Clinical trial NCT05795153
Conditions: Chronic Spontaneous Urticaria
Keywords: Chronic Spontaneous Urticaria (CSU) remibrutinib Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP) Ambulator Blood Pressure Monitoring (ABPM) H1 antihistamines (H1-AH) treatment
Sponsor: Novartis Pharmaceuticals
Start date: 2023-04-05; Completion date: 2024-04-25
Enrollment: 144 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the effect of remibrutinib 25 mg twice a day (b.i.d.) open-label on Systolic Blood Pressure (SBP) measured as a change in 24-hour weighted average SBP from baseline to Week 4 assessed by Ambulator Blood Pressure Monitoring (ABPM); and to assess overall safety and efficacy over 12 weeks in adult participants with Chronic Spontaneous Urticaria (CSU) inadequately controlled with second generation H1 antihistamines (H1-AH) treatment. ABPM was chosen for the blood pressure assessment in this trial as recommended by the FDA for drugs intended for chronic use (Assessment of Pressor Effects of Drugs Guidance for Industry (FDA 2022)).

Detailed description:
This study consisted of a screening period of up to 4 weeks, a 12-week open-label treatment period and a treatment-free follow-up period of 4 weeks, with a total study duration of up to 20 weeks.

At the end of the treatment phase, participants had the option to continue in an extension study (CLOU064A2303B (NCT05513001)) if approved in the country and at the site.

Arms: arm 1: All participants were assigned to remibrutinib 25 mg b.i.d. for 12 weeks.
Interventions: intervention 1: LOU064
Intervention descriptions: intervention 1: One film-coated tablet (25 mg) was to be taken in the morning and evening, respectively, with a 12-hour interval at approximately the same time everyday.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
Clinical Trial Protocol Title: 
A multicenter, open-label Phase 3 study: ambulatory blood 
pressure monitoring in adult patients with chronic 
spontaneous urticaria inadequately controlled by H1-
antihistamines treated with remibrutinib up to 12 weeks. 
Clinical Trial Protocol Number: CLOU064A2305 / NCT05795153
Version Number: 00 (Original Protocol) 
Compound: LOU064 
Brief Title: A multicenter, open-label Phase 3 study: ambulatory blood pressure 
monitoring in adult patients with chronic spontaneous urticaria inadequately 
controlled by H1-antihistamines treated with remibrutinib up to 12 weeks. 
Study Phase: III 
Sponsor Name: Novartis 
Regulatory Agency Identifier Numbers: EudraCT - 2022-002838-13, IND-131325 
Approval Date: 07-Oct-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 5.0 dated 14-Jan-2022 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
1 
Protocol summary ................................................................................................................ 8 
1.1 
Summary .................................................................................................................. 8 
1.2 
Schema ................................................................................................................... 11 
1.3 
Schedule of activities (SoA) .................................................................................. 11 
2 
Introduction ....................................................................................................................... 16 
2.1 
Study rationale ....................................................................................................... 16 
2.2 
Background ............................................................................................................ 16 
2.3 
Benefit/Risk assessment ........................................................................................ 17 
3 
Objectives, endpoints, and estimands ................................................................................ 19 
3.1 
Primary estimands ................................................................................................. 20 
3.2 
Secondary estimands ............................................................................................. 21 
4 
Study design ...................................................................................................................... 22 
4.1 
Overall design ........................................................................................................ 22 
4.2 
Scientific rationale for study design ...................................................................... 23 
4.3 
Justification for dose .............................................................................................. 23 
4.3.1 
Rationale for choice of background therapy ......................................... 24 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 24 
4.5 
Rationale for public health emergency mitigation procedures .............................. 24 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.7 
End of study definition .......................................................................................... 25 
5 
Study population ................................................................................................................ 25 
5.1 
Inclusion criteria .................................................................................................... 25 
5.2 
Exclusion criteria ................................................................................................... 25 
5.3 
Screen failures ....................................................................................................... 28 
5.3.1 
Replacement policy ............................................................................... 29 
5.3.2 
Participant numbering ........................................................................... 29 
5.4 
Lifestyle considerations ......................................................................................... 29 
5.4.1 
Caffeine, alcohol, and tobacco .............................................................. 29 
5.4.2 
Activity .................................................................................................. 29 
6 
Study treatment(s) and concomitant therapy ..................................................................... 30 
6.1 
Study treatment(s) .................................................................................................. 30 
6.1.1 
Additional study treatments .................................................................. 30 


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6.1.2 
Treatment arms/group ........................................................................... 30 
6.1.3 
Treatment duration ................................................................................ 30 
6.2 
Preparation, handling, storage, and accountability ................................................ 30 
6.2.1 
Handling of study treatment .................................................................. 31 
6.2.2 
Handling of other treatment .................................................................. 31 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 31 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 32 
6.3.1 
Treatment assignment, randomization .................................................. 32 
6.3.2 
Treatment blinding ................................................................................ 32 
6.3.3 
Emergency breaking of assigned treatment code .................................. 32 
6.4 
Study treatment compliance .................................................................................. 32 
6.4.1 
Recommended treatment of adverse events .......................................... 33 
6.5 
Dose modification .................................................................................................. 33 
6.5.1 
Dose escalation guidelines .................................................................... 33 
6.5.2 
Definitions of dose limiting toxicities (DLTs) ...................................... 33 
6.5.3 
Dose modifications ................................................................................ 33 
6.5.4 
Follow-up for toxicities ......................................................................... 34 
6.6 
Continued access to study treatment after the end of the study ............................. 36 
6.6.1 
Post trial access ..................................................................................... 36 
6.7 
Treatment of overdose ........................................................................................... 37 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 37 
6.8 
Concomitant and other therapy .............................................................................. 37 
6.8.1 
Concomitant therapy ............................................................................. 37 
6.8.2 
Prohibited medication ........................................................................... 38 
6.8.3 
Rescue medicine .................................................................................... 41 
6.8.4 
Considerations for concomitant and prohibited medications and 
substances potentially affecting blood pressure assessment ................. 42 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 43 
7.1 
Discontinuation of study treatment ........................................................................ 43 
7.2 
Participant discontinuation from the study ............................................................ 45 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 45 
7.4 
Lost to follow-up ................................................................................................... 45 
7.5 
Early study termination by the Sponsor ................................................................. 46 
8 
Study Assessments and Procedures ................................................................................... 47 
8.1 
Screening ............................................................................................................... 47 
8.2 
Participant demographics/other baseline characteristics ....................................... 47 


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8.3 
Efficacy assessments ............................................................................................. 48 
8.3.1 
Ambulatory blood pressure monitoring (ABPM) ................................. 48 
8.3.2 
Patient Reported Outcomes ................................................................... 50 
 
 53 
8.4 
Safety assessments ................................................................................................. 54 
8.4.1 
Physical examinations ........................................................................... 54 
8.4.2 
Vital signs.............................................................................................. 55 
8.4.3 
Electrocardiograms ............................................................................... 55 
8.4.4 
Clinical safety laboratory tests .............................................................. 56 
8.4.5 
Pregnancy testing .................................................................................. 57 
8.4.6 
Appropriateness of safety measurements .............................................. 58 
8.5 
Additional assessments .......................................................................................... 58 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 58 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 59 
8.6.1 
Adverse events ...................................................................................... 59 
8.6.2 
Serious adverse events .......................................................................... 60 
8.6.3 
SAE reporting........................................................................................ 61 
8.6.4 
Pregnancy .............................................................................................. 62 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 63 
8.6.6 
Adverse events of special interest ......................................................... 63 
 
 63 
 
 64 
8.9 
Immunogenicity assessments ................................................................................. 65 
8.10 
Health economics OR Medical resource utilization and health economics .......... 65 
9 
Statistical considerations ................................................................................................... 65 
9.1 
Analysis sets .......................................................................................................... 65 
9.2 
Statistical analyses ................................................................................................. 66 
9.2.1 
General considerations .......................................................................... 66 
9.2.2 
Participant demographics and other baseline characteristics ................ 66 
9.2.3 
Treatments ............................................................................................. 66 
9.3 
Primary endpoint(s)/estimand(s) analysis .............................................................. 67 
9.3.1 
Definition of primary endpoint(s) ......................................................... 67 
9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 67 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) .... 67 
9.3.4 
Handling of missing values not related to intercurrent event ............... 67 


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9.3.5 
Multiplicity adjustment (if applicable) .................................................. 68 
9.3.6 
Sensitivity analyses ............................................................................... 68 
9.3.7 
Supplementary analysis ......................................................................... 68 
9.4 
Secondary endpoint(s)/estimand(s) analysis .......................................................... 68 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 68 
9.4.2 
Safety endpoints .................................................................................... 69 
 
 70 
 
 71 
 
 71 
 
 71 
9.6 
(Other) Safety analyses .......................................................................................... 72 
9.7 
Other analyses ........................................................................................................ 72 
9.8 
Interim analysis ...................................................................................................... 72 
 
 72 
 
 72 
10 Supporting documentation and operational considerations ............................................... 73 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ................... 73 
10.1.1 
Regulatory and ethical considerations .................................................. 73 
10.1.2 
Informed consent process ...................................................................... 74 
10.1.3 
Data protection ...................................................................................... 75 
10.1.4 
Committees structure ............................................................................ 76 
10.1.5 
Data quality assurance ........................................................................... 76 
10.1.6 
Source documents ................................................................................. 77 
10.1.7 
Publication policy.................................................................................. 78 
10.1.8 
Protocol adherence and protocol amendments ...................................... 78 
10.2 
Appendix 2: Abbreviations and definitions ........................................................... 80 
10.2.1 
List of abbreviations .............................................................................. 80 
10.2.2 
Definitions ............................................................................................. 83 
10.3 
Appendix 3: Clinical laboratory tests .................................................................... 85 
10.3.1 
Clinically notable laboratory values and vital signs ............................. 85 
10.4 
Appendix 4: Participant Engagement .................................................................... 86 
10.5 
Appendix 5: Liver safety monitoring .................................................................... 87 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................... 87 
10.6 
Appendix 6: Renal safety monitoring .................................................................... 90 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up .......... 90 


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10.7 
PRO tools ............................................................................................................... 92 
 99 
11 References ....................................................................................................................... 100 
 
List of tables 
Table 1-1 
Objectives, Endpoints, and Estimands .................................................... 8 
Table 1-2 
Assessment Schedule ............................................................................ 13 
Table 3-1 
Objectives and related endpoints .......................................................... 19 
Table 6-1 
Investigational drug ............................................................................... 30 
Table 6-2 
Guidance on specific clinical and diagnostic assessments to be 
performed to rule-out possible alternative causes of observed Liver 
Function Tests (LFT) abnormalities ...................................................... 36 
 
 38 
Table 6-4 
Prohibited medications (From Screening to EOS) ................................ 38 
 
 
 40 
 
 51 
 
 51 
 
 51 
 
 52 
 
 52 
 
 53 
Table 8-7 
Laboratory assessments ......................................................................... 56 
Table 10-1 
Liver event and laboratory trigger definitions ...................................... 87 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 88 
Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 89 
Table 10-4 
Specific Renal Alert Criteria and Actions and Event Follow-up .......... 90 
Table 10-5 
Renal Events Follow-up ........................................................................ 91 
 
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List of figures 
Figure 1-1 
Study Design ......................................................................................... 11 
Figure 8-1 
Timing of study procedures .................................................................. 55 
 
 92 
 
 97 
 
 98 
 


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1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A multicenter, open-label Phase 3 study: ambulatory blood pressure monitoring in adult patients 
with chronic spontaneous urticaria inadequately controlled by H1-antihistamines treated with 
remibrutinib up to 12 weeks. 
Brief Title: 
A multicenter, open-label Phase 3 study: ambulatory blood pressure monitoring in adult patients 
with chronic spontaneous urticaria inadequately controlled by H1-antihistamines treated with 
remibrutinib up to 12 weeks. 
Purpose: 
The purpose of this study is to assess the effect of remibrutinib 25 milligrams (mg) b.i.d. open 
label on systolic blood pressure (SBP) measured as a change in 24-hour average SBP from 
baseline to Week 4 assessed by ambulatory blood pressure monitoring (ABPM); and to evaluate 
the overall safety and efficacy over 12 weeks in participants with chronic spontaneous urticaria 
(CSU) inadequately controlled by H1-antihistamines (H1-AH). 
Study Indication /Medical Condition: 
Chronic spontaneous urticaria (CSU) 
Treatment type: 
Drug 
Study type: 
Interventional 
Table 1-1 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
● To rule out an increase of >3mmHg in 24-hour 
average SBP at steady state (Week 4) compared to 
baseline, measured by ABPM. 
● The change in the ABPM-measured 24-hour 
weighted average SBP at Week 4 compared to 
baseline 
Secondary 
● To evaluate changes in daytime and nighttime 
SBP at 4 weeks 
● The change in the ABPM-measured 24-hour 
weighted average SBP at Week 4 compared to 
baseline 
● To evaluate changes in 24-hour , daytime and 
nighttime average diastolic blood pressure (DBP) at 4 
weeks 
● The change in the measured ABPM 24-hour 
weighted average DBP at Week 4 compared to 
baseline 


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● To evaluate changes in daytime and nighttime 
average SBP over Week 4 
● The change in the measured ABPM daytime and 
nighttime weighted average SBP at Week 4 
● To evaluate changes in daytime and nighttime 
average DBP at Week 4 
● The change in the measured ABPM daytime and 
nighttime weighted average DBP at Week 4 
● To evaluate 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, 
evaluation of laboratory and vital signs data 
Trial Design: 
This is a global, open label Phase 3 study assessing the safety of remibrutinib 25 mg b.i.d., in 
adult participants with CSU inadequately controlled by second generation H1‑AH in regards to 
a change in 24-hour weighted average SBP at Week 4 measured by ABPM at baseline and 
Week 4 and overall efficacy, safety and tolerability over 12 weeks. 
This study consists of up to 4 weeks of screening period, a 12-week treatment period and a 
treatment-free follow-up period of 4 weeks, with a total study duration of up to 20 weeks. 
At the end of the treatment phase, participants have the option to continue in an extension study 
(CLOU064A2303B) if approved in the country and at the site. 
This study will be included in the program level 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. 
Brief Summary: 
The primary objective of the study is to rule out an increase of >3mmHg in 24-hour average 
Systolic Blood Pressure at steady state (Week 4) compared to baseline. ABPM was chosen for 
the blood pressure assessment in this trial as recommended by the FDA for drugs intended for 
chronic use (Assessment of Pressor Effects of Drugs Guidance for Industry (FDA 2022)). It 
allows the observation over a 24-hour period and the measure of an individual’s blood pressure 
throughout an entire day. This ABPM study will be performed in a patient population similar 
to the ongoing Phase 3 studies. 
The study duration will be up to 20 weeks. The treatment duration will be up to 12 weeks and 
the visit frequency will be once every 4 weeks with additional 2 visits for application of the 
ABPM device before baseline and Week 4 visits. 
Treatment of interest: 
Participants will be treated with remibrutinib 25 mg b.i.d. 
Number of Participants: 
Approximately, 136 participants will be enrolled in the study. 


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Key Inclusion criteria: 
• Signed informed consent must be obtained prior to participation in the study 
• Male and female adult participants ≥ 18 years of age 
• 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-AH at the time of 
baseline (Day 1) defined as: 
• The presence of itch and hives for ≥ 6 consecutive weeks prior to screening despite 
the use of second generation H1-AH during this time period. 
• Weekly Urticaria Activity Score (UAS7) score (range 0-42) ≥ 16, Weekly Itch 
Severity Score (ISS7) score (range 0-21) ≥ 6 and Weekly Hives Severity Score 
(HSS7) score (range 0-21) ≥ 6 during the 7 days prior to baseline (Day 1). 
• Documentation of hives within three months before baseline (either at screening and/or at 
baseline (Day 1); 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 two missing UPDD entry (either morning or 
evening) in the 7 days prior to baseline (Day 1). 
Key Exclusion criteria: 
• Participants unable to tolerate 24-hour ambulatory blood pressure measurement using 
automatic ABPM device 
• Ongoing or past history of hypertension and/or SBP ≥140 or ≤90 OR DBP ≥90 or ≤60 
mmHg at screening 
• Known history or evidence of ongoing alcohol or drug abuse within the last 6 months 
before baseline (Day 1) 
• Participants working night shifts 
• Participants with an arm circumference greater than 50cm 
• Participants taking/requiring medications prohibited by the protocol (including those 
known to interfere with blood pressure assessments in the study) 
• 
 
• 
 
• Evidence of clinically significant cardiovascular, 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 
Treatment Groups: 
All participants will receive open-label remibrutinib 25 mg b.i.d. 


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Data Monitoring/Other Committee: 
Yes (see Section 10.1.4 Committees Structure) 
Key words 
BTK inhibitor; Ambulatory Blood Pressure Monitoring, Chronic spontaneous urticaria; 
Urticaria activity score; Hives severity score; Itch severity score 
1.2 
Schema 
Figure 1-1 
Study Design 
 
N= Number of treated participants; BSL: Baseline; hr: hour; ABPM: Ambulatory Blood Pressure 
Monitoring; b.i.d.: twice a day. 
1.3 
Schedule of activities (SoA) 
The SoA lists all of the assessments when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation. 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. 
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. Missed or rescheduled visits should not lead to automatic 
discontinuation. 
Participants who discontinue from study treatment are to complete the end of treatment visit as 
soon as possible, and attend the follow-up visit as indicated in the SoA. 
Participants who discontinue from study 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 


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the adverse events and concomitant medications not previously reported must be recorded on 
the case report form (CRF). 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural and man-made disaster or geopolitical instability, that limits 
or prevents on-site study visits, alternative methods of providing continuing care may be 
implemented by the investigator as the situation dictates. If allowable by a local health authority, 
national and local regulations and depending on operational capabilities, phone calls, virtual 
contacts (e.g., tele consultation) or visits by site staff/ off-site healthcare professional(s) staff to 
the participant´s home, can replace certain protocol assessments, for the duration of the 
disruption until it is safe for the participant to visit the site again. If the investigator delegates 
tasks to an off-site healthcare professional, the investigator must ensure the individual(s) is/are 
qualified and appropriately trained to perform assigned duties. The investigator must oversee 
their conduct and remain responsible for the evaluation of the data collected. 






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Period 
Screening 
Treatment 
Follow-up 
/End of Study 
Unscheduled 
visit 
Visit Name Screening 
Visit 11 
Screening 
Visit 2 
Baseline Week 4 -1 day Week 41 
Week 8 Week 12/ End 
of Treatment 
Early Treatment 
Discontinuation 
Week 16 
Unscheduled 
visit 
Days 
-28 to -1 
 -4 to -1 
1 
28 
29 
57 
85 
- 
113 
- 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV screen13 
X 
  
  
  
  
  
  
  
  
  
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Participant to come fasting for ≥8 hours (h) (ideally overnight) for Screening Visit 1 and Week 4.  
2 Serum pregnancy test and fertility assessment will be done at Screening. Urine pregnancy test to be completed every 4 weeks by WoCBP from Day 1 through to Study 
completion visit. Any positive or undetermined test result must be confirmed by a serum pregnancy test done by central lab and results received electronically. In the 
case that participant cannot visit the site an alternative (local lab) can be used. Urine pregnancy results are reported as source. 
3 To include Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) 
4 Complete physical exam at screening, short physical exam at all subsequent visits 
5 Height collected at screening visit only 
6 Participants eDiary will be returned to site at either Week 12 or study discontinuation 
7 
 
 
 
 
9 Dispensation 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 Follow-up visit only compliance to be 
checked 
 
 
11 Hepatitis B re-activation monitoring only for participants who were Hepatitis B virus surface antigen (HBsAg) negative and HBcAb (anti-HBc) positive with a negative 
HBV Deoxyribonucleric Acid (DNA) test at Screening. 
 
 
13 Optional, depending on local requirements 


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2 
Introduction 
2.1 
Study rationale 
The purpose of this study is to assess the effect of remibrutinib 25 mg b.i.d. open label on SBP 
measured as a change in 24-hour weighted average SBP from baseline to Week 4 assessed by 
ambulatory blood pressure monitoring (ABPM); and to assess overall safety and efficacy over 
12 weeks in participants with chronic spontaneous urticaria (CSU) inadequately controlled by 
H1-AH. 
2.2 
Background 
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, Saini, Kaplan 2018, Zuberbier et al 2021). 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 disease activity states of 
CSU are commonly defined as complete control, well controlled, mild, moderate and severe 
(Stull et al 2017). 
Second generation H1-AH are recommended as first-line treatment for patients with CSU, 
including up-titration to 4-fold the approved dose (Zuberbier et al 2021). Omalizumab is an 
effective second-line therapy for CSU patients as an add-on therapy to antihistamines at the 
licensed dose of 300 mg every 4 weeks subcutaneously (Zuberbier et al 2021). Cyclosporine, 
as a 3rd line option, is an immunosuppressive drug associated with a high incidence of adverse 
effects (Zuberbier et al 2021). Finally, short courses of systemic corticosteroids are sometimes 
added to the treatment regimen, but they are not recommended for long-term use due to the 
well-known adverse effects. Therefore, there is a high unmet medical need for new treatment 
options for CSU patients inadequately controlled by H1-AH. 
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and member of the TEC kinase 
family and is expressed in selected cells of the adaptive and innate immune systems. BTK is 
indispensable for signaling through the Fc epsilon receptor (FcεR1 for IgE), the activating Fc 
gamma receptors (FcγR for IgG) and the B cell antigen receptor (BCR), important signaling 
nodes in the activation/degranulation of B cells, macrophages, mast cells or basophils (Rip et 
al 2018). Targeting BTK is regarded as a promising new approach for the treatment of various 
immunomediated conditions, including CSU. BTK inhibitors (BTKi) like ibrutinib were first 
approved for the treatment of B cell malignancies (Hendriks et al 2014) and certain safety 
concerns are described for one or more of the compounds: risk of infections, potential 
myelomodulating effects, risk for bleeding and also, for ibrutinib, cardiovascular effects, 
including cardiac failure and hypertension. Notably, the risk of hypertension has not been seen 
with newer more selective approved BTK inhibitors, acalabrutinib and zanubrutinib. Based on 
the current understanding, effects on cardiovascular system with ibrutinib, including 
hypertension and cardiac failure could be explained by off-target kinase inhibition effects, e.g., 
blocking ERBB2/HER2 by ibrutinib results in cardiomyocyte dysfunction and reduced heart 
contractile efficiency (Estupiñán et al 2021). 


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Remibrutinib is a low molecular weight compound for oral administration that covalently binds 
and inhibits BTK with high selectivity (Angst et al 2020, Gabizon, London 2020). Remibrutinib 
is seen to offer a novel therapeutic approach for patients with CSU and is currently being 
investigated in two pivotal Phase 3 clinical trials (CLOU064A2301 and CLOU064A2302) with 
treatment duration up to 52 weeks. In completed (CLOU064A2201) and interim analysis of an 
ongoing open-label extension (CLOU064A2201E1) Phase 2 remibrutinib clinical studies in 
CSU (which allowed inclusion of patients with medical history of hypertension), no safety 
concern on elevated blood pressure was noted in the analysis of adverse events and vital signs. 
Elevated blood pressure increases the risk of adverse cardiovascular events and death and 
characterizing the off-target blood pressure effects of drugs became an important component of 
regulatory benefit-risk assessment and post-marketing clinical decision-making. In February 
2022, the US Food and Drug Administration (FDA) released revision 1 of the draft Assessment 
of Pressor Effects of Drugs Guidance for Industry intended to advise sponsors on the 
premarketing assessment of a drug’s effect on blood pressure. In the draft Guidance, FDA 
recommends the use of ambulatory blood pressure (BP) monitoring (ABPM) rather than routine 
clinic blood pressure measurement for drugs intended to be used chronically (12 weeks or more) 
as ABPM provides more accurate measurements of BP throughout the day. This study is 
planned to address the question of the potential pressor effect of remibrutinib 25 mg b.i.d on 
BP, as assessed by measuring the change in 24-hour average SBP between baseline and at Week 
4 as assessed by ABPM. 
2.3 
Benefit/Risk assessment 
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. In Phase 1, remibrutinib was 
well-tolerated at all doses without any dose-limiting toxicity (DLT) and showed encouraging 
blood and skin pharmacodynamics with a favorable safety profile. The Phase 2b clinical trial 
CLOU064A2201 demonstrated clinical efficacy of remibrutinib in the treatment of CSU 
patients with a fast onset of action and a favorable safety profile. Based on these data, 25 mg 
b.i.d. has been selected as the optimal dosing regimen for the Phase 3 trials. 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. 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. Furthermore, the oral route of administration of 
remibrutinib offers additional convenience compared to injectable biologics. 
The available clinical safety experience has demonstrated favorable safety and tolerability of 
remibrutinib. 
 
 
 


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In the final analysis of the Phase 2b trial CLOU064A2201 in patients with CSU, 309 
participants (safety set) 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. Serious events reported with remibrutinib 
were rare (1.9%), and no deaths were reported. Remibrutinib was also well tolerated with AEs 
leading to discontinuation being also rare, reported in 2.6% of patients receiving any 
remibrutinib. The most frequent adverse events were reported in 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%). Overall, AEs by SOC were balanced between 
any remibrutinib and placebo groups, with the exception of SOC Skin and subcutaneous tissue 
disorders - the difference in this SOC was primarily driven by events of chronic spontaneous 
urticaria (see below). The most frequent AEs (defined by MedDRA (Medical dictionary for 
regulatory activities) 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 ongoing Phase 2b long-term open-label 
extension trial CLOU064A2201E1 data from 183 CSU patients enrolled with a median 
exposure to remibrutinib 100 mg b.i.d. of 35.14 weeks showed 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%), Coronavirus disease 2019 (COVID-19) (4.9%), and diarrhea (4.9%). No 
notable trends in vital signs, including assessment of SBP and DBP values was evident. 
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), 
 
 
. No major concerns with regards to the mentioned 
risks was notable in remibrutinib completed and ongoing clinical trials to date, including long-
term exposure in Phase 2b open-label extension study CLOU064A2201E1. Corresponding 
eligibility and monitoring criteria are set to safeguard participants in this clinical trial. 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 


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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). 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the 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 
current Investigator Brochure (IB). 
In summary, CSU patients with inadequate response to H1-AH (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 effects of 
remibrutinib on BP. Risks mentioned above 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. 
3 
Objectives, endpoints, and estimands 
Table 3-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary objective 
Endpoints for primary objective 
● To rule out an increase of >3mmHg in 24-
hour average SBP at steady state (Week 4) 
compared to baseline, measured by ABPM. 
● the change in the ABPM-measured 24-hour weighted 
average SBP at Week 4 compared to baseline 
Secondary objectives 
Endpoint(s) for secondary objectives 
● To evaluate changes in 24-hour average SBP 
at steady state (Week 4) compared to baseline 
● the change in the ABPM-measured 24-hour weighted 
average SBP at Week 4 compared to baseline 
● To evaluate changes in 24-hour average 
DBP at steady state (Week 4) compared to 
baseline 
● the change in the measured ABPM 24-hour weighted 
average DBP at Week 4 compared to baseline 
● To evaluate changes in daytime and 
nighttime average SBP at 4 weeks. 
● the change in the measured ABPM daytime and 
nighttime weighted average SBP at Week 4 
● To evaluate changes in daytime and 
nighttime average DBP at 4 weeks. 
● the change in the measured ABPM daytime and 
nighttime weighted average DBP at Week 4 
● To evaluate 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, 
evaluation of laboratory and vital signs data 


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Objectives 
Endpoints 
3.1 
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). 
The primary clinical question of interest is: Does remibrutinib treatment increase on average 
the 24-hour weighted average SBP at a steady state (Week 4) compared to baseline, by more 
than 3 mmHg, in adult participants without ongoing or past history of hypertension and with 90 
< SBP <140mmHg, 60 < DBP< 90 mmHg at screening, with CSU who are inadequately 
controlled by H1-AH and receiving a stable local label-approved standard dose of a second 
generation H1-AH, excluding participants who discontinue from study treatment for any reason 
before Week 4 and considering intake of prohibited antihypertensive treatment as an 
unfavorable outcome? 


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The primary estimand is described by the following attributes: 
1. Population: participants without ongoing or past history of hypertension and with 90< 
SBP <140mmHg, 60< DBP<90 mmHg at screening, with inadequately controlled CSU 
despite treatment with second generation H1-AH who have CSU duration ≥ 6 months, a 
UAS7 score ≥ 16, ISS7 ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to Baseline (Day 
1). 
2. Endpoint: change from baseline in 24-hour weighted average SBP at Week 4. 
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.). 
4. Summary Measurement: the mean change from baseline. 
5. Handling of intercurrent events: 
• Discontinuation of study treatment due to any reason prior to Week 4: participants 
will be excluded from the analysis 
• Intake of prohibited antihypertensive treatment prior to Week 4 (see Section 6.8.2): 
Composite strategy (irrespective of potential occurrence of other intercurrent events). 
Measurements after this event will be excluded from the analysis and will be imputed 
using an increase of 3mmHg in 24-hour average SBP from baseline at Week 4. 
3.2 
Secondary estimands 
The secondary clinical question of interest is: What is the effect of remibrutinib treatment on 
the change from baseline in 24-hour weighted average SBP at steady state (Week 4) compared 
to baseline in adult participants without ongoing or past history of hypertension and with 90< 
SBP <140mmHg, 60< DBP<90 mmHg at screening, with CSU who are inadequately controlled 
by H1-AH and receiving a stable local label-approved standard dose of a second generation H1-
AH, excluding participants who discontinue from study treatment for any reason before Week 
4 and considering intake of prohibited antihypertensive treatment as an unfavorable outcome? 
The secondary estimand attributes are identical to the ones described in Section 3.1. 
Secondary estimand on the secondary endpoints 
Similar Estimand approach will be implemented for Change from baseline in 24-hour weighted 
average DBP at Week 4 as for Change from baseline in 24-hour weighted average SBP at Week 
4. 
Similar Estimand approach will be implemented for Change from baseline in daytime weighted 
average SBP at Week 4 as for Change from baseline in daytime weighted average SBP at Week 
4. 
Similar Estimand approach will be implemented for Change from baseline in nighttime 
weighted average SBP at Week 4 as for Change from baseline in nighttime weighted average 
SBP at Week 4. 
Similar Estimand approach will be implemented for Change from baseline in daytime weighted 
average DBP at Week 4 as for Change from baseline in daytime weighted average DBP at Week 
4. 


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Similar Estimand approach will be implemented for Change from baseline in nighttime 
weighted average DBP at Week 4 as for Change from baseline in nighttime weighted average 
DBP at Week 4. 
4 
Study design 
This is a global, open label Phase 3 study assessing the safety of remibrutinib 25 mg b.i.d., in 
adult participants with CSU inadequately controlled by second generation H1‑AH in regards to 
a change in 24-hour weighted average SBP at Week 4 measured by ABPM at baseline and 
Week 4 and overall efficacy, safety and tolerability over 12 weeks. 
This study consists of a screening period of up to 4 weeks , a 12-week treatment period and a 
treatment-free follow-up period of 4 weeks, with a total study duration of up to 20 weeks. 
At the end of the treatment phase, participants have the option to continue in an extension study 
(CLOU064A2303B) if approved in the country and at the site. 
4.1 
Overall design 
Refer to Section 1.2 Schema for study design figure. 
All participants will be on a stable, local label-approved standard dose of a second generation 
H1-AH (“background therapy”) throughout the entire study (starting at screening until the end 
of the study). In addition to that, to treat unbearable symptoms of potential CSU flares, 
participants will be allowed to use another second generation H1-AH on an as-needed basis 
(“rescue therapy”). 
Screening period: 
The screening period of up to 4 weeks allows for the assessment of eligibility, determination of 
baseline disease activity and wash-out of prohibited medications (please see prohibited 
medications Table 6-4 and Table 6-5). 
Treatment period: 
At baseline, all eligible participants will be assigned to remibrutinib 25 mg b.i.d.: After a 
baseline 24 hour ABPM measurement, all participants will receive remibrutinib 25 mg b.i.d. 
for 12 weeks. 
Participants who complete the treatment period at Week 12 are invited to roll-over to the Phase 
3 extension study CLOU064A2303B, where they, if eligible, enter Epoch 2 of the extension 
study. 
Participants who do not roll over to the extension study proceed to the follow-up period. 
Follow-up period: 
There will be a 4-week, treatment-free, safety follow-up period (for patients who do not roll-
over to the extension study CLOU064A2303B). 


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Remote procedures: 
Not applicable 
4.2 
Scientific rationale for study design 
The primary objective of the study is to rule out an increase of >3mmHg in 24-hour average 
SBP at steady state (Week 4) compared to baseline, as assessed by evaluation of change from 
baseline in 24-hour average SBP pressure at Week 4 measured by ABPM. 
This Phase 3 study is based on prior experience with remibrutinib in completed and ongoing 
studies in adult CSU patients. The analysis of the Phase 2b dose-range finding study 
CLOU064A2201 demonstrated that treatment with remibrutinib 25 mg b.i.d. over 12 weeks 
substantially improved the signs and symptoms of CSU compared to placebo, in participants 
who have not adequately responded to prior treatment with H1-AH and other CSU therapies. 
No safety signals on mean increase of SBP or DBP was notable in this study. One Phase 2 
extension study (CLOU064A2201-E1) and two Phase 3 randomized, placebo-controlled studies 
(CLOU064A2301 and CLOU064A2302) are ongoing to confirm and further evaluate the 
efficacy and safety of remibrutinib at a dose of 25 mg b.i.d. given up to 52 weeks in adult CSU 
patients. 
ABPM was chosen for the blood pressure assessment in this trial as recommended by the 
FDA for drugs intended for chronic use (Assessment of Pressor Effects of Drugs Guidance for 
Industry (FDA 2022)). It allows the observation over a 24-hour period and the measure of an 
individual’s blood pressure throughout an entire day besides other benefits. Since ABPM 
studies with duration shorter than 12 weeks suggest there is little or no change on placebo, it 
is not required to have a placebo group in this proposed short duration study. The ABPM 
study will be performed in a patient population similar to the ongoing Phase 3 studies. 
Participants will be treated for 12 weeks to enable an assessment of the treatment response to 
evaluate the benefit risk for each patient for the optional long-term treatment in the extension 
study. 
4.3 
Justification for dose 
The analysis of the Phase 2b dose-range finding study CLOU064A2201 demonstrated that 
treatment with remibrutinib 25 mg b.i.d. substantially improved the signs and symptoms of CSU 
compared to placebo, in participants who have not adequately responded to prior treatment with 
H1-AH and other CSU therapies. One Phase 2 extension study (CLOU064A2201-E1) and two 
Phase 3 randomized, placebo-controlled studies (CLOU064A2301 and CLOU064A2302) are 
ongoing to confirm and further evaluate the efficacy and safety of remibrutinib at a dose of 25 
mg b.i.d. in adult CSU patients. 
Based on the safety data from the completed and ongoing remibrutinib trials, the clinical safety 
profile of remibrutinib is favorable and supported the whole dose range studied in the Phase 2 
program (10mg q.d.-100mg b.i.d.), including the selected dose of 25 mg b.i.d. In the final 
analysis 
 
 
 
In 


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addition, the clinical safety data from the completed 
 
 
For more detailed information on the safety profile of remibrutinib, see protocol (Section 2.3) 
and the LOU064 IB. In the 
 
 
 
 
 
 
 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. 
 
 
 
 
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. 
 
 
 
 
4.3.1 
Rationale for choice of background therapy 
Second-generation H1-AH 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-AH background therapy in CSU patients who are not 
adequately controlled by H1-AH (Zuberbier et al 2021). 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 
4.5 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e., 
pandemic, epidemic or natural disaster and man-made disaster or geopolitical instability), 
mitigation procedures may be required to ensure participant safety and trial integrity and are 
listed in relevant sections of the study protocol. Notification of the public health emergency 
should be discussed with Novartis prior to implementation of mitigation procedures, and 
permitted/approved by local or regional health authorities and ethics committees as appropriate. 


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4.6 
Purpose and timing of interim analyses/design adaptations 
A primary analysis may be conducted when all participants have completed their Week 4 visit 
or discontinued early. It will focus on ABPM, safety 
 data. The results of the primary 
analysis will further inform decision making for the remibrutinib development program. 
4.7 
End of study definition 
Study completion is defined as when the last participant finishes their last study visit and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator. 
5 
Study population 
The study population will consist of approximately 136 adult participants with CSU 
inadequately controlled by second generation H1-AH. 
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-AH at the time of 
baseline (Day 1) defined as: 
• The presence of itch and hives for ≥6 consecutive weeks prior to screening despite the 
use of second generation H1-AH during this time period. 
• UAS7 score (range 0-42) ≥16, ISS7 score (range 0-21) ≥ 6 and HSS7 score (range 0-
21) ≥ 6 during the 7 days prior to baseline (Day 1). 
5. Documentation of hives within three months before baseline (either at screening and/or at 
baseline (Day 1); 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 two missing UPDD entry (either morning or 
evening) in the 7 days prior to baseline (Day 1). 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
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. 


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3. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 
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. Ongoing or past history of hypertension and/or SBP ≥140 or ≤90 and/or DBP ≥90 or ≤60 
mmHg at screening. 
6. Participants unable to tolerate 24-hour ambulatory blood pressure measurement prior to 
baseline. 
7. Participants with an arm circumference greater than 50cm. 
8. Other diseases with symptoms of urticaria or angioedema, including but not limited to 
urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary 
angioedema, or drug-induced urticaria. 
9. 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. 
10. Participants taking/requiring medications prohibited by the protocol (see Table 6-4 and 
Table 6-5). 
11. Known history or evidence of ongoing alcohol or drug abuse within the last 6 months 
before baseline (Day 1). 
12. Participants working night shifts. 
13. 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. 
14. Pregnant or nursing (lactating) women. 
15. 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 the last dose of study drug). 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 6 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. 


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• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception, or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal 
hormone contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS). In case of use of oral or hormonal contraception, women should have 
been stable on the same pill or medication 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 tubal ligation at least 6 weeks ago. In the 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 ICF. 
16. Major surgery within 8 weeks prior to screening or planned surgery for the duration of the 
study. 
17. History of live attenuated vaccine use within 6 weeks prior to baseline (Day 1) or 
requirement to receive these vaccinations at any time during the study. 
18. 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 ongoing 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. 
19. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares 
are commonly treated with oral or parenteral corticosteroids. 
20. Hematology parameters at screening: 
• Hemoglobin: < 10 g/dl 
• Platelets: < 100 000/mm3 
• Leucocytes: < 3 000/mm3 
• Neutrophils: < 1 500/mm3 
21. Significant bleeding risk or coagulation disorders. 
22. History of gastrointestinal bleeding. 
 
 
 
 


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25. 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. 
26. History of renal disease, creatinine level above 1.5x ULN, or estimated Glomerular 
Filtration Rate (eGFR) <45 milliliters (ml)/min (using the Cockcroft-Gault equation) at 
screening. 
27. Evidence of an ongoing Hepatitis C infection (e.g., defined by the detection of HCV-RNA 
at screening) and/or an ongoing Hepatitis B infection (defined by the detection of HBsAg 
and/or HBV-DNA at screening; participants who are positive for anti-HBc antibodies but 
who are negative for HBsAG and HBV-DNA can be included into the study if they agree 
to monitoring for HBsAg and HBV-DNA re-activation). 
28. 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 and allowed according to local regulations at screening. 
5.3 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to inclusion in the trial will be considered as screen failures. The reason for screen failure 
should be recorded on the appropriate Case Report Form. The demographic information, 
informed consent, and Inclusion/Exclusion pages must also be completed for screen failure 
participants. No other data will be entered into the clinical database for participants who are 
screen failures, unless the participant experienced a serious adverse event during the screening 
period (see SAE Section 8.6.3 for reporting details). If the participant fails to be included, the 
investigator/ designated site personnel update the IRT system within 2 days of the screen fail 
that the participant was not included in the trial. Data and samples collected from participants 
prior to screen failure may still be analyzed. 
Participants who are included in the trial and fail to start treatment, e.g., participants included 
in error, will be considered an early terminator. The reason should be recorded on the 
appropriate Case Report Form. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once (refer Section 8.1). 
In the case where a safety laboratory assessment at screening and/or initial baseline is outside 
of the range specified in the eligibility criteria, the assessment may be repeated once prior to 


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inclusion. If the repeat value remains outside of the specified range, the participant must be 
excluded from the study. ABPM may be repeated, if initial assessment failed, within 4 days 
prior to baseline visit. 
5.3.1 
Replacement policy 
Not applicable. 
5.3.2 
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 rescreened. The Participant No. consists of the Site 
Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to rescreen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
5.4 
Lifestyle considerations 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. In general, it is recommended to avoid major changes in lifestyle, 
including avoiding the use and/or major change in the use of substances (See Section 5.4.1 
below) or change in physical activities for the period of ABPM assessment (from Screening to 
Week 4). 
5.4.1 
Caffeine, alcohol, and tobacco 
The intake of substances potentially affecting blood pressure should generally be avoided from 
the first (Screening Visit 2) until second (Week 4) ABPM measurements. Excessive use of 
alcohol or caffeine; use of certain substances, such as certain herbs, traditional medicine, 
cannabis or drugs for recreational use; are the examples of such substances and should be 
avoided. If the participant is consuming alcohol or caffeine (in the low-risk levels, e.g., 
according to local guidelines and practices) or is a smoker, the ongoing use of such substances, 
e.g., alcohol, or caffeine, or nicotine should not variate significantly during the study, 
particularly up until completion of the second ABPM measurement (Week 4). 
5.4.2 
Activity 
No strenuous physical exercise (e.g., weight training, aerobics, football) until 24 hours before 
start and until the completion of ABPM measurement (both at Screening Visit 2 and Week 4-1 
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6 
Study treatment(s) and concomitant therapy 
6.1 
Study treatment(s) 
Novartis Global Clinical Supply (GCS) will supply the following Investigational Medicinal 
Product (IMP) in the trial in appropriately labeled bottles: 
Table 6-1 
Investigational drug 
Investigational 
Drug 
Treatment Form 
or Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor (global 
or local) 
LOU064 25 mg 
(remibrutinib) 
Film coated tablets 
Oral use 
Open label, 
Patient specific kit 
Novartis Pharma 
AG (global) 
No other supplies apart from these will be provided by GCS. 
6.1.1 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
Participants will continue to take their background therapy (H1-AH at local label-approved 
doses) with a stable regimen during the study (Section 6.8.1.1). 
6.1.2 
Treatment arms/group 
All participants are assigned to remibrutinib. 
6.1.3 
Treatment duration 
The planned treatment duration of the study is 12 weeks. Participants may discontinue from 
study treatment earlier at the discretion of the investigator or the participant, e.g., due to AEs 
(see Section 7) or lack/loss of efficacy. See Section 6.6 for information on continued access to 
study treatment after the end of the study. 
6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study treatment in packaging as described under 
Table 6-1 Investigational drug section. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster and man-made disaster or geopolitical instability 
that limits or prevents on-site study visits, delivery of IMP directly to a participant's home may 
be permitted (if allowed by local or regional health authorities and ethics committees, as 


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appropriate) in the event the investigator has decided that an on-site visit by the participant is 
no longer appropriate or possible, and that it is in the interest of the participant's health to 
administer the study treatment even without performing an on-site visit. The dispatch of IMP 
from the site to the participant’s home remains under the accountability of the investigator. Each 
shipment/provisioning will be for a maximum of 1-month's supply. In this case, regular phone 
calls or virtual contacts (every 2 weeks or more frequently if needed) will occur between the 
site and the participant 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 the participants can resume visits at the study site. 
6.2.1 
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 or designated site staff 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 site or remote monitoring visits, and at the 
completion of the trial. 
If study treatment is administered at home, e.g. oral medication, participants will be asked to 
return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 
6.2.2 
Handling of other treatment 
Not applicable. 
6.2.3 
Instruction for prescribing and taking study treatment 
Every participant should take one film-coated tablet of remibrutinib 25 mg 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 


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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 for the 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 usual 
morning/evening dosing. That dose should be omitted, and the participant should continue 
treatment with the next scheduled dose. 
H1-AH taken either as background medication or as rescue medication, respectively, should be 
taken according to the locally labeled treatment instructions. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
All participants will be assigned to remibrutinib 25 mg b.i.d. 
At baseline visit (Day 1), all eligible participants will be included in the trial via Interactive 
Response Technology (IRT). 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 participant number to the participant, which is retained for the participant throughout his/her 
participation in the trial. 
As this is an open-label study a separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment. 
6.3.2 
Treatment blinding 
Not applicable. 
6.3.3 
Emergency breaking of assigned treatment code 
Not applicable. 
6.4 
Study treatment compliance 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 


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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. 
6.4.1 
Recommended treatment of adverse events 
At present, there is insufficient information to provide specific recommendations regarding 
treatment of AEs apart from management of a significant bleeding event. 
In case of a significant bleeding event, remibrutinib must be discontinued immediately. Please 
refer to the current version of IB for more details. 
Medication used to treat AEs must be recorded on the appropriate eCRF. 
6.5 
Dose modification 
Investigational study treatment dose adjustments and/or interruptions are not permitted. 
6.5.1 
Dose escalation guidelines 
Dose adjustments are not foreseen in this study. 
6.5.1.1 
Starting dose 
The dose level of remibrutinib 25 mg b.i.d., is foreseen for the whole study treatment duration. 
6.5.2 
Definitions of dose limiting toxicities (DLTs) 
No dose-limiting toxicities were identified for remibrutinib. For the management of liver 
function test and renal function test abnormalities, refer to Table 10-2,Table 10-3, Table 10-4 
and Table 10-5 as well as Section 10.5 and Section 10.6 respectively. 
6.5.3 
Dose modifications 
Investigational or other study treatment dose adjustments are not foreseen in the study. For the 
management (including study treatment interruption and discontinuation) of liver function test 
and renal function test abnormalities, refer to Section 10.5 and Section 10.6 respectively. 
Study treatment interruptions are permitted in order to manage the AEs if in the opinion of the 
investigator it is warranted to avoid risks resulting from the continuous study treatment 
administration in a trial participant. In such cases, study treatment should be interrupted only 
during the time that this risk is present and ongoing. Study treatment can be restarted after 
resolution of the safety risk. In addition, study treatment interruption is recommended in the 
following events/cases: 
 
 
 
. 
 
 
. 


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. 
Study treatment interruptions (interruption date and re-start date) must be captured on the 
appropriate eCRF. 
6.5.3.1 
Dose adjustments for QTcF prolongation 
In case of QTcF >500 msec or QTcF prolongation >60 msec from screening 
• Assess the quality of the ECG recording and the QT value and repeat if needed 
• Determine serum electrolyte levels (in particular hypokalemia, hypomagnesemia). 
• Review concomitant medication use for other causes for QT prolongation (refer to 
qtdrugs.org for known QT prolonging drugs) and for drugs with the potential to increase 
the risk of drug exposure related QT prolongation i.e., concomitant use of CYP3A4 
inhibitors. 
• Check treatment compliance 
After confirming ECG reading at site, if QTcF > 500 msec or QTcF 
prolongation >60 msec from screening 
• Assess the benefit-risk of continued study treatment administration and evaluate if study 
treatment interruption is warranted 
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed > 500 msec: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify clinical 
conditions that could potentially prolong the QT as per the ECG and QTc Clinical 
Safety Standards Guidelines. 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec 
• After resolution to ≤ 480 msec and if the study treatment was interrupted, consider re-
introducing treatment and increase ECG monitoring (i.e., at least every study visit): 
• If QTcF recurs > 500 msec, consult study medical monitor and evaluate benefit-risk 
for continued study treatment for the participant. 
6.5.4 
Follow-up for toxicities 
Follow-up criteria for clinically notable laboratory values and vital signs is provided in Section 
10.3. Follow up requirements for liver and renal events are provided in Section 10.5 and Section 
10.6, 
respectively. 
For 
management 
of 
notable 
ECG 
abnormalities, 
see 
Section 6.5.3.1. 


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6.5.4.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT > 2 x baseline] OR [AST or ALT >3.0 U/L], whichever occurs first combined with 
[total bilirubin > 2 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, 
Gamma-glutamyl transferase (GGT), prothrombin time (PT)/INR, alkaline phosphatase, 
albumin, and creatine kinase. If available, testing of Glutamate Dehydrogenase (GLDH) is 
additionally recommended. 
Perform relevant examinations (Ultrasound or Magnetic resonance imaging (MRI), Endoscopic 
retrograde cholangiopancreatography (ERCP)) as appropriate, to rule-out an extrahepatic cause 
of cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). The R value is calculated by dividing the ALT by the ALP, 
using multiples of the ULN for both values. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 
may be less specific than ALP as a marker of cholestatic injury, since GGT can also be elevated 
by enzyme induction or by ethanol consumption. It is more sensitive than ALP for detecting 
bile duct injury. 
Table 6-2 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule-out possible alternative causes of observed LFT abnormalities. 


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Table 6-2 
Guidance on specific clinical and diagnostic assessments to be 
performed to rule-out possible alternative causes of observed Liver 
Function Tests (LFT) abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
● IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV 
DNA; anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV 
RNA 
CMV, HSV, EBV infection 
● IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & 
IgG anti-EBV 
Autoimmune hepatitis 
● Antinuclear Antibodies (ANA) & Anti-Smooth 
Muscle Antibody (ASMA) titers, total IgM, IgG, IgE, 
IgA 
Alcoholic hepatitis 
● Ethanol history, GGT, Mean Corpuscular Volume 
(MCV), CD-transferrin 
Nonalcoholic steatohepatitis 
● Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
● Medical history: acute or chronic congestive heart 
failure, hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI. 
Biliary tract disease 
● Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 years old) 
● Caeruloplasmin 
Hemochromatosis 
● Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
● Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes mellitus / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” (i.e., >50% likely), if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant” and thus, meet the definition of SAE and should be reported as a SAE using the 
term “potential treatment-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 
6.6 
Continued access to study treatment after the end of the study 
A Phase 3b extension study (CLOU064A2303B) will allow participants from CLOU064A2305 
to join once they have received the last dose of study treatment. 
6.6.1 
Post trial access 
Participants who complete participation in the 12-week treatment period of this trial may be 
eligible to receive remibrutinib as part of an open-label extension study if they meet the 
eligibility criteria defined in the extension study protocol. 


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The open-label extension will require endorsement in participating countries and sites as per 
local laws and regulations. 
6.7 
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 due to low solubility and highly under-proportional exposure increase at doses >100 
mg b.i.d. 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, see IB. 
There is no specific antidote to remibrutinib; therefore, adverse events will be managed 
symptomatically according to standard of care and applicable clinical guidelines, see IB. 
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. 
6.7.1 
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 (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, 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. Study treatment 
errors and uses outside of what is foreseen in the protocol, 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. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 
6.8 
Concomitant and other therapy 
6.8.1 
Concomitant therapy 
Throughout the study, participants must take a second-generation H1-AH at a local label-
approved standard dose (background therapy). For detailed information on the background 
medication, refer to the corresponding country-specific prescribing information. Even if up-
titration is specified in the national prescribing information, this is not allowed per protocol. 
Background therapy should not be changed during the study. 


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All concomitant medication at screening will be recorded in the eCRF. 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 drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 
Prior medication for treatment of CSU will be recorded in the eCRF. In addition to all 
concomitant medication at screening, prior medication that has been terminated within 4 weeks 
prior to screening will be recorded. 
 
 
 
 
 
6.8.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed after enrollment. 
Table 6-4 
Prohibited medications (From Screening to EOS) 
Medications 
Prohibition 
period 
Action taken during study 
Biologics for treatment of CSU (including 
omalizumab and ligelizumab) 
From 
screening 
until EOS 
Discontinue biologic treatment and 
closely monitor for potential associated 
adverse events 
Intravenous (i.v.)/Intramuscular 
(IM)/Intraarticular (IA) corticosteroids 
From 
screening 
until EOS 
Discontinue i.v./IM/IA corticosteroids if 
medically justifiable and closely monitor 
for potential associated adverse events. If 


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Medications 
Prohibition 
period 
Action taken during study 
discontinuation of i.v./IM/IA 
corticosteroids is not possible, 
discontinue study treatment. 
Leukotriene antagonists (including 
montelukast and zafirlukast) 
From 
screening 
until EOS 
Discontinue Leukotriene antagonists and 
closely monitor for potential associated 
adverse events. 
H2-antihistamines 
From 
screening 
until EOS 
Discontinue H2-antihistamines and 
closely monitor for potential associated 
adverse events. 
First-generation antihistamines 
From 
screening 
until EOS 
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 
screening 
until EOS 
Discontinue all second-generation H1-AH 
but the defined background and rescue 
medication and closely monitor for 
potential associated adverse events 
Other 
immunosuppressive/immunomodulating 
medication with or without known effect 
on CSU including but not limited to 
hydroxychloroquine, methotrexate, 
cyclosporine A, cyclophosphamide, 
tacrolimus and mycophenolate mofetil 
From 
screening 
until EOS 
Discontinue 
immunosuppressive/immunomodulating 
medication if medically justifiable and 
closely monitor for potential associated 
adverse events. If discontinuation not 
possible, discontinue study treatment. 
Intravenous (i.v.) immunoglobulins or 
plasmapheresis 
From 
screening 
until EOS 
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 EOS 
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 
screening 
until EOS 
Discontinue any therapy intended for the 
treatment of urticaria and closely monitor 
for potential associated adverse events. 


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Medications 
Prohibition 
period 
Action taken during study 
Table 6-5 
Prohibited medications (From Screening From screening until Week 4 
ABPM assessment is completed) 
Medications 
Prohibition period 
Action taken during study 
Routine (more than 3 doses 
over a 5-day period) oral 
corticosteroids 
From screening until Week 4 
ABPM assessment is 
completed: Oral corticosteroids 
as an additional rescue therapy 
for CSU are NOT allowed 
Other preparations of 
corticosteroids with limited 
systemic exposure for non-
CSU indications (e.g., 
intranasal or any topical 
corticosteroids) 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. 
Herbal supplements (e.g., Ma 
Huang [ephedra], St. John’s 
wort [with MAO inhibitors, 
yohimbine, arnica, ginseng, 
guarana]) with a BP effect 
From screening until Week 4 
ABPM assessment is 
completed 
Discontinue any therapy with a 
BP effect and closely monitor 
for potential associated 
adverse events 


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Medications 
Prohibition period 
Action taken during study 
6.8.3 
Rescue medicine 
H1-antihistamines: In addition to being used as background medication, second generation 
H1-AH are allowed as rescue medication, used on an as needed basis for participants with CSU 
flare-ups of unbearable symptoms. 


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For each individual participant, the H1-AH used as rescue medication must differ from the H1-
AH used as background medication. The daily dose of H1-AH rescue medication should not 
exceed 4-fold of the approved dose, as recommended by the current Urticaria treatment 
guidelines (Zuberbier et al 2021). For detailed information on the rescue medication, refer to 
the corresponding national prescribing information. Rescue medication should not be used for 
24 hours before and during the ABPM measurements. 
Oral corticosteroids: 
Participants will be permitted to use oral corticosteroids such as prednisone or its equivalents, 
as rescue medication if needed for CSU flare-ups of unbearable symptoms after the Week 4 
ABPM assessment is completed. The selection of the oral corticosteroid to be used as rescue 
medication 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 5 days in a 30-day period and a maximum of 
10 days during each (Re-)treatment period, to avoid chronic corticosteroid exposure and 
confounding suppression of signs and symptoms of CSU. The recommended dose is 20 - 50 mg 
prednisone or equivalent per day, as suggested by the current urticaria treatment guidelines 
(Zuberbier et al 2021). 
Rescue medication will be sourced locally. Use of H1-AH rescue medication only for CSU 
must be recorded in the Electronic Diary (eDiary) by the participant (number of tablets taken) 
and the name and dose will be captured on the appropriate eCRF. All relevant information for 
oral corticosteroid rescue therapy will be captured in the appropriate eCRF. 
6.8.4 
Considerations for concomitant and prohibited medications and 
substances potentially affecting blood pressure assessment 
The purpose of this study is to assess the effect of remibrutinib 25 mg b.i.d. on SBP measured 
by ABPM at baseline and Week 4 visits. It's important to minimize the impact of other 
parameters, such as lifestyle (see Section 5.4.1), and concomitant medications on blood pressure 
measurements. The use of certain medication (see Table 6-4,Table 6-5, Section 6.8.2) is not 
allowed until Week 4 or for the whole duration of the study. 
Starting 24 hours before the first ( screening visit 2) ABPM assessment visit and throughout 
Week 4 visit, particularly 24 hours before and during the 24-hour ABPM measurement at visits, 
participants should be instructed not to do any major change and amend to their lifestyle and 
concomitant medications. 
This includes avoiding excessive exercise, change in nutrition pattern (i.e., type and amount of 
consumed food, use of diets), use of nutritional supplements, change in the consumption of 
alcohol and caffeine (this should be within low-risk limits throughout the study) and change in 
the smoking habit. 
Also, background therapy for treatment of CSU should not be changed and rescue medications 
should not be used during the 24 hour-period before and during ABPM measurement (Section 
6.8.1). 


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7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision (requested in writing or verbally) 
• Pregnancy 
• Use of prohibited treatment requiring study treatment discontinuation as per 
recommendations in the prohibited treatment Section 6.8.2 or discontinuation of highly 
effective methods of contraception as detailed in Section 5.2. 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Following emergency unblinding 


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• Emergence of the following adverse events: 
• any adverse events that in the judgement of investigator, taking into consideration the 
participant's overall status, prevent 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) 
• Abnormal laboratory and instrumental findings, including platelet counts < 75 000/mm3 
(see Section 10.3) 
• Abnormal renal laboratory results requiring discontinuation (see Section 10.6) 
• Abnormal liver laboratory results requiring discontinuation (see Section 10.5) 
• Any 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 
assessments listed under Early Treatment Discontinuation visit at the time of treatment 
discontinuation (as per the Assessment Schedule Table 1-1). 
If a participant declines to continue with assessments as per the visit schedule, he/she will 
remain in the study for a 4-week treatment-free safety follow up, then complete the safety 
follow-up visit and exit the study. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 


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7.2 
Participant discontinuation from the study 
Discontinuation from the study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in Section 1.3 SoA. Participants who discontinue study during the 
treatment should complete Early Treatment Discontinuation visit and follow-up visits. 
7.3 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
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 as per local regulations (e.g., in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g., to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definitions of these terms. 
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/exercise data privacy rights and record this information. The investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
7.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 


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data privacy rights), 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. 
7.5 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to): 
• 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 treatment development in this indication 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site. 
Reasons for early termination (but not limited to): 
• Failure by the participant and/or the study site to comply with the protocol (e.g., 
noncompliance), the requirements of the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) or local health authorities, the Sponsor's 
procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator/ failure of the investigator to 
enter study participants at an acceptable rate 
• Recommendations from applicable board(s) after review of safety data based on the 
number and/or severity of suspected unexpected serious adverse reactions 
(SUSARs)/SAEs/AEs in the study, or new data becoming available, which raise concern 
about the safety profile of the study treatment. 
• High frequency of adverse event 
• Recommendations from DMCafter review of safety data 
• Discontinuation of further study treatment 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 the study drug intake. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the participant’s interests. The investigator 
or Novartis depending on local regulation will be responsible for informing IRBs/IECs of the 
early termination of the trial. 


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8 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in Section 1.3. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with Novartis upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
• Adherence to the study design requirements, including those specified in Section 1.3, is 
essential and required for study conduct. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1 
Screening 
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 8.4.4 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. ABPM, if 
assessment failed, may be repeated between Day -4 day and Baseline visit. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 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. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
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 
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 


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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. 
8.3 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in Section 1.3 SoA. 
8.3.1 
Ambulatory blood pressure monitoring (ABPM) 
ABPM over a 24-hour period will be conducted at two time points during the study in all 
participants: 
• The first 24-hour ABPM evaluation will commence and complete within 4 days prior to 
Baseline visit. After a successful completion of ABPM, the participant will start the 
treatment phase. 
• The second 24-hour ABPM evaluation will begin after approximately 4 weeks of study 
medication treatment at visit "Week 4 -1 day" and will be completed the following day at 
visit Week 4. All remaining Week 4 assessments will be performed after successful 
completion of ABPM or after repeated measurement, if the previous measurement is 
failed, to get a valid recording. 
The procedure below will be followed for each 24-hour ABPM period (see [ABPM Study 
Training/Reference Manual] for more details): 
• The ABPM device will be attached to the NON-DOMINANT arm (i.e., left arm for right-
handed and right arm for left-handed) of the participant. 
• A correlation will be made between the ABPM device readings and the measurements 
taken with a sphygmomanometer. 
Following the successful correlation procedure, BP 
will be measured using the 
ABPM device at study specified intervals. 
Further details on the ABPM assessment will be provided in the [ABPM Study 
Training/Reference Manual]. 
8.3.1.1 
ABPM procedures 
Start of first ABMP evaluation/"Day -1": Application of ABPM device 
If the participant has met inclusion and none of the exclusion criteria (see Section 5.1 for 
details), he/she will present at the site between Day -4 and Day -1 before 11:00 AM local time. 
The ABPM will be placed on the non-dominant arm after sphygmomanometer readings. 
Correlation readings will be obtained as described in the ABPM Study Training/Reference 
Manual and recorded in the source documentation. When the correlation procedure is 
successful, the investigator/study coordinator will initiate the “Beginning of Test” reading. The 
participant will then be instructed regarding ABPM procedures and will be required to return 
to the site after 24 hours for removal of the device. 


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Baseline/Day 1: Removal of ABPM device 
The ABPM is removed only after it has been worn for a minimum of 24 hours from the 
“Beginning of Test” reading. The ABPM data will be downloaded and quality control evaluated 
on site, using the study specific ABPM software. The quality control criteria for the specific 
monitoring will be immediately displayed on the ABPM laptop. 
If the criteria for successful readings are not met, ABPM procedures may be repeated twice 
within 24 to 48 hours. In this case, the participant will be re-instructed regarding ABPM 
procedures. 
Following completion of the ABPM session, if the ABPM quality control criteria are met, all 
Baseline (Day 1) procedures will then be performed, and the participant will be dispensed the 
first dose of study medication. 
The time of study drug (morning dose) intake will be recorded in the eCRF. 
Start of second ABPM evaluation/"Week 4-1 day": Application of ABPM device 
At "Week 4 -1 day", the participant will present at the site at approximately the same time of 
the day as he/she did for initial ABPM completed at Baseline (Day 1) in order to ensure that the 
second ABPM will cover the same period of time as the first ABPM. 
The ABPM will be placed on the non-dominant arm after sphygmomanometer readings. 
Correlation readings will be obtained as described in ABPM Study Training/Reference Manual 
and recorded in the source documentation. When the correlation procedure is successful, the 
investigator/study coordinator will initiate the “Beginning of Test” reading and the participant 
will take the morning dose of study drug. 
The time of study drug (morning dose) intake will be recorded in the eCRF. If the participant 
has taken the morning dose at home/ before the visit, the investigator will ask the participant at 
what time he/she had taken the morning dose and will enter the corresponding time onto the 
eCRF. The participant will then be re-instructed regarding ABPM procedures and will be 
required to return to the site after 24 hours for removal of the device. 
 
 
 
 
Week 4: Removal of ABPM device 
The ABPM is removed only after it has been worn for a minimum of 24 hours from the 
“Beginning of Test” reading. The ABPM data will be downloaded and quality control evaluated 
on site, using the study specific ABPM software. The quality control criteria for the specific 
monitoring will be immediately displayed on the ABPM laptop. BP results will remain blinded. 
If the criteria for successful readings are not met at Week 4, ABPM procedures may be repeated 
twice within 24 to 48 hours. In this case, the participant will continue to take study drug and 
will be re-instructed regarding ABPM procedures. The investigator/site coordinator will have 
to ensure the participant has sufficient study drug to last until the ABPM can be re-scheduled. 


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If three unsuccessful attempts are made, not further ABPM measurements should be completed 
and participant may continue to participate in the trial. 
The time of study drug (morning dose) intake will be recorded in the eCRF. If the participant 
has taken the morning dose at home/before the visit, the investigator will ask the participant at 
what time he/she had taken the morning dose and will enter the corresponding time onto the 
eCRF. 
Table 1-1 includes all assessments associated with ABPM and indicates with an “X” the visits 
when they are performed. 
8.3.2 
Patient Reported Outcomes 
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) or as detailed in the assessment schedule. 
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. 
 
 
 
 
8.3.2.1 
 
 
 
 
 


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8.3.2.1.6 H1-AH rescue medication use 
The number of tablets of rescue medication used over the past 24 hours to control conditions 
such as itch or hives is recorded once daily in the evening in the eDiary by the participant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.2.1.8 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. 


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8.4 
Safety assessments 
Safety assessments are specified below within Section 1.3 SoA detailing when each assessment 
is to be performed. 
For details on AE collection and reporting, refer to Section 8.6. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
8.4.1 
Physical examinations 
A complete physical examination (performed at screening visit of the respective core study) 
includes the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. 
A short physical exam will include the examination of general appearance, assessment of the 
skin for signs of urticaria and other skin lesions and vital signs (Blood Pressure [SBP and DBP], 
pulse and body temperature measurement as per local practice). A short physical examination 
will be at all visits starting from Visit 1 except where a complete physical examination is 
required (see above). 
Body temperature (Celsius degree) will be measured as per local practice (the same method to 
be used consistently for all participants at each site), will be included in both complete and short 
physical examinations. 
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 1-1. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
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 


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after signing informed consent which meet the definition of an Adverse Event must be recorded 
as an adverse event. 
8.4.2 
Vital signs 
Vital signs include BP and pulse measurements. After the participant has been sitting for five 
minutes, with the back supported and both feet placed on the floor, SBP and DBP 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. Vital signs will be measured at all visits, except at the time of extension study entry 
where it will be transferred from the preceding core study. 
Clinical notable vital signs are defined in Section 10.3. 
8.4.3 
Electrocardiograms 
Figure 8-1 
Timing of study procedures 
 
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. 
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 (i.e., severe 
arrhythmia, conduction abnormality of QTcF > 500 msec, 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 
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Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.4 
Clinical safety laboratory tests 
A central laboratory will be used for analysis of all specimens detailed in this Table 1-1 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. 
As per Section 4.5, 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, if 
participants cannot visit the site for protocol-specified safety lab assessments, an alternative lab 
(local) collection site may be used. 
Clinically notable laboratory and instrumental findings, liver and renal laboratory findings are 
defined in Appendices Section 10.3, Section 10.5 and Section 10.6. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
Table 8-7 
Laboratory assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, [in the case of clinically significant anemia the following 
parameters will be assessed: Ery. 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 
participants at Week 12/EOT and when deemed necessary by the investigator at 
later visits 
Fasting glucose assessed at screening visit 
Urinalysis 
Done on site (unless prohibited by local guidelines, then sample to be sent to 
central laboratory): Macroscopic Panel (Dipstick (Occult Blood, Macroscopic 
Blood)) 
Coagulation 
Prothrombin time (PT), International normalized ratio [INR]), Activated partial 
thromboplastin time (APTT) 
Hepatitis markers 
Hepatitis B screening: Antibodies against Hepatitis B virus core antigen (HBcAb or 
anti-HBc); antibodies against Hepatitis B virus surface antigen -HBsAg antibodies 
(HBsAb); Hepatitis B surface antigen (HBsAg, only in participants who are positive 


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for HBcAb/anti-HBc), and Hepatitis B-Deoxyribonucleic acid (HBV-DNA, only in 
participants who are positive for HBcAb/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 
Liver Event Testing and 
Liver Follow-Up Testing 
Refer to Section 10.5.1Section 10.5 and Table 10-1 for complete definitions of liver 
laboratory triggers, and Table 10-2 and Table 10-3 for actions required in case of 
liver events 
Renal follow-up 
Refer to Section 10.6, Section 10.6.1 and Table 10-4 for renal laboratory alerts or 
renal safety events, and Table 10-4 and Table 10-5 for actions required for renal 
events follow-up 
 
 
Pregnancy Test and 
Assessments of Fertility 
Serum / Urine pregnancy test for WoCBP (refer to Section 8.4.5) 
8.4.5 
Pregnancy testing 
All pre-menopausal women who are not surgically sterile will have pregnancy testing at 
screening (serum), at baseline (Day 1, before administration of study medication (urine)), and 
every 4 weeks thereafter (urine). Where the visit interval is greater than 4 weeks, or in the case 
that the participants cannot visit the site, the participants will be provided with urine pregnancy 
tests kits to be used at home. Results must be provided to the investigator at the next scheduled 
visit. Participants should be instructed to perform the urine pregnancy test first and only if the 
test result is negative proceed with the administration of the study treatment. A positive urine 
pregnancy test needs to be confirmed with a serum test. Where a home urine pregnancy test is 
positive the participant must contact the investigator and return to site for a serum pregnancy 
test, in the case that participants cannot visit the site an alternative (local lab) can be used. If 
positive the participant must be discontinued from study treatment. A communication process 
should be established with the participant so that the site is informed and can verify the 
pregnancy test results (e.g., following country-specific measures). Additional pregnancy testing 
might be performed if requested by local requirements. 
Assessments of fertility 
A woman is considered of childbearing potential from menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 


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8.4.6 
Appropriateness of safety measurements 
The selected safety monitoring assessments (including laboratory assessments covering clinical 
chemistry, hematology, coagulation status and immunoglobulins, 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 
No additional tests will be performed on participants entered into this study. 
8.5.1 
Clinical Outcome Assessments (COAs) 
Trial feedback 
This study includes an optional anonymized questionnaire, the ‘Trial Feedback Questionnaire’ 
(TFQ) for trial participants to provide feedback on their clinical trial experience at the end of 
the trial about the trial experience, as appropriate and in adherence to local regulations and 
guidelines. TFQ will be made available in eDiary device. Individual trial participant responses 
will not be reviewed by investigators. Responses may be used by Novartis to understand where 
improvements can be made in the clinical trial process. This feedback asks questions about trial 
experience. It 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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8.6 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 8.6. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs or AEs that are serious, considered related to the study treatment or the study (see 
Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 8.6.3. 
8.6.1 
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 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 8.6.2): 
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 8.6.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 


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All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• Dose not changed 
• Drug interrupted/permanently discontinued 
6. Its outcome (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 28 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 not recovered/not resolved (e.g., continuing at the end of the study), and assessment must be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
See appendices Section 10.5 and Section 10.6 for alert ranges for laboratory and other test 
abnormalities. 
8.6.2 
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). 


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• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or 
birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
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. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective of whether a clinical event has occurred. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
8.6.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 28 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, 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) Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. 


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1. Screen Failures (e.g., a participant who is screened but is not treated or included in the 
trial): SAEs occurring after the participant has provided informed consent until the time 
the participant is deemed a Screen Failure must be reported to Novartis within 24 hours of 
learning of it's occurrence. 
2. Enrolled OR Treated Participants: SAEs collected between time participant signs ICF until 
30 days after the participant has discontinued from study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the IB (new occurrence) and is thought to be related 
to the study treatment, a 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 28-day period following the last administration of the 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. 
8.6.4 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of study 
treatment and until 1 year after the last study drug intake. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• Any post study pregnancy-related SAE considered reasonably related to the study 
treatment by the investigator will be reported to Novartis as described in Section 8.6.3. 
While the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 


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Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
8.6.5 
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs 
Not applicable 
8.6.6 
Adverse events of special interest 
Analysis of Adverse events of special interest (AESI) will be according to Statistical Analysis 
Plan (SAP) and AESIs will be specified in SAP. 
 
 
 
 
 
 
 
 
 
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Residual Samples 
If the participant agrees, the samples that remain after analysis is completed (blood, plasma, 
serum, etc.) may be kept for up to 15 years to be used for additional studies related to 
remibrutinib, or CSU, including research to help develop ways to detect, monitor, or treat 
related diseases. 
 
The list may be changed or expanded further, as it is recognized that more relevant or novel 
biomarkers may be discovered during the conduct of the trial. Sample(s) will be collected at the 
time point(s) defined in the SoA Table 1-1. 
Optional Additional Research 
If the participant agrees, by signing the optional consent for Additional Research, biological 
samples and data that remain after analysis is completed may be used for additional research to 
help better understand how the study treatment works, learn more about the disease, improve 
the way clinical studies are conducted, or to help develop ways to detect, monitor or treat human 
diseases. A decision to perform such exploratory research studies would be based on outcome 
data from this study or from new scientific findings related to the drug class or disease, as well 
as assay availability. 
8.9 
Immunogenicity assessments 
Immunogenicity is not evaluated in this study. 
8.10 
Health economics OR Medical resource utilization and health 
economics 
Health economics OR Medical resource utilization and health economics parameters are not 
evaluated in this study. 
9 
Statistical considerations 
The analysis will be conducted 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. 
9.1 
Analysis sets 
The following analysis sets will be used in this study. 
Safety Set (SAF): The Safety Set includes all participants who received at least one dose of 
study treatment. The safety set will be used in the analysis of all safety variables. 
Full Analysis Set (FAS): The FAS comprises all participants to whom study treatment has been 
assigned and received at least one dose of the treatment. The FAS will be used for all efficacy 
variables, unless otherwise stated. 


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Note that the Safety Set and the FAS are the same except that the Safety Set allows inclusion 
of participants to whom study treatment has not been assigned but received study drug in error. 
9.2 
Statistical analyses 
9.2.1 
General considerations 
For all efficacy analyses, the FAS will be used whereas for all safety analyses, the SAF will be 
used. 
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. 
Baseline for safety is the last assessment (including unscheduled visits) obtained on or before 
the day of the first dose of study treatment. All assessments obtained after the first dose of study 
treatment are considered as post-baseline unless otherwise specified. 
 
For other assessments, baseline is the 
assessment on or before Day 1. 
9.2.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the Safety set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
SOC and preferred term for the Safety Set. 
9.2.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in weeks to remibrutinib will be summarized by means of descriptive 
statistics using the safety set. 
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) 
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9.3 
Primary endpoint(s)/estimand(s) analysis 
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). 
The primary clinical question of interest is: does remibrutinib treatment increase on average the 
24-hour weighted SBP pressure between baseline and Week 4 by more than 3 mmHg, in adult 
participants without ongoing or past history of hypertension and with 90<SBP <140mmHg, 60< 
DBP<90 mmHg at screening, with CSU who are inadequately controlled by H1-AH and 
receiving a stable local label-approved standard dose of a second generation H1-AH, excluding 
participants who discontinue from study treatment for any reason before Week 4 and 
considering intake of prohibited antihypertensive treatment as an unfavorable outcome? 
9.3.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is the change in the ABPM-measured 24-hour weighted 
average SBP at Week 4 compared to baseline. 
9.3.2 
Statistical model, hypothesis, and method of analysis 
A linear regression model will be used with baseline SBP as a covariate to analyze the primary 
efficacy endpoint. The change in SBP from baseline to Week 4 will be predicted at the median 
baseline level, and the predicted value, standard error and 95% confidence interval will be 
listed. The upper limit of 95% CI will be compared with 3 mmHg. 
Change from baseline of 24-hour weighted average SBP will be calculated using the time 
weighted average of area under the curve (AUC divided by time duration) of SBP obtained over 
24-hours. That is, the time weighted average of AUC of 24-hour SBP obtained at baseline will 
be subtracted from corresponding time weighted average of AUC of SBP at Week 4. 
Median weighted average of SBP at baseline is the sample median of the weighted average of 
AUC of SBP at baseline. 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) 
The analysis will account for different intercurrent events as explained in the following 
• Discontinuation of study treatment due to any reason prior to Week 4: participants will be 
excluded from the analysis as there is no data at Week 4. 
• Intake of prohibited antihypertensive treatment prior to Week 4 (see Section 6.8.2): 
Composite strategy (irrespective of potential occurrence of other intercurrent events). 
Measurements after this event will be excluded from the analysis and will be imputed 
using an increase by 3mmHg in 24-hour SBP from baseline at Week 4. 
9.3.4 
Handling of missing values not related to intercurrent event 
If a participant’s data is missing at the start or the end, the values will be considered missing 
for the computation of averages, the actual times for analyzing the average will be taken based 
on the data available. 


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If a participant’s data is missing in the middle of the data collection window, it will be 
considered as missing for the given timepoints and the average will be computed based on the 
area under the curve for the remaining timepoints. 
For a participant if there is data missing at baseline and / or at the end of the study for a complete 
hour, for the purpose of computing the average values, the corresponding times from both the 
baseline and end of study will be considered missing. For example, at baseline if a participant’s 
data is missing from 2 to 3 PM in the afternoon, however corresponding exit values are 
available, for assessing change from baseline, the average calculation will not consider the 2 to 
3 PM data even at the end of the study. 
This approach is true only if an entire hour data is missing. If there is partial data within an hour 
missing, the all the available data will be used in computation of averages. 
Participants with a missing 24-hour SBP baseline value will be excluded from the analysis. For 
missing 24-hour SBP values at Week 4 for participants who did not discontinue study treatment, 
the missing at random (MAR) assumption will be applied. 
9.3.5 
Multiplicity adjustment (if applicable) 
Not applicable. 
9.3.6 
Sensitivity analyses 
A sensitivity analysis will be performed on the missing 24-hour SBP values at Week 4 for 
participants who did not discontinue study treatment and handled under the MAR assumption 
in the primary analysis. For the primary endpoint, the sensitivity analysis will exclude 
participants who did not discontinue treatment and have a missing 24-hour SBP value at Week 
4. 
9.3.7 
Supplementary analysis 
The supplementary analysis is planned for the primary endpoint. 
In addition to the intercurrent events (IE)s described in Section 3.1, the following IE will be 
considered in the analysis of the primary endpoint: 
• Intake of prohibited BP-modifying treatment (see Section 6.8.2) prior to Week 4: 
Composite strategy (irrespective of potential occurrence of other IEs). Measurements after 
this event will be excluded from the analysis and will be imputed using an increase by 
3mmHg in 24-hour SBP from baseline at Week 4. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
This section will detail the statistical analysis of the secondary (efficacy) estimands  
(see Section 3.2). 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) 
For all secondary endpoints analyses, the FAS will be used. 
The secondary clinical question of interest is: What is the effect of remibrutinib treatment on 
the change from baseline in 24-hour average SBP after 4 weeks treatment in adult participants 


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without past or ongoing history of hypertension and with 90< SBP <140mmHg, 60< DBP<90 
mmHg at screening, with CSU who are inadequately controlled by H1-AH and receiving a 
stable local label-approved standard dose of a second generation H1-AH, excluding participants 
who discontinue from study treatment for any reason before Week 4 and considering intake of 
prohibited antihypertensive treatment as an unfavorable outcome? 
Other secondary endpoints are listed below: 
• the change in the ABPM-measured 24-hour weighted average SBP at Week 4 compared to 
baseline 
The change in 24-hour weighted average SBP will be analyzed using linear regression model 
with baseline SBP as a covariate. 
• the change in the ABPM-measured 24-hour weighted average DBP at Week 4 compared 
to baseline 
The change in 24-hour weighted average DBP will be analyzed using linear regression model 
with baseline DBP as a covariate. 
• the change in the measured ABPM daytime and nighttime weighted average SBP at Week 
4 compared to baseline 
The change in daytime (respectively nighttime) weighted average SBP will be analyzed using 
linear regression model with baseline weighted average daytime SBP (respectively nighttime) 
as a covariate. 
• the change in the measured ABPM daytime and nighttime weighted average DBP at Week 
4 compared to baseline 
The change in weighted average daytime (respectively nighttime) DBP will be analyzed using 
linear regression model with baseline daytime weighted average DBP (respectively nighttime) 
as a covariate. 
The analyses will be performed based on the data after the missing data imputation for the 
intercurrent events have been performed. Same intercurrent events defined for the primary 
estimand will be used for the secondary estimands and will be handled in the same way. 
For missing data not related to intercurrent events, the strategy for the primary endpoint will be 
followed. 
9.4.2 
Safety endpoints 
For all safety analyses (i.e., AEs, laboratory data, vital signs, and ECG), the SAF will be used. 
All listings and tables will be presented by treatment. 
Adverse events 
All information obtained on adverse events will be displayed by treatment and participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized in the following ways: 
• by treatment, primary SOC and preferred term. 
• by treatment, primary SOC, preferred term and maximum severity. 


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• 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. 
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. 
A participant with multiple adverse events within a primary SOC is only counted once towards 
the total of the primary SOC. 
If a participant reported more than 1 AE with the same preferred term, the AE with the greatest 
severity will be presented. If a participant reported more than 1 AE within the same primary 
SOC, the participant will be counted only once with the greatest severity at the SOC level, 
where applicable. 
All AEs with onset in the follow-up period will be considered as treatment emergent. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign. Change from baseline will only be summarized for participant with both baseline 
and post-baseline values. Participants with notable vital signs will be listed. 
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 participant and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by participant and visit and if normal ranges are available 
abnormalities will be flagged. 
Summary statistics for the change from baseline will be provided by visit. Change from baseline 
will only be summarized for subjects with both baseline and post baseline values. 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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9.6 
(Other) Safety analyses 
Not applicable. 
9.7 
Other analyses 
Not applicable. 
9.8 
Interim analysis 
A primary analysis may be conducted when all participants have completed their Week 4 visit 
or discontinued early. It will focus on ABPM, safety and 
 data. The results of the primary 
analysis will further inform decision making for the remibrutinib development program. 
 
 
 
 
 
 


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10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
Signing 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 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority 
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 


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local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
10.1.2 
Informed consent process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
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. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/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. 
Information about common side effects already known about the investigational treatment can 
be found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant upon obtaining consent and also 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 IN or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the participant. 


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The following informed consents are included in this study: 
• Main study consent, which also includes: 
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• Optional consent for activities that may be done outside of the study site 
• Pregnancy Outcomes Reporting Consent for female participants 
 
 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.5, 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.). 
10.1.3 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 


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10.1.4 
Committees structure 
10.1.4.1 Data Monitoring Committee 
This study will be included in the program level 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 Novartis 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 Novartis and the DMC. 
10.1.5 
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan, contracts. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
10.1.5.1 Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 


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10.1.5.2 Database management and quality control 
Novartis personnel (or designated clinical research organisation (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 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, screen failures and study completion, and data about all study treatment 
(s) dispensed to the participant will be tracked using an Interactive Response Technology (IRT). 
The system will be supplied by a vendor, who will also manage the database. The data will be 
sent electronically to Novartis (or a designated CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The investigator must also keep the original 
informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in, e.g., source data 
acknowledgment or monitoring guidelines. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
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 & 


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identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight. 
10.1.7 
Publication policy 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT public website. In addition, after study completion (defined as last 
participant last visit) and finalization of the study report the results of this trial will be submitted 
for publication and posted in a publicly accessible database of clinical trial results, such as the 
Novartis clinical trial results website and all required health authority websites (e.g., 
Clinicaltrials.gov, EudraCT etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
10.1.8 
Protocol adherence and protocol amendments 
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. 
10.1.8.1 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. 


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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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10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
List of abbreviations 
AAS 
Angioedema Activity Score 
AAS7 
Weekly Angioedema Activity Score 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACEi 
Angiotensin Converting Enzyme inhibitor 
ACR 
albumin-creatinine ratio 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
APTT 
Activated Partial Thromboplastin Time 
ARBs 
Angiotensin II Receptor Blockers 
ASMA 
Anti-smooth muscle antibody 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
b.i.d. 
bis in die/twice a day 
BCRP 
breast cancer resistance protein 
BP 
Blood pressure 
BTK 
Bruton’s Tyrosine Kinase 
BUN 
Blood Urea Nitrogen 
CCBs 
Calcium Channel Blockers 
CIU 
Chronic Idiopathic Urticaria 
CK 
Creatine Kinase 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
CQA 
Clinical Quality Assurance 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-reactive Protein 
CSR 
Clinical study report 
CSU 
Chronic Spontaneous Urticaria 
CU 
Chronic Urticaria 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
DILI 
Drug-Induced Liver Injury 
DIN 
Drug Inducted Nephrotoxicity 
DLQI 
Dermatology Life Quality Index 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 


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DNA 
Deoxyribonucleric Acid 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated Glomerular Filtration Rate 
EOS 
End of Study 
ERCP 
Endoscopic retrograde cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
h 
Hour 
H1-AH 
H1-antihistimines 
HBcAb 
Hepatitis B virus core antigen 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCP 
Healthcare Professional 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
HSS7 
Weekly Hives Severity Score 
HSV 
Herpes Simplex Virus 
i.v. 
intravenous 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human 
Use 
IE 
Intercurrent Event 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISS7 
Weekly Itch Severity Score 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LC-MS 
Liquid Chromatography–Mass Spectrometry 
LDH 
lactate dehydrogenase 
LDL 
Low-Density Lipoprotein 


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LFT 
Liver function test 
LLOQ 
lower limit of quantification 
MAO 
Monoamine Oxidase 
MAOIs 
Monoamine Oxidase Inhibitors 
MAR 
Missing at Random 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MRI 
Magnetic resonance imaging 
NOAC 
Novel Oral Anti-Coagulants 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs 
NYHA 
New York Heart Association 
OHP 
Off-site Healthcare Professional 
OTC 
Over the Counter 
PCR 
protein-creatinine ratio 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PT 
prothrombin time 
QoL 
Quality of Life 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
RMS 
Relapsing Multiple Sclerosis 
RNA 
Ribonucleic Acid 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAF  
Safety Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
standard deviation 
SjS 
Sjoegren’s Syndrome 
SMQ 
Standardized MedDRA Query 
SNRIs 
Serotonin and norepinephrine reuptake inhibitors 
SoA 
Schedule of Activities 
SOC 
system organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCAs 
Tricyclic Antidepressants 
TFQ 
Trial Feedback Questionnaire 
TPO 
IgGs 
Anti-Thyroid Peroxidase Antibodies 
TSH 
Thyroid Stimulating Hormone 
UAS 
Urticaria Activity Score 
UAS7 
Weekly Urticaria Activity Score 
ULN 
upper limit of normal 
UPDD 
Urticaria Patient Daily Diary 


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UV 
Ultraviolet 
WHO 
World Health Organization 
WoCBP 
Women of child-bearing potential 
10.2.2 
Definitions 
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 
Auxiliary medicinal 
product 
Medicinal product used for the needs of a clinical trial as described in the protocol, but 
not as an investigational medicinal product (e.g., rescue medication, challenge agents, 
background treatment or medicinal products used to assess end-points in the clinical 
trial). 
Concomitant therapy is not considered as AMP. 
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 
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 intervention administration, if any). 
Participant agrees to the other protocol required assessments including follow-up. No 
specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g., 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant. 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same participants 
under different treatment conditions being compared. Attributes of an estimand include 
the population, variable (or endpoint) and treatment of interest, as well as the 
specification of how the remaining intercurrent events are addressed and a population-
level summary for the variable. 
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 


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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. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, who performs certain protocol procedures for the 
participant in an off-site location such as a participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e., 
concomitant or rescue therapy) 
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 participant about the 
status of a participant's health condition without amendment or interpretation of the 
participant'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. 
Remote 
Describes any trial activities performed at a location that is not the investigative site. 
Rescreening 
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 
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 electronic source (eSource) 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g., as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 
Withdrawal of 
consent 
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and/or 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. 
This request should be distinguished from a request to discontinue the study. Other 
study participant's privacy rights are described in the corresponding informed consent 
form. 


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10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
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 Table 10-5 for clinically notable laboratory values for hepatotoxicity. 
Refer to Section 10.6 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 ≥60 msec from 
baseline 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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10.4 
Appendix 4: 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 time points 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 
• Trial Feedback Questionnaires (TFQ) - end of trial 


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10.5 
Appendix 5: 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 10-1 in Section 10.5 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 10-1 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 10-2, 
Table 10-3. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include 
• These investigations can 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. 
10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-1 
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 


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Definition/ threshold 
● Any adverse event potentially indicative of a liver toxicity 
ALP: Alkaline phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ULN: upper 
limit of normal 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in baseline 
TBL 
None 
● No change to 
study treatment 
● Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
● Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
 
If normal at 
baseline: 
ALT > 5 x ULN for 
more than two 
weeks 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in baseline 
TBL 
None 
● Interrupt study 
treatment 
● Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
● Follow-up for 
symptoms. 
● Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
● Study treatment 
can be restarted 
only if another 
etiology is identiﬁed 
and liver enzymes 
return to baseline. 
If elevated at 
baseline: 
ALT > 3 x baseline 
AND > 5 x ULN for 
more than two 
weeks 
 
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
 
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or 
INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x baseline 
AND > 3 x ULN 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x baseline 
AND > 3 x ULN 


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Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin 
(isolated) 
 
 
>1.5 – 3.0 ULN 
● Maintain treatment 
● Repeat LFTs within 48-72 hours 
Monitor LFTs weekly until resolution to 
≤ Grade 1 or to baseline 
> 3 - 10 × ULN (in 
the absence of 
known Gilbert 
syndrome) 
● Interrupt treatment 
● Repeat LFT within 48-72 hours 
● Hospitalize if clinically appropriate 
● Establish causality 
● Record the AE and contributing factors 
(e.g., conmeds, med hx, lab) in the 
appropriate CRF 
Monitor LFTs weekly until resolution to 
≤ Grade 1 or to baseline (ALT, AST, 
total bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
● Discontinue the study treatment 
immediately 
● Hospitalize the participant 
● Establish causality 
● Record the AE and contributing 
factors(e.g., conmeds, med hx, lab)in the 
appropriate CRF 
ALT, AST, total bilirubin, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator discretion) 
Any AE potentially 
indicative of a liver 
toxicity 
● Consider study treatment interruption or 
discontinuation 
● Hospitalization if clinically appropriate 
● Establish causality 
● Record the AE and contributing factors 
(e.g., conmeds, med hx, lab)in the 
appropriate CRF 
Investigator discretion 


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10.6 
Appendix 6: Renal safety monitoring 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trail staff as summarized 
in Table 10-4. 
Every renal laboratory trigger or renal event should be followed up by the investigator or 
designated personnel at the trial site as summarized in Table 10-5. 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up 
Table 10-4 
Specific Renal Alert Criteria and Actions and Event Follow-up 
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 
● Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic failure, contrast 
media or other known nephrotoxin administration, or other diseases or causes, e.g., dehydration due to 
delirium, tumor lysis. 
 


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Table 10-5 
Renal Events 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, blood urea nitrogen (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 albumin-creatinine ratio 
(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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10.7 
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) 
Figure 10-1 
Patient Diary: Urticaria Patient Daily Diary (UPDD) 
 
 


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Participant Diary: Angioedema Activity Score (AAS) 
Figure 10-2 
Angioedema Activity Score 
 
 


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11 
References 
References are available upon request 
Angst D, Gessier F, Janser P, et al (2020) Discovery of LOU064 (Remibrutinib), a Potent and 
Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. J Med Chem; 63(10):5102-
18. 
Biagtan MJ, Viswanathan RK, Evans MD, et al (2011) Clinical utility of the Chronic Urticaria 
Index. J Allergy Clin Immunol; 127(6):1626-7. 
Estupiñán HY, Berglöf A, Zain R, et al (2021) Comparative Analysis of BTK Inhibitors and 
Mechanisms Underlying Adverse Effects. Front Cell Dev Biol; 9:630942. 
Finlay AY (2005) Current severe psoriasis and the rule of tens. Br J Dermatol; 152(5):861-7. 
 
Food and Drug Administration (2022) Guidance for Industry. Assessment of Pressor Effects 
of Drugs. US Department of Health and Human Services. Center for Drug Evaluation and 
Research (CDER). February 2022. Clinical/Medical 
Gabizon R, London N (2020) A Fast and Clean BTK Inhibitor. J Med Chem; 63(10):5100-01. 
Greaves MW (2003) Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol; 3(5):363-
8. 
Hawro T, Ohanyan T, Schoepke N, et al (2018) The Urticaria Activity Score-Validity, 
Reliability, and Responsiveness. J Allergy Clin Immunol Pract: 6(4);1185-1190. 
Hendriks RW, Yuvaraj S, Kil LP (2014) Targeting Bruton's tyrosine kinase in B cell 
malignancies. Nat Rev Cancer; 14(4):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; 
125(4):659-64. 
. 
Powell RJ, Du Toit GL, Siddique N, et al (2007) BSACI guidelines for the management of 
chronic urticaria and angio-oedema. Clin Exp Allergy; 37(5):631-50. 
Rip J, Van Der Ploeg EK, Hendriks RW, et al (2018) The Role of Bruton's Tyrosine Kinase in 
Immune Cell Signaling and Systemic Autoimmunity. Crit Rev Immunol; 38(1):17-62. 
Saini SS, Kaplan (2018) AP Chronic Spontaneous Urticaria: The Devil's Itch. J Allergy Clin 
Immunol Pract:1097-106. 
 
 


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Zauli D, Grassi A, Ballardini G, et al (2002) Thyroid autoimmunity in chronic urticaria: 
Implications for Therapy. Am J Clin Dermatol; 3(8):525-8. 
Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al (2021) The international 
EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, 
diagnosis, and management of urticaria. Allergy; 77(3):734-766. 
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; 69(7):868-87. 

SAP_001.pdf: 
Clinical Development 
LOU064/Remibrutinib 
CLOU064A2305 / NCT05795153
A multicenter, open-label Phase 3 study: ambulatory blood 
pressure monitoring in adult patients with chronic 
spontaneous urticaria inadequately controlled by H1-
antihistamines treated with remibrutinib up to 12 weeks. 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final – Addendum 1 
Release date: 
18-Sep-2024
Number of pages: 
36 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 6.0, Effective from 23-Nov-2022 


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Study No. CLOU064A2305 
 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
21-Mar-
2023 
Prior 
to DB 
lock 
Creation of 
final version 
N/A - First version 
NA 
15-Mar-
2024 
Prior 
to DB 
lock 
Addresses the 
findings and 
comments 
from dry run 
and TFL shells 
review 
SAP Amendment 1 
 
Updated the Edit Check Plan version 
Section 1 
Corrected the reference endpoint  
Section 1.2.2 
Added R as possible software 
We do not show p-values (non-inferiority study) 
Specified Week 4 for ABPM 
Section 2.1 
 
Replaced ‘Geographic region’ with ‘Country’ 
Section 2.3.2 
Background medication based on Enrolled Set 
Section 2.4.2 
Changed the PD used according to the new Edit 
Check Plan 
Sections 2.5.3; 2.5.6 
Added a clarification on the intercurrent events 
for the sensitivity analysis  
Section 2.5.5 
Updated the “Derivation of the ABPM based 
averages” section with more details 
Section 2.5.4 
Updated Table 2-15 and the urinalysis paragraph 
Section 2.7.3 
Changed Pulse into Heart rate in Table 2-18 to 
align with the protocol 
  
Section 2.7.4.2 
Completed the SAS pseudo-code according to 
the description 
Section 5.4.1 
Adapted the text to be consistent also with more 
than 48h of data 
Section 5.4.1.1 
Updated Table 5-2 
Section 5.5 
Minor corrections (typos, removed ‘by treatment’ 
as it is only one arm, etc.) 
Entire document 
7-May-
2024 
Prior 
to DB 
lock 
Addresses the 
findings from 
the CDC dry 
run  
Updated the definition of “on-treatment” to avoid 
inflating the exposure time and ensure alignment 
with the pivotal studies. Added also its use cases. 
Section 2.1.1 
 
 
 
Specified the source for background and rescue 
medications 
Section 2.4.2 
 
 
 
Made the handling of an intercurrent event more 
precise. The intercurrent event and the estimand 
did not change 
Section 2.5.3 
12-
Sep-
2024 
After 
DB 
lock 
Minor edits for 
documentation 
SAP Addendum 1 
 
 
 
 
Added ETD remapping information 
Section 2.1.1 
 
 
 
Updated text: “For the combination criteria of 
parameters, except potential Hy’s Law case, all 
the elevations must occur at the same post-
baseline timepoint.” 
Section 2.7.3 
 
 
 
Updated to match used criteria 
Section 2.7.4.1 
 
 
 
Updated imputation rule to match the programs 
Section 5.1.3 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives, endpoints and estimands ............................................................. 8 
1.2.1 
Primary estimand(s) ................................................................................ 9 
1.2.2 
Secondary estimand(s) .......................................................................... 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 14 
2.3.2 
Demographics and other baseline characteristics ................................. 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 16 
2.5 
Analysis supporting primary objective(s) .............................................................. 17 
2.5.1 
Primary endpoint(s) ............................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.5.3 
Handling of intercurrent events ............................................................. 18 
2.5.4 
Handling of missing values not related to intercurrent event ............... 18 
2.5.5 
Sensitivity analyses ............................................................................... 19 
2.5.6 
Supplementary analyses ........................................................................ 19 
2.6 
Analysis supporting secondary objectives ............................................................. 19 
2.6.1 
Secondary endpoint(s) ........................................................................... 19 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.6.3 
Handling of intercurrent events ............................................................. 20 
2.6.4 
Handling of missing values not related to intercurrent event ............... 20 
2.6.5 
Sensitivity analyses ............................................................................... 20 
2.6.6 
Supplementary analyses ........................................................................ 20 
2.7 
Safety analyses ....................................................................................................... 20 


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2.7.1 
Adverse events (AEs) ............................................................................ 20 
2.7.2 
Deaths .................................................................................................... 22 
2.7.3 
Laboratory data ..................................................................................... 22 
2.7.4 
Other safety data ................................................................................... 25 
 
 26 
 
 26 
 
27 
 
 28 
2.12 
Other Exploratory analyses .................................................................................... 28 
2.13 
Interim analysis ...................................................................................................... 29 
 
 29 
4 
Change to protocol specified analyses .............................................................................. 29 
5 
Appendix ........................................................................................................................... 29 
5.1 
Imputation rules ..................................................................................................... 29 
5.1.1 
Study drug ............................................................................................. 29 
5.1.2 
AE date imputation ............................................................................... 29 
5.1.3 
Concomitant medication date imputation ............................................. 30 
5.2 
AEs coding/grading ............................................................................................... 31 
5.3 
Laboratory parameters derivations ........................................................................ 31 
5.4 
Statistical models ................................................................................................... 32 
 
 32 
5.4.2 
Analysis supporting secondary objective(s).......................................... 35 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 35 
6 
Reference ........................................................................................................................... 36 
 
List of tables 
Table 1-1 
Objectives and Endpoints ........................................................................ 8 
 
 12 
 
 12 
Table 2-3 
Assessment windows by assessment ..................................................... 13 
Table 2-13 
Overview of safety analyses on TEAEs ................................................ 21 
Table 2-14 
Overview of safety analyses on laboratory data ................................... 22 
Table 2-15 
CTCAE grades for laboratory parameters to be analyzed .................... 23 
Table 2-16 
Liver enzyme abnormalities .................................................................. 24 
Table 2-17 
Specific renal alert criteria .................................................................... 25 
 
 26 


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Table 5-2 
Subject Classification ............................................................................ 35 
 
List of figures 
 
 35 
 


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List of abbreviations 
AAS7 
Weekly Angioedema Activity Score 
ABPM 
Ambulatory Blood Pressure Monitoring 
AE 
Adverse Event 
ALP 
ALT 
Alkaline Phosphatase 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
b.i.d. 
bis in diem/twice a day 
BMI 
Body Mass Index 
CINDU 
Chronic Inducible Urticaria 
CM 
Concomitant Medication 
CRF 
CSR 
CSU 
Case Report Form 
Clinical Study Report 
Chronic Spontaneous Urticaria 
CTCAE 
Common Terminology Criteria for Adverse Event 
CU 
Chronic Urticaria 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
 
 
DMS 
Document Management System 
FAS 
Full Analysis Set 
GGT 
Gamma-Glutamyl Transferase 
H1-AH 
H1-antihistamine 
HR 
Heart Rate 
HSS7 
Weekly Hives Severity Score 
IA 
Interim Analyses 
IE 
Intercurrent Event 
Ig 
Immunoglobulin 
ISS7 
Weekly Itch Severity Score 
LLN 
Lower Limit of Normal range 
LLOQ 
Lower Limit Of Quantification 
MAP 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PD 
Protocol deviation 
PK 
Pharmacokinetics 
PRO 
Patient-reported Outcomes 
PT 
Preferred Term 
RAP 
Reporting & Analysis Process 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
SAS 
Statistical Analysis Plan 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 


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TBL 
Total Bilirubin 
TEAE 
Treatment Emergent AE 
TFLs 
Tables, Figures, Listings 
 
 
ULN 
Upper Limit of Normal range 
ULOQ 
Upper Limit Of Quantification 
WHO 
World Health Organization 


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1 
Introduction 
Data will be analyzed by Novartis according to the data analysis Section 12 of the 
CLOU064A2305 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 4), if 
conducted, and the final analysis of CLOU064A2305 study with reference to 
• the study protocol version 1.0 
• The Edit Check Plan version 8.0 
1.1 
Study design 
This is a global, open-label Phase 3 study assessing the safety of remibrutinib 25 mg b.i.d., in 
adult participants with CSU inadequately controlled by second generation H1‑AH in regards to 
change from baseline in 24-hour weighted average SBP at Week 4 measured by ABPM at 
baseline and Week 4 and overall efficacy, safety and tolerability over 12 weeks. 
This study consists of a screening period of up to 4 weeks, a 12-week treatment period and a 
treatment-free follow-up period of 4 weeks, with a total study duration of up to 20 weeks. 
A primary analysis may be conducted once all participants have completed their Week 4 visit 
or discontinued early. 
A final analysis will be conducted once all participants have completed the study or 
discontinued early. 
1.2 
Study objectives, endpoints and estimands  
Table 1-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To rule out an increase of >3mmHg in 24-hour 
average SBP at steady state (Week 4) compared 
to baseline, measured by ABPM. 
• 
The change in the ABPM-measured 24-hour 
weighted average SBP at Week 4 compared to 
baseline 
Secondary 
• 
To evaluate changes in 24-hour average SBP at 
steady state (Week 4) compared to baseline 
• 
The change in the ABPM-measured 24-hour 
weighted average SBP at Week 4 compared to 
baseline 
• 
To evaluate changes in 24-hour average DBP at 
steady state (Week 4) compared to baseline 
• 
The change in the measured ABPM 24-hour 
weighted average DBP at Week 4 compared to 
baseline 
• 
To evaluate changes in daytime and nighttime 
SBP at 4 weeks 
• 
The change in the measured ABPM daytime and 
nighttime weighted average SBP at Week 4 
• 
To evaluate changes in daytime and nighttime 
average DBP at 4 weeks. 
• 
The change in the measured ABPM daytime and 
nighttime weighted average DBP at Week 4 


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• 
To evaluate 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, evaluation of laboratory and vital signs 
data 
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). 
The primary clinical question of interest is: Does remibrutinib treatment increase on average 
the 24-hour weighted average SBP at a steady state (Week 4) compared to baseline, by more 
than 3 mmHg, in adult participants without ongoing or past history of hypertension and with 90 
< SBP <140mmHg, 60 < DBP< 90 mmHg at screening, with CSU who are inadequately 
controlled by H1-AH and receiving a stable local label-approved standard dose of a second 
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before Week 4 and considering intake of prohibited antihypertensive treatment as an 
unfavorable outcome? 
The primary estimand is described by the following attributes: 
1. Population: participants without ongoing or past history of hypertension and with 90< 
SBP <140mmHg, 60< DBP<90 mmHg at screening, with inadequately controlled CSU 
despite treatment with second generation H1-AH who have CSU duration ≥ 6 months, a 
UAS7 score ≥ 16, ISS7 ≥ 6 and HSS7 score ≥ 6 in the last 7 days prior to Baseline (Day 
1). 
2. Endpoint: change from baseline in 24-hour weighted average SBP at Week 4 measured 
by ABPM. 
3. Treatment of interest: the study treatment (remibrutinib 25 mg b.i.d.). 
4. Summary Measurement: the mean change from baseline. 
5. Handling of intercurrent events: 
• Discontinuation of study treatment due to any reason prior to Week 4: participants 
will be excluded from the analysis 
• Intake of prohibited antihypertensive treatment prior to Week 4: Composite strategy 
(irrespective of potential occurrence of other intercurrent events). Measurements after 
this event will be excluded from the analysis and will be imputed using an increase of 
3mmHg in 24-hour average SBP from baseline at Week 4. 
1.2.2 
Secondary estimand(s) 
The secondary clinical question of interest is: What is the effect of remibrutinib treatment on 
the change from baseline in 24-hour weighted average SBP at steady state (Week 4) compared 
to baseline in adult participants without ongoing or past history of hypertension and with 90< 
SBP <140mmHg, 60< DBP<90 mmHg at screening, with CSU who are inadequately controlled 
by H1-AH and receiving a stable local label-approved standard dose of a second generation H1-
AH, excluding participants who discontinue from study treatment for any reason before Week 
4 and considering intake of prohibited antihypertensive treatment as an unfavorable outcome? 
The secondary estimand attributes are identical to the ones described in Section 1.2.1. 
Secondary estimand on the secondary endpoints 
A similar estimand approach will be implemented for Change from baseline in 24-hour 
weighted average DBP at Week 4 measured by ABPM as for Change from baseline in 24-hour 
weighted average SBP at Week 4 measured by ABPM. 
A similar estimand approach will be implemented for Change from baseline in daytime 
weighted average SBP at Week 4 measured by ABPM as for Change from baseline in 24-hour 
weighted average SBP at Week 4 measured by ABPM. 
A similar estimand approach will be implemented for Change from baseline in nighttime 
weighted average SBP at Week 4 measured by ABPM as for Change from baseline in 24-hour 
weighted average SBP at Week 4 measured by ABPM. 


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A similar estimand approach will be implemented for Change from baseline in daytime 
weighted average DBP at Week 4 measured by ABPM as for Change from baseline in 24-hour 
weighted average SBP at Week 4 measured by ABPM. 
A similar estimand approach will be implemented for Change from baseline in nighttime 
weighted average DBP at Week 4 measured by ABPM as for Change from baseline in 24-hour 
weighted average SBP at Week 4 measured by ABPM. 
2 
Statistical methods 
2.1 
Data analysis general information 
The statistical analysis will be performed by Novartis personnel, using R version 4.1 or above 
and/or SAS version 9.4 or above. 
Statistical Analysis Plan for the DMC analyses will be prepared separately. 
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. 
95% confidence intervals will be displayed and will be two-sided if not specified otherwise. 
2.1.1 
General definitions  
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 intake] + 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 
intake], 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. 
Baseline for safety is the last assessment (including unscheduled visits) obtained on or before 
the day of the first dose of study treatment. All assessments obtained after the first dose of study 
treatment are considered as post-baseline unless otherwise specified. 
 
 For other assessments, baseline is the 
assessment on or before Day 1. For the ABPM based assessments baseline is the last assessment 
on or before the day of the first dose of study treatment. 
For the ABPM based assessments Week 4 is the last assessment on or after Week 4 - 1 day.  
The On-treatment period is defined as the minimum between the period from the first date of 
dose intake of treatment to either (i) the last date of dose intake + 28 days or (ii) and the end of 
study. This is the reference for safety analyses of adverse events, laboratory, vital signs, etc., as 
well as exposure-adjusted incidence rates. 


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Assessment window for the assessments performed at study until Week 12 
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. ETD 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). 
Table 2-3 shows the assessment windows for the assessments collected at every visit (i.e., Vital 
signs, Clinical Chemistry, Hematology, Urinalysis).  
If more than one assessment falls into the interval,  
• Then if there is the scheduled visit recorded in eDiary or eCRF, this visit will be chosen. 
• If not, the earliest visit day will be chosen. 
 
Table 2-3 
Assessment windows by assessment 
Assessment Visit 
Week 4 
Week 8 
Week 12 
Scheduled visit day 
29 
57 
85 
Vital Signs 
2-29 
30-57 
58-85 
Weight 
- 
- 
2-85 
ECG 
 
 
 
Clinical Chemistry 
Hematology 
Urinalysis 
 
2-29 
- 
30-85 
 
2.2 
Analysis sets  
The following analysis sets will be used in this study. 
Enrolled Analysis Set: The Enrolled Analysis Set consists of all participants who have been 
enrolled, regardless of whether or not they receive a dose of study drug. This set substitutes the 
Randomized Analysis Set as this study is open label. Hence, screen failures are not part of the 
Enrolled Analysis Set. 


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Safety Set (SAF): The Safety Set includes all participants who received at least one dose of 
study treatment. The safety set will be used in the analysis of all safety variables. 
Full Analysis Set (FAS): The FAS comprises all participants to whom study treatment has 
been assigned and received at least one dose of the treatment. The FAS will be used for all 
efficacy variables, unless otherwise stated. 
Mis-enrolled participants will be excluded from the FAS. 
Mis-enrolled participants are defined as cases where IRT contacts were made by the site either 
prematurely or inappropriately prior to confirmation of the subject’s final enrollment eligibility 
and no study medication was administered to the subject. 
Note that the SAF and the FAS are the same except that the Safety Set allows inclusion of 
participants to whom study treatment has not been assigned but received study drug in error. 
2.2.1 
Subgroup of interest 
Not applicable 
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 for 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 Enrolled analysis set who completed the study 
treatment period, who discontinued the study treatment and the reason for treatment 
discontinuation will be presented. 
The number and percentage of participants in the Enrolled analysis 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 (Enrolled analysis set, FAS and SAF) will be 
presented. The reason for exclusion from any analysis set will be listed. 
The number and percentage of participants who have experienced protocol deviations (PD) will 
be tabulated by deviation category. The summary of overall important PDs (including COVID-
19 related PDs), important COVID-19 related PDs will be provided for the Enrolled analysis 
set. 
2.3.2 
Demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for the Enrolled analysis set. 


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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 
 
 
 
 
 
 
 
 
 
 
• Duration of CSU defined as Time since diagnosis of urticaria (years) = (informed consent 
date – diagnosis date + 1)/365.25 
• Baseline SBP and DBP (vital signs, not measured by ABPM) 
Categorical variables: 
• Age categories (≥18 - <65, ≥ 65 - <85years , ≥85 years) 
• Gender  
• Race 
• Ethnicity 
• BMI groups (< 25, 25 - <30, ≥ 30 kg/m2) 
 
 
 
 
 
• Previous exposure to anti-IgE therapy (Yes, No) 
• Country 
• Previous experience of Angioedema (Yes, No) 
• Baseline CU-index category (Positive:>=10, Negative: <10)  
• Baseline total IgE level (Normal/High: >43 IU/mL, Low: ≤ 43 IU/mL)  
Relevant medical histories and current medical conditions at baseline will be summarized 
combined by system organ class and preferred term, for the Enrolled analysis set. 
• CSU related history (CSU, Urticaria related history) 
• Non-CSU related history (general medical history) 


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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. 
The first (last) dose of study treatment is defined as the date of the first (last) dose intake. The 
last study visit is defined as the maximum among Week 12, the date of study discontinuation, 
the date of study completion, the date of the last safety follow-up. 
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 
The duration of exposure and duration of study in weeks of LOU064 25mg b.i.d. will be 
summarized. 
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) will be displayed. 
2.4.2 
Prior, concomitant and post therapies 
Medications will be identified using the WHODrug including Anatomical Therapeutic 
Chemical (ATC) code. In the summary tables, medications (including background or rescue 
medications) will be presented in alphabetical order, by ATC codes and preferred term. Tables 
will show the overall number and percentage of participants receiving at least one drug of a 
particular ATC code and at least one drug in a particular preferred term.  
Prior medications are defined as drugs taken and stopped prior to first dose of study medication. 
Any medication given at least once between the day of first dose of study treatment and the last 
day of study visit will be a concomitant medication, including those which were started pre-
baseline and continued into the treatment period. Prior or concomitant medication will be 
identified based on recorded or imputed start and end dates of medication taking.  
Prior urticaria medications and prior non-urticaria medications will be summarized 
separately by ATC code and preferred term in the Enrolled analysis set.  
Concomitant urticaria medications (excluding background or rescue medications) and 
concomitant non-urticaria medications will be summarized separately by ATC code, 
preferred term in the Safety set.  


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Background medications will be summarized by ATC code, preferred term, and dose per 
administration in the Enrolled set. 
Rescue medication: H1-antihistamines will be summarized by ATC code, preferred term, and 
dose per tablet in the Safety set. 
Rescue medication: oral corticosteroids will be summarized by ATC code, preferred term, 
and dose per tablet 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 in the Enrolled analysis set. Concomitant non-drug therapies/procedures 
will be summarized in the Safety set. 
Background and rescue medications will be filtered from the concomitant medications. 
2.5 
Analysis supporting primary objective(s) 
All analyses for efficacy data will be based on the FAS. 
A primary analysis may be conducted when all participants have completed their Week 4 visit 
or discontinued early. 
2.5.1 
Primary endpoint(s) 
The primary clinical question of interest is: does remibrutinib treatment increase on average the 
24-hour weighted SBP pressure between baseline and Week 4 by more than 3 mmHg, in adult 
participants without ongoing or past history of hypertension and with 90<SBP <140mmHg, 60< 
DBP<90 mmHg at screening, with CSU who are inadequately controlled by H1-AH and 
receiving a stable local label-approved standard dose of a second generation H1-AH, excluding 
participants who discontinue from study treatment for any reason before Week 4 and 
considering intake of prohibited antihypertensive treatment as an unfavorable outcome? 
The primary endpoint of the study is the change in the ABPM-measured 24-hour weighted 
average SBP at Week 4 compared to baseline. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
A linear regression model will be used with baseline SBP as a covariate to analyze the primary 
efficacy endpoint. The change in SBP from baseline to Week 4 will be predicted at the median 
baseline level, and the predicted value, standard error and 95% confidence interval will be listed. 
The upper limit of 95% CI will be compared with 3 mmHg. 
Change from baseline of 24-hour weighted average SBP measured by ABPM will be calculated 
using the time weighted average of area under the curve (AUC divided by time duration) of 
SBP obtained over 24-hours. That is, the time weighted average of AUC of 24-hour SBP 
obtained at baseline will be subtracted from corresponding time weighted average of AUC of 
SBP at Week 4. 
Median weighted average of SBP at baseline is the sample median of the weighted average of 
AUC of SBP at baseline. 


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The statistical hypothesis test for the primary endpoint being tested is that the change from 
baseline of 24-hour weighted average SBP at Week 4 measured by ABPM is greater or equal 
than 3mmHg i.e. 
H01: µ remibrutinib ≥ 3mmHg versus HA1: µ remibrutinib < 3mmHg 
where µ is the change from baseline of 24-hour weighted average SBP at Week 4 measured by 
ABPM. 
2.5.3 
Handling of intercurrent events  
The analysis will account for different intercurrent events as explained in the following 
• Discontinuation of study treatment due to any reason prior to Week 4: participants will be 
excluded from the analysis. 
• Intake of prohibited antihypertensive treatment prior to Week 4 (PD M-COMD05): 
Composite strategy (irrespective of potential occurrence of other intercurrent events). 
Measurements after this event will be excluded from the analysis and will be imputed 
using an increase by 3mmHg in 24-hour SBP from baseline at Week 4.  
For the first intercurrent event Week 4 is defined as the date of the first dose intake + 28 days. 
2.5.4 
Handling of missing values not related to intercurrent event 
If a participant’s data are missing at the start or the end, the values will be considered missing 
for the computation of averages, the actual times for analyzing the average will be taken based 
on the data available. 
If a participant’s data are missing in the middle of the data collection window, the values will 
be considered as missing for the given timepoints and the average will be computed based on 
the area under the curve for the remaining timepoints. 
For a participant if there are data missing at Baseline and / or at Week 4 for a complete hour, 
for the purpose of computing the average values, the corresponding times from both the 
Baseline and Week 4 will be considered missing. For example, at baseline if a participant’s data 
are missing from 2 to 3 PM in the afternoon, however corresponding exit values are available, 
for assessing change from baseline, the average calculation will not consider the 2 to 3 PM data 
even at Week 4. 
This approach is true only if an entire hour of data are missing. If there are partial data within 
an hour missing, then all of the available data will be used in computation of averages. 
Participants with a missing 24-hour SBP baseline value will be excluded from the analysis. For 
missing 24-hour SBP values at Week 4 for participants who did not discontinue study treatment, 
the missing at random (MAR) assumption will be applied. Participants with a missing 24-hour 
SBP change from baseline at Week 4 will be excluded from the analysis. This can happen if the 
intersection of the time intervals for which we have data at Baseline and Week 4 is empty. See 
Section 5.4.1.1 for more details on the derivation of the change from baseline. 


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2.5.5 
Sensitivity analyses  
A sensitivity analysis will be performed on the missing 24-hour SBP values at Week 4 for 
participants who did not discontinue study treatment and handled under the MAR assumption 
in the primary analysis. For the primary endpoint, the sensitivity analysis will exclude 
participants who did not discontinue treatment and have a missing 24-hour SBP value at  
Week 4. All other intercurrent events will remain the same. 
2.5.6 
Supplementary analyses 
In addition to the intercurrent events (IEs) described in Section 1.2.1, the following IE will be 
considered in the analysis of the primary endpoint: 
• Intake of prohibited BP-modifying treatment prior to Week 4 (PD M-COMD02, M-
COMD03, M-COMD05 & M-COMD06 ): Composite strategy (irrespective of potential 
occurrence of other IEs). Measurements after this event will be excluded from the analysis 
and will be imputed using an increase by 3mmHg in 24-hour SBP from baseline at Week 
4. 
2.6 
Analysis supporting secondary objectives  
For all secondary endpoints analyses, the FAS will be used. 
2.6.1 
Secondary endpoint(s) 
The secondary clinical question of interest is: What is the effect of remibrutinib treatment on 
the change from baseline in 24-hour average SBP after 4 weeks treatment in adult participants 
without past or ongoing history of hypertension and with 90< SBP <140mmHg, 60< DBP<90 
mmHg at screening, with CSU who are inadequately controlled by H1-AH and receiving a 
stable local label-approved standard dose of a second generation H1-AH, excluding participants 
who discontinue from study treatment for any reason before Week 4 and considering intake of 
prohibited antihypertensive treatment as an unfavorable outcome? 
Other secondary endpoints are listed below: 
• the change in the ABPM-measured 24-hour weighted average SBP at Week 4 compared to 
baseline 
The change in 24-hour weighted average SBP will be analyzed using linear regression model 
with baseline SBP as a covariate. 
• the change in the ABPM-measured 24-hour weighted average DBP at Week 4 compared 
to baseline 
The change in 24-hour weighted average DBP will be analyzed using linear regression model 
with baseline DBP as a covariate. 
• the change in the measured ABPM daytime and nighttime weighted average SBP at Week 
4 compared to baseline 
The change in daytime (respectively nighttime) weighted average SBP will be analyzed using 
linear regression model with baseline weighted average daytime SBP (respectively nighttime) 
as a covariate. 


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• the change in the measured ABPM daytime and nighttime weighted average DBP at Week 
4 compared to baseline 
The change in weighted average daytime (respectively nighttime) DBP will be analyzed using 
linear regression model with baseline daytime weighted average DBP (respectively nighttime) 
as a covariate. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
The same analysis described for the primary endpoint in Section 2.5.2 will be performed. 
2.6.3 
Handling of intercurrent events  
The same intercurrent events defined for the primary estimand will be used for the secondary 
estimands and will be handled in the same way. 
2.6.4 
Handling of missing values not related to intercurrent event 
For missing data not related to intercurrent events, the same strategy described for the primary 
endpoint will be followed. 
2.6.5 
Sensitivity analyses 
Not applicable. 
2.6.6 
Supplementary analyses 
Not applicable.  
2.7 
Safety analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented 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. 
2.7.1 
Adverse events (AEs) 
All information obtained on adverse events will be listed by 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 in the following 
ways: 
• primary system organ class and preferred term. 
• primary system organ class, preferred term and maximum severity. 
• Standardized MedDRA Query (SMQ, narrow) and preferred term. 


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
The most common adverse events reported ( 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 b.i.d. starting from the most common 
event. The cut-off of 3% can be re-evaluated based on the 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. The rate estimates will be reported with exact Poisson 95% CIs (Garwood 
1936, Sahai and Khurshid 1993). 
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 / 
Final 
analysis 
 
Entire 
study 
• 
LOU064 25mg b.i.d. 
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. Exposure-adjusted incidence rate will also be provided for the 
entire study period. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent AEs: non-serious AEs with an incidence greater than 5% , and deaths and serious AEs 
(SAEs) including the events suspected to be related to study treatment, will be provided by SOC 
and PT on the Safety Set. The cut-off of 5% can be re-evaluated based on the 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: 


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• 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 participant, and visit and if normal ranges are available 
abnormalities will be flagged.  
For Hematology and Serum chemistry, central laboratory data will be included in the summary 
tables. Local laboratory data will only be listed but not be included in the summary tables. 
For Urinalysis, local laboratory data will be included in the summary tables. For participants 
who have only central laboratory data, central data will be used in the summary tables. 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) 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 / 
Final 
analysis 
Entire 
study 
• 
LOU064 25mg b.i.d. 
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 laboratory test. 


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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. 
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 
relative to whether or not the baseline value was normal, low, or high. These summaries will be 
presented by laboratory test. 
The laboratory parameters given in Table 2-15 will be analyzed with respect to numerical 
Common Terminology Criteria for Adverse Event (CTCAE) grades (version 5.0). 
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. 
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;  
Serum amylase 
increased 
Amylase 
>ULN - 1.5 x 
ULN 
>1.5 - 2.0 x 
ULN 
>2.0 - 5.0 x ULN 
>5.0 x ULN  
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 
Platelet count 
decreased  
Platelet 
<LLN-
75,000/mm;  
<75,000- 
50,000/mm3;  
<50,000- 
25,000/mm3;  
<25,000/mm3;  
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 
Creatine 
phosphokinase 
(CPK) 
Creatine 
phosphokinase 
>ULN - 2.5 x 
ULN 
>2.5 x ULN - 5 
x ULN 
>5x ULN - 10 x 
ULN 
>10 x ULN 
White blood cell 
decreased  
White blood cell 
<LLN- 
3000/mm3;  
<3000- 
2000/mm3;  
<2000- 
1000/mm3;  
<1000/mm3;  


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CTCAE term 
Laboratory 
assessment 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Lipase increased 
Lipase 
>ULN - 1.5 x 
ULN 
>1.5 - 2.0 x 
ULN; 
>2.0 - 5.0 x ULN  >5.0 x ULN  
Hemoglobin 
increased 
Hemoglobin 
>0 - 2 g/dL 
>2 - 4 g/dL 
>4 g/dL 
- 
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;  
 
Lymphocyte 
count increased  
lymphocytes  
-  
>4000/mm3 - 
20,000/mm3 
>20,000/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 x 
baseline; >3.0 - 
6.0 x ULN  
 
>6.0 x ULN  
Blood bilirubin 
increased 
Total bilirubin 
(TBL) 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN  
>3.0 - 10.0 x 
ULN 
>10.0 x ULN  
GGT increased 
Gamma-glutamyl 
transferase 
(GGT) 
>ULN - 2.5 x 
ULN  
>2.5 - 5.0 x 
ULN  
>5.0 - 20.0 x 
ULN  
>20.0 x ULN  
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  
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, e.g. 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. 
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 


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Parameter 
Criterion 
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 participant and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by visit. 
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. 
The number and percentage of participants with the following criteria will be summarized: 
• QT Interval > 500 msec;  
• Absolute QTc (Fridericia’s) interval > 450 msec (males), absolute QTc (Fridericia’s) 
interval > 460 msec (females);  
• 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% 
2.7.4.2 
Vital signs 
All vital signs data will be listed by participant, and visit/time and if ranges are available, 
abnormalities (and relevant changes) will be flagged. Summary statistics will be provided by 
visit. 
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: 


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• change from baseline = post-baseline value – baseline value 
The number and percentage of participants with clinically notable vital signs changes from 
baseline will be presented. Clinically notable vital sign results are provided in Table 2-18 below. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 


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• 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
 
  
 
 
 
 
 
 
 
 
 
: 
• 
 
 
 
• 
 
  
 
 
  


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2.12 
 Other Exploratory analyses 
Not applicable. 


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2.13 
Interim analysis 
A primary analysis may be conducted when all participants have completed their Week 4 visit 
or discontinued early. It will focus on ABPM, safety 
. The results of the primary 
analysis will further inform decision making for the remibrutinib development program. 
 
 
4 
Change to protocol specified analyses 
Demographics and baseline characteristics will be reported using the Enrolled analysis set 
instead of the SAF. 
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:  


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a. If AE ‘month’ is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).  
b. Else if AE ‘month’ is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).  
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore:  
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).  
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).  
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:  
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).  


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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.  
5.1.3.1 
Prior therapies date imputation 
Not applicable. 
5.1.3.2 
Post therapies date imputation 
Not applicable. 
5.1.3.3 
Concomitant therapies 
Please see Section 5.1.3. 
5.1.3.4 
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). 
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. 


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5.4 
Statistical models 
Summary statistics for continuous variables (including N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum) will be provided for continuous data by visit. 
If applicable and not otherwise stated, means +/- SE will be plotted. If appropriate, summary 
statistics will also be derived for absolute and percentage changes from baseline. 
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies. If applicable, confidence intervals 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, 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
. 
Note: if L > (100 x p) then L = (100 x p) and if U < (100 x p) then U = (100 x p). 
p
q
−
=1
(
),
0
for
0
,0
=
=

p
L
p
(
),
1
for
1
,1
=
=

p
U
p


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5.5 
Rule of exclusion criteria of analysis sets  
Table 5-2 
Subject Classification 
Analysis Set 
PD ID that 
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
Enrolled 
analysis set 
Not enrolled/Mis-enrolled/serious GCP violation at 
site 
FAS 
Not in the enrolled analysis set; 
SAF 
Not in the enrolled analysis set; No study drug taken 
* Written informed consent must be obtained before any assessment is performed. 


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6 
Reference 
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453. 
ICH E9(R1) Harmonized Guideline: addendum on estimands and sensitivity analysis in 
clinical trials to the guideline on statistical principles for clinical trials. Final version on 20 
November 2019.  
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Stat Med; 17(8):857–72. 
Rubin DB (1987) Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons, Inc. 
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867