided informed consent until the time the 
participant is deemed a Screen Failure must be reported to Novartis with 24 hours of 
learning of its occurrence.
2. Randomized OR Treated Participants: SAEs collected between time participant signs ICF 
until 30 days after the participant has discontinued from study treatment.


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode
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 Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and
Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period 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.


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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.
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.
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.


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
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.
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) ≥1g/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.


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10.3.2
Steering Committee
A steering committee has been established comprising of investigators participating in the trial, 
that 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.
11
Data Collection and Database management
11.1
Data collection
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 (or designated Contract Research Organization (CRO)) 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, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment(s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 


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will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. 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/delegated CRO representative will review the protocol and data capture requirements 
(i.e., electronic source (eSource) DDE or eCRFs) with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 
and to Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits. Continuous remote monitoring 
of each site’s data may be performed by a centralized Novartis/delegated CRO/CRA 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight.
The investigator must maintain source documents for each 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 at the time of the primary analysis and on all participants' data 
at the time the trial ends. Any data analysis carried out independently by the investigator should 
be submitted to Novartis before publication or presentation.


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12.1
Analysis sets
The following analysis sets will be used in this trial:

Randomized set (RAS): The RAS set consists of all randomized participants, regardless of 
whether or not they receive a dose of study drug. Participants will be analyzed according to 
the treatment they are assigned.

The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. FAS will be used for all efficacy variables, unless otherwise 
stated. Mis-randomized participants (mis-randomized in IRT) will be included in the 
Randomized set but will be excluded from FAS.

Mis-randomized participants are defined as cases where IRT contacts were made by the site 
either prematurely or inappropriately prior to confirmation of the participant’s final 
randomization eligibility and no study medication was administered to the participant.

The Safety Set (SAF) includes all participants who received at least one dose of study 
treatment, whether or not being randomized. Participants will be analyzed according to the 
study treatment received. The safety set will be used in the analysis of all safety variables. 
The actual treatment will be defined as the treatment received over the study. In case of 
error in dispensation, the actual treatment will correspond to the treatment which was given 
most often.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the randomized 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 
combined by system organ class and preferred term, by treatment group for the randomized set.
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 and placebo will be summarized by treatment 
group, by study period and for entire study. The duration of study will also be summarized by 
treatment group.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by treatment group.


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12.4
Analysis supporting primary objectives
This section will detail the statistical analysis of the primary estimand. Details of the hypothesis 
testing strategy including primary and secondary endpoints to handle multiplicity are provided 
in Section 12.5.1.
12.4.1
Definition of primary endpoint(s)
Primary estimand for scenario with UAS7 as the primary efficacy endpoint
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo 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 and regardless of intake of a different second 
generation H1-antihistamine as rescue medication and considering strongly confounding 
prohibited medication as an unfavourable outcome?
The primary efficacy endpoint 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.
Primary estimand for scenario with ISS7 and HSS7 as the co-primary efficacy endpoints
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the change from baseline in ISS7 and change from baseline in HSS7 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 and regardless of 
intake of a different second generation H1-antihistamine as rescue medication and considering 
strongly confounding prohibited medication as an unfavourable outcome?
The co-primary efficacy endpoints are the absolute change from baseline in ISS7 score at Week 
12 and absolute change from baseline in HSS7 score at Week 12, which is the ISS7 score 
(respectively HSS7 score) at Week 12 minus the ISS7 score (respectively HSS7 score at 
baseline). The weekly scores ISS7 and HSS7 range from 0-21, and will be derived by adding 
up the average daily scores of the 7 days preceding the visit.
12.4.2
Statistical model, hypothesis, and method of analysis
Statistical model, hypothesis, and method of analysis for scenario with UAS7 as the 
primary efficacy endpoint
The statistical hypothesis test for the primary endpoint being tested is that the absolute change 
from baseline in UAS7 score at Week 12 in remibrutinib is not superior to the placebo group 
i.e.:
H01: µ remibrutinib ≥µPlacebo versus HA1: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in UAS7 at Week 12.


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A linear mixed model with repeated measures (MMRM) will be used to estimate treatment 
differences for change from baseline in UAS7 score at Week 12, based on the FAS. The MMRM 
model will include treatment group, baseline UAS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline UAS7 score by week as 
fixed effects. Repeated measures within participant are modeled using an unstructured 
covariance of the error terms. Additional important covariates may be added to the model. For 
the primary analysis, data up to Week 12 will be used in the model.
The detailed testing strategy including the primary endpoint analysis is provided in Section 12.5.
Statistical model, hypothesis, and method of analysis for scenario with ISS7/HSS7 as the 
co-primary efficacy endpoints
The statistical hypothesis test for the co-primary endpoints tests the union null hypothesis that 
the absolute change from baseline in ISS7 score at Week 12 in remibrutinib is not superior to 
the placebo group or the absolute change from baseline in HSS7 score at Week 12 in 
remibrutinib is not superior to the placebo group i.e.:
H01a: µ remibrutinib ≥µPlacebo versus HA1a: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in ISS7 at Week 12.
H01b: µ remibrutinib ≥µPlacebo versus HA1b: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in HSS7 at Week 12.
The union null hypothesis is rejected if both elementary null hypotheses (H01a, H01b) are rejected.
A linear mixed model with repeated measures (MMRM) will be used to estimate treatment 
differences for change from baseline in ISS7 score (respectively HSS7) at Week 12, based on 
the FAS. The MMRM model will include treatment group, baseline ISS7 score (respectively 
HSS7), randomization strata variables, week and both interaction of treatment by week and 
interaction of baseline ISS7 score (respectively HSS7) by week as fixed effects. Repeated 
measures within participant are modeled using an unstructured covariance of the error terms. 
Additional important covariates may be added to the model. For the primary analysis, data up 
to Week 12 will be used in the model.
The detailed testing strategy including the primary endpoint analysis is provided in Section 12.5.
12.4.3
Handling of intercurrent events of primary 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 (Treatment 
policy strategy), 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 
assigned at randomization: RDO data collected after study treatment discontinuation will 
be used for analysis.


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
Intake of rescue medication as per protocol, or switch of background medication, or intake 
of other prohibited medication, or participants non-compliant to treatment prior to Week 
12: ignore (Treatment policy strategy), data collected after these events will be used for 
analysis.

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 8): 
(Composite strategy) 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 
and 21 for co-primary endpoints ISS7 score or HSS7 score at week 12).
12.4.4
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 participant 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.

If there are less than 4 non-missing daily scores within the prior 7 days, then the weekly 
score for HSS or ISS will be considered as missing for that week. Accordingly, no UAS7 
can be calculated.
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. These are considered as RDO participants.
For any intercurrent events handled with treatment policy strategy: If no RDO data was 
collected after study treatment permanent discontinuation, missing data will be imputed based 
on the following rules:

For participants in the active treatment arms, if sufficient RDO data, missing data will be 
imputed using MI based on observed RDO data in the corresponding active arm. If not 
feasible (e.g., very limited RDO data), missing data will be imputed based on observed data 
in the placebo arm under the assumption of jump to reference (J2R) using MI.

For participants in the placebo arm, if sufficient RDO data, missing data will be imputed 
using MI based on observed RDO placebo arm data. If not feasible (e.g., very limited RDO 
data), missing data will be imputed using MI under the MAR assumption based on the 
observed placebo arm data.


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12.4.5
Sensitivity analyses
The following sensitivity analysis will be performed for the primary estimand to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis. The sensitivity analysis will be implemented with the same target population, 
the primary variables and the summary measure as for the primary estimand, but using the 
different assumptions or handling of intercurrent events.
Sensitivity analysis: The change from baseline in UAS7, ISS7 and HSS7 score at week 12 will 
be imputed using zero (i.e., no clinical improvement from baseline) for the intercurrent event 
of “Intake of strongly confounding prohibited medication (e.g., biologics treatment at any time 
before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 8)” handled 
with composite strategy.
12.4.6
Supplementary analysis
Supplementary estimand
The clinical question of interest is: What is the effect of remibrutinib treatment versus placebo 
on the change from baseline in UAS7 score (respectively for co-primary endpoints ISS7 and 
HSS7) after 12 weeks treatment in adult patients 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 and regardless of 
intake 
of 
a 
different 
second 
generation 
H1-antihistamine and 
rescue 
medication, and as if strongly confounding prohibited medication was not taken?
The supplementary estimand is described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥6 months, a UAS7 score ≥16, ISS7 score 
≥6 and HSS7 score ≥6 in the last 7 days prior to randomization.
2. Endpoint: Change in UAS7 (respectively for co-primary endpoints ISS7 and HSS7) from 
baseline at Week 12.
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or placebo) 
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 difference between treatment groups.
5. Handling of intercurrent events:

Discontinuation of study treatment due to any reason: Treatment policy strategy

Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 
8): Hypothetical strategy (irrespective of potential occurrence of other intercurrent events)

Intake of rescue medication, switch of background medication, intake of other prohibited 
medication: Treatment policy strategy


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12.5
Analysis supporting secondary objectives
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)

Improvement of UAS7, assessed as absolute change from baseline in UAS7 score at Week 
12 (For scenario with ISS7/HSS7 as the co-primary efficacy endpoints).
The absolute change from baseline in UAS7 score at Week 12 will be analyzed using MMRM 
modeling including treatment group, baseline UAS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline UAS7 score by week as 
fixed effects.

Disease activity control at Week 12, assessed as % of participants achieving UAS7 ≤ 6.
The proportion of participants with UAS7 ≤ 6 at Week 12 will be analyzed using a logistic 
regression model including treatment group, region, prior exposure to anti-IgE biologics and 
baseline UAS7 score as covariate.

Complete absence of hives and itch at Week 12, assessed as % of participants achieving 
UAS7 = 0.
The proportion of participants with UAS7 = 0 at Week 12 will be analyzed using a logistic 
regression model including treatment group, region, prior exposure to anti-IgE biologics and 
baseline UAS7 score as covariate.

Improvement of severity of itch, assessed as absolute change from baseline in ISS7 score 
at Week 12 (For scenario with UAS7 as the primary efficacy endpoint).
The absolute change from baseline in ISS7 score at Week 12 will be analyzed using MMRM 
modeling including treatment group, baseline ISS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline ISS7 score by week as 
fixed effects.

Improvement of severity of hives, assessed as absolute change from baseline in HSS7 
score at Week 12 (For scenario with UAS7 as the primary efficacy endpoint).
The absolute change from baseline in HSS7 score at Week 12 will be analyzed using MMRM 
modeling including treatment group, baseline HSS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline HSS7 score by week as 
fixed effects.

Disease activity control at Week 2, assessed as proportion of participants achieving 
UAS7 ≤ 6.
The proportion of participants with UAS7 ≤ 6 at Week 2 will be analyzed using a logistic 
regression model including treatment group, region, prior exposure to anti-IgE biologics and 
baseline UAS7 score as covariate.

No impact on participants’ dermatology quality of life at Week 12, assessed as proportion 
of participants achieving DLQI = 0-1.
An overall score will be calculated according to the scoring manual. The proportion of 
participants with overall DLQI scores ≤ 1 at Week 12 will be analyzed using a logistic 
regression model which includes treatment group, region, prior exposure to anti-IgE biologics 
and baseline DLQI score.


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
Cumulative number of weeks that participants achieve UAS7 ≤ 6 responses 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. The cumulative number of weeks achieving UAS7 ≤ 6 
response between baseline and Week 12 will be modelled using a negative binomial regression 
model with log link, using treatment group, region, and prior exposure to anti-IgE biologics. 
The number of weeks stay on the trial will be used as an offset.

Cumulative number of weeks that participants achieve AAS7 = 0 responses 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 and UPDD diary. A weekly AAS7 score will be 
derived by adding up the daily scores of the 7 days preceding the visit, and ranges from 0 to 
105. If the AAS7 assessment is missing, it will be considered as a non-response for the 
cumulative number of weeks that participants achieve AAS7 = 0 response calculation.
The cumulative number of weeks achieving AAS7 = 0 response between baseline and Week 12 
will be modelled using a negative binomial regression model with log link, using treatment 
group, region, prior exposure to anti-IgE biologics and baseline AAS7 = 0 status.
Statistical model, hypothesis, and method of analysis for scenario with UAS7 as the 
primary efficacy endpoint
Testing strategy
The following null hypotheses (H0) will be tested against the respective alternative hypotheses 
(HA) in a closed testing procedure (Bretz et al 2009), thus controlling the family-wise type I 
error which is set to 0.025 (one-sided):
Primary:
UAS7 score change from baseline at Week 12
H01: µ remibrutinib ≥µPlacebo versus HA1: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in UAS7 at Week 12,
Secondaries:

UAS7 ≤ 6 at Week 12
H02: p remibrutinib ≤pPlacebo versus HA2: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7 ≤6 at Week 12,

UAS7 = 0 at Week 12
H03: p remibrutinib ≤pPlacebo versus HA3: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7 = 0 at Week 12,

ISS7 score change from baseline at Week 12
H04: µ remibrutinib ≥µPlacebo versus HA4: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in ISS7 at Week 12,


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
HSS7 score change from baseline at Week 12
H05: µ remibrutinib ≥µPlacebo versus HA5: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in HSS7 at Week 12,

UAS7 ≤ 6 at Week 2
H06: p remibrutinib ≤pPlacebo versus HA6: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7 ≤6 at Week 2,

DLQI = 0/1 at Week 12
H07: p remibrutinib ≤pPlacebo versus HA7: p remibrutinib >pPlacebo
where p is the proportion of participants achieving DLQI = 0/1 at Week 12,

Cumulative number of weeks with an UAS7 ≤6 response between baseline and Week 
12
H08: µ remibrutinib ≤µPlacebo versus HA8: µ remibrutinib > µPlacebo
where µ is the mean cumulative number of weeks that participants achieve UAS7 ≤6 response 
between baseline and Week 12,

Cumulative number of weeks with an AAS7= 0 response between baseline and Week 
12
H09: µ remibrutinib ≤µPlacebo versus HA9: µ remibrutinib > µPlacebo
where µ is the mean cumulative number of weeks that participants achieve AAS7 = 0 response 
between baseline and Week 12,
A graphical representation of the testing strategy is presented in Figure 12-1
Figure 12-1
Testing strategy with UAS7 as the primary endpoint
The value inside the circle represents the significance level. The arrow and value inside the square 
represent the "alpha-propagation".
The first hypothesis is tested with full level alpha (0.025 one-sided). If significant, the second 
hypothesis is tested with full-level alpha; otherwise, the testing procedure stops. The testing is 
strictly hierarchical, so that null hypotheses can be tested along the pre-defined order at the level 
assigned until a null hypothesis cannot be rejected, at which point the testing stops. Furthermore, 
the testing strategy reflects the separation of primary and secondary endpoints, so that 
hypotheses related to secondary endpoints will only be tested if the null hypothesis related to 
the primary endpoint is rejected.
Statistical model, hypothesis, and method of analysis for scenario with ISS7/HSS7 as the 
co-primary efficacy endpoints
Testing strategy


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The following null hypotheses (H0) will be tested against the respective alternative hypotheses 
(HA) in a closed testing procedure (Bretz et al 2009), thus controlling the family-wise type I 
error which is set to 0.025 (one-sided):
Co-Primary:

ISS7 score change from baseline at Week 12
H01a: µ remibrutinib ≥µPlacebo versus HA1a: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in ISS7 at Week 12,

HSS7 score change from baseline at Week 12
and H01b: µ remibrutinib ≥µPlacebo versus HA1b: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in HSS7 at Week 12,
Secondaries:

UAS7 score change from baseline at Week 12
H02: µ remibrutinib ≥µPlacebo versus HA2: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in UAS7 at Week 12,

UAS7 ≤ 6 at Week 12
H03: p remibrutinib ≤pPlacebo versus HA3: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7≤6 at Week 12,

UAS7 = 0 at Week 12
H04: p remibrutinib ≤pPlacebo versus HA4: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7=0 at Week 12,

UAS7 ≤ 6 at Week 2
H05: p remibrutinib ≤pPlacebo versus HA5: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7≤6 at Week 2,

DLQI = 0/1 at Week 12
H06: p remibrutinib ≤pPlacebo versus HA6: p remibrutinib >pPlacebo
where p is the proportion of participants achieving DLQI = 0/1 at Week 12,

Cumulative number of weeks with an UAS7 ≤6 response between baseline and Week 
12
H07: µ remibrutinib ≤µPlacebo versus HA7: µ remibrutinib > µPlacebo
where µ is the mean cumulative number of weeks that participants achieve UAS7 ≤6 response 
between baseline and Week 12,

Cumulative number of weeks with an AAS7= 0 response between baseline and Week 
12
H08: µ remibrutinib ≤µPlacebo versus HA8: µ remibrutinib > µPlacebo


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where µ is the mean cumulative number of weeks that participants achieve AAS7=0 response 
between baseline and Week 12,
A graphical representation of the testing strategy is presented in Figure 12-2
Figure 12-2
Testing strategy with ISS7/HSS7 as the co-primary endpoints
The value inside the circle represents the significance level. The arrow and value inside the square 
represent the "alpha-propagation".
The first two hypotheses are tested: both H1a and H1b are tested with full level alpha (0.025 one-
sided) and only if both are rejected, then H2 hypothesis is tested with full-level alpha; otherwise, 
the testing procedure stops. The testing is strictly hierarchical, so that null hypotheses can be 
tested along the pre-defined order at the level assigned until a null hypothesis cannot be rejected, 
at which point the testing stops. Furthermore, the testing strategy reflects the separation of 
primary and secondary endpoints, so that hypotheses related to secondary endpoints will only 
be tested if both null hypotheses related to the co-primary endpoints are rejected.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
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). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
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.
Due to the open-label period after the double-bind period, the on-treatment double-blind period 
will stop at the earliest on:

the date of the last actual dose intake of remibrutinib double-blind

the date of first dose intake of open-label treatment
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:


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
by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation by treatment group 
and study period.
The number (and proportion) of participants with adverse events of special interest for 
remibrutinib (related to identified and potential risks) will be summarized by treatment group 
and study period.
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.
Vital signs
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant changes) will be flagged. Summary statistics will be 
provided by treatment and visit.
12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted centrally.
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, participant, and visit and if normal ranges 
are available abnormalities will be flagged. Summary statistics for the change from baseline 
will be provided by treatment and visit. Shift tables using the low/normal/high/ (low and 
high) classification will be used to compare baseline to the worst on-treatment value.
 
 
 
 
 
 
 


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Dermatology Life Quality Index (DLQI)
For DLQI total score, summary statistics will be provided for absolute change from baseline as 
well as for percent change from baseline by treatment group and visit.
The proportion of participants achieving DLQI = 0-1 will be provided by treatment group and 
visit.
Angioedema Activity Score (AAS)
For AAS7 score, summary statistics will be provided for absolute change from baseline as well 
as for percent change from baseline over time by treatment group, in participants with 
angioedema at baseline (AAS7 >0) and in all participants.


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The proportion of participants achieving AAS7 = 0 will be provided over time by treatment 
group.
For angioedema burdened days, summary statistics will be provided for absolute change from 
baseline as well as for percent change from baseline over time by treatment group.
 
 
 
 
 


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12.7
Interim analyses
A primary analysis may be conducted when all participants have completed their Week 24 visit 
or discontinued early and when a minimum of 150 participants across both Phase 3 pivotal 
studies have completed the treatment period (a second, nearly identical Phase 3 study will be 
conducted in parallel). The minimum of 150 participants reaching week 52 should enable 
analysis on a minimum of 100 participants exposed to remibrutinib for 52 weeks, considering 
the initial randomization to either the remibrutinib or the placebo arm (2:1). The results of the 
primary analysis will further inform decision-making for the remibrutinib development 
program. Formal testing of the primary endpoint and key secondary endpoints will only be 
performed at the primary analysis time point; thus, no adjustment for multiplicity is required.
After the primary analysis and/or after all participants entered the open-label treatment period, 
additional optional interim analyses may be conducted at the discretion of the Sponsor to 
support potential Health Authority requests and interactions (these interim analyses are not 
expected to have any impact on the conduct or scientific integrity of the study). The decision to 
conduct optional interim analyses and the timing of these analyses will be documented in the 
Statistical Analysis Plan prior to the conduct of any interim analysis. These interim analyses 
will be performed and interpreted by members of the Novartis clinical team.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
In order to fulfill registration and ICH E1 requirements on the number of participants treated 
for 6 months and 12 months in the development program, a sample size of 300 participants in 
the active arm and 150 in the placebo arm is targeted. Hence, the total sample size is 450 
randomized participants.
From an efficacy point of view, the sample size justification is based on UAS7 change from 
baseline (for scenario with one primary endpoint), ISS7 and HSS7 change from baseline (for 
scenario with co-primary endpoints) and achievement of UAS7≤6 and UAS7=0 at Week 12. 
To avoid assigning an unnecessary large number of participants to placebo, participants will be 
randomized in a 2:1 ratio to remibrutinib 25 mg b.i.d. and placebo arms, respectively.
All calculations were performed with nQuery Advisor 8.4.1.0 and Ri386 4.0.2 softwares.
For scenario with UAS7 as the primary efficacy endpoint
UAS7 change from baseline at Week 12
Approximately 10% drop-out is expected at week 12, thus with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo if the mean change of UAS7 from baseline 
to Week 12 is at least 10 in favor of remibrutinib, with common standard deviation of 
approximately 12 (based on the primary endpoint analysis of Phase 2b study 
(CLOU064A2201)), based on a t-test, assuming type I error 0.025 (one-sided).
For scenario with ISS7/HSS7 as the co-primary efficacy endpoints
ISS7 change from baseline at Week 12


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Approximately 10% drop-out is expected at week 12, thus with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo if the mean change of ISS7 from baseline 
to Week 12 is at least 4 in favor of remibrutinib, with common standard deviation of 
approximately 6 (based on the primary endpoint analysis of Phase 2b study (CLOU064A2201)), 
based on a t-test, assuming type I error 0.025 (one-sided).
HSS7 change from baseline at Week 12
Approximately 10% drop-out is expected at week 12, thus with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo if the mean change of HSS7 from baseline 
to Week 12 is at least 4 in favor of remibrutinib, with common standard deviation of 
approximately 6 (based on the primary endpoint analysis of Phase 2b study (CLOU064A2201)),
based on a t-test, assuming type I error 0.025 (one-sided).
With 300 participants in the active arm and 150 participants in the placebo arm randomized in 
this study, this gives a power of more than >90% to detect a difference between remibrutinib 
and placebo in both mean change of ISS7 and HSS7 from baseline to Week 12 when correlation 
between endpoints is 0 (conservative assumption, as higher the correlation is, higher the power 
is).
12.8.2
Secondary endpoint(s)
Achievement of UAS7 = 0 at Week 12
Similarly, with approximately 10% drop-out at week 12, then with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo arm assuming a proportion of complete 
response (UAS7=0) of 0.35 in the remibrutinib arm and of 0.10 in the placebo arm, based upon 
a 2-group continuity corrected χ2 test with a 0.025 one-sided significance level.
Achievement of UAS7 ≤6 at Week 12
Similarly, with approximately 10% drop-out at week 12, then with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo arm assuming a proportion of disease 
activity control response (UAS7≤6) of 0.53 in the remibrutinib arm and of 0.15 in the placebo 
arm, based upon a 2-group continuity corrected χ2 test with a 0.025 one-sided significance level.
The primary and secondary endpoints analyses are planned to use the multiple testing strategy 
to control the family-wise error at α=0.025 (one-sided). It is considered, however, this 
hierarchical approach could impact the sample size compared to the separate endpoint approach, 
which depends on how the recycled alpha will be used. In both scenarios, the “family-wise” 
power (power to reject all null hypotheses) is >90% when correlation between endpoints is 0 
(Higher the correlation is, higher the power is).


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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 at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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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.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
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Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. J Med Chem p. 5102-5118.
Bernstein JA, Lang DM, Khan DA, et al (2014) The diagnosis and management of acute and 
chronic urticaria: 2014 update. J Allergy Clin Immunol p. 1270-7.
 
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med p. 586-604.
Brukinsa® Prescribing Information (2021) BeiGene, Brukinsa (zanubrutinib) 80 mg capsule 
(Internet). 
Available 
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<https://www.brukinsa.com/prescribing-information.pdf> 
(Accessed 22-Mar-2022).
Brukinsa® SmPC (2022) BeiGene, Brukinsa (zanubrutinib) 80 mg capsule (Internet). Available 
from: <https://www.ema.europa.eu/en/documents/product-information/brukinsa-epar-product-
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Bye AP, Unsworth AJ, Vaiyapuri S, et al (2015) Ibrutinib inhibits platelet integrin αIIbβ3 
outside-in signaling and thrombus stability but not adhesion to collagen. Arterioscler Thromb 
Vasc Biol; 35(11):2326-35.
Calquence® Prescribing Information (2019) AstraZeneca, Calquence (acalabrutinib) 100 mg 
capsules (Internet). Available from: <https://www.azpicentral.com> (Accessed 26-Apr-2022).
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Available from: <https://www.ema.europa.eu/en/documents/product-information/calquence-
epar-product-information_en.pdf> (Accessed 26-Apr-2022).
Dispenza MC, Pongracic JA, Singh AM, et al (2018) Short-term ibrutinib therapy suppresses 
skin test responses and eliminates IgE-mediated basophil activation in adults with peanut or 
tree nut allergy. J. Allergy Clin. Immunol. p. 1914-1916.e7.
Dispenza MC, Regan JA, Bochner BS (2017) Potential applications of Bruton's tyrosine 
kinase inhibitors for the prevention of allergic reactions. Expert Rev Clin Immunol p. 921-
923.
Ferrer M (2015) Immunological events in chronic spontaneous urticaria. Clin Transl Allergy 
p. 30.
Farez et al (2019) Practice guideline update summary: Vaccine-preventable infections and 
immunization in multiple sclerosis: Report of the Guideline Development, Dissemination, and 
Implementation Subcommittee of the American Academy of Neurology. Neurology. 2019 Sep 
24;93(13):584-594
Finlay AY (2005) Current severe psoriasis and the rule of tens. Br. J. Dermatol. p. 861-7.


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Finlay AY, Khan GK (1994) Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin. Exp. Dermatol. p. 210-6.
Futatani T, Watanabe C, Baba Y, et al (2001) Bruton's tyrosine kinase is present in normal 
platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier 
females. Br J Haematol p. 141-9.
Gabizon R, London N (2020) A Fast and Clean BTK Inhibitor. J Med Chem p. 5100-5101.
Gonçalo M, Gimenéz-Arnau A, Al-Ahmad M, et al (2021) The global burden of chronic 
urticaria for the patient and society. Br J Dermatol p. 226-236.
Greaves MW (2003) Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol p. 363-8.
Guillén-Aguinaga S, Jáuregui Presa I, Aguinaga-Ontoso E, et al (2016) Updosing nonsedating 
antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-
analysis. Br J Dermatol p. 1153-1165.
 
Hawro T, Ohanyan T, Schoepke N, et al (2018) The Urticaria Activity Score-Validity, 
Reliability, and Responsiveness. J Allergy Clin Immunol Pract p. 1185-1190.e1.
Hendriks RW, Yuvaraj S, Kil LP (2014) Targeting Bruton's tyrosine kinase in B cell 
malignancies. Nat Rev Cancer p. 219-32.
Hongbo Y, Thomas CL, Harrison MA, et al (2005) Translating the science of quality of life 
into practice: What do dermatology life quality index scores mean? J. Invest. Dermatol. p. 
659-64.
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(ibrutinib) 
70 
and 
140 
mg 
hard 
capsules 
(Internet). 
Available 
from: 
<https://www.imbruvica.com/files/prescribing-information.pdf> (Accessed on 26-Apr-2022).
Imbruvica® SmPC (2022) Janssen-Cilag International NV, Imbruvica (ibrutinib) 140 mg hard 
capsules. 
Summary 
of 
Product 
Characteristics. 
Available 
from 
< 
https://www.ema.europa.eu/en/documents/product-information/imbruvica-epar-product-
information_en.pdf> (Accessed on 26-Apr-2022).
Kaplan A, Ferrer M, Bernstein JA, et al (2016) Timing and duration of omalizumab response 
in patients with chronic idiopathic/spontaneous urticaria. J Allergy Clin Immunol p. 474-81.
Kaplan AP, Horáková Z, Katz SI (1978) Assessment of tissue fluid histamine levels in 
patients with urticaria. J Allergy Clin Immunol p. 350-4.
Kaul M, Storim J, End P, et al (2019) LOU064: A highly selective and potent covalent oral 
BTK inhibitor with promising pharmacodynamic effects in skin p. 333-376.
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BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I 
trial p. 1-13.


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Maurer M, Abuzakouk M, Bérard F, et al (2017) The burden of chronic spontaneous urticaria 
is substantial: Real-world evidence from ASSURE-CSU. Allergy p. 2005-2016.
Maurer M, Rosén K, Hsieh HJ, et al (2013) Omalizumab for the treatment of chronic 
idiopathic or spontaneous urticaria. N Engl J Med p. 924-35.
 
 
Młynek A, Zalewska-Janowska A, Martus P, et al (2008) How to assess disease activity in 
patients with chronic urticaria? Allergy p. 777-80.
O'Donnell BF, Lawlor F, Simpson J, et al (1997) The impact of chronic urticaria on the 
quality of life. Br J Dermatol p. 197-201.
 
Pleyer et al (2021) Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted 
recombinant hepatitis B and zoster vaccines. Blood. 2021 Jan 14;137(2):185-189
Powell RJ, Du Toit GL, Siddique N, et al (2007) BSACI guidelines for the management of 
chronic urticaria and angio-oedema. Clin Exp Allergy p. 631-50.
Regan JA, Cao Y, Dispenza MC, et al (2017) Ibrutinib, a Bruton's tyrosine kinase inhibitor 
used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and 
basophil activation test reactivity. J. Allergy Clin. Immunol. p. 875-879.e1.
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Immune Cell Signaling and Systemic Autoimmunity. Crit Rev Immunol p. 17-62.
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Immunol Pract p. 1097-1106.
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IgE-mediated histamine release in human basophils. Allergy p. 1666-1676.
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Weller K, Groffik A, Magerl M, et al (2013) Development, validation, and initial results of 
the Angioedema Activity Score. Allergy p. 1185-92.
Zuberbier T, Aberer W, Asero R, et al (2014) The EAACI/GA(2) LEN/EDF/WAO Guideline 
for the definition, classification, diagnosis, and management of urticaria: the 2013 revision 
and update. Allergy p. 868-87.
Zuberbier T, Aberer W, Asero R, et al (2018) The EAACI/GA²LEN/EDF/WAO guideline for 
the definition, classification, diagnosis and management of urticaria. Allergy p. 1393-1414.
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guideline: management of urticaria. Allergy p. 1427-43.


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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 msec for males or greater than 460 msec for females or QTcF increase of ≥60 msec 
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.


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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal at 
baseline:

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known 
bone pathology)

Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent 
term)

ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a 
liver toxicity
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
Action Taken
Trigger
Liver Symptoms
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


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Action Taken
Trigger
Liver Symptoms
Monitoring
Follow-up 
Monitoring
Study Medication
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 
Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin
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 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
ALT, AST, total 
bilirubin, Alb, 
PT/INR, ALP and 
GGT until 
resolution1 (frequ
Discontinue 
treatment 
immediately


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Action Taken
Trigger
Liver Symptoms
Monitoring
Follow-up 
Monitoring
Study Medication
Record the AE 
and contributing 
factors(e.g.,
conmeds, med 
hx, lab) in the 
appropriate CRF
ency at 
investigator 
discretion)
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
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 × 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
ALT, AST, total bilirubin, Alb,
PT/INR, ALP and GGT until 
resolution (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
- Record the AE and 
contributing factors
(e.g., conmeds, med hx, lab) in 
the appropriate CRF
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.


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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific renal alert criteria and actions
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 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) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥ 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


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Protocol No. CLOU064A2301

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
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


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16.4
Appendix 4: PRO Tools
Samples of questionnaires provided here are for illustrative purpose only. The text format and 
wording might slightly vary.
Patient Diary: Urticaria Patient Daily Diary (UPDD)


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Patient Diary: Angioedema Activity Score (AAS)


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Dermatology Life Quality Index (DLQI):


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SAP_001.pdf: 
Clinical Development
LOU064/Remibrutinib
CLOU064A2301 / NCT05030311
A multicenter, randomized, double-blind, placebo-controlled Phase 
3 study of remibrutinib (LOU064) to investigate the efficacy, safety 
and tolerability for 52 weeks in adult chronic spontaneous urticaria 
patients inadequately controlled by H1-antihistamines  
Statistical Analysis Plan (SAP)  
Document type:
SAP Documentation
Document status:
Amendment 4
Release date:
25-Jan-2024
Number of pages:
85
Property of Novartis
 Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 4.0, Effective from 23-Apr-2021


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted (Current)
23-
Nov-
2021
Prior to 
FPFV
Creation of 
final version
N/A - First 
version
NA
14-
Jun-
2022
Prior to 
the 
primary 
analysis
Protocol 
amendment 
V01
Adress the 
comments 
from TFL shell 
review
SAP 
Amendment 
1
 
Section 1.2.1, Section 1.2.2, Section 2.5.1.3,  
Section 2.5.1.6, Section 2.5.2.1, Section 
2.6.1.6  update the handling of intercurrent 
events
Section 2.1.1.5 update the assessment 
window for weekly scores from eDiary data, 
update the assessment window for the 
assessments performed at study visit
 
Section 2.4.2 update the medication dictionary
Section 2.5.1.5, Section 2.6.1.5 remove the 
tipping point analysis as sensitivity analysis
Section 2.5.2.2 add details of MMRM
Section 2.7.1 specify narrow SMQ search
Section 2.7.3 add the handling of local 
laboratory data for urinalysis, 
Add the summary table of maximum change 
for Hematology and Serum chemistry
Add the description of newly occurring and 
worsening abnormality
Add the analysis of renal alert criteria
Section 2.10 remove the treatment difference 
from by-visit summary
Add the summary table by treament and visit


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Date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted (Current)
 
Section 6 add the reference
28-
Apr-
2023
Prior to 
the 
primary 
analysis
Add new 
safety 
analyses
Add details for 
implementation 
of statistical 
modeling 
analyses and 
missing data 
imputation
Add estimand 
up to Week 24 
on the primary 
and secondary 
endpoints 
based on FDA 
feedback (from 
March 2023)
Add lab 
parameters 
with CTCAE 
grades.
SAP 
Amendment 
2
Section 1 Update the version of reference 
document
Section 1.2 Add the statement for Japan and 
China registration
Section 2.1.1.1 Add long term efficacy 
analysis beyond Week 24
Section 2.1.1.4 Update the definition of on -
treatment period at final analysis.
Section 2.1.1.5 Update the assessment 
schedule of weight in Table 2-6 and the 
assessment window of weight in Table 2-9.
 
 
Section 2.4.2 combine the summary of 
concomitant medications for urticaria and non-
urticaria
 
Section 2.5.1.1 add the handling of duplicated 
data in eDiary
Section 2.5.1.4 add details for the handling of 
missing values, imputation steps
Section 2.5.2.1 change the imputation method 
for missing response variables
Section 2.5.2.2 add details for the offset 
variable on negative binomial regression 
model
Section 2.7.1 add new analysis for infections 
and infestations (SOC)


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Date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted (Current)
Section 2.7.1.1 add new analyses for the 
selected AESIs
Section 2.7.3 add the handling of urinalysis 
central laboratory data
Update the CTCAE grade based on internal 
guidance (Version 5.0)
Add graphical presentation for liver enzyme 
test abnormalities
Section 2.7.4.1 Update QTcF (Fridericia’s) 
interval change from baseline.
Section 2.10 Update PRO analyses to include 
efficacy analyses beyond Week 24 at primary 
analysis.
 
Section 5.4.1.1, Section 5.4.2.1, Section 
5.4.2.3 add details for implementation of 
statistical modeling analyses
Section 5.4.2.5 new section of exposure 
adjusted occurrence rate
Section 5.4.2.6 new section of confidence 
interval for proportion of binary data
Section 5.4.3 added details for implementation 
of multiple imputation
3-
Jul-
2023
Prior to 
the 
primary 
analysis
Add detailed 
descriptions on 
multiple 
imputation
SAP 
Amendment 
3
List of abbreviations: Add CIR and CR.
Section 1 Update the version of edit check 
specifications.
Section 2.1.1.5: The start date of eDiary data 
after Week 24 is updated to the Date of Day 1 
of open-label period
Section 2.3.2: Add definition of categorized 
Duration of CSU in the categorical variables.


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Date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted (Current)
Section 2.4.1: Include Placebo group in the 
Entire study period for primary analysis; 
Update the definition of Last study visit in 
Tables 2-10 and 2-11.
Section 2.7.4.1, Section 2.7.4.2 and Section 
2.10: Add description on the handling of 
scheduled and unscheduled visits for by-visit 
summary tables for corresponding 
assessments.
Section 5.4.1.1: Add text “If the computation of 
the MMRM model takes extreme amount of 
time, the ddfm=bw option could be 
considered.”
Section 5.4.2.3 add description of offset 
variable for the analysis at Week 24
Section 5.4.2.6 Update text to clarify that 
confidence interval based on the score 
method including continuity correction are 
used for observed response rate and adverse 
event incidence rate.
Section 5.4.3: Add more details on multiple 
imputations, including the macros we will use 
and the imputation steps, with example codes.
Section 6: Update and add references.
25-
Jan-
2024
Prior to 
the final 
analysis
Correction and 
clarification
SAP 
amendment 
4
Section 1.2.1, section 1.2.2, and section 
2.6.1.6 Add “or participants non-compliant to 
treatment prior to Week 12” for consistency.
Section 2.1.1.4 Add a sentence to clarify the 
on-treatment double-blind period for safety 
assessments.
Section 2.1.1.5 Update the assessment 
schedule of weight in Table 2-6 and the 
assessment window of weight in Table 2-9.
Section 2.4.1 Table 2-11 The definition of last 
study visit is updated for clarification.


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Date
Time 
point
Reason for 
update
Outcome 
for update
Section and title impacted (Current)
Section 2.4.2 For the analysis of rescue 
medication in oral corticosteroids, remove “by 
dose per tablet” for correction.
Section 2.7.3 Update CTCAE grade for 
neutrophil count decrease and lymphocyte 
count decreased according to updated internal 
CTCAE guidance. Add Box plots for selected 
parameters.
Section 2.7.4.1 Add the description of a shift 
table for completeness.
Section 2.7.4.1 and section 2.7.4.2 Add the 
description of notable summary tables for 
clarification.
Section 2.11 Remove percent change from 
baseline for correction. Add that normal range 
will be presented in the figures. 
 
 


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Study No. CLOU064A2301
Table of contents
Table of contents..................................................................................................................7
List of abbreviations ............................................................................................................9
1
Introduction........................................................................................................................11
1.1
Study design...........................................................................................................11
1.2
Study objectives, endpoints and estimands............................................................12
1.2.1
Primary estimand(s)...............................................................................17
1.2.2
Secondary estimand(s)...........................................................................18
2
Statistical methods .............................................................................................................20
2.1
Data analysis general information..........................................................................20
2.1.1
General definitions ................................................................................20
2.2
Analysis sets...........................................................................................................36
2.2.1
Subgroup of interest ..............................................................................37
2.3
Patient disposition, demographics and other baseline characteristics....................37
2.3.1
Patient disposition .................................................................................37
2.3.2
Demographics and other baseline characteristics..................................38
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................39
2.4.1
Study treatment / compliance................................................................39
2.4.2
Prior, concomitant and post therapies ...................................................42
2.5
Analysis plan for the scenario with UAS7 as the primary efficacy endpoint........43
2.5.1
Analysis supporting primary objective..................................................43
2.5.2
Analysis supporting secondary objectives.............................................47
2.6
Analysis plan for the scenario with ISS7 and HSS7 as the co-primary efficacy 
endpoints................................................................................................................53
2.6.1
Analysis supporting primary objective(s) .............................................53
2.6.2
Analysis supporting secondary objectives.............................................55
2.7
Safety analyses.......................................................................................................58
2.7.1
Adverse events (AEs)............................................................................58
2.7.2
Deaths....................................................................................................60
2.7.3
Laboratory data......................................................................................60
2.7.4
Other safety data....................................................................................64
66
66
2.10
Patient-reported outcomes......................................................................................66
68


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.69
70
2.13
Interim analysis......................................................................................................71
3
Sample size calculation......................................................................................................72
3.1
Primary endpoint(s)................................................................................................72
3.2
Secondary endpoint(s)............................................................................................73
4
Change to protocol specified analyses...............................................................................73
5
Appendix............................................................................................................................74
5.1
Imputation rules .....................................................................................................74
5.1.1
Study drug .............................................................................................74
5.1.2
AE date imputation................................................................................74
5.1.3
Concomitant medication date imputation..............................................75
5.1.4
Concomitant therapies...........................................................................76
5.1.5
Other imputations..................................................................................76
5.2
AEs coding/grading................................................................................................77
5.3
Laboratory parameters derivations.........................................................................77
5.4
Statistical models ...................................................................................................77
5.4.1
Analysis supporting primary objective(s) .............................................77
5.4.2
Analysis supporting secondary objective(s)..........................................79
5.4.3
Multiple imputations .............................................................................82
5.5
Rule of exclusion criteria of analysis sets..............................................................84
84
6
Reference ...........................................................................................................................85


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List of abbreviations
AAS
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
BUN
Blood Urea Nitrogen
CIR
Copy Increments in Reference
CR
Copy Reference
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical Study Report
CSU
Chronic Spontaneous Urticaria
DLQI
Dermatology Life Quality Index
EAIR
Exposure Adjusted Incidence Rate
EAOR
Exposure Adjusted Occurrence Rate
ECG
Electrocardiogram
eDiary
Electronic Diary
FAS
Full Analysis Set
GGT
Gamma-glutamyl transferase
HDL
High-Density Lipoprotein
HLGT
Hight Level Group Term
HLT
High Level Term
HSS
Hives Severity Score
HSS7
Weekly Hives Severity Score
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
INR
International Normalized Ratio
IRT
Interactive Response Technology
ISS
Itch Severity Score
ISS7
Weekly Itch Severity Score
J2R
Jump to Reference
MAR
Missing At Random
MedDRA
Medical dictionary for regulatory activities 
mg
Milligram(s)
MMRM
Mixed effect Model for Repeated Measurements
PD
Pharmacodynamic(s)


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PRO
Patient Reported Outcomes
PT
Preferred Term
QTcF
QT interval corrected by Fridericia’s formula
RAS
Randomized Set
RAP
Reporting & Analysis Process
RDO
Retrieved Drop Out
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard Deviation
SMQ
Standardized MedDRA Query
SOC 
System Organ Class
TBL
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
TFLs
Tables, Figures, Listings
UAS
Urticaria Activity Score
UAS7
Weekly Urticaria Activity Score
ULN
Upper Limit of Normal
UPDD
Urticaria Patient Daily Diary
WHODrug
World Health Organization Drug Dictionary


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1
Introduction
Data will be analyzed by Novartis according to the data analysis Section 12 of the 
CLOU064A2301 study protocol which will be made available in Appendix 16.1.1 of the 
Clinical Study Report (CSR). Important information is given in the following sections and 
details are provided, as applicable, in Appendix 16.1.9 of the CSR.
This document covers statistical and analytical plans for the primary analysis (at Week 24) if 
conducted, and the final analysis of CLOU064A2301 study with reference to: 
•
the study protocol Version 01
•
the case report form (CRFs) Version 6.0
•
the LOU064A master analysis plan (MAP) Version 2.0
•
 
A separate statistical analysis plan for the program DMC will be prepared.
1.1
Study design
Study CLOU064A2301 is a global Phase 3 multicenter, randomized, double-blind, parallel-
group, placebo-controlled study investigating the efficacy, safety and tolerability of 
remibrutinib (25 mg b.i.d.) in adult participants with Chronic Spontaneous Urticaria (CSU) 
inadequately controlled by second generation H1-antihistamines. 
The study consists of four periods, the total study duration is up to 60 weeks:
•
Screening period: up to 4 weeks.
•
Double-blind treatment period: 24 weeks of double-blind treatment with remibrutinib 
(25 mg b.i.d.) or placebo. 
•
Open-label treatment period: 28 weeks of open-label treatment with remibrutinib (25 
mg b.i.d.).
•
Follow-up period: 4 weeks of treatment-free follow-up (only for participants who do 
not enroll into the extension study). 
Approximately 450 participants will be randomized in a 2:1 ratio (300 in treatment arm and 150 
in the placebo arm) stratified by prior exposure to anti-IgE biologics and by geographic region 
to the following arms: 
•
LOU064 25 mg b.i.d.: 25 mg LOU064 twice daily 
•
Placebo: LOU064 matching placebo twice daily
Maximum number of participants with prior exposure to anti-IgE biologics will be limited to 
approximately 30% of the total study population.


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All participants will be on a stable, locally label approved dose of a second generation H1-
antihistamine (“background therapy”) throughout the entire study (starting a minimum of 7 days 
prior to randomization 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
D1: Day 1, b.i.d.: bis in die/twice a day, mg: milligram(s), Pbo: placebo, PA: Primary Analysis, PE: 
Primary Endpoint, Scr: Screening, W: Week
A primary analysis may be conducted when all participants have completed their Week 24 visit 
or discontinued early and when a minimum of 150 participants across both Phase 3 pivotal 
studies, CLOU064A2301 and CLOU064A2302 (a second nearly identical Phase 3 study 
conducted in parallel) have completed the treatment period at Week 52. After the primary 
analysis and/or after all participants have entered the open label treatment period, additional 
optional interim analyses may be conducted.
A final analysis will be performed when all participants have completed the study or 
discontinued early.
1.2
Study objectives, endpoints and estimands 
There are two primary objective scenarios based on regional regulatory precedent and Health 
Authorities’ feedback. These two primary objective scenarios will be tested in two distinct 
testing strategies (Table 1-1 and Table 1-2). Distinctions in the secondary objectives reflect the 
corresponding scenario: the primary objective in one scenario is presented as secondary 
objective(-s) in another. The other secondary 
 objectives are identical in both 
scenarios. To support Japan and China registration, scenario with UAS7 as the primary efficacy 
endpoint listed in Table 1-1 will be adopted.


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Table 1-1
Objectives and related endpoints – Scenario with UAS7 as the primary 
efficacy endpoint
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with 
respect to change from baseline in UAS7 
at Week 12
•
Absolute change from baseline in UAS7 at 
Week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
To demonstrate that a greater proportion 
of participants achieve disease activity 
control (UAS7 ≤ 6) at Week 12 who are 
treated with remibrutinib (25 mg b.i.d.) 
compared to placebo-treated participants
•
Achievement of UAS7 ≤ 6 (yes/no) at Week 12
•
To demonstrate that a greater proportion 
of participants achieve complete absence 
of hives and itch (UAS7 = 0) at Week 12 
who are treated with remibrutinib (25 mg 
b.i.d.) compared to placebo-treated 
participants
•
Achievement of UAS7 = 0 (yes/no) at Week 12
•
To demonstrate the superiority of 
remibrutinib (25 mg b.i.d.) treated 
participants with respect to a reduction 
from baseline in the weekly itch severity 
score at Week 12 compared to placebo-
treated participants
•
Improvement of severity of itch, assessed as 
absolute change from baseline in ISS7 score at 
Week 12
•
To demonstrate the superiority of 
remibrutinib (25 mg b.i.d.) treated 
participants with respect to a reduction 
from baseline in the weekly hive severity 
score at Week 12 compared to placebo-
treated participants
•
Improvement of severity of hives, assessed as 
absolute change from baseline in HSS7 score 
at Week 12
•
To demonstrate that a greater proportion 
of participants achieve UAS7 ≤ 6 at Week 
2 who are treated with remibrutinib (25 
mg b.i.d.) compared to placebo-treated 
participants
•
Achieving early onset of disease activity 
control, as defined as achievement of UAS7≤ 6 
(yes/no) at Week 2
•
To demonstrate that a greater proportion 
of participants who are treated with 
remibrutinib (25 mg b.i.d.) achieve DLQI 
= 0-1 at Week 12 compared to placebo-
treated participants
•
No impact on participants' dermatology-quality 
of life, as defined by achievement of DLQI = 0-1 
(yes/no) at Week 12
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants maintain 
disease activity control (defined as 
UAS7≤6) for more weeks compared to 
placebo treated participants over 12 
weeks
•
Achieving sustained disease activity control, 
assessed as cumulative number of weeks with 
an UAS7≤6 response between baseline and 
Week 12


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Objective(s)
Endpoint(s)
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants have more 
angioedema occurrence-free weeks over 
12 weeks compared with placebo-treated 
participants
•
Number of weeks without angioedema, 
assessed by the cumulative number of weeks 
with an AAS7 = 0 response between baseline 
and Week 12
•
To demonstrate the safety and tolerability 
of remibrutinib (25 mg b.i.d.)
•
Occurrence of treatment emergent adverse 
events and serious adverse events during the 
study


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Objective(s)
Endpoint(s)


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Table 1-2
Objectives and related endpoints - Scenario with ISS7 and HSS7 as 
the co-primary efficacy endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with 
respect to change from baseline in ISS7 and 
HSS7 at Week 12
•
Absolute change from baseline in ISS7 at 
Week 12
•
Absolute change from baseline in HSS7 at 
Week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) is superior to placebo in CSU with 
respect to change from baseline in UAS7 at 
Week 12
•
 Absolute change from baseline in UAS7 at 
Week 12
•
To demonstrate that a greater proportion of 
participants achieve disease activity control 
(UAS7 ≤ 6) at Week 12 who are treated with 
remibrutinib (25 mg b.i.d.) compared to 
placebo-treated participants
•
 Achievement of UAS7≤ 6 (yes/no) at Week 
12
•
To demonstrate that a greater proportion of 
participants achieve complete absence of 
hives and itch (UAS7 = 0) at Week 12 who 
are treated with remibrutinib (25 mg b.i.d.) 
compared to placebo-treated participants
•
Achievement of UAS7 = 0 (yes/no) at Week 
12
•
To demonstrate that a greater proportion of 
participants achieve UAS7 ≤ 6 at Week 2 
who are treated with remibrutinib (25 mg 
b.i.d.) compared to placebo-treated 
participants
•
Achieving early onset of disease activity 
control, as defined as achievement of 
UAS7≤ 6 (yes/no) at Week 2
•
To demonstrate that a greater proportion of 
participants who are treated with 
remibrutinib (25 mg b.i.d.) achieve DLQI = 0-
1 at Week 12 compared to placebo-treated 
participants
•
No impact on participants' dermatology 
quality of life as defined by achievement of 
DLQI = 0-1 (yes/no) at Week 12.
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants maintain disease 
activity control (defined as UAS7≤6) for 
more weeks compared to placebo treated 
participants over 12 weeks
•
Achieving sustained disease activity control, 
assessed as cumulative number of weeks 
with an UAS7≤6 response between baseline 
and Week 12
•
To demonstrate that remibrutinib (25 mg 
b.i.d.) treated participants have more 
angioedema occurrence-free weeks over 12 
weeks compared with placebo-treated 
participants
•
Number of weeks without angioedema, 
assessed by the cumulative number of 
weeks with an AAS7= 0 response between 
baseline and Week 12
•
To demonstrate the safety and tolerability of 
remibrutinib (25 mg b.i.d.)
•
Occurrence of treatment emergent adverse 
events and serious adverse events during 
the study


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Objective(s)
Endpoint(s)
1.2.1
Primary estimand(s)
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment).
Primary estimand for scenario with UAS7 as primary efficacy endpoint
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the change from baseline in UAS7 score after 12 weeks 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 
discontinuation from study treatment for any reason and regardless of intake of a different 
second generation H1-antihistamine as rescue medication and considering strongly 
confounding prohibited medication as an unfavourable outcome?
The primary estimand is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥ 6 months, a UAS7 score ≥ 16, 
ISS7 ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint: Change in UAS7 from baseline at Week 12.
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: the mean difference between treatment groups.
5. Handling of intercurrent events:
•
Discontinuation of study treatment due to any reason: Treatment policy strategy
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 8): 
Composite strategy (irrespective of potential occurrence of other intercurrent events)
•
Intake of rescue medication, switch of background medication, intake of other prohibited 
medication, or participants non-compliant to treatment prior to Week 12: Treatment policy 
strategy
Primary estimand for scenario with ISS7/HSS7 as co-primary efficacy endpoints 
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the co-primary endpoints change from baseline in ISS7 score and change from 
baseline in HSS7 score after treatment in adult participants with CSU who are inadequately 


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controlled by H1-antihistamine and receiving a stable locally label approved dose of a second 
generation H1-antihistamine, regardless of discontinuation from study treatment for any reason 
and regardless of intake of a different second generation H1-antihistamine as rescue medication 
and considering strongly confounding prohibited medication as an unfavourable outcome?
The primary estimand is described by the following attributes:
1. Population: participants with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥ 6 months, a UAS7 score ≥ 16, 
ISS7 ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint (co-primary): Change in ISS7 from baseline at Week 12 and change in HSS7 
from baseline at Week 12.
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: the mean difference between treatment groups.
5. Handling of intercurrent events:
•
Discontinuation of study treatment due to any reasons: Treatment policy strategy
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent 
events)
•
Intake of rescue medication, switch of background medication, intake of other 
prohibited medication, or participants non-compliant to treatment prior to Week 12: 
Treatment policy strategy
1.2.2
Secondary estimand(s) 
Secondary estimand on the secondary endpoint UAS7 ≤ 6 response at week 12
The secondary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the UAS7 ≤ 6 response after 12 weeks 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 and regardless of intake of a different second generation H1-antihistamine as rescue 
medication and considering strongly confounding prohibited medication as an unfavourable 
outcome?
The secondary estimand is described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥6 months, a UAS7 score ≥ 16, 
ISS7 score ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint: UAS7 ≤ 6 response at Week 12.


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3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: the odds ratio between treatment groups.
5. Handling of intercurrent events:
•
Discontinuation of study treatment due to any reasons: Treatment policy strategy
•
Intake of strongly confounding prohibited medication (e.g., biologics treatment at any 
time before Week 12, cyclosporin after Week 8, systemic corticosteroids after Week 
8): Composite strategy (irrespective of potential occurrence of other intercurrent 
events)
•
Intake of rescue medication, switch of background medication, intake of other 
prohibited medication, or participants non-compliant to treatment prior to Week 12: 
Treatment policy strategy
Secondary estimand on the secondary endpoint UAS7 = 0 response at week 12
Similar Estimand approach will be implemented for UAS7= 0 as for UAS7 ≤ 6.
Other secondary estimand on the other secondary endpoints as defined in Table 1-1 and 
Table 1-2.
Similar Estimand approach will be implemented for these endpoints as the primary Estimand 
or co-primary Estimand.


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2
Statistical methods
2.1
Data analysis general information
The statistical analysis will be performed by Novartis personnel, using SAS Version 9.4 or 
above.
Summary statistics for continuous variables will include N, mean, standard deviation, 
minimum, first quartile, median, third quartile, maximum.
Summary statistics for categorical variables will be presented in contingency tables and will 
include frequencies and percentages.
The p-values will be presented as one-sided with level of significance 2.5%. 95% confidence 
intervals will be displayed and will always be two-sided.
The primary analysis may be conducted when all participants have completed their Week 24 
visit or discontinued early and when a minimum of 150 participants across both Phase 3 pivotal 
studies (A2301 and A2302) have completed the 52 week treatment period. Details are given in 
this document.
The final analysis will be performed based on the final database lock when all participants have 
completed the study or discontinued early.
2.1.1
General definitions 
2.1.1.1
Analysis period and treatment groups
Primary analysis 
When the primary analysis is conducted, the efficacy analysis will include visits up to Week 24 
and include the primary endpoint at Week 12. Long term efficacy analysis including all data 
available at the cut-off date (beyond Week 24) will be evaluated in addition.
The safety analysis will be conducted at the time of primary analysis. This analysis will include 
separate analysis for the double blind period (comparing LOU064 vs placebo up to Week 24) 
and the entire study period data available at the cut-off date (including beyond Week 24). The 
safety data during all periods of double blind, open label and safety follow up will be included.
The treatment groups and the data to be used for primary analysis are provided in Table 2-1. 
Table 2-1
Treatment groups for primary analysis
Endpoint
Study period
Treatment group
Details
LOU064 25mg
Participants initially randomized to LOU064 
Efficacy from baseline up to Week 24
Note: the primary endpoint is at Week 12
Efficacy
Double blind 
Placebo
Participants initially randomized to placebo 
Efficacy from baseline up to Week 24
Note: the primary endpoint is at Week 12


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Endpoint
Study period
Treatment group
Details
Entire study 
(DB period + 
OL period)
LOU064 25mg
Participants initially randomized to LOU064 
Efficacy from baseline up to cut-off
Placebo - LOU064 
25mg
Participants initially randomized to placebo 
regardless of entering into OL period, i.e., 
including participants who discontinued during 
DB period and not entered into OL period, 
participants who entered into OL period and 
switched to LOU064 
Efficacy from baseline up to cut-off
LOU064 25mg
Participants initially randomized to LOU064 
Safety from baseline up to Week 24
Double blind 
Placebo
Participants initially randomized to placebo
Safety from baseline up to Week 24
LOU064 25mg
Participants initially randomized to LOU064 
Safety from baseline up to cut-off
Placebo
Participants initially randomized to placebo
Safety from baseline up to Week 24
Safety
Entire study 
(DB period + 
OL period + 
FW period)
Transitioned to 
LOU064 25mg
Participants initially randomized to placebo and 
switched to LOU064 
Safety after switching to LOU064 up to cut-off
DB: double-blind, OL: open-label, FW: follow-up


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Final analysis
Final efficacy and safety analyses will be conducted on the entire study period (all periods of 
double blind, open label and safety follow up).
The treatment groups and the data to be used for final analysis are shown in Table 2-2.
Please note: efficacy analysis for “Placebo – LOU064 25mg “ treatment group will be provided 
for all participants initially randomized to placebo regardless of entering the open-label 
treatment. The efficacy data from baseline to Week 24 will be assessed under placebo. The data 
after the first dose of LOU064 will be assessed under LOU064 25mg treatment, but separated 
from the LOU064 25mg treatment group (participants initially randomized to LOU064).  Safety 
analysis for “Transitioned to LOU064” group will be conducted using safety data after 
switching to LOU064 25 mg treatment.
Table 2-2
Treatment groups for final analyses
Endpoint
Period
Treatment group
Details
Efficacy
Entire study
LOU064 25mg
Participants initially randomized to LOU064 
Efficacy from baseline to Week 52
LOU064 25mg
Placebo
DB period - Efficacy/Safety
LOU064 25mg
Entire period - Safety
Transitioned to LOU064 25mg
Placebo
Entire period - Efficacy
LOU064 25mg
Placebo-LOU064 25mg


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Endpoint
Period
Treatment group
Details
(DB period + 
OL period)
Placebo - LOU064 
25mg
Participants initially randomized to placebo 
regardless of entering into OL period, i.e. 
including participants who discontinued during 
DB period and not entered into OL period, 
participants who entered into OL period and 
switched to LOU064. 
Efficacy from baseline up to Week 52
Note: the data from baseline to Week 24 is 
under placebo, the data after the first dose of 
LOU064 is under LOU064 25mg
LOU064 25mg
Participants initially randomized to LOU064 
Safety from baseline up to the end of study
Placebo
Participants initially randomized to placebo
Safety from baseline up to Week 24
Safety
Entire study 
(DB period + 
OL period + 
FW period)
Transitioned to 
LOU064 25mg
Participants initially randomized to placebo and 
switched to LOU064 25mg
Safety after switching to LOU064 up to the end 
of study
DB: double-blind, OL: open-label, FW: follow-up
2.1.1.2
Baseline and post-baseline definitions
Baseline for safety (in treatment period) 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.
LOU064 25mg
Entire period - Safety
Entire period - Efficacy
LOU064 25mg
Transitioned to LOU064 25mg
Placebo-LOU064 25mg
Placebo


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Baseline for efficacy (in treatment period) is comprised of the 7 days prior to the randomization 
day for weekly scores (UAS7, HSS7, ISS7, AAS7, 
 
, etc. ). For other assessments (DLQI,
 etc.), 
baseline is the assessment on or before the randomization day.
2.1.1.3
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 randomization 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)/Randomization (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)/Randomization (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.
2.1.1.4
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.
Double blind period
The on-treatment DB period will be defined as 
•
starting from the date of the first actual dose intake of DB treatment and 
•
ending at the minimum between (i) the date of the last actual dose intake of DB treatment 
plus 4 weeks (28 days) or (ii) the end of DB period
The end of DB period is minimum of (one day before the date of the first actual dose intake of 
OL treatment, or the date of study discontinuation, or safety follow-up).
For the participants who entered open-label period more than 28 days later than the last actual 
dose intake of DB treatment, their end date of on-treatment DB period is defined as one day 
before the date of the first actual dose intake of OL treatment.


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The safety assessment performed at the visit on the day of the first actual dose intake of OL 
treatment belongs to DB period, assuming that this assessment is performed before the actual 
dose intake of OL treatment.
This definition will be applied to both of LOU064 25mg treatment group and placebo group.
Entire study period
At the primary analysis, for LOU064 25mg group, the on-treatment period for entire study 
period will be defined as 
•
starting from the date of the first actual dose intake of LOU064 treatment 
i.e., the first day of LOU064 DB treatment 
•
ending at the minimum between (i) the date of the last actual dose intake of LOU064 
treatment plus 4 weeks (28 days) or (ii) the end of study 
The end of study is either of the date of Week 52 visit, or study discontinuation, or study 
completion, or safety follow-up or cut-off date of primary analysis, depending on participant’s 
status.
For Transitioned to LOU064 25mg group, the on-treatment period for entire study period 
will be defined as 
•
starting from the date of the first actual dose intake of LOU064 treatment (i.e., the first 
day of LOU064 OL treatment)
•
ending at the minimum between (i) the date of the last actual dose intake of LOU064 
OL treatment plus 4 weeks (28 days) or (ii) the end of study
The end of study is either of the date of Week 52 visit, or study discontinuation, or study 
completion, or safety follow-up or cut-off date of primary analysis, depending on participant’s 
status.
For Placebo group, the definition of on-treatment period is same as the on-treatment DB 
period.  
At the final analysis, for LOU064 25mg group, the on-treatment period for entire study 
period will be defined as 
•
starting from the date of the first actual dose intake of LOU064 treatment (i.e. the first 
day of LOU064 DB treatment) and 
•
ending at the minimum between (i) the date of the last actual dose intake of LOU064 
treatment plus 4 weeks (28 days), or (ii) the end of study
The end of study is either of the date of Week 52 visit, or study discontinuation, or study 
completion, or safety follow-up.
For Transitioned to LOU064 25mg group, the on-treatment period for entire study period 
will be defined as 
•
starting from the date of the first actual dose intake of LOU064 treatment (i.e., the first 
day of LOU064 OL treatment) and 
•
ending at the minimum between (i) the date of the last actual dose intake of LOU064 
treatment plus 4 weeks (28 days) or (ii) the end of study 


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The end of study is either of the date of Week 52 visit, or study discontinuation, or study 
completion, or safety follow-up.
For Placebo group, the definition of on-treatment period is same as the on-treatment DB 
period.  
2.1.1.5
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 24 are defined based on the study days starting 
with Day 1 (Randomization Day). The study day for the eDiary date will be calculated as [Date 
of Diary] – [Date of Randomization] + 1 for post-baseline assessment and [Date of Diary] – 
[Date of Randomization] for baseline assessment. 
The analysis Week 1 through Week 23 of the treatment period will be derived based on 
scheduled visit day as defined in Table 2-3. eDiary data on or before Day -1 of actual Week 24 
study visit will be used for weekly score calculation up to Week 23. 
The analysis Week 24 score will be derived as Day -7 to Day -1 of actual Week 24 study visit 
day. 
After Week 24 until Week 51, weekly score will be derived based on the study days starting 
with Day 1 of open-label period (i.e., Date of first study treatment in open-label period). The 
study day for the eDiary date will be calculated as [Date of Diary] – [Day 1 of open-label period] 
+ 1. The analysis Week 25 through Week 51 of the treatment period will be derived based on 
scheduled visit day as defined in Table 2-3. 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.
Table 2-3
Assessment window for weekly scores based on eDiary (for 
completers) 
Analysis period
Analysis visit
Scheduled 
Visit Day
eDiary Assessment Window
Double-blind
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


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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
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 -7 to Day -1 of Week 24 study visit
Open label
Week 25
-
Day 1 (Date of first study treatment in 
open-label period) to Day 7 of open-
label period
Week 26
-
Day 8 to Day 14 of open-label period
Week 27
-
Day 15 to Day 21 of open-label period
Week 28
-
Day 22 to Day 28 of open-label period
Week 29
-
Day 29 to Day 35 of open-label period
Week 30
-
Day 36 to Day 42 of open-label period
Week 31
-
Day 43 to Day 49 of open-label period
Week 32
225
Day 50 to Day 56 of open-label period


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Week 33
-
Day 57 to Day 63 of open-label period
Week 34
-
Day 64 to Day 70 of open-label period
Week 35
-
Day 71 to Day 77 of open-label period
Week 36
-
 Day 78 to Day 84 of open-label period
Week 37
-
 Day 85 to Day 91 of open-label period
Week 38
-
 Day 92 to Day 98 of open-label period
Week 39
-
 Day 99 to Day 105 of open-label period
Week 40
281
 Day 106 to Day 112 of open-label 
period
Week 41
-
Day 113 to Day 119 of open-label 
period
Week 42
-
Day 120 to Day 126 of open-label 
period
Week 43
-
Day 127 to Day 133 of open-label 
period
Week 44
-
Day 134 to Day 140 of open-label 
period
Week 45
-
Day 141 to Day 147 of open-label 
period
Week 46
-
Day 148 to Day 154 of open-label 
period
Week 47
-
Day 155 to Day 161 of open-label 
period
Week 48
-
Day 162 to Day 168 of open-label 
period
Week 49
-
Day 169 to Day 175 of open-label 
period
Week 50
-
Day 176 to Day 182 of open-label 
period
Week 51
-
Day 183 to Day 189 of open-label 
period
Week 52
365
Day -7 to Day -1 of Week 52 study visit


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Note: Week 52 study visit is during treatment epoch. eDiary data on this day will not be taken 
into 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 24, assessment 
will follow rules as defined in Table 2-4 up to Week 24. After Week 25, weekly scores will 
not be derived even when the eDiary data are collected.
Table 2-4
Assessment window for weekly scores based on eDiary (for early 
treatment discontinued participants earlier than Week 24)
Analysis period
Analysis visit
Scheduled 
Visit Day
eDiary Assessment Window
Double blind
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 


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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
No further analysis visit
For participants who discontinued study treatment after Week 24, assessment will follow 
the rules as defined in Table 2-5 up to Week 52. 
Table 2-5
Assessment window for weekly scores based on eDiary (for early 
treatment discontinued participants after Week 24)
Analysis period
Analysis visit
Scheduled 
Visit Day
eDiary Assessment Window
Double blind
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


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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 -7 to Day -1 of Week 24 study 
visit
Open label
Week 25
-
Day 1 (Date of first study treatment in 
open-label period) to Day 7 of open-
label period
Week 26
-
Day 8 to Day 14 of open-label period
Week 27
-
Day 15 to Day 21 of open-label period
Week 28
-
Day 22 to Day 28 of open-label period
Week 29
-
Day 29 to Day 35 of open-label period
Week 30
-
Day 36 to Day 42 of open-label period
Week 31
-
Day 43 to Day 49 of open-label period
Week 32
225
Day 50 to Day 56 of open-label period
Week 33
-
Day 57 to Day 63 of open-label period
Week 34
-
Day 64 to Day 70 of open-label period
Week 35
-
Day 71 to Day 77 of open-label period
Week 36
-
 Day 78 to Day 84 of open-label 
period
Week 37
-
 Day 85 to Day 91 of open-label 
period


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Week 38
-
 Day 92 to Day 98 of open-label 
period
Week 39
-
 Day 99 to Day 105 of open-label 
period
Week 40
281
 Day 106 to Day 112 of open-label 
period
Week 41
-
Day 113 to Day 119 of open-label 
period
Week 42
-
Day 120 to Day 126 of open-label 
period
Week 43
-
Day 127 to Day 133 of open-label 
period
Week 44
-
Day 134 to Day 140 of open-label 
period
Week 45
-
Day 141 to Day 147 of open-label 
period
Week 46
-
Day 148 to Day 154 of open-label 
period
Week 47
-
Day 155 to Day 161 of open-label 
period
Week 48
-
Day 162 to Day 168 of open-label 
period
Week 49
-
Day 169 to Day 175 of open-label 
period
Week 50
-
Day 176 to Day 182 of open-label 
period
Week 51
-
Day 183 to Day 189 of open-label 
period
Week 52
365
Day 190 to Day 196 of open-label 
period
No further analysis visit


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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 end of treatment (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 considered as 
baseline).
The assessment window is based on the study assessment schedule. For participants initially 
randomized to placebo and switched to LOU064, the date of first OL study treatment will be 
considered. The assessments under placebo treatment will not be remapped to the visits during 
OL period and the assessments under LOU064 treatment will not be remapped to the visits 
during DB period.
The protocol defined assessment schedule is shown in Table 2-6. For ECG, at Week 2, 12, 52 
and SD visit pre and post-dose assessments will be collected. ETD visit can be remapped to 
Week 24 only, and SD visit can be remapped to Week 2, 12 and 52.   
Table 2-6
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
ECG
X
X2
 
 
X2
 
 
X
 
 
X2
X
X2
DLQI
X
 
X
 
X
 
 
X
 
 
X
X
X


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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
-
-
X: to be recorded, BSL: baseline, ETD: early treatment discontinuation, SD: study discontinuation
1 only post-baseline assessments
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.
Table 2-7 shows the assessment windows for the assessments collected at every visit (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.
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, 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, 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 2-7
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 


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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), 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 follows:
Table 2-8
Assessment window for DLQI until Week 52
Assessment visit
Scheduled 
Visit Day
Assessment Window
Week 4
29
Day 2 to Day 29
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 2-9 shows the assessment windows of days for each assessment.  
Table 2-9
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


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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
Weight
2-85
86-365
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 trial:
•
The Randomized Analysis Set (RAS) consists of all randomized participants, 
regardless of whether or not they receive a dose of study drug. Participants will be 
analyzed according to the treatment they are assigned.
•
The Full Analysis Set (FAS) comprises all participants to whom study treatment has 
been assigned by randomization. FAS will be used for all efficacy variables, unless 
otherwise stated. Mis-randomized participants (mis-randomized in IRT) will be 
included in the Randomized set but will be excluded from FAS.
Mis-randomized participants are defined as cases where IRT contacts were made by the 
site either prematurely or inappropriately prior to confirmation of the participant’s final 
randomization eligibility and no study medication was administered to the participant.
•
The Safety Set (SAF) includes all participants who received at least one dose of study 
treatment, whether or not being randomized. Participants will be analyzed according to 
the study treatment received. The safety set will be used in the analysis of all safety 
variables. The actual treatment will be defined as the treatment received over the study. 
In case of error in dispensation, the actual treatment will correspond to the treatment 
which was given most often.


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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 (for co-primary endpoints ISS7/HSS7) 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, >5years )
Subgroup analyses will be performed for the primary endpoint and secondary endpoints using 
the randomization strata subgroups. If the actual stratum is different to the assigned stratum in 
IRT, the actual stratum will be used in the analysis.
Randomization strata
•
Previous exposure to anti-IgE biologics (Yes/No)
•
Geographic region (LaCAN (Latin America, Caribbean and Canada), RE (Region 
Europe), Japan, US, AMEA (Asia, Middle East & Africa)
In addition, to support local regulatory requirements, analysis of key efficacy and safety data 
for the subgroup of participants from a specific country will be provided. 
•
Japanese patients (Geographic region=Japan) (only required for Japan submission)
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 Randomized set who completed the study 
treatment period, who discontinued the study treatment and the reason for treatment 
discontinuation will be presented for each treatment group and all participants (total) by study 


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period. LOU064 25 mg and Placebo treatment groups will be presented for DB period, LOU064 
25 mg and Placebo-LOU064 25mg treatment groups will be presented for entire period.
The number and percentage of participants in the Randomized set who completed the study 
(including FU period), who discontinued the study and the reason for discontinuation will be 
presented as well.
The number of participants in each analysis set (Randomized, FAS and Safety) will be presented 
for each treatment group and all participants (total) by study period (as presented in Table 2-1 
and Table 2-2). 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 for each treatment group and all participants (total). The 
summary of overall important PDs (including COVID-19 related PDs), important COVID-19 
related PDs will be provided by study period for the Randomized set.
2.3.2
Demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for each initially randomized treatment group (LOU064 25mg, Placebo) and for 
all participants (total) for the Randomized set.
The following common background, demographic and disease characteristics variables will be 
analyzed:
Continuous variables:
•
Screening Age (years)   
•
Height (cm)
•
Weight (kg)
•
Body mass index (BMI) calculated as (body weight in kilograms) / (height 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 years, ≥85 years)
•
Gender 
•
Race


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•
Ethnicity
•
BMI groups (< 25, 25 - <30, ≥ 30 kg/m2)
•
Baseline UAS7 category (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)
•
Geographic region (Japan, AMEA, US, LaCAN, RE)
•
Previous experience of Angioedema (Yes, No)
 
 
•
Duration of CSU groups, defined as categorical groups of duration of CSU ( ≤1 
year, >1 to 3 years, >3 to 5 years, >5 years )
Relevant medical histories and current medical conditions at baseline will be summarized 
combined by system organ class and preferred term, by treatment group initially randomized 
treatment group (LOU064 25mg, Placebo) for the Randomized 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/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


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The duration of exposure and duration of study in weeks to LOU064 25mg and placebo will be 
summarized by treatment group and by study period (DB period and entire study period). 
Primary analysis
For double-blind period, the duration of exposure/study in weeks and total duration in years 
(subject-years) to LOU064 25 mg and placebo will be summarized by treatment group 
(LOU064 25mg and Placebo).
The number of participants with the duration of exposure/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 - <24 weeks, ≥24 
weeks) will be displayed.
For entire study period, the duration of exposure/study in weeks and total duration in years 
(subject-years) to LOU064 25 mg will be summarized by treatment group (LOU064 25 mg, 
Placebo, Transitioned to LOU064 25 mg)
The number of participants with the duration of exposure/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 - <24 weeks, ≥24 
weeks - <32 weeks, ≥32 weeks - <40 weeks, ≥40 weeks - <52 weeks and ≥52 weeks) will be 
displayed.
Table 2-10
Definitions of first dose of study treatment, last dose of study 
treatment, last study visit for primary analysis
Study 
period
Treatment 
group
First dose of study 
treatment
Last dose of study 
treatment
Last study visit
Double 
blind 
LOU064 
25mg
Date of first dose 
intake in DB period
Date of last dose 
intake in DB period
Minimum (one day 
before the date of 
Week 24 study visit, 
the date of study 
discontinuation/safety 
follow-up)
Placebo
Date of first dose 
intake in DB period
Date of last dose 
intake in DB period
Minimum (one day 
before the date of 
week 24 study visit, the 
date of study 
discontinuation/safety 
follow-up)
Entire 
study 
LOU064 
25mg
Date of first dose 
intake in DB period
Date of last dose 
intake in DB/OL period
Minimum (Week 52/the 
date of study 
discontinuation/study 
completion/safety 
follow-up,cut-off date of 
primary analysis)*


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Study 
period
Treatment 
group
First dose of study 
treatment
Last dose of study 
treatment
Last study visit
Placebo
Date of first dose 
intake in DB period
Date of last dose 
intake in DB period
Minimum (one day 
before the date of 
week 24 study visit/the 
date of study 
discontinuation/safety 
follow-up)
Transitioned 
to LOU064 
25mg
Date of first dose 
intake in OL period
Date of last dose 
intake in OL period
Minimum (Week 52/ 
the date of study 
discontinuation/study 
completion/safety 
follow-up/cut-off date of 
primary analysis)
DB: Double blind, OL: Open label
*: If both Week 52 and study completion visits are present, the date of study completion will be used
Final analysis
For entire study period, the duration of exposure/study in weeks and total duration in subject 
years to LOU064 25 mg and placebo will be summarized by treatment group (LOU064 25 mg, 
Placebo, Transitioned to LOU064 25 mg)
The number of participants with the duration of exposure/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 - <24 weeks, ≥24 
weeks - <32 weeks, ≥32 weeks - <40 weeks, ≥40 weeks - < 52 weeks and ≥52 weeks) will be 
displayed.
Table 2-11
Definitions of first dose of study treatment, last dose of study 
treatment, last study visit for final analysis
Study 
period
Treatment 
group
First dose of study 
treatment
Last dose of study 
treatment
Last study visit
Entire 
study 
LOU064 
25mg
Date of first dose 
intake in DB period
Date of last dose 
intake in DB/OL period
Maximum(Week 52/the 
date of study 
discontinuation/study 
completion/safety 
follow-up)
Placebo
Date of first dose 
intake in DB period
Date of last dose 
intake in DB period
Minimum (one day 
before the date of 
week 24 study visit/the 
date of study 
discontinuation/safety 
follow-up)


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Study 
period
Treatment 
group
First dose of study 
treatment
Last dose of study 
treatment
Last study visit
Transitioned 
to LOU064 
25mg
Date of first dose 
intake in OL period
Date of last dose 
intake in OL period
Maximum(Week 52/ 
the date of study 
discontinuation/study 
completion/safety 
follow-up)
DB: Double blind, OL: Open label
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. 
Prior urticaria medications and prior non-urticaria medications will be summarized 
separately by ATC code, preferred term for initially randomized treatment group (LOU064 
25mg, Placebo) in the Randomized set. 
Concomitant medications (excluding background or rescue medications)  will be 
summarized by ATC code, preferred term for study period and treatment group in the Safety 
set. 
Background medications will be summarized by ATC code, preferred term, and dose per 
administration for study period and treatment group in the Randomized set.
Rescue medication: H1-antihistamines will be summarized by ATC code, preferred term, and 
dose per tablet for study period and treatment group in the Safety set.
Rescue medication: oral corticosteroids will be summarized by ATC code and preferred term 
for study period and treatment group in the Safety set.
In addition, non-drug therapies/procedures will be summarized separately by primary system 
organ class and preferred term of MedDRA dictionary. Prior non-drug therapies/procedures 
will be summarized for initially randomized treatment group (LOU064 25mg, Placebo) in the 
Randomized set. Concomitant non-drug therapies/procedures will be summarized for study 
period and treatment group in the Safety set.


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2.5
Analysis plan for the scenario with UAS7 as the primary efficacy 
endpoint
2.5.1
Analysis supporting primary objective
All analyses for efficacy data will be based on the FAS.
2.5.1.1
Primary endpoint
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo 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 and regardless of intake of a different second 
generation H1-antihistamine as rescue medication and considering strongly confounding 
prohibited medication as an unfavourable outcome?
The primary efficacy endpoint 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 2.1.1.5). 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


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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. 
2.5.1.2
Statistical hypothesis, model, and method of analysis 
The statistical hypothesis test for the primary endpoint being tested is that the absolute change 
from baseline in UAS7 score at Week 12 in remibrutinib is not superior to the placebo group 
i.e.:
H01: µ remibrutinib ≥µPlacebo versus HA1: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in UAS7 at Week 12.
A linear mixed model with repeated measures (MMRM) will be used to estimate treatment 
differences for change from baseline in UAS7 score at Week 12, based on the FAS. The MMRM 
model will include treatment group, baseline UAS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline UAS7 score by week as 
fixed effects. Repeated measures within participant are modeled using an unstructured 
covariance of the error terms. Additional important covariates may be added to the model. For 
the primary analysis, data up to Week 12 will be used in the model. The treatment difference 
LOU064 25 mg – placebo at Week 12 will be estimated using the LS mean and 95% CI, and p-
value for treatment comparison will be presented.
The detailed testing strategy including the primary endpoint analysis is provided in 
Section 2.5.2.1.
2.5.1.3
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 
Retrieved drop out (RDO) participants.
The analysis will account for different intercurrent events as explained in the following:
1. Discontinuation of study treatment prior to Week 12 due to any reasons:
A treatment policy strategy will be applied and these intercurrent events will be ignored. 
Data collection will be maintained and available measurements post-treatment 
discontinuation will be used as if they had been obtained under the treatment assigned at 
randomization. i.e., RDO data collected after study treatment discontinuation will be used 
for analysis. In case of missing values, a multiple imputation approach will be applied (see 
Section 2.5.1.4 for details).
2. Intake of rescue medication as per protocol, or switch of background medication, or intake 
of other prohibited medication (except for strongly confounding prohibited medication 
listed below), or participants non-compliant (dose interruption) to treatment prior to Week 
12: 
A treatment policy strategy will be applied in the same way as described above.  Data 
collected after these events will be used for analysis.
3. Intake of strongly confounding prohibited medication: 


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•
Biologics treatment at any time before Week 12 (as identified by PD M-COMD03)
•
Cyclosporin 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)
A composite strategy will be applied. Measurements after this event will be excluded 
from the analysis and will be imputed using the worst value of the endpoint (i.e., 42 for 
UAS7).
2.5.1.4
Handling of missing values 
Missing data imputation will be performed for the analyses when using statistical model.  
Handing of missing RDO data
If no RDO data was collected after study treatment permanent discontinuation, missing data 
will be imputed based on the following rules:
•
For participants in the active treatment arms, if sufficient RDO data, missing data will be 
imputed using MI based on observed RDO data in the corresponding active arm. If not 
feasible (e.g., very limited RDO data), missing data will be imputed based on observed 
data in the placebo arm under the assumption of jump to reference (J2R) using MI.
•
For participants in the placebo arm, if sufficient RDO data, missing data will be imputed 
using MI based on observed RDO placebo arm data. If not feasible (e.g., very limited 
RDO data), missing data will be imputed using MI under the MAR assumption based on 
the observed placebo arm data.
Handling of other missing data
If there is any missing data prior to Week 12, the missing data will be handled following the 
MAR assumption. 
The detailed steps for handling of the intercurrent events and analyses are described below;
Step 1: Identify the participants with intercurrent events 
Step 2: For participants with intercurrent event 1 (Discontinuation of study treatment prior to 
Week 12 due to any reasons), determine the imputation strategy based on the amount of 
RDO data
•
Calculate the percentage of RDO data available at Week 12 in participants with 
intercurrent event 1 by treatment group
•
If >=50 % of participants had RDO data at Week 12, consider RDO data is sufficient
•
If <50% of participants had RDO data at Week 12, consider RDO data is not sufficient
Step 3: Perform the missing data imputation
•
For participants with intercurrent event 3 (Intake of strongly confounding prohibited 
medication), set missing at all visits after the event
•
Perform the missing data imputation of missing RDO data under MI framework 
according to the imputation strategy on Step 2. At the same time, missing data 


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imputation of other missing data (i.e. non RDO data) will also be performed. The 
details on MI are described in Section 5.4.3  
•
Replace the values at all visits after the intercurrent event 3 with the worst value
Step 4: Perform the analysis
2.5.1.5
Sensitivity analyses 
The following sensitivity analysis will be performed for the primary estimand to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis. The sensitivity analysis will be implemented with the same target population, 
the primary variables and the summary measure as for the primary estimand, but using the 
different assumptions or handling of intercurrent events.
Sensitivity analysis: The change from baseline in UAS7 score up to week 12 will be imputed 
using zero (i.e., no clinical improvement from baseline) for the intercurrent event of “Intake of 
strongly confounding prohibited medication (e.g. biologics treatment at any time before Week 
12, cyclosporin after Week 8 to Week 12, systemic corticosteroids after Week 8 to Week 12)” 
handled with composite strategy.
2.5.1.6
Supplementary analyses
Supplementary estimand
The clinical question of interest is: What is the effect of remibrutinib treatment versus placebo 
on the change from baseline in UAS7 score after 12 weeks treatment in adult patients 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 and regardless of intake of a different second generation H1-antihistamine as 
rescue medication, and as if strongly confounding prohibited medication was not taken?
The supplementary estimand is described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥6 months, a UAS7 score ≥16, ISS7 score 
≥6 and HSS7 score ≥6 in the last 7 days prior to randomization.
2. Endpoint: Change in UAS7 from baseline at Week 12.
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or placebo) 
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 difference between treatment groups.
5. Handling of intercurrent events:
•
Discontinuation of study treatment prior to Week 12 due to any reasons: Treatment 
policy strategy (same as in Section 2.5.1.3)
•
Intake of rescue medication as per protocol, or switch of background medication, or intake 
of other prohibited medication (except for strongly confounding prohibited medication 


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listed below), or participants non-compliant to treatment prior to Week 12: Treatment 
policy strategy  (same as in Section 2.5.1.3)
•
Intake of strongly confounding prohibited medication (e.g. biologics treatment at any time 
before Week 12, cyclosporin after Week 8 to Week 12, systemic corticosteroids after 
Week 8 to Week 12): Hypothetical strategy will be applied irrespective of potential 
occurrence of other intercurrent events. Measurements after this event will be excluded 
from the analysis and will be imputed via a modeling approach.
o
For participants in the active treatment arms, hypothetical data will be imputed 
using multiple imputation under missing at random (MAR) assumptions using 
LOU064 data.
o
For participants in the placebo arm, hypothetical data will be imputed using 
multiple imputation under MAR assumptions using Placebo data.
For detailed data handling, please see Section 2.5.1.3 and Section 2.5.1.4.
2.5.2
Analysis supporting secondary objectives 
2.5.2.1
Secondary endpoint(s)
The secondary endpoints of the scenario with UAS7 as the primary efficacy endpoint are as 
follows:
1. Disease activity control at Week 12, assessed as % of participants achieving UAS7 ≤ 6.
2. Complete absence of hives and itch at Week 12, assessed as % of participants achieving 
UAS7 =0.
3. Improvement of severity of itch at Week 12, assessed as absolute change from baseline in 
ISS7 score 
4. Improvement of severity of hives at Week 12, assessed as absolute change from baseline 
in HSS7 score
5. Disease activity control at Week 2, assessed as proportion of participants achieving 
UAS7 ≤ 6.
For derivation of UAS7, HSS7 and ISS7 scores, please see Section 2.5.1.1. The response 
variables (e.g., UAS7 ≤ 6) will be derived using the corresponding weekly score. 
6. 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.


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7. Cumulative number of weeks that participants achieve UAS7 ≤ 6 responses 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). 
8. Cumulative number of weeks that participants achieve AAS7 = 0 responses 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 score: A weekly AAS7 score will be derived by adding up the daily scores 
(possible ranges 0 to 15) of the 7 days preceding the visit, and ranges from 0 to 105 (please 
refer to the assessment window in Section 2.1.1.5). 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, ASS7 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, ASS7 will be considered as missing for 
that week. 
Secondary estimand
For each secondary endpoint, the following secondary estimand will be considered:
The secondary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on secondary endpoints after 12 weeks 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 and regardless of intake of a different second generation H1-antihistamine as rescue 
medication and considering strongly confounding prohibited medication as an unfavourable 
outcome?
The secondary estimand is described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥6 months, a UAS7 score ≥ 16, 
ISS7 score ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to randomization.
2. Endpoint: see below
3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or 
placebo) regardless of treatment compliance, with background medication of locally label 
approved dose second generation H1-antihistamine, and a different second generation 
H1-antihistamine as rescue medication.
4. Summary Measurement: see below


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5. Handling of intercurrent events: the intercurrent events are the same for the primary 
endpoint as described in Section 2.5.1.3. For the handling of intercurrent events, please 
see below.
Table 2-12
Estimand attributes for secondary endpoints
Endpoint
Summary 
measurement
Handing of intercurrent event
UAS7 ≤ 6 at Week 12
Odds ratio between 
treatment groups
A treatment policy strategy: RDO data or data 
collected after the IE will be used. In case of 
missing values of RDO data, derivation based 
on the multiply imputed UAS7 described in 
Section 2.5.1.3 will be applied.
A composite strategy: UAS7 response after the 
intercurrent event will be excluded and UAS7 ≤ 6 
will be derived from imputed UAS7 score using 
the worst value (i.e., 42).
UAS7 = 0 at Week 12
Odds ratio between 
treatment groups
Same as UAS7 ≤ 6 at Week 12. 
ISS7 score change 
from baseline to Week 
12
Mean difference 
between treatment 
groups
Same as the primary estimand, see Section 
2.5.1.3
HSS7 score change 
from baseline to Week 
12
Mean difference 
between treatment 
groups
Same as the primary estimand, see Section 
2.5.1.3
UAS7 ≤ 6 at Week 2
Odds ratio between 
treatment groups
Same as UAS7 ≤ 6 at Week 12. 
Note: As this endpoint is for the score at W2, 
some intercurrent events, e.g. intake of strongly 
confounding prohibited medication, will not be 
considered.
DLQI 0/1 at Week 12
Odds ratio between 
treatment groups
Same as UAS7 ≤ 6 at Week 12. In case of 
missing values of RDO data, derivation based 
on the multiply imputed DLQI score with same 
approach as UAS7 will be applied. 
Cumulative number of 
weeks with an UAS7 
≤6 response between 
baseline and Week 12
Ratio of response rate 
between treatment 
groups
Same as UAS7 ≤ 6 at Week 12. Derivation 
based on the multiply imputed UAS7 described 
in Section 2.5.1.3 will be applied.
Cumulative number of 
weeks with an AAS7= 
0 response between 
baseline and Week 12
Ratio of response rate 
between treatment 
groups
Same as UAS7 ≤ 6 at Week 12. Derivation 
based on the multiply imputed AAS7 with same 
approach as UAS7 will be applied.
2.5.2.2
Statistical hypothesis, model, and method of analysis
Statistical hypothesis and testing strategy


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The following null hypotheses (H0) will be tested against the respective alternative hypotheses 
(HA) in a closed testing procedure (Bretz et al 2009), thus controlling the family-wise type I 
error which is set to 0.025 (one-sided):
Primary:
UAS7 score change from baseline at Week 12
H01: µ remibrutinib ≥µPlacebo versus HA1: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in UAS7 at Week 12
Secondaries:
•
UAS7 ≤ 6 at Week 12
H02: p remibrutinib ≤pPlacebo versus HA2: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7≤6 at Week 12,
•
UAS7 = 0 at Week 12
H03: p remibrutinib ≤pPlacebo versus HA3: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7=0 at Week 12,
•
ISS7 score change from baseline at Week 12
H04: µ remibrutinib ≥µPlacebo versus HA4: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in ISS7 at Week 12,
•
HSS7 score change from baseline at Week 12
H05: µ remibrutinib ≥µPlacebo versus HA5: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in HSS7 at Week 12,
•
UAS7 ≤ 6  at Week 2
H06: p remibrutinib ≤pPlacebo versus HA6: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7 ≤6 at Week 2,
•
DLQI = 0/1 at Week 12
H07: p remibrutinib ≤pPlacebo versus HA7: p remibrutinib >pPlacebo
where p is the proportion of participants achieving DLQI = 0/1 at Week 12,
•
Cumulative number of weeks with an UAS7 ≤6 response between baseline and Week 
12
H08: µ remibrutinib ≤µPlacebo versus HA8: µ remibrutinib > µPlacebo
where µ is the mean cumulative number of weeks that participants achieve UAS7 ≤6 response 
between baseline and Week 12,
•
Cumulative number of weeks with an AAS7= 0 response between baseline and Week 
12
H09: µ remibrutinib ≤µPlacebo versus HA9: µ remibrutinib > µPlacebo


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where µ is the mean cumulative number of weeks that participants achieve AAS7=0 response 
between baseline and Week 12,
A graphical representation of the testing strategy is presented in Figure 2-1
Figure 2-1
Testing strategy with UAS7 as the primary endpoint
 
The value inside the circle represents the significance level. The arrow and value inside the square 
represent the "alpha-propagation".
The first hypothesis is tested with full level alpha (0.025 one-sided). If significant, the second 
hypothesis is tested with full-level alpha; otherwise, the testing procedure stops. The testing is 
strictly hierarchical, so that null hypotheses can be tested along the pre-defined order at the level 
assigned until a null hypothesis cannot be rejected, at which point the testing stops. Furthermore, 
the testing strategy reflects the separation of primary and secondary endpoints, so that 
hypotheses related to secondary endpoints will only be tested if the null hypothesis related to 
the primary endpoint is rejected.
Statistical model and method of analysis
1. UAS7 ≤ 6 at Week 12
The proportion of participants with UAS7 ≤ 6 at Week 12 will be analyzed using a logistic 
regression model including treatment group, region, prior exposure to anti-IgE biologics and 
baseline UAS7 score as covariate. 
2. UAS7 = 0 at Week 12
The proportion of participants with UAS7 = 0 at Week 12 will be analyzed using a logistic 
regression model including treatment group, region, prior exposure to anti-IgE biologics and 
baseline UAS7 score as covariate. 
3. ISS7 score change from baseline at Week 12
The absolute change from baseline in ISS7 score at Week 12 will be analyzed using MMRM 
modeling including treatment group, baseline ISS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline ISS7 score by week as 
fixed effects.
4. HSS7 score change from baseline at Week 12
The absolute change from baseline in HSS7 score at Week 12 will be analyzed using MMRM 
modeling including treatment group, baseline HSS7 score, randomization strata variables, week 
and both interaction of treatment by week and interaction of baseline HSS7 score by week as 
fixed effects.
5. UAS7 ≤ 6  at Week 2


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The proportion of participants with UAS7 ≤ 6 at Week 2 will be analyzed using a logistic 
regression model including treatment group, region, prior exposure to anti-IgE biologics and 
baseline UAS7 score as covariate.
6. DLQI = 0/1 at Week 12
The proportion of participants with overall DLQI scores ≤ 1 at Week 12 will be analyzed using 
a logistic regression model which includes treatment group, region, prior exposure to anti-IgE 
biologics and baseline DLQI score.
7. Cumulative number of weeks with an UAS7 ≤6 response between baseline and Week 
12
The cumulative number of weeks achieving UAS7 ≤ 6 response between baseline and Week 12 
will be modelled using a negative binomial regression model with log link, using treatment 
group, region, and prior exposure to anti-IgE biologics. The patient’s time in the treatment 
period up to Week 12 (natural log of proportion of time in treatment period, i.e., natural log of 
[number of weeks with the response variable in treatment period/12 weeks]) is used as an offset 
variable to obtain the UAS7 ≤ 6 rate, adjusted for the varying lengths of patient’s time in the 
randomized treatment period.
8. Cumulative number of weeks with an AAS7= 0 response between baseline and Week 
12
The cumulative number of weeks achieving AAS7 = 0 response between baseline and Week 12 
will be modelled using a negative binomial regression model with log link, using treatment 
group, region, prior exposure to anti-IgE biologics and baseline AAS7 = 0 status. The patient’s 
time in the treatment period up to Week 12 (natural log of proportion of time in treatment period, 
i.e., natural log of [number of weeks with the response variable in treatment period/12 weeks]) 
is used as an offset variable to obtain the AAS7=0 rate, adjusted for the varying lengths of 
patient’s time in the randomized treatment period.
2.5.2.3
Handling of intercurrent events 
See Section 2.5.2.1
2.5.2.4
Handling of missing values
See Section 2.5.1.4 for missing data of continuous variables. Missing data of response 
variables will be derived using the multiply imputed data for corresponding continuous 
variables. 
2.5.2.5
Sensitivity analyses
Not applicable
2.5.2.6
Supplementary analyses
For binary variables (UAS7 ≤ 6 at Week 12, UAS7 = 0 at Week 12, UAS7 ≤ 6 at Week 2, DLQI 
0/1 at Week 12), the treatment difference adjusting covariates as region, prior exposure to anti-
IgE biologics and baseline UAS7 score will be provided.


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2.6
Analysis plan for the scenario with ISS7 and HSS7 as the co-
primary efficacy endpoints
2.6.1
Analysis supporting primary objective(s)
All analyses for efficacy data will be based on the FAS.
2.6.1.1
Primary endpoints
Primary estimand for scenario with ISS7 and HSS7 as the co-primary efficacy endpoints 
The primary clinical question of interest is: What is the effect of remibrutinib treatment versus 
placebo on the change from baseline in ISS7 score and change from baseline in HSS7 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 and regardless of 
intake of a different second generation H1-antihistamine as rescue medication and considering 
strongly confounding prohibited medication as an unfavourable outcome?
The co-primary efficacy endpoints are the absolute change from baseline in ISS7 score at Week 
12 and absolute change from baseline in HSS7 score at Week 12, which is the ISS7 score 
(respectively HSS7 score) at Week 12 minus the ISS7 score (respectively HSS7 score at 
baseline). The weekly scores ISS7 and HSS7 range from 0-21, and will be derived by adding 
up the average daily scores of the 7 days preceding the visit.
Derivation of primary endpoints
See Section 2.5.1.1 
2.6.1.2
Statistical hypothesis, model, and method of analysis 
The statistical hypothesis test for the co-primary endpoints tests the union null hypothesis that 
the absolute change from baseline in ISS7 score at Week 12 in remibrutinib is not superior to 
the placebo group or the absolute change from baseline in HSS7 score at Week 12 in 
remibrutinib is not superior to the placebo group i.e.: 
H01a: µ remibrutinib ≥µPlacebo versus HA1a: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in ISS7 at Week 12.
H01b: µ remibrutinib ≥µPlacebo versus HA1b: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in HSS7 at Week 12.
The union null hypothesis is rejected if both elementary null hypotheses (H01a, H01b) are rejected.
A linear mixed model with repeated measures (MMRM) will be used to estimate treatment 
differences for change from baseline in ISS7 score (respectively HSS7) at Week 12, based on 
the FAS. The MMRM model will include treatment group, baseline ISS7 score (respectively 
HSS7), randomization strata variables, week and both interaction of treatment by week and 
interaction of baseline ISS7 score (respectively HSS7) by week as fixed effects. Repeated 
measures within participant are modeled using an unstructured covariance of the error terms. 


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Additional important covariates may be added to the model. For the primary analysis, data up 
to Week 12 will be used in the model. The treatment difference LOU064 25 mg – placebo at 
Week 12 will be estimated using the LS mean and 95% CI, and p-value for treatment 
comparison will be presented.
The detailed testing strategy including the primary endpoint analysis is provided in Section 
2.6.2.2.
2.6.1.3
Handling of intercurrent events 
See Section 2.5.2.1
2.6.1.4
Handling of missing values
See Section 2.5.1.4 
2.6.1.5
Sensitivity analyses 
The following sensitivity analysis will be performed for the primary estimand to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis. The sensitivity analysis will be implemented with the same target population, 
the primary variables and the summary measure as for the primary estimand, but using the 
different assumptions or handling of intercurrent events.
Sensitivity analysis: The change from baseline in ISS7 and HSS7 score up to Week 12 will be 
imputed using zero (i.e. no clinical improvement from baseline) for the intercurrent event of 
“Intake of strongly confounding prohibited medication (e.g. biologics treatment at any time 
before Week 12, cyclosporin after Week 8 to Week 12, systemic corticosteroids after Week 8 
to Week 12)” handled with composite strategy.
2.6.1.6
Supplementary analyses
Supplementary estimand
The clinical question of interest is: What is the effect of remibrutinib treatment versus placebo 
on the change from baseline in ISS7 score and change from baseline in HSS7 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 and regardless of 
intake 
of 
a 
different 
second 
generation 
H1-antihistamine as 
rescue 
medication, and as if strongly confounding prohibited medication was not taken?
The supplementary estimand is described by the following attributes:
1. Population: patients with inadequately controlled CSU despite treatment with second 
generation H1-antihistamine who have CSU duration ≥6 months, a UAS7 score ≥16, ISS7 score 
≥6 and HSS7 score ≥6 in the last 7 days prior to randomization.
2. Endpoint: Change in ISS7 from baseline at Week 12 and change in HSS7 from baseline at 
Week 12.


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3. Treatment of interest: the randomized study treatment (remibrutinib 25 mg b.i.d. or placebo) 
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 difference between treatment groups.
5. Handling of intercurrent events:
•
Discontinuation of study treatment due to any reasons, treatment non-compliance (dose 
interruption): Treatment policy strategy (same as in Section 2.5.1.3)
•
Intake of rescue medication, switch of background medication, intake of other prohibited 
medication, or participants non-compliant to treatment prior to Week 12: Treatment 
policy strategy (same as in Section 2.5.1.3)
•
Intake of strongly confounding prohibited medication (e.g. biologics treatment at any time 
before Week 12, cyclosporin after Week 8 to Week 12, systemic corticosteroids after 
Week 8 to Week 12): Hypothetical strategy (irrespective of potential occurrence of other 
intercurrent events)   (same as in Section 2.5.1.6)
For detailed data handling, please see Section 2.5.1.3 and Section 2.5.1.4.
2.6.2
Analysis supporting secondary objectives 
2.6.2.1
Secondary endpoint(s)
The secondary endpoints of the scenario with ISS7 and HSS7 as the co-primary efficacy 
endpoints as follows:
1. Improvement of UAS7 at Week 12, assessed as absolute change from baseline in UAS7 
score at Week 12 
2. Disease activity control at Week 12, assessed as % of participants achieving UAS7 ≤ 6.
3. Complete absence of hives and itch at Week 12, assessed as % of participants achieving 
UAS7 =0.
4. Disease activity control at Week 2, assessed as proportion of participants achieving 
UAS7 ≤ 6.
5. No impact on participants’ dermatology quality of life at Week 12, assessed as proportion 
of participants achieving DLQI = 0-1.
6. Cumulative number of weeks that participants achieve UAS7 ≤ 6 responses between 
baseline and Week 12.
7. Cumulative number of weeks that participants achieve AAS7 = 0 responses between 
baseline and Week 12.
For derivation of each endpoint, please see Section 2.5.2.1.
Secondary estimand
See Section 2.5.1.1 for UAS7 score change from baseline at Week 12, and Section 2.5.2.1 for 
others.


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2.6.2.2
Statistical hypothesis, model, and method of analysis
Statistical model, hypothesis, and method of analysis for scenario with ISS7/HSS7 as the 
co-primary efficacy endpoints
Testing strategy
The following null hypotheses (H0) will be tested against the respective alternative hypotheses 
(HA) in a closed testing procedure (Bretz et al 2009), thus controlling the family-wise type I 
error which is set to 0.025 (one-sided):
Co-Primary:
•
ISS7 score change from baseline at Week 12
•
HSS7 score change from baseline at Week 12
H01a: µ remibrutinib ≥µPlacebo versus HA1a: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in ISS7 at Week 12.
H01b: µ remibrutinib ≥µPlacebo versus HA1b: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in HSS7 at Week 12.
The union null hypothesis is rejected if both elementary null hypotheses (H01a, H01b) are rejected.
Secondaries:
•
UAS7 score change from baseline at Week 12
H02: µ remibrutinib ≥µPlacebo versus HA2: µ remibrutinib < µPlacebo
where µ is the mean change from baseline in UAS7 at Week 12,
•
UAS7 ≤ 6 at Week 12
H03: p remibrutinib ≤pPlacebo versus HA3: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7≤6 at Week 12,
•
UAS7 = 0 at Week 12
H04: p remibrutinib ≤pPlacebo versus HA4: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7=0 at Week 12,
•
UAS7≤ 6  at Week 2
H05: p remibrutinib ≤pPlacebo versus HA5: p remibrutinib >pPlacebo
where p is the proportion of participants achieving UAS7≤6 at Week 2,
•
DLQI = 0/1 at Week 12
H06: p remibrutinib ≤pPlacebo versus HA6: p remibrutinib >pPlacebo
where p is the proportion of participants achieving DLQI = 0/1 at Week 12,
•
Cumulative number of weeks with an UAS7≤6 response between baseline and Week 
12
H07: µ remibrutinib ≤µPlacebo versus HA7: µ remibrutinib > µPlacebo


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where µ is the mean cumulative number of weeks that participants achieve UAS7≤6 response 
between baseline and Week 12,
•
Cumulative number of weeks with an AAS7= 0 response between baseline and Week 
12
H08: µ remibrutinib ≤µPlacebo versus HA8: µ remibrutinib > µPlacebo
where µ is the mean cumulative number of weeks that participants achieve AAS7=0 response 
between baseline and Week 12,
A graphical representation of the testing strategy is presented in Figure 2-2
Figure 2-2
Testing strategy with ISS7/HSS7 as the co-primary endpoints 
 
The value inside the circle represents the significance level. The arrow and value inside the square 
represent the "alpha-propagation".
The first two hypotheses are tested: both H1a and H1b are tested with full level alpha (0.025 one-
sided) and only if both are rejected, then H2 hypothesis is tested with full-level alpha; otherwise, 
the testing procedure stops. The testing is strictly hierarchical, so that null hypotheses can be 
tested along the pre-defined order at the level assigned until a null hypothesis cannot be rejected, 
at which point the testing stops. Furthermore, the testing strategy reflects the separation of 
primary and secondary endpoints, so that hypotheses related to secondary endpoints will only 
be tested if both null hypotheses related to the co-primary endpoints are rejected.
Statistical model and method of analysis
See Section 2.5.1.2 for UAS7 score change from baseline at Week 12, and Section 2.5.2.2 for 
others.
2.6.2.3
Handling of intercurrent events 
See Section 2.5.1.3 for UAS7 score change from baseline at Week 12, and Section 2.5.2.1 for 
others.
2.6.2.4
 Handling of missing values
See Section 2.5.2.4
2.6.2.5
Sensitivity analyses
Not applicable.
2.6.2.6
Supplementary analyses
See Section 2.5.2.6


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2.7
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group and by visit.
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 2.1.1.4.
2.7.1
Adverse events (AEs)
All information obtained on adverse events will be listed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events (the events 
which occurred during the on-treatment period, TEAE) will be summarized by study period in 
the following ways:
•
by treatment group, primary system organ class and preferred term.
•
by treatment group, primary system organ class, preferred term and maximum severity.
•
by treatment group, 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 by study period and 
treatment group.
The most common adverse events reported ( 3 % in any group for each preferred term in the 
SOC-PT table or  3 % in any group for each SMQ table) will be presented in descending 
frequency according to its incidence in LOU064A 25mg bid starting from the most common 
event. The cut-off of 3% can be re-evaluated based on number of participants and 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 of AEs by severity, 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.
In addition, for adverse events and serious adverse events, exposure adjusted incidence rates 
will be estimated by treatment group for the double-blind period and 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 5.4.2.4 for details.
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 for the double-blind 
period and the entire study period.


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Table 2-13 presents overview of analyses on TEAEs.
Table 2-13
Overview of safety analyses on TEAEs
Analysis 
Study 
period
Treatment groups
AEs,
SAEs, 
AESI
AEs by severity, 
AEs by SMQ, Study 
med. related AEs, 
Death,
AEs leading to 
discontinuation, 
Primary 
analysis
Double 
blind
•
LOU064 25mg
•
Placebo
Crude incidence
EAIR
Crude incidence 
Entire 
study
•
LOU064 25mg
•
Placebo
•
Transitioned to LOU064 25mg 
(under LOU064 treatment)
Crude incidence
EAIR
Crude incidence
Final 
analysis
Entire 
study
•
LOU064 25mg
•
Placebo
•
Transitioned to LOU064 25mg 
(under LOU064 treatment)
Crude incidence
EAIR
Crude incidence
EAIR: Exposure Adjusted Incidence Rate, AESI: Adverse Events of Special Interest
2.7.1.1
Adverse events of special interest / grouping of AEs
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 TEAEs.
The number (and percentage) of participants with AESI will be summarized by safety topic of 
interest (i.e. risk name) and PT for study period and treatment group. Exposure adjusted 
incidence rate will also be provided by treatment group for the double blind period and the 
entire study period.
In addition, for the selected AESIs (Infections, Bleeding, Cytopenias), the number of AESI 
events will be summarized by safety topic of interest (i.e., risk name) for study period and 
treatment group. 
Summaries will also include the exposure adjusted occurrence rate and the corresponding 95% 
CI, the number of events per participant, time to onset of first event, duration of the events, the 
severity of the events, the outcome of events, treatment related events, the action taken with the 
study treatment for each event and duration of study drug interruption for events leading to 
study drug interruption.
•
Exposure Adjusted Occurrence Rate (EAOR) will be calculated as follows:


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EAOR = 100* total number of events / total exposure subject-time (years)
The exact Poisson 95% CIs (Garwood 1936, Sahai and Khurshid 1993) will be used. Please see 
Section 5.4.2.5 for details.
For duration of study drug interruption (in days), once the events leading to study drug 
interruption are selected, drug interruption occurring within 7 days of the event onset date will 
be considered. If there are more than one interruption, only the first interruption will be 
considered.
For the selected AESIs (Infections, Bleeding, Cytopenias), during the double-blind period, the 
number of events (per risk name), EAOR, and number of participants at risk occurring between 
0-£4 weeks, 4-£12 weeks, 12-<24 weeks will be displayed by treatment group.
2.7.1.2
Requirements of ClinicalTrials.gov and EudraCT
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent AEs: non-serious AEs with an incidence greater than 3% , and deaths and serious AEs 
(SAEs) including the events suspected to be related to study treatment, will be provided by SOC 
and PT on the Safety Set. The cut-off of 3% can be re-evaluated based on number of participants.
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 AE's 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
A separate summary for death including on treatment and post treatment deaths will be provided. 
If there are few deaths, only listing will be provided.
2.7.3
Laboratory data
All laboratory data will be listed by treatment group, 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 be listed and be included in the notable summary tables, but 
not be included in the by-visit summary tables.


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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 2.1.1.5) 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
Table 2-14 presents overview of safety analysis on laboratory data.
Table 2-14
Overview of safety analyses on laboratory data
Analysis 
Period
Treatment groups
Summary by visit
 Notables
Primary 
analysis
Double 
blind
•
LOU064 25mg
•
Placebo
X (up to Week 24)
X (up to Week 
24 including 
unscheduled 
visits of Week 
24)
Entire 
study
•
LOU064 25mg
•
Placebo
•
Transitioned to LOU064 25mg 
(under LOU064 treatment)
X (after Week 24)
X
Final 
analysis
Entire 
study
•
LOU064 25mg
•
Placebo
•
Transitioned to LOU064 25mg 
(under LOU064 treatment)
X
X
X: to be provided
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(Hematology, Serum chemistry and Urinalysis).
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 study period, 
laboratory test and treatment group. 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 by treatment group during the double-blind period.
In addition, for laboratory parameters where normal ranges are available, shift tables will be 
provided for all parameters to compare a subject’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 


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relative to whether or not the baseline value was normal, low, or high. These summaries will be 
presented by study period, laboratory test and treatment group.
Box plots for selected parameters will be provided by treatment group and study period.
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 2-15: 
hemoglobin, platelets, white blood cell count, neutrophils, lymphocytes, 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, 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 by study 
period and treatment group.
Table 2-15
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 
Platelet
<LLN-
75,000/mm 
<75,000- 
50,000/mm3 
<50,000- 
25,000/mm3 
<25,000/mm3 
White blood cell 
decreased 
White blood cell
<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
>1-1.5 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 


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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 
Alanine 
aminotransferase 
increased 
Alanine 
aminotransferase 
(ALT)
>ULN - 3.0 x 
ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Aspartate 
aminotransferase 
increased 
Aspartate 
aminotransferase 
(AST)
>ULN - 3.0 x 
ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 x 
ULN 
>20.0 x ULN 
Alkaline 
phosphatase 
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.
To evaluate potential drug-induced liver injury, newly occurring liver enzyme abnormalities 
will also be summarized based on the event criteria given in Table 2-16. 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 2-17.
In addition for 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.


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Table 2-16
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 2-17
Specific renal alert criteria
Parameter
Notable criterion
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
12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted centrally.
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by study period, treatment group and visit/time.
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; 
•
Absolute QTc (Fridericia’s) interval > 450 msec (males), absolute QTc (Fridericia’s) 
interval > 460 msec (females); 


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•
QTc (Fridericia’s) interval change from baseline > 30 msec to < 60 msec, ≥60 msec; 
•
PR Interval > 250 msec.
•
PR Interval > 250 msec and PR Interval increase from baseline > 25%
•
QRS Duration >110 msec, >120 msec
•
QRS Duration > 120 msec and QRS Duration increase from baseline > 25%
For by-visit summary tables, scheduled visits (including remapped visits following the 
assessment window in Section 2.1.1.5) 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.
2.7.4.2
Vital signs
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant changes) will be flagged. Summary statistics will be 
provided by study period, treatment group and visit.
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 2-18 below.
Table 2-18
Clinically notable changes in vital signs
Vital sign (unit)
Clinically notable criteria
Systolic blood pressure (mmHg)
< 90 mmHg
≥ 140 mmHg 
Diastolic blood pressure (mmHg)
< 60 mmHg
≥ 90 mmHg
Pulse (bpm)
< 50 bpm  
> 100 bpm 
For by-visit summary tables, scheduled visits (including remapped visits following the 
assessment window in Section 2.1.1.5) 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.


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2.10
Patient-reported outcomes
At the primary analysis and the final analysis, the values from baseline to the end of study 
will be summarized for LOU064 25 mg and Placebo-LOU064 25 mg treatment groups. 
For by-visit summary tables, scheduled visits (including remapped visits following the 
assessment window in Section 2.1.1.5) will be considered in the analysis. Unscheduled visits 
will not be included.
 
 
 
•
 
 
 
 
 
 
 
 
 
 
 


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Dermatology Life Quality Index (DLQI)
For the following DLQI assessments, summary statistics will be presented by treatment group 
for the FAS.
.
•
DLQI = 0-1: the proportion of participants achieving DLQI = 0-1 response 
.
Angioedema Activity Score (AAS)
For the following AAS assessments based on AAS eDiary, summary statistics will be presented 
by treatment group for the FAS. Please see Section 2.5.2.1 for derivation of AAS7 score and 
AAS7 = 0 response.
•
 
 
•
 
 
 
 
 
 
 
 
 
 


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2.13
Interim analysis
A primary analysis may be conducted when all participants have completed their Week 24 visit 
or discontinued early and when a minimum of 150 participants across both Phase 3 pivotal 
studies (A2301 and A2302) have completed the treatment period. The minimum of 150 
participants reaching week 52 should enable analysis on a minimum of 100 participants exposed 
to remibrutinib for 52 weeks, considering the initial randomization to either the remibrutinib or 
the placebo arm (2:1). The results of the primary analysis will further inform decision-making 
for the remibrutinib development program. Formal testing of the primary endpoint and key 
secondary endpoints will only be performed at the primary analysis time point; thus, no 
adjustment for multiplicity is required.
After the primary analysis and/or after all participants entered the open-label treatment period, 
additional optional interim analyses may be conducted at the discretion of the Sponsor to 
support potential Health Authority requests and interactions (these interim analyses are not 
expected to have any impact on the conduct or scientific integrity of the study). The decision to 
conduct optional interim analyses and the timing of these analyses will be documented in the 
Statistical Analysis Plan prior to the conduct of any interim analysis. These interim analyses 
will be performed and interpreted by members of the Novartis clinical team


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3
Sample size calculation
3.1
Primary endpoint(s)
In order to fulfill registration and ICH E1 requirements on the number of participants treated 
for 6 months and 12 months in the development program, a sample size of 300 participants in 
the active arm and 150 in the placebo arm is targeted. Hence, the total sample size is 450 
randomized participants.
From an efficacy point of view, the sample size justification is based on UAS7 change from 
baseline (for scenario with one primary endpoint), ISS7 and HSS7 change from baseline (for 
scenario with co-primary endpoints) and achievement of UAS7≤6 and UAS7=0 at Week 12. 
To avoid assigning an unnecessary large number of participants to placebo, participants will be 
randomized in a 2:1 ratio to remibrutinib 25 mg b.i.d. and placebo arms, respectively.
All calculations were performed with nQuery Advisor 8.4.1.0 and Ri386 4.0.2 softwares.
For scenario with UAS7 as the primary efficacy endpoint
UAS7 change from baseline at Week 12
Approximately 10% drop-out is expected at week 12, thus with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo if the mean change of UAS7 from baseline 
to Week 12 is at least 10 in favor of remibrutinib, with common standard deviation of 
approximately 12 (based on the primary endpoint analysis of Phase 2b study 
(CLOU064A2201)), based on a t-test, assuming type I error 0.025 (one-sided).
For scenario with ISS7/HSS7 as the co-primary efficacy endpoints
ISS7 change from baseline at Week 12
Approximately 10% drop-out is expected at week 12, thus with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo if the mean change of ISS7 from baseline 
to Week 12 is at least 4 in favor of remibrutinib, with common standard deviation of 
approximately 6 (based on the primary endpoint analysis of Phase 2b study (CLOU064A2201)), 
based on a t-test, assuming type I error 0.025 (one-sided).
HSS7 change from baseline at Week 12
Approximately 10% drop-out is expected at week 12, thus with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo if the mean change of HSS7 from baseline 
to Week 12 is at least 4 in favor of remibrutinib, with common standard deviation of 
approximately 6 (based on the primary endpoint analysis of Phase 2b study (CLOU064A2201)), 
based on a t-test, assuming type I error 0.025 (one-sided).
With 300 participants in the active arm and 150 participants in the placebo arm randomized in 
this study, this gives a power of more than >90% to detect a difference between remibrutinib 
and placebo in both mean change of ISS7 and HSS7 from baseline to Week 12 when correlation 


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between endpoints is 0 (conservative assumption, as higher the correlation is, higher the power 
is).
3.2
Secondary endpoint(s)
Achievement of UAS7 = 0 at Week 12
Similarly, with approximately 10% drop-out at week 12, then with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo arm assuming a proportion of complete 
response (UAS7=0) of 0.35 in the remibrutinib arm and of 0.10 in the placebo arm, based upon 
a 2-group continuity corrected χ2 test with a 0.025 one-sided significance level.
Achievement of UAS7 ≤6 at Week 12
Similarly, with approximately 10% drop-out at week 12, then with 270 participants in the active 
arm and 135 participants in the placebo arm, this gives a nominal power of more than >99% to 
detect a difference between remibrutinib and placebo arm assuming a proportion of disease 
activity control response (UAS7≤6) of 0.53 in the remibrutinib arm and of 0.15 in the placebo 
arm, based upon a 2-group continuity corrected χ2 test with a 0.025 one-sided significance level.
The primary and secondary endpoints analyses are planned to use the multiple testing strategy 
to control the family-wise error at α=0.025 (one-sided). It is considered, however, this 
hierarchical approach could impact the sample size compared to the separate endpoint approach, 
which depends on how the recycled alpha will be used. In both scenarios, the “family-wise” 
power (power to reject all null hypotheses) is >90% when correlation between endpoints is 0 
(Higher the correlation is, higher the power is). 
4
Change to protocol specified analyses
No change


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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
Impute 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 AE ‘year’ is missing or AE is ongoing, the end date will not be imputed. 
Impute 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 < 
treatment  start date then AE start reference date = min(informed consent date, 
earliest visit date). 
•
Else AE start reference date = treatment start date 
1. If the AE start date ‘year’ value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
2. If the AE start date ‘year’ value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If AE ‘month’ is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE ‘month’ is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 


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a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date. 
5.1.3
Concomitant medication date imputation
Impute concomitant medication (CM) end date: 
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY). 
3. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date. 
Impute CM start date: 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 


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a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date. 
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date. 
5.1.4
Concomitant therapies
Please see Section 5.1.3.
5.1.5
Other imputations
First diagnosis date imputation
1. If the first diagnosis day/ month are missing and the year is non-missing:
a. If the year part of the first diagnosis date is equal to the year part of the inform 
consent date, then the imputed first diagnosis date is set to the year start point 
(01JanYYYY).


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b. Otherwise the imputed first diagnosis date is set to the mid-year point 
(01JulYYYY).
2. If the first diagnosis day is missing and the month/year are non-missing:
a. If the month and year part of the first diagnosis date is equal to the month and year 
part of the inform consent date, then the imputed first diagnosis date is set to the 
month start point (01MONYYYY).
b. Otherwise the imputed first diagnosis date is set to the mid-month point 
(15MONYYYY).
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
Mixed model with repeated measures
For the primary efficacy endpoints (change from baseline in UAS7 or ISS7 or HSS7), a linear 
mixed model with repeated measures (MMRM) will be used to estimate treatment differences, 
based on the FAS. The MMRM model will include treatment group, the corresponding baseline 
score, actual randomization strata variables, week and both interaction of treatment by week 
and interaction of the corresponding baseline score by week as fixed effects. Repeated measures 
within subject are modeled using an unstructured covariance of the error terms.
The primary analysis will be performed based on the data after the missing data imputation for 
the intercurrent events have been performed. All data up to Week 12 will be included in the 
MMRM model for primary analysis. 
The SAS procedure proc mixed will be used for this analysis with the following code:
ods output DIFFS=diff LSMeans=mean ConvergenceStatus=conv_mmrm1;
proc mixed data=…… covtest;
by _imputation_;
class subject group week region antige;
model change=baseline group week region antige group*week baseline*week/s 
ddfm=kr cl;
repeated week/ type=UN subject=subject r;
lsmeans group*week /cl diff;
run;
where change   = change from baseline UAS7 score
           baseline = baseline UAS7 score


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           group     = planned treatment group  (1 = LOU064  2 = Placebo)
           week      = study week
           region    = geographic region
           antige     = prior exposure to anti-IgE biologics 
           subject   = subject
           _imputation_ = the index for imputation times
Note that the mean and diff datasets created will include all the treatment interactions for each 
week. The estimates for the right weeks, e.g. Week 12, and right treatment comparisons, e.g. 
LOU064 vs Placebo, should be subsetted by taking “week = 12 and _week=12” and “group= 1 
and _group=2”.
If the computation of the MMRM model takes extreme amount of time, the ddfm=bw option 
could be considered. If the model with an unstructured covariance matrix does not converge, 
SAS will give a warning as “Unable to make hessian positive definite” or “Unable to 
Converge”. Meanwhile, the Status variable in the “convest” dataset created will take on the 
value 1 or 2. In this case, the compound-symmetry structure should be used. 
Rubin’s Rule: 
Rubin’s Rule will be applied to combine the multiple sets of estimates to produce the overall 
estimates, standard error, confidence interval and p-values. 
The SAS procedure proc mianalyze will be used for this analysis with the following code:
proc mianalyze data=mean(where=(week=12));
by group;
ModelEffects estimate;
stderr stderr;
ods output ParameterEstimates=est_mean;
run;
proc mianalyze data=diff(where=(week=12 & _week=12));
by group _group;
ModelEffects estimate;
stderr stderr;
ods output ParameterEstimates=est_diff;
run;
where est_mean includes the results for LS mean in each group, and est_diff includes the results 
for the treatment difference between groups. 
If the datasets between imputations are identical after multiple imputation step, which will cause 
the SAS procedure proc mianalyze not runnable, the dataset with _imputation_=1 will be used 
to create the results. 


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5.4.2
Analysis supporting secondary objective(s)
5.4.2.1
Logistic regression
Binary outcome variables including UAS7=0 “Complete Response” or UAS7≤6 “Disease 
control” will be evaluated using a logistic regression model with treatment, and randomization 
actual strata variables (i.e. geographical region and prior exposure to anti-IgE biologics). Odds 
ratios will be computed for treated participants with response relative to control participants 
utilizing the logistic regression model fitted.
The odds ratio will be calculated such that an odds ratio > 1 is favorable for LOU064 drug. The 
SAS procedure PROC LOGISTIC will be used for this analysis with the following code:
proc logistic data = ...;
by_imputation_;
class group antige region/ param = glm;
model response (event = '1') = group antige region baseline;
estimate "LOU064 vs Placebo" trt01p 1 -1;
ods output ESTIMATEs=estimates;
run;
where response = binary outcome variable.
If separation occurs, the Firth’s method will be implemented using the firth option in the 
MODEL statement. 
The SAS procedure PROC MIANALYZE will be used to combine the results. The odds ratios 
and the 95% confidence interval for the odds ratio will be generated using an exponential 
transformation of the model estimates.
5.4.2.2
Covariate adjustment for treatment difference with binary outcome 
variable
For binary outcome variables, the treatment difference and the corresponding 95 % confidence 
interval will be provided besides odds ratios. 
FDA guidance introduces the following steps for one statistically reliable method of covariate 
adjustment for treatment difference with binary outcome (Adjusting for Covariates in 
Randomized Clinical Trials for Drugs and Biological Products, Guidance for Industry, Draft 
guidance, May 2021).
5.4.2.3
Negative binomial regression
Count variable including the cumulative number of weeks achieving AAS7= 0 response 
between baseline and Week 12 or the cumulative number of weeks achieving UAS7≤6 response 
will be modelled using a negative binomial regression model with log link, using treatment 
group, randomization strata factors (i.e. geographical region and prior exposure to anti-IgE 
biologics, and baseline AAS7=0 status (for AAS7 = 0 response only). The patient’s time in the 
treatment period up to Week 12 (natural log of proportion of time in treatment period, i.e., 
natural log of [number of weeks with the response variable in treatment period/12 weeks]) is 
used as an offset variable. For the cumulative number of weeks achieving UAS7 ≤ 6 or AAS7 


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= 0 response between baseline and Week 24, the patient’s time in the treatment period up to 
Week 24 (natural log of proportion of time in treatment period, i.e., natural log of [number of 
weeks with the response variable in treatment period/24 weeks]) is used as an offset variable. 
If the AAS7 = 0 (respectively UAS7≤6) assessment is missing, it will be considered as a non-
response for the cumulative number of weeks that participants achieve AAS7= 0 response 
calculation (respectively UAS7≤6). 
The negative binomial model accounts for any over dispersion that may result from assuming 
a Poisson distribution by allowing a different Poisson rate for each patient and assuming that 
these rates as a set are distributed across participants according to a gamma distribution. 
The SAS procedure PROC GENMOD will be used for this analysis with the following code:
proc genmod data=...;
by impnb;
class group antige region baseline/ param = glm;
model count = baseline group antige region/ DIST= NEGBIN LINK= LOG 
offset=offset;
lsmeans group / cl exp diff ilink e OM;
estimate "LOU064 v.s pbo" group 1 -1;
ods output Estimates=estimates LSMeans=lsmeans;
run;
where baseline = baseline AAS7=0 status (for AAS7 = 0 response only).
The SAS procedure PROC MIANALYZE will be used to combine the results. The risk ratio  
and the 95% confidence interval for the risk ratio will be generated using an exponential 
transformation of the model estimates.
5.4.2.4
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 



n
j
jt
T
1
 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   
T
c
L
D
2,2
/
5.0


 for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0






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where
k
c ,

 is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.4.2.5
Exposure adjusted occurrence 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) is the 
observation period. The number of occurrences of the 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 



n
j
jt
T
1
 and D is total number of events. 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   
T
c
L
D
2,2
/
5.0


 for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0




where
k
c ,

is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.4.2.6
Confidence interval for proportion of binary data
Confidence intervals for proportion of binary data including observed 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 
Then the lower limit is for 























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is for 























2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
p
q

1

,
0
for
0
,0



p
L
p

,
1
for
1
,1


<
p
U
p


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5.4.3
Multiple imputations
Multiple imputation is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods. Rubin (1987) presented rules how to combine the multiple 
sets of estimates to produce overall estimates and confidence intervals that adequately 
incorporate missing data uncertainty. The multiple imputation analysis will be imputed based 
on the individual treatment arm information.
Missing values for UAS7/HSS7/ISS7/AAS7/DLQI will be imputed separately. The imputation 
is done on the original post-baseline score and the imputation model will include treatment 
group, the corresponding baseline score, actual randomization strata variables, week and both 
interaction of treatment by week and interaction of the corresponding baseline score by week. 
The number of imputations is 100. The imputed values may exceed possible range of variables. 
In this case, the imputed values which exceed possible maximum value (e.g., 42 for UAS7) will 
be replaced with the maximum value, the imputed values which exceed possible minimum value 
(e.g., 0 for UAS7) will be replaced with the minimum value. 
Multiple imputation will be implemented using the RMConjPlus20 and RefBTBV04 SAS 
macro. The macros are available from the website of London school of Hygiene & tropical 
medicine (LSHTM) on  https://www.lshtm.ac.uk/research/centres-projects-groups/missing-
data#dia-missing-data . The purpose and activities of each of the two macros is described below. 
For more details of these two macros please see “The RMConjPlus and RefbTbV SAS macros” 
by 
James 
H. 
Roger 
(2023) 
at 
https://www.lshtm.ac.uk/research/centres-projects-
groups/missing-data#dia-missing-data. 
The %RefBTBV SAS macro is used to set up the design matrix for reference-based imputation. 
This macro creates an input data set for %RMConjPlus by generating the required 
Treatment*Visit part of the design matrix based on the chosen reference-based imputation 
method (J2R, CIR, CR, etc.). 
The %RMConjPlus SAS macro is applied for reference-based imputation (J2R in this study) 
where an individual patient’s means model for those on active treatment is modified after trial 
withdrawal to closer represent the reference (placebo) arm (Carpenter et al, 2013). The 
imputation is done by two stages. In stage 1, it fits a Bayesian Repeated Measures model where 
there are a fixed number of visits. A multivariate Normal model is assumed with a series of one 
or more unstructured covariance matrices. Each subject uses only one of these matrices. Data 
within subject are related while data between subjects are assumed independent. In stage 2, it 
builds a set of imputed values for missed observations directly as part of the MCMC process 
using an pre-specified imputation model (J2R in this study).
This is example code to implement the primary analysis:
%RefbTBV(
Data= inputdata,
Out=RefB_Out,
Subject= usubjid,


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Visit= week,
OnTreatment= OT, 
Treatment= group,
Method= Mymethod, 
Reference= Placebo);
where usubjid = unique subject identifier
           week =study week
           group= planned treatment group 
           (1 = LOU064  2 = Placebo)
           OT = indicator of on/off treatment status
           Mymethod = Method used to impute missing data. For example, this could be specified 
as J2R to indicate that Jump to reference is used to impute missing data for LOU064 patients 
who discontinued treatment and MAR otherwise, where Placebo is used as reference. 
%RMConjPlus(
   Data=RefB_Out ,              
   OUT_Imp= out_imp,    
   Subject=usubjid, 
   Visit=week,    
   Response=aval,   
   Model=&RefbTbV base*week antige region,        
   Class=week group antige region,          
   seed=23012,       
   Nimpute=100);
Where usubjid = unique subject identifier
            week =study week
            aval = UAS7 weekly score
            base = baseline UAS7 score
            antige     = prior exposure to anti-IgE biologics
            region    = geographic region
            &RefbTbV = design matrix generated from RefbTBV macro.
If the imputation model has warnings regarding auto-correlation, a larger number of autocorlag 
parameter could be specified (e.g., autocorlag=70 in the RMConjPlus macro). Any missing 
baseline values will be multiply imputed using baseline characteristics variables before putting 
into the %RefBTBV and %RMConjPlus using Proc MI. The example code for imputing 
baseline of DLQI is shown below:
proc mi data= dlqi_base_imp out=dlqi_regpmm nimpute = 100 seed = 23012;
class group sex antige region;
FCS regpmm(base/details);
var age sex group antige region base ;
run;


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Where group= planned treatment group 
           (1 = LOU064  2 = Placebo)
            age = age at screening of study participants
            sex = gender of study participants
            antige     = prior exposure to anti-IgE biologics
            region    = geographic region
            base = baseline DLQI score
5.5
Rule of exclusion criteria of analysis sets 
Table 5-1
Criteria leading to exclusion from analysis sets
Analysis Set
Protocol deviations* that cause a 
participant to be excluded
Non-PD criteria that cause a participant 
to be excluded 
RAS
P-INCL01B-ICF not signed
Not randomized
FAS 
P-INCL01B-ICF not signed
M-OTH12-ICH-GCP non compliance
Not in RAS;
Mistakenly randomized and no double-
blind study drug taken
SAF
P-INCL01B-ICF not signed
M-OTH12-ICH-GCP non compliance
Not dosed 
P-INCL01B-ICF not signed: Written informed consent was not signed or missing
M-OTH12-ICH-GCP non compliance: Severe ICH-GCP non compliance of study site
* Reference from the edit check specifications Version 13.0. The latest version should be considered 
at time of the analysis.


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6
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