Clinical trial NCT04109313
Conditions: Chronic Spontaneous Urticaria
Keywords: Chronic spontaneous urticaria BTK Inhibitor Long term safety Urticaria activity score
Sponsor: Novartis Pharmaceuticals
Start date: 2019-10-24; Completion date: 2022-09-09
Enrollment: 229 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective to assess the long-term safety and tolerability of LOU064 in patients with chronic spontaneous urticaria (CSU) who have participated in study CLOU064A2201 (NCT03926611)

Detailed description:
This was an open-label, single-arm, multicenter, long-term safety and tolerability extension study for CSU patients rolling over from study CLOU064A2201 (NCT03926611).

Subjects rolling over from CLOU064A2201 with a weekly Urticaria Activity Score (UAS7)\<16 after the follow-up period at Week 16 were further followed up without receiving LOU064 for up to 12 weeks (observational period). If there was a relapse (UAS7≥16 at least once), the 12-week observational period was terminated, and subjects entered the treatment period. Subjects who never relapsed within 12 weeks completed the study after the observational period without treatment.

Subjects who rolled over from CLOU064A2201 with a UAS7≥16 at Week 12 or Week 16, as well as those subjects who relapsed during the 12-week observational period, were treated with 100 mg LOU064 twice a day (b.i.d.) open-label for 52 weeks. No background medication with a second-generation H1-antihistamine was permitted up to Week 4 of the treatment period. Subjects who completed the treatment period or who discontinued treatment early were followed-up for a minimum duration of 4 weeks. Subjects who had a UAS7≤6 at Week 52 of the treatment period had their follow-up period extended until relapse (UAS7≥16) for up to a total of 16 weeks.

Arms: arm 1: Participants with UAS7\<16 at Week 16 of CLOU064A2201 were followed up to 12 weeks without receiving treatment (observational period). If participants relapsed (UAS7≥16 at least once), they were transitioned to the treatment period. Otherwise, they were discontinued from the study.

Participants with a UAS7≥16 at Week 12 or Week 16 in the CLOU064A2201, as well as participants who experienced a relapse during the 12-week observational period, were administered 100 mg of LOU064 b.i.d. open-label for up to 52 weeks.
Interventions: intervention 1: LOU064
Intervention descriptions: intervention 1: Participants with a UAS7≥16 at Week 12 or Week 16 in the CLOU064A2201, as well as participants who experienced a relapse during the 12-week observational period, were administered LOU064 50mg capsules b.i.d. (i.e. two capsules of LOU064 50mg in the morning and two capsules of LOU064 50mg in the evening) from Day 1 up to Week 52 of the Treatment period.

Protocol documents:
Prot_000.pdf: 


Novartis
Confidential
Page 2
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol Amendment 3 (08-Sep-2021).....................................................................................12
Protocol Amendment 2 (05-Apr-2021) ....................................................................................13
Local Protocol Amendment 1 (for Canada only, 30-Oct-2019)........................................15
Protocol Amendment 1 (02-Oct-2019)..............................................................................16
Protocol summary..............................................................................................................18
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose ..................................................................................................................21
2
Objectives and endpoints...................................................................................................22
3
Study design ......................................................................................................................23
4
Rationale............................................................................................................................25
4.1
Rationale for study design .....................................................................................25
4.1.1
Rationale for choice of background therapy.........................................25
4.2
Rationale for dose/regimen and duration of treatment ..........................................26
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................26
26
4.5
Risks and benefits..................................................................................................26
4.6
Rationale for Public Health Emergency mitigation procedures ............................29
5
Population..........................................................................................................................29
5.1
Inclusion criteria ....................................................................................................29
5.2
Exclusion criteria...................................................................................................30
6
Treatment...........................................................................................................................32
6.1
Study treatment......................................................................................................32
6.1.1
Investigational and control drugs..........................................................32
6.1.2
Additional study treatments ..................................................................33
6.1.3
Treatment arms/group ...........................................................................33
6.1.4
Treatment duration................................................................................33
6.2
Other treatment(s)..................................................................................................33
6.2.1
Concomitant therapy.............................................................................33
6.2.2
Prohibited medication ...........................................................................34


Novartis
Confidential
Page 3
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
35
6.3
Subject numbering, treatment assignment, randomization....................................35
6.3.1
Subject numbering ................................................................................35
6.3.2
Treatment assignment, randomization ..................................................35
6.4
Treatment blinding.................................................................................................35
6.5
Dose escalation and dose modification..................................................................35
6.6
Additional treatment guidance...............................................................................35
6.6.1
Treatment compliance...........................................................................35
6.6.2
Emergency breaking of assigned treatment code..................................36
6.7
Preparation and dispensation.................................................................................36
6.7.1
Handling of study treatment and additional treatment..........................36
6.7.2
Instruction for prescribing and taking study treatment .........................37
7
Informed consent procedures ............................................................................................37
8
Visit schedule and assessments .........................................................................................38
8.1
Screening ...............................................................................................................45
8.1.1
Information to be collected on screening failures.................................45
8.2
Subject demographics/other baseline characteristics.............................................45
8.3
Efficacy..................................................................................................................45
8.3.1
eDiary assessments................................................................................46
49
8.3.3
Appropriateness of efficacy assessments..............................................49
8.4
Safety/Tolerability.................................................................................................49
8.4.1
Laboratory evaluations..........................................................................50
8.4.2
Electrocardiogram (ECG) .....................................................................51
8.4.3
Pregnancy..............................................................................................52
8.4.4
Other safety evaluations........................................................................52
8.4.5
Appropriateness of safety measurements..............................................52
.52
52
53
9
Study discontinuation and completion ..............................................................................53
9.1
Discontinuation......................................................................................................53
9.1.1
Discontinuation of study treatment .......................................................53
9.1.2
Withdrawal of informed consent...........................................................55
9.1.3
Lost to follow-up...................................................................................55
9.1.4
Early study termination by the sponsor.................................................55
9.2
Study completion and post-study treatment ..........................................................56


Novartis
Confidential
Page 4
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
10 Safety monitoring and reporting........................................................................................56
10.1
Definition of adverse events and reporting requirements......................................56
10.1.1
Adverse events ......................................................................................56
10.1.2
Serious adverse events ..........................................................................58
10.1.3
SAE reporting........................................................................................59
10.1.4
Pregnancy reporting ..............................................................................59
10.1.5
Reporting of study treatment errors including misuse/abuse................60
10.2
Additional Safety Monitoring................................................................................60
10.2.1
Liver safety monitoring.........................................................................60
10.2.2
Renal safety monitoring........................................................................61
10.2.3
Data Monitoring Committee .................................................................62
10.2.4
Steering Committee...............................................................................62
11 Data Collection and Database management......................................................................62
11.1
Data collection.......................................................................................................62
11.2
Database management and quality control............................................................62
11.3
Site monitoring ......................................................................................................63
12 Data analysis and statistical methods ................................................................................64
12.1
Analysis sets ..........................................................................................................64
12.2
Subject demographics and other baseline characteristics......................................64
12.3
Treatments .............................................................................................................65
12.4
Analysis of the primary endpoint(s) ......................................................................65
12.4.1
Definition of primary endpoint(s).........................................................65
12.4.2
Statistical model, hypothesis, and method of analysis..........................66
12.4.3
Handling of missing values/censoring/discontinuations.......................66
12.4.4
Sensitivity and Supportive analyses......................................................66
12.5
Analysis of secondary endpoints ...........................................................................67
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................67
12.5.2
Safety endpoints....................................................................................67
67
68
12.8
Sample size calculation..........................................................................................69
12.8.1
Primary endpoint(s)...............................................................................69
12.8.2
Secondary endpoint(s)...........................................................................69
13 Ethical considerations and administrative procedures ......................................................69
13.1
Regulatory and ethical compliance........................................................................69
13.2
Responsibilities of the investigator and IRB/IEC..................................................69
13.3
Publication of study protocol and results...............................................................69


Novartis
Confidential
Page 5
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
13.4
Quality Control and Quality Assurance.................................................................70
14 Protocol adherence ............................................................................................................70
14.1
Protocol Amendments ...........................................................................................70
15 References .........................................................................................................................71
16 Appendices ........................................................................................................................73
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................73
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................74
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......77
16.4
Appendix 4: Prohibited medications .....................................................................79
80
85
List of tables
Table 2-1
Objectives and related endpoints ..........................................................22
Table 6-1
Investigational drug...............................................................................32
Table 6-2
Prohibited medication ...........................................................................34
Table 8-1
Assessment Schedule, Treatment period and Follow-up period...........40
Table 8-2
Assessment Schedule, Observational period.........................................43
Table 8-3
UPDD....................................................................................................46
Table 8-4
Hives Severity Score.............................................................................47
Table 8-5
Itch Severity Score ...............................................................................47
47
47
49
Table 8-9
Physical Assessments...........................................................................50
Table 8-10
Laboratory assessments........................................................................51
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................60
69
Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................74
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers...74
Table 16-3
Specific renal alert criteria and actions.................................................77
Table 16-4
Renal event follow-up...........................................................................78
Table 16-5
Moderate and strong inhibitors of CYP3A4 .........................................79
Table 16-6
Moderate and strong inducers of CYP3A4 ...........................................79
85


Novartis
Confidential
Page 6
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
85
List of figures
Figure 3-1
Study design..........................................................................................24
Figure 3-2
Patient flow from CLOU064A2201......................................................25


Novartis
Confidential
Page 7
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
List of abbreviations
AE
Adverse Event
Alb
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AV block
Atrioventricular block 
BCR
B Cell Receptor
BCRP
Breast cancer resistance protein
b.i.d.
bis in die / twice a day
BP
Blood Pressure
BTK
Bruton’s Tyrosine Kinase
BTKi
Bruton’s Tyrosine Kinase Inhibitor
BUN
Blood Urea Nitrogen
CK
Creatine Kinase
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
COA
Clinical Outcomes Assessment
COVID-19
Coronavirus Disease of 2019
CRA
Clinical Research Associate
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
CYP
Cytochrome P
DBP
Diastolic Blood Pressure
DDE
Direct Data Entry
DDI
Drug-Drug Interaction
DIN
Drug-Induced Nephrotoxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
eSource 
Electronic Source 


Novartis
Confidential
Page 8
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
EU
European Union
FAS
Full Analysis Set
FcεR
Fc epsilon receptor
FcγR
Fc gamma receptor
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
hour
HCP
Health Care Professional
HDL
High-Density Lipoprotein
hERG
human Ether-à-go-go Related Gene
HIV
Human immunodeficiency Virus
HRQoL
Health-Related Quality of Life
HSS7
Weekly Hives Severity Score
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IMP
Investigational Medical 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
i.v.
intravenous
LDH
lactate dehydrogenase
LDL
Low-Density Lipoprotein
LFT
Liver function test 
LLOQ
lower limit of quantification
MAD
Multiple Ascending Dose
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)


Novartis
Confidential
Page 9
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
MRI
Magnetic Resonance Imaging
ng
Nanogram(s)
NOAC
Novel Oral Anti-Coagulant
NOAEL
No-Observed Adverse Event Level
NSAID
Nonsteroidal Anti-Inflammatory Drug
PCR
Protein-creatinine ratio
PD
Pharmacodynamic(s)
P-gp
Permeability glycoprotein, P-glycoprotein
PT
prothrombin time
q.d.
quaque die / once a day
QMS
Quality Management System
QoL
Quality of Life
QTcF
QT interval corrected by Fridericia’s formula
RBC
Red Blood Cell(s)
RNA
Ribonucleic Acid
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SC
Steering Committee
sCr
Serum Creatinine
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SOP
Standard Operating Procedure
SPT
Skin Prick Test
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total Bilirubin
UAS
Urticaria Activity Score
ULN
Upper Limit of Normal
ULOQ
Upper Limit Of Quantification
UPDD
Urticaria Patient Daily Diary
US
United States (of America)
UTI
Urinary Tract Infection
WBC
White Blood Cell(s)
WHO
World Health Organization 
WoCBP
Women of Child-Bearing Potential
XLA
X-linked Agammaglobulinemia


Novartis
Confidential
Page 10
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy).
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject 
Cohort
A specific group of subjects fulfilling certain criteria and generally treated 
at the same time
Control drug
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care.
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last subject or 
at a later point in time as defined by the protocol. 
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits. 
eSource combines source documents and case report forms (CRFs) into 
1 application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to be 
a study participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
subjects
Mis-randomized subjects are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study.
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in subjects with established 
disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study phases 
and will be used in clinical trial database setup and eventually in analysis.


Novartis
Confidential
Page 11
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned.
Randomization number
A unique identifier assigned to each randomized subject
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject.
Study treatment
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; 
may or may not also be the point/time of study discontinuation 
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of study 
consent 
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data






Novartis
Confidential
Page 14
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1

Section 4.6 added for Public Health Emergency mitigation procedures. Section 6.7, 
Section 7, Section 8, Section 8.3, Section 8.4, Section 8.4.1, Section 8.4.3 and Section 
8.5.2 have been updated accordingly. Section 5.2 - Deletion of exclusion criterion #11 
pertaining to male contraception. All other relevant sections of the protocol have been 
updated to reflect this change (Section 4.5, Section 7, Section 8.4.3 and Section 10.1.4).
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority
approval according to local regulations prior to implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for
approval a revised Informed Consent that takes into account the changes described in this
protocol amendment.


Novartis
Confidential
Page 15
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Local Protocol Amendment 1 (for Canada only, 30-Oct-2019)
The purpose of this amendment is to:
1) Add a threshold for the estimated glomerular filtration rate (eGFR) to exclusion criterion #22
2) Update actions after detection of a renal adverse event.
Changes to protocol and rationale
Section 5.2 Exclusion criteria: Following the recommendation of Health Canada for 
the preceding core study (CLOU064A2201), an eGFR <45 ml/min threshold was added
to exclusion criterion #22.
Section 8.4.1 Laboratory evaluation: eGFR added to Table 8-10 Laboratory 
assessments.
Section 10.2.2 Renal safety monitoring: Following the recommendation of Health 
Canada for the preceding core study (CLOU064A2201), the timelines after detection of
a renal adverse event have been changed.
Section 16.3 Appendix 3: Specific renal alert criteria and actions and event 
follow-up: Following the request of Health Canada for the preceding core study 
(CLOU064A2201), necessary actions after the detection of a renal adverse event have 
been clarified and a rise of serum creatinine ≥50% compared to baseline now leads to a 
mandatory interruption of the investigational treatment.


Novartis
Confidential
Page 16
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Protocol Amendment 1 (02-Oct-2019) 
The main purpose of this amendment is to address requests from health authorities and to align 
eligibility criteria of this study with amended eligibility criteria of the preceding core study 
CLOU064A2201:

Deletion of inclusion criterion #4 (this change triggers several changes throughout the 
document, including changing the study title, modification of inclusion criterion #3 
 
).

Lowering the minimum required resting heart rate to 50 bpm (from 60 bpm) to align with 
amended exclusion criterion #6b in CLOU064A2201. This also aligns the eligibility 
criterion for resting heart rate with normal resting heart rates of CSU patients and does not 
impact patient safety as LOU064 does not have a negative chronotropic effect.

Clarification that investigators need to assess the benefit-risk ratio for each subject 
throughout the study. Both, lack of or inadequate treatment response and/or emergence of 
adverse events that outweigh the benefits, can lead to study treatment discontinuation.

Adding urine pregnancy testing every 4 weeks with at home assessments between study 
visits for women of childbearing potential starting after the Week 20 visit of the treatment 
period.
Additionally, editorial errors were addressed and clarity was improved.
As the study population is affected, the changes described in this amended protocol require 
IRB/IEC approval prior to implementation. Additionally, some changes affect the Informed 
Consent. Sites are required to update and submit for approval a revised Informed Consent that 
takes into account the changes described in this protocol amendment.
Changes to protocol and rationale
Changes are shown in the track changes version of the protocol using strike through red font 
for deletions and red underlined for insertions. 

Section 5.1: Following a request from health authorities, inclusion criterion #4 (i.e. 
rollover of patients from not-yet specified studies with LOU064) was deleted. 
Additionally, inclusion criterion #3 needed to be updated to inclusion criterion #3a in 
order to clarify, that all subjects must have completed the Week 12 or Week 16 visit of 
CLOU064A2201 prior to enrollment into this extension study. As no patients from other 
studies can rollover from other not-yet specified preceding studies anymore, the 
reference to other preceding studies needed to be deleted in several sections of the 
protocol:
o
Protocol title
o
Section 1.2 (Purpose)
o
Section 2 (Objectives and Endpoints, including Table 2-1)
o
Section 3 (Study Design, including Figure 3-1)
o
Section 5 (Population)
o
Section 12.8.1 (Primary Endpoints, in Section 12.8, Sample size calculation)

Section 5.2, exclusion criterion #6 has been updated to exclusion criterion #6a: This 
exclusion criterion aims to exclude patients with a pre-existing cardiac risk from 






Novartis
Confidential
Page 19
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
to the treatment period or the observational period of CLOU064A2201E1 based 
on the UAS7 score (of the 7 days prior to the respective visit) as follows:

Subjects rolling over at Week 12 of CLOU064A2201 with a UAS7≥16 will be 
allocated to the Treatment period (note: subjects with UAS7<16 at Week 
12 are not eligible to roll-over into CLOU064A2201E1 but need to enter 
the follow-up period of CLOU064A2201).

Subjects rolling over at Week 16 of CLOU064A2201 with a UAS7≥16 will be 
allocated to the Treatment period.

Subjects rolling over at Week 16 of CLOU064A2201 with a UAS7<16 will be 
allocated to the Observational period.
Key Exclusion 
criteria
Subjects having a clearly defined predominant or sole trigger of their chronic 
urticaria (chronic inducible urticaria) including urticaria factitia (symptomatic 
dermographism), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, 
cholinergic-, or contact-urticaria
Other diseases with symptoms of urticaria or angioedema, including but not limited 
to urticaria vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, 
hereditary urticaria, or acquired/drug-induced urticaria
Any other skin disease associated with chronic itching that might influence in the 
investigators opinion the study evaluations and results, e.g. atopic dermatitis, 
bullous pemphigoid, dermatitis herpetiformis, senile pruritus or psoriasis
History or current diagnosis of ECG abnormalities indicating significant risk of 
safety for subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained 
ventricular tachycardia, and clinically significant second or third degree AV 
block without a pacemaker

History of familial long QT syndrome or known family history of Torsades de 
Pointes

Resting heart rate (as measured by 12 lead ECG) < 50 bpm

Resting QTcF ≥450 msec (male) or ≥460 msec (female) at day 1 of the 
treatment period or inability to determine the QTcF interval

Use of agents known to prolong the QT interval unless it can be permanently 
discontinued for the duration of study
Significant bleeding risk or coagulation disorders
Known or suspected history of an ongoing, chronic or recurrent infectious disease 
including but not limited to opportunistic infections (e.g. tuberculosis, atypical 
mycobacterioses, listeriosis or aspergillosis), HIV, Hepatitis B/C
Study 
treatment
LOU064 capsules 50 mg
Efficacy 
assessments

Urticaria Patient Daily Diary (UPDD), including Urticaria Activity Score (UAS)




Novartis
Confidential
Page 21
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
1
Introduction
1.1
Background
Chronic Spontaneous Urticaria (CSU) is defined as the spontaneous occurrence of itchy wheals 
(hives), angioedema or both lasting for at least 6 weeks (Zuberbier et al 2018). The classic 
description of urticaria is a wheal and flare with a pale elevated lesion and surrounding erythema, 
ranging in size from a few millimeters to a few centimeters across, usually occurring in groups 
and often coalescing to form large confluent lesions. CSU can be debilitating and is associated 
with intense itching and has a major impact on patient’s well-being, suggested to be comparable 
to that of severe coronary artery disease (Greaves 2003). The symptoms of urticaria and 
urticarial-associated angioedema adversely affect daily activities and sleep (O'Donnell et 
al 1997). The burden of CSU on health-related quality of life (HRQoL) and work productivity 
is substantial (Maurer et al 2017).
Second generation H1-antihistamines are recommended as first line treatment for subjects with 
CSU but less than 40% of these subjects respond adequately (Guillén-Aguinaga et al 2016). 
While uptitration of second generation antihistamines is recommended by most CSU treatment 
guidelines as second line therapy (Zuberbier et al 2018), the efficacy of uptitrated H1-
antihistamines in CSU, beyond the approved label dose, has not been studied in larger clinical 
studies. Omalizumab is a highly effective third line therapy for CSU subjects. However, less 
than 50% of subjects treated with omalizumab reach a complete control of signs and symptoms 
of CSU (Kaplan et al 2016). Therefore, there is a high medical need for new treatment options 
for CSU subjects.
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and member of the TEC kinase 
family. BTK is expressed in selected cells of the adaptive and innate immune system including 
B cells, macrophages, mast cells/basophils and thrombocytes. BTK is indispensable for 
signaling through the Fc epsilon receptor (FcεR1 for IgE) and the activating Fc gamma 
receptors (FcγR for IgG), as well as the B cell antigen receptor (BCR) and BTK inhibitors 
(BTKi) like ibrutinib are approved for the treatment of B cell malignancies 
(Hendriks et al 2014). Recently, it has been demonstrated that inhibition of BTK leads to 
inhibition of mast cell and basophil activation/degranulation in vitro and to reduced wheal sizes 
in skin prick tests with patients suffering from IgE-mediated allergies (Smiljkovic et al 2017; 
Regan et al 2017; Dispenza et al 2018). Thus, BTK inhibition is a promising therapeutic 
concept for the treatment of chronic urticaria.
LOU064 is a low molecular weight compound for oral administration that covalently binds and 
inhibits BTK with high selectivity. It has been shown to effectively inhibit basophil activation 
in healthy volunteers and CSU patients as measured by the inhibition of CD63 up-regulation. 
Additionally, LOU064 reduced wheal sizes in skin prick tests. The pre-clinical and clinical 
safety profile of LOU064 is favorable (for detailed information please refer to the Investigator`s 
Brochure (IB)). Thus, LOU064 may offer a novel therapeutic option for treating CSU.
1.2
Purpose
The purpose of this study is to evaluate long-term safety and tolerability as well as efficacy 
outcome of LOU064 in patients who roll-over from CLOU064A2201. 
 




Novartis
Confidential
Page 23
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
3
Study design
This study is an open-label, single arm, multicenter, long-term safety and tolerability extension 
study for CSU patients rolling-over from CLOU064A2201. It consists of three periods (Figure 
3-1):

Observational period: Subjects rolling over from CLOU064A2201 with UAS7<16 after 
the follow-up period at Week 16 will be further followed up without receiving LOU064 
for up to 12 weeks. After relapse (UAS7≥16 at least once), the observational period can be 
terminated immediately at any time during these 12 weeks and subjects may enter the 
treatment period. Continuation of background therapy with an H1-antihistamine is at the 
discretion of the investigator; however, background therapy should only be interrupted in 
subjects with controlled CSU (e.g. UAS7≤6). Subjects who have never relapsed within 12 
weeks will discontinue the study after the observational period.

Treatment period: Subjects will be treated with 100 mg LOU064 bid for 52 weeks. Until 
Week 4 of treatment, no background medication with H1-antihistamines is permitted. 
After Week 4, subjects may start a background therapy with H1-antihistamines if deemed 
necessary by the investigator.

Follow-up period: Treatment-free follow-up period following the treatment period. The 
minimum duration of treatment-free follow-up is 4 weeks for all subjects who stop 
treatment with LOU064 (either after completing the treatment period or after an early 
discontinuation of study treatment). Subjects who have a UAS7≤6 at Week 52 of the 
treatment period will extend their follow-up period until relapse (UAS7≥16) for up to a 
total of 16 weeks.
Rescue therapy to treat unbearable symptoms of urticaria on a day-to-day basis with an 
H1-antihistamine will be allowed throughout the study. A post-trial access program (which may 
be another extension study or a managed access program) for subjects who complete this study 
is under consideration.


Novartis
Confidential
Page 24
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Figure 3-1
Study design
1) Only when UAS7<16 at Week 16 of CLOU064A2201: Treatment-free observational period for up to 
12 weeks. After relapse (UAS7≥16 at least once), subjects may immediately initiate treatment period. 
Subjects who have never relapsed within 12 weeks will discontinue the study after the observational 
period. 
2) The minimum duration of the follow-up period will be 4 weeks for all subjects who stop treatment 
with LOU064. Subjects who achieve a UAS7≤6 at Week 52 of the treatment period will extend their 
follow-up period until they relapse (UAS7≥16). Follow-up will stop at Week 68 for all subjects.
3) Background therapy is a second generation H1-antihistamine at a locally approved licensed 
posology given with a stable treatment regimen. Administration/discontinuation of the background H1-
antihistamine is at the discretion of the investigator. Background therapy must not be taken from Day 1 
until Week 4 of the Treatment period. It may be re-initiated at Week 4 if deemed necessary.
4) Rescue therapy is a second generation H1-antihistamine at a locally approved licensed posology 
that is eliminated primarily via renal excretion (e.g. cetirizine, levocetirizine or bilastine). The rescue 
H1-antihistamine must differ from the background H1-antihistamine and may only be given to treat 
unbearable symptoms (itch) of CSU on a day-to-day basis.
Subjects rolling over from CLOU064A2201 will be assigned to one of the periods as follows 
(Figure 3-2):

Subjects with a UAS7≥16 at Week 12 or Week 16 will directly enter the treatment period.

Subjects with a UAS7 < 16 at Week 12 will not rollover into the extension study but enter 
the follow-up period of the core study CLOU064A2201.

Subjects with a UAS7<16 at Week 16 (i.e., who have not relapsed during the follow-up 
period of CLOU064A2201) will be assigned to the observational period.






Novartis
Confidential
Page 27
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
BTK inhibition may offer a new therapeutic principle for treating CSU that differs significantly 
from H1-antihistamines and anti-IgE biologics. BTK inhibition with LOU064 may therefore 
offer treatment options for patients with contraindications against or having an inadequate 
response to approved treatment options for CSU including biologics.
To date, 213 healthy volunteers have received LOU064 up to 600 mg q.d. for up to 18 days in 
four studies. In the study CLOU064X2101, 30 healthy volunteers received total daily doses 
≥100 mg for a period of 12 days. No serious or severe AE have been associated with the 
administration of LOU064, the majority of observed AEs were singular events and there was 
no relationship between LOU064 doses and AEs or the number of all observed AEs. A summary 
of AEs and of the pre-clinical safety data can be found in the Investigator’s Brochure (Sections 
4.3 and 5.2).
Based on a thorough review of safety information currently available in the literature together 
with an assessment of safety data obtained from both clinical and preclinical experience with 
LOU064, the following safety topics are considered as potential risks for LOU064 and require 
close monitoring in the proposed study. Of important note, many safety risks identified for 
ibrutinib and acalabrutinib, two BTK inhibitors approved for the treatment of B cell 
malignancies, are less likely related to the pharmacology of inhibition of the BTK, but rather to 
the underlying indications being treated, for example, tumor lysis syndrome, second primary 
malignancies, etc. Therefore, when comparing the safety risks between the approved BTKi 
(e.g.: ibrutinib and acalabrutinib) and LOU064, the relevance and importance of the study 
patient populations must be taken into consideration.

Infections: BTK is an important signaling kinase downstream of cell surface receptors and 
expressed in several immune cells of the adaptive and innate system, including B cells, 
macrophages and mast cells/basophils. Therefore, LOU064 has the potential to increase 
the risk of infections. Patients with X-linked agammaglobulinemia (XLA) – a genetic 
defect associated with a lack of BTK – suffer from recurrent bacterial and enteroviral 
infections which may be associated with neutropenia (Kumar et al 2006). However, in 
XLA BTK-deficiency leads to impaired B cell and plasma cell development and in turn to 
a close to complete absence of immunoglobulins. Since BTK is not expressed in mature 
plasma cells, it is not expected that BTK inhibition in adults would lead to rapid or marked 
decrease in total immunoglobulin levels within the study time-frame. (Hendriks et al 2014; 
Sun et al 2015; Nutt et al 2015). Administration of ibrutinib and acalabrutinib is associated 
with a risk of infection in patients suffering from B cell malignancies (see Summary of 
Product Characteristics (SmPC) for ibrutinib and acalabrutinib). All patients participating 
in LOU064 clinical studies will be monitored closely for signs and symptoms of infections 
while in the study. Patients with a known history of chronic recurrent or active ongoing 
infections will be excluded from the study (refer to Section 5.2 for details).

Impaired platelet function: BTK is a signaling kinase in one of several platelet activation 
pathways. In the prescribing information for both ibrutinib and acalabrutinib, 
bleeding/bruising events are very common and affecting approximately 50% of patients 
with hematologic malignancies. Warnings on hemorrhagic events including deaths have 
also been described (see SmPC for ibrutinib and acalabrutinib). Compared to other drugs 
in the same class, LOU064 demonstrated a higher selectivity for BTK vs. other TEC 
kinases. Thus, bleeding may be less a safety concern when compared to ibrutinib and 
acalabrutinib. Patients receiving LOU064 must be closely monitored for any signs and 




Novartis
Confidential
Page 29
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
acalabrutinib, embryofetal toxicity in animals is reported (see SmPCs). Highly effective 
methods of contraception must be practiced for women of child-bearing potential while 
taking study treatment and for 7 days after stopping study medication.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not enter or continue in the study.
In summary, CSU patients with inadequate response to H1-antihistamines and other available 
treatment options participating in this clinical trial may benefit from treatment with LOU064 
due to its impact on mast cell and basophil activation. Additionally, this study will help improve 
the scientific understanding of LOU064 in the management of CSU and offer the potential of 
developing an innovative drug that could potentially improve the quality of life for CSU patients 
beyond the conventional treatment modalities currently available to them. Potential risks are 
mitigated by compliance with inclusion/exclusion criteria, study procedures, close clinical 
monitoring and study drug discontinuation rules. As with investigational drugs in general, not 
all safety risks are known. Patients and investigators participating in this study will be informed 
should important new safety information become available.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities, i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.
5
Population
The study population will consist of male and female adult CSU patients who received various 
doses of LOU064 or placebo in the core study (CLOU064A2201). Subjects with a UAS7 ≥ 16 
at Week 12 or Week 16 of the core study will directly enter the treatment period whereas 
subjects with a UAS7 < 16 at Week 16 of the core study will be allocated to the observational 
period (see Section 3). In theory, all expected 308 patients from the core trial CLOU064A2201 
could enter the extension protocol. However, we estimate that approximately 250 patients will 
enroll into this extension study. 
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Willing and able to complete a daily symptom eDiary for the duration of the study and 
adhere to the study visit schedules.
3a Subjects must have completed the Week 12 visit (end of treatment period) or the Week 16 
visit (end of the follow-up period) of CLOU064A2201 and will be allocated to the 


Novartis
Confidential
Page 30
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
treatment period or the observational period of CLOU064A2201E1 based on the UAS7 
score (of the 7 days prior to the respective visit) as follows:

Subjects rolling over at Week 12 of CLOU064A2201 with a UAS7≥16 will be 
allocated to the Treatment period (note: subjects with UAS7<16 at Week 12 are not 
eligible to rollover into CLOU064A2201E1 but need to enter the follow-up period of 
CLOU064A2201).

Subjects rolling over at Week 16 of CLOU064A2201 with a UAS7≥16 will be 
allocated to the Treatment period.

Subjects rolling over at Week 16 of CLOU064A2201 with a UAS7<16 will be 
allocated to the Observational period.
5.2
Exclusion criteria
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days (for 
small molecules) prior to enrollment or until the expected pharmacodynamic (PD) effect 
has returned to baseline (for biologics), whichever is longer; or longer if required by local 
regulations.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
3. Subjects 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
4. Other diseases with symptoms of urticaria or angioedema, including but not limited to 
urticaria vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary 
urticaria, or acquired/drug-induced urticaria
5. Any other skin disease associated with chronic itching that might influence in the 
investigators opinion the study evaluations and results, e.g. atopic dermatitis, bullous 
pemphigoid, dermatitis herpetiformis, senile pruritus or psoriasis
6a History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes

Resting heart rate (as measured by 12 lead ECG) < 50 bpm at day 1 of treatment

Resting QTcF ≥450 msec (male) or ≥460 msec (female) at day 1 of the treatment 
period or inability to determine the QTcF interval

Use of agents known to prolong the QT interval unless they can be permanently 
discontinued for the duration of study
7. Patients/subjects taking medications prohibited by the protocol 
(see Section 6.2.2, Table 6-2)


Novartis
Confidential
Page 31
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
8. 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.
9. Pregnant or nursing (lactating) women
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 7 days after stopping study medication. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). 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 tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six 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.
11. Exclusion criterion had become irrelevant.
12. Major surgery within 8 weeks prior to enrollment or surgery planned prior to end of the 
treatment period.
13. History of live attenuated vaccine within 6 weeks prior to enrollment or requirement to 
receive these vaccinations at any time during study drug treatment
14. Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, 
hepatic, endocrine, metabolic, hematological disorders or gastrointestinal disease that, in 
the investigator's opinion, would compromise the safety of the participant, interfere with 
the interpretation of the study results or otherwise preclude participant participation.
15. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares 
are commonly treated with oral or parenteral corticosteroids
16. Hematology parameters at last visit before Day 1 of the Treatment period (either last 
available value from CLOU064A2201 or most recent value taken during observational 
period):


Novartis
Confidential
Page 32
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1

Hemoglobin: < 10 g/dl

Platelets: < 100 000/mm3

White blood cells: < 3 000/mm3

Neutrophils: < 1 500/mm3
17. Significant bleeding risk or coagulation disorders
18. History of gastrointestinal bleeding, e.g. in association with use of Nonsteroidal Anti-
Inflammatory Drug (NSAID)
19. Requirement for anti-platelet or anticoagulant medication (for example, warfarin, or 
clopidogrel or Novel Oral Anti-Coagulant - NOAC) other than acetylsalicylic acid (up to 
100 mg/d)
20. History or presence of thrombotic or thromboembolic event, or increased risk for 
thrombotic or thromboembolic event
21. History or current treatment for 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) at last visit before Day 1 of the Treatment period (either last available value from 
CLOU064A2201 or most recent value taken during observational period)
22. History of renal disease or creatinine level above 1.5x ULN at last visit before Day 1 of 
the Treatment period (either last available value from CLOU064A2201 or most recent 
value taken during observational period)
[Canada only: History of renal disease, creatinine level above 1.5x ULN or eGFR 
<45ml/min (using the Cockcroft-Gault equation) at last visit before Day 1 of the 
Treatment period (either last available value from CLOU064A2201 or most recent value 
taken during observational period)]
23. Known or suspected history of an ongoing, chronic or recurrent infectious disease 
including but not limited to opportunistic infections (e.g. tuberculosis, atypical 
mycobacterioses, listeriosis or aspergillosis), HIV, Hepatitis B/C
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects
6
Treatment
6.1
Study treatment
Novartis Global Clinical Supply (GCS) will provide the IMP for the study. Background and 
concomitant medication will not be supplied by Novartis GCS.
6.1.1
Investigational and control drugs
Table 6-1
Investigational drug
Investigational
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply type
Sponsor (global 
or local)
LOU064 50 mg
Hard gelatin 
capsule
Oral use
Open-label 
supplies, bottles
Novartis Pharma 
AG (Global)








Novartis
Confidential
Page 36
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
12 hours. The subject must also be instructed to contact the investigator if he/she is unable for 
any reason to take the study treatment as prescribed. Compliance with study treatment will be 
recorded by the subject in the eDiary. In addition, compliance will be assessed by the 
investigator and/or study personnel at each visit using capsules counts and information provided 
by the subject and captured in the source document at each visit. All study treatment dispensed 
and returned must be recorded in the Drug Accountability Log.
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs Section 6.1.1.
An IRT system would be used in the study for medication management purposes.
Investigator staff will identify the study medication kits to dispense to the subject 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 subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
At each dispensation visit, study personnel delegated for this activity would contact IRT and 
provide the patient with the assigned bottles to accommodate patient needs till the next 
dispensation visit. The number of bottles dispensed would vary depending on the duration 
between visits.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, delivery of IMP directly to a participant’s home may be permitted (if allowed by Local 
or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. The dispatch of IMP from the site to the participant’s 
home remains under the accountability of the Investigator. Each shipment/provisioning will be 
for a maximum of one-month supply. In this case, regular phone calls or virtual contacts (every 
4 weeks or more frequently if needed) will occur between the site and the participant for 
instructional purposes, safety monitoring, drug accountability, investigation of any adverse 
events, ensuring participants continue to benefit from treatment, and discussion of the 
participant’s health status until the participants can resume visits at the study site.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 




Novartis
Confidential
Page 38
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site, for which a separate 
signature is required if the participant agrees. It is required as part of this protocol that the 
Investigator presents this option to the participant, as permitted by national and local governing 
regulations. The process for obtaining consent should be exactly the same as described above 
for the main informed consent.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs
by trial participant and person obtaining informed consent, etc.).
8
Visit schedule and assessments
The assessment schedule lists all of the assessments and indicates with an “X” or “S”, the visits 
when they are performed. All data obtained from these assessments must be supported in the 
subject’s source documentation.


Novartis
Confidential
Page 39
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Subjects should be seen/contacted for all visits/assessments as outlined in the assessment 
schedule or as close to the designated day/time as possible. Missed or rescheduled visits should 
not lead to automatic discontinuation.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/home nursing 
staff to the participant’s home can replace on-site study visits for the duration of the disruption 
until it is safe for the participant to visit the site again.










Novartis
Confidential
Page 44
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
X: recorded in the eCRF; S: recorded in the source documents only 
1 UPDD: Urticaria Patient Daily Diary; UAS: Urticaria Activity Score; 
3 Only assess if day 1 of observational period is more than 1 week after Week 16 of core study
4 If CSU relapse is detected at the visit: please directly perform an EoOP visit instead of the preplanned day 29 or day 57 visit
5 EoOP: End of Observational Period can be directly after a CSU relapse (defined as UAS7≥16) was detected (either during a scheduled or an unscheduled visit); in case, 
EoOP and day 1 of the treatment period are at the same day, assessments only need to be done once.


Novartis
Confidential
Page 45
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
8.1
Screening
At day 1 of the treatment period and at day 1 of the observational period (if applicable), all 
inclusion and exclusion criteria will be checked. For all laboratory assessments, the results from 
the last visit before Day 1 of the treatment period (either the last available value from 
CLOU064A2201 or most recent value taken during observational period) will be used. 
Eligibility for this study will be assessed at Week 12 and Week 16 of the preceding core study 
CLOU064A2201. Subjects who are not eligible for enrollment into this extension study at 
Week 12 for any reason will not be assigned to a subject number for this extension study but 
will enter the follow-up period of CLOU064A2201. Re-screening of subjects who are not 
eligible at Week 16 is not permitted. 
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason other 
than never relapsing during the observational period will be considered a screen failure. The 
reason for not being started on treatment will be entered on the screening phase disposition page. 
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure patients. No other data will be entered into the clinical database for 
patients who are screen failures, unless the patient experienced a serious adverse event during 
the screening phase (see SAE Section for reporting details). 
8.2
Subject demographics/other baseline characteristics
Baseline CSU activity will be assessed using the eDiary from Day -7 to Day -1 of the day 1 
visit of the treatment period. Subject demographic and baseline characteristic data including 
sex, race and ethnicity that was collected as a part of the core study will be used for this 
extension 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 subjects’ family history of malignancies will be collected on the respective 
eCRF page, only when a subject has a malignancy event reported during the study, to assess 
possible risk factors related to any malignancies.
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF.
8.3
Efficacy
All subjects will be provided with an electronic device (eDiary) that contains the following 
assessments: Urticaria Patient Daily Diary (UPDD), 
 
.
Site and subjects will receive appropriate training and guidance on the use of the eDiary and 
will receive clear instructions on the completion of the assessments. Investigators need to 
review the eDiary at every visit.
Assessments will be completed twice daily (UPDD), 
 
 or as detailed in the assessment schedule. 




Novartis
Confidential
Page 47
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Table 8-4
Hives Severity Score
Score
Hives (Wheals) (every 12 hours)
0
None
1
1-6 hives/12 hours
2
7-12/12 hours
3
> 12 hives/12 hours
8.3.1.1.2 Weekly Itch Severity Score (ISS7)
The severity of the itch will be recorded by the subject twice daily in their eDiary, on a scale of 
0 (none) to 3 (severe) (Table 8-5). A weekly score (ISS7) is derived by adding up the average 
daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 
0 - 21.
Table 8-5
Itch Severity Score
Score
Pruritus (Itch) (every 12 hours)
0
None
1
Mild (minimal awareness, easily tolerated)
2
Moderate (definite awareness, bothersome but tolerable)
3
Severe (difficult to tolerate)
8.3.1.1.3 Weekly Urticaria Activity Score (UAS7)
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly 
UAS7 score is 0 – 42 (highest activity).


Novartis
Confidential
Page 48
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1




Novartis
Confidential
Page 50
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Main safety and tolerability assessments include:

AEs and SAEs, including AEs leading to treatment discontinuation and events of interest 
such as infections, bleeding/bruising, QT-prolongation and myelomodulating effects (i.e. 
cytopenias)

Physical examination

Vital signs

Laboratory evaluations

ECG
Table 8-9
Physical Assessments
Assessment
Specification
Physical 
examination
A complete physical examination (performed at enrollment, see Table 8-1 ) will 
include the examination of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.
A short physical exam (performed at visits indicated 
in Table 8-1 and Table 8-2) will include the examination of general 
appearance, assessment of the skin for sign of urticaria and other skin lesions, 
and vital signs (blood pressure [SBP and DBP] and pulse).
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior 
to signing informed consent must be recorded on the appropriate eCRF that 
captures medical history. Significant findings made after signing the informed 
consent which meet the definition of an AE must be recorded as an AE.
Vital signs
Vital signs include BP and pulse measurements. After the subject has been 
sitting for five minutes, with back supported and both feet placed on the floor, 
systolic and diastolic blood pressure will be measured 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 subject's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used.
Clinically notable vital signs are defined in Section 16.1.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for 
safety monitoring and discussion of the participant’s health status until it is safe for the 
participant to visit the site again.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section 
(Table 8-10) 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.


Novartis
Confidential
Page 51
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
If participants cannot visit the site for protocol specified safety lab assessments (per Section 4.6), 
an alternative lab (local) collection may be used.
Clinically notable laboratory findings are defined in Appendix 1.
Clinically significant abnormalities must be recorded on the relevant section of the eCRFs 
capturing medical history/current medical conditions/AEs.
Table 8-10
Laboratory assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin [only in case of clinically significant anemia, the 
following parameters will be assessed: Mean Corpuscular Hemoglobin (MCH), 
Mean Corpuscular Hemoglobin Concentration (MCHC), Mean Corpuscular 
Volume (MCV)], Platelets, Red blood cells (RBC), White blood cells (WBC) and 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Bands)
Chemistry
Albumin, Alkaline phosphatase (ALP), ALT, AST , Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Creatine Kinase (CK), Creatinine, 
total Bilirubin (in case of clinically significant elevation: direct Bilirubin and 
indirect Bilirubin will be assessed), [Canada only: eGFR]
Only at baseline (day 1), Week 28 and 52: total Cholesterol, Low density 
Lipoprotein (LDL), High density Lipoprotein (HDL), Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose 
(fasting)
Only at baseline and when deemed necessary by the investigator: C-reactive 
Protein (CRP)
Urinalysis
Done on site: Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen)
Coagulation
Prothrombin time (PT)/International normalized ratio (INR), Activated partial 
thromboplastin time (APTT)
Additional tests
IgE, 
serum pregnancy test (for WoCBP)
Pregnancy Test
Urine pregnancy test for WoCBP
8.4.2
Electrocardiogram (ECG)
ECGs will be analyzed centrally and performed with ECG machines supplied by the central 
provider. Standard 12-lead ECGs (single readings) must be recorded after 10 minutes rest in the 
supine position according to the ECG investigator manual at the timepoints indicated 
in Table 8-1. 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.
For any ECGs with treatment emergent abnormalities, two additional ECGs must be performed 
to confirm the abnormal finding and copies forwarded to the central ECG laboratory for
assessment. A monitoring or review process should be in place for clinically significant ECG 
findings throughout the study and especially at baseline before administration of study 
treatment.






Novartis
Confidential
Page 54
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1

lack of or inadequate response to study treatment in the opinion of the investigator 
and/or the subject,

emergence of AEs that outweigh the benefits of study treatment in the opinion of the 
investigator and/or the subjects.
Study treatment must be discontinued under the following circumstances:

Subject decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section

Any situation in which study participation might result in a safety risk to the subject, e.g. 
required surgical interventions associated with a risk for clinically significant bleeding

Emergence of the following AEs:

AEs including hypersensitivity reactions, severe/serious infections (i.e., requiring 
specific intravenous/intramuscular anti-infectious therapy and/or hospitalization), 
thromboembolism, clinically significant spontaneous bleeding events and clinically 
significant ECG abnormalities (e.g. QT prolongation) for which continued exposure 
to the study drug would be detrimental

Abnormal liver laboratory results requiring discontinuation(see Appendix 2)

Abnormal renal laboratory results requiring discontinuation (see Appendix 3)

Platelets < 75 000/mm3

Any other laboratory abnormalities that in the judgment of the investigator, taking 
into consideration the subject’s overall status, prevents the subject from continuing 
participation in the study

Patient received a live virus vaccination during the study
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent, Section 9.1.2). Subjects should perform the 
End-of-Treatment visit (EoTV) as quickly after their last dose as possible. Then, subjects should 
be asked to return to the study site 4 weeks later for Study Completion Visit (SCV). If they fail 
to return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the subject/pre-designated contact as specified in the lost to follow-
up section. This contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events


Novartis
Confidential
Page 55
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to retain and use all research results (data) that have already been
collected for the study evaluation.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn subject. The investigator may be informed of 


Novartis
Confidential
Page 56
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
In the event of an early study termination, all subjects should perform the Week 52 visit (End-
of-Treatment visit) as quickly as possible after their last dose and the Week 56 Follow-up visit 
(4 weeks later).
A post-trial access program (which may be another extension study or a managed access 
program) for subjects who complete this study is under consideration.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities


Novartis
Confidential
Page 57
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome 

not recovered/not resolved

recovered/resolved

recovering/resolving

recovered/resolved with sequelae

fatal

unknown
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 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


Novartis
Confidential
Page 58
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. See Appendix 1, Appendix 2 and Appendix 3 for alert ranges for 
laboratory and other test abnormalities.
10.1.2
Serious adverse events
A SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred (see details in Section 10.1.5).


Novartis
Confidential
Page 59
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
No pre-specified study endpoints are considered to be exempted from SAE reporting.
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis within 24-hours of learning of its 
occurrence.
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 
30 days after the subject has discontinued or stopped 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 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
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 
SAE experienced during pregnancy must be reported.


Novartis
Confidential
Page 60
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with a SAE. Misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in AE eCRF
Complete SAE form
Unintentional study treatment 
error
Only if associated with an AE
Only if associated with an SAE
Misuse/Abuse
Yes
Yes, even if not associated with 
a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 10.1.1, Section 10.1.2, and Section 10.1.3.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 16-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2.


Novartis
Confidential
Page 61
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1

Repeat liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation. These liver chemistry repeats will be performed using the central laboratory. If 
results will not be available from the central laboratory, then the repeats can also be 
performed at a local laboratory to monitor the safety of the subject. If a liver event is 
subsequently reported, any local liver chemistry tests previously conducted that are 
associated with this event should have results recorded on the appropriate eCRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
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 subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event. These investigations can include based on 
investigator’s discretion: serology tests, imaging and pathology assessments, 
hepatologist’s consultancy

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.

Exclusion of underlying liver disease

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the eCRF.
10.2.2
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Urine protein-creatinine ratio ≥1g/g or ≥100 mg/mmol, OR new onset dipstick proteinuria ≥ 
3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation, Urinary 
Tract Infection (UTI), extreme exercise, or trauma)
Renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first assessment. 
[Canada only: Renal event findings must be confirmed within ≤ 5 days after first assessment].
Every renal laboratory trigger or renal event as defined in Table 16-3 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in Table 
16-4 in Appendix 3. 


Novartis
Confidential
Page 62
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
10.2.3
Data Monitoring Committee
In contrast to the core study CLOU064A2201, this extension study is not blinded. Therefore, 
an independent safety monitoring board as described in the protocol of the core study is not 
necessary.
10.2.4
Steering Committee
A steering committee (SC) may be established with experts in the field of CSU including 
investigators participating in the trial and Novartis representatives.
If established, the SC will ensure transparent management of the study according to the protocol 
through recommending and approving modifications as circumstances require. The SC will 
review protocol amendments as appropriate. Together with the clinical trial team, the SC will 
also develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated 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 
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.


Novartis
Confidential
Page 63
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
ECG readings will be processed centrally and results will be sent electronically to Novartis.
Patients will fill in their eDiary data on a device at home. The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to Novartis 
personnel.
Data about all study treatment(s) dispensed to the subject and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (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 and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. electronic source (eSource) DDE or eCRFs) with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of subject records, the accuracy of data capture/data entry, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis/delegated CRO/Clinical Research 
Associate (CRA) organization. Additionally, a central analytics organization may analyze data 
& identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on eCRFs must be traceable to these source documents in the subject’s file. The 
investigator must also keep the original ICF signed by the subject (a signed copy is given to the 
subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.


Novartis
Confidential
Page 64
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
12
Data analysis and statistical methods
12.1
Analysis sets
The Safety Analysis Set (SAF) includes all subjects who received at least one dose of study 
treatment during the treatment period of this extension study.
For the observational period, the observational Full Analysis Set (oFAS) includes all subjects 
who enrolled in the observational period.
All enrolled subjects includes all subjects who enrolled in this extension study.
12.2
Subject demographics and other baseline characteristics
Demographics and baseline characteristics
Demographic and baseline disease characteristics will be summarized for SAF and oFAS. 
Listing will be provided for all subjects enrolled.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, lower quartile, median, upper quartile, minimum, and maximum will be 
presented.
Medical history
Relevant medical histories and current medical conditions before first dose of study treatment 
in the treatment period will be summarized by system organ class and preferred term according 
to MedDRA dictionary for SAF. Urticaria related medical history will be summarized 
separately for SAF.
All relevant medical histories and current medical conditions will be listed for all subjects 
enrolled. Cardiovascular history and family malignancy history for subjects developed 
malignancy during the treatment period will be listed for SAF.


Novartis
Confidential
Page 65
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
12.3
Treatments
Study Treatment 
The duration of exposure (in weeks) will be summarized by means of descriptive statistics using 
the SAF. In addition, the number and percentage of subjects with exposure of at least certain 
thresholds (e.g. any exposure, >=1 week, >= 2 weeks, >= 3 weeks, >= 4 Weeks, ..., etc.) will 
be displayed.
Prior and Concomitant medication
Prior, non-urticaria related concomitant medications and urticaria related medication will be 
summarized separately by Anatomical Therapeutic Chemical (ATC) codes and main group for 
SAF.
Prior treatments are defined as treatment taken and stopped prior to first dose of study treatment 
in the treatment period. Any treatment given at least once between the day of first dose of study 
treatment during treatment period and the last day of study visit will be a concomitant treatment, 
including those which were started prior to enter the treatment period.
In addition, prior and concomitant medical procedures and significant non-drug therapies will 
be summarized by primary system organ class and MedDRA preferred term for SAF.
12.4
Analysis of the primary endpoint(s)
The primary analysis will focus on the safety variables. The primary safety analysis will be 
analyzed using SAF.
12.4.1
Definition of primary endpoint(s)
The primary objective of this study is to investigate the long-term safety and tolerability of 
LOU064 in subjects with CSU.
The primary variables are: AEs/SAEs, ECGs, laboratory assessment, and vital signs, etc. 
Baseline for safety analysis is defined as the last measurement before the first dose of study 
medication in the treatment period of this extension study.
Adverse events
All adverse events which newly start on the same day or after the first dose of study medication 
in the treatment period of this extension study OR get worsening on the same day or after the 
first dose of study medication and within end of study visit will be considered as treatment 
emergent adverse event for this extension study.
Number and percentage of subjects having any treatment emergent adverse events during the 
extension study, by system organ class and preferred term will be provided for:

All adverse events

Adverse events by maximum severity

Drug related adverse events

Serious Adverse events

Adverse events leading to treatment discontinuation


Novartis
Confidential
Page 66
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Adverse events by standardized MedCRA Query (SMQ) and preferred term will be provided.
Separate summaries will be provided for deaths, SAEs, and other significant AEs leading to 
discontinuation.
For the definition of AEs and SAEs please see Section 10.1.1 and 
Section 10.1.2.
Laboratory data
Baseline is defined as last assessment (including unscheduled assessments) before the first dose 
day of treatment period.
Descriptive summary statistics for laboratory data (hematology and serum chemistry) will be 
provided at baseline and post-baseline by test category, parameter, and visit during the treatment 
period.
Shift table on normal range between baseline and post baseline visits will be provided.
Number and percentage of patients with newly occurring clinical notable laboratory values (see 
Appendix 16.1, Appendix 16.2, and Appendix 16.3) will also be provided.
ECGs
Summary statistics will be provided for ECG parameters by visit during treatment period. Shift 
table on normal ranges and number and percentage of notable abnormalities will also be 
summarized.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. Shifts with respect to normal ranges and number 
and percentage of notable abnormalities will also be summarized.
12.4.2
Statistical model, hypothesis, and method of analysis
No hypothesis testing is planned for the primary objective.
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum.
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies.
12.4.3
Handling of missing values/censoring/discontinuations
Not applicable.
12.4.4
Sensitivity and Supportive analyses
Not applicable.








Novartis
Confidential
Page 70
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 






Novartis
Confidential
Page 73
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The following specific criteria have been identified for this study. Should these criteria be met, 
a re-test must be done within 5 days after the first assessment. Discontinuation of the study 
treatment should be considered if the abnormal hematology parameter is confirmed:
Hemoglobin: < 10 g/dl
Platelets: < 75 000/mm3
White blood cells: < 3 000/mm3
Neutrophils: < 1 500/mm3
For all other laboratory assessments, the central laboratory will flag laboratory values falling 
outside of the normal ranges on the central laboratory report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the eCRF.
Notable values for vital signs and change from baseline will be summarized. 
Notable values are defined as follows: heart rate of < 50 and > 100 bpm; systolic blood pressure 
of < 90 and ≥ 140 mmHg; diastolic blood pressure of < 60 and ≥ 90 mmHg.
For ECGs a notable QTc value is defined as a QTc (Fridericia’s) interval of greater than 450 
msec for males or greater than 460 msec for females – all such ECGs will be flagged by the 
central CRO’s cardiologist and require assessment for clinical relevance by the investigator. 


Novartis
Confidential
Page 74
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS
3 x ULN < ALT / AST ≤ 5 x ULN
1.5 x ULN < TBL ≤2 x ULN
LIVER EVENTS
- ALT or AST > 5 × ULN
- ALP > 2 × ULN (in the absence of known bone pathology)
- TBL > 2 × ULN (in the absence of known Gilbert syndrome)
- ALT or AST > 3 × ULN and INR > 1.5
- Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 
2 × ULN [mainly conjugated fraction] without notable increase in ALP to 
> 2 × ULN)
- Any clinical event of jaundice (or equivalent term)
- ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
- Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
- Discontinue the study treatment immediately
- Hospitalize, if clinically appropriate
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, 
Alb, PT/INR, ALP and GGT 
until resolutionc (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN
- Discontinue the study treatment immediately
- Hospitalize, if clinically appropriate
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, 
Alb, PT/INR, ALP and GGT 
until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and INR 
> 1.5
- Discontinue the study treatment immediately
- Hospitalize, if clinically appropriate
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, 
Alb, PT/INR, ALP and GGT 
until resolutionc (frequency 
at investigator discretion)


Novartis
Confidential
Page 75
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Criteria
Actions required
Follow-up monitoring
> 5 to ≤ 8 × ULN
- Repeat LFT within 48 hours
- If elevation persists, continue follow-up 
monitoring
- If elevation persists for more than 2 weeks, 
discontinue the study drug
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, 
Alb, PT/INR, ALP and GGT 
until resolutionc (frequency 
at investigator discretion)
> 3 × ULN 
accompanied by 
symptomsb
- Discontinue the study treatment immediately
- Hospitalize, if clinically appropriate
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, 
Alb, PT/INR, ALP and GGT 
until resolutionc (frequency 
at investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)
- Repeat LFT within the next week
- If elevation is confirmed, initiate close 
observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)
- Repeat LFT within 48 hours
- If elevation persists, establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known
Gilbert syndrome)
- Repeat LFT within 48 hours
- If elevation persists, discontinue the study 
drug immediately
- Hospitalize if clinically appropriate
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, 
Alb, PT/INR, ALP and GGT 
until resolutionc (frequency 
at investigator discretion)
Test for hemolysis 
(e.g., reticulocytes, 
haptoglobin, unconjugated 
[indirect] bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)
- Repeat LFT within the next week
- If elevation is confirmed, initiate close 
observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice
- Discontinue the study treatment immediately
- Hospitalize the patient
- Establish causality
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*
- Consider study treatment interruption or 
discontinuation
- Hospitalization if clinically appropriate
- Establish causality
Investigator discretion


Novartis
Confidential
Page 76
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
Criteria
Actions required
Follow-up monitoring
- Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory values) in the appropriate eCRF
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after 
a maximum of 6 months, (4) liver transplantation, and (5) death.
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms.
Based on investigator’s discretion, investigation(s) for contributing factors for the liver event 
can include: serology tests, imaging and pathology assessments, hepatologist’s consultancy, 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


Novartis
Confidential
Page 77
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific renal alert criteria and actions
Renal Alert
Actions
Confirmed serum creatinine increase 25 – 49% 
[Canada only] 

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             
[Canada only]

Consider causes and possible interventions 
and initiate renal investigation

Repeat assessment within 24-48h if possible

Interruption of study drug, close follow-up 
(every 24-48 h), consider patient 
hospitalization and specialized treatment 
until creatinine is <125% of baseline value
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase ≥50 % 1

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+
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 ≥ 3+ on urine dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
1 Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: in exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 


Novartis
Confidential
Page 78
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
to make slide specimen available for evaluation by the Renal Safety Group to potentially 
identify project-wide patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis
Table 16-4
Renal event follow-up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF

Urine dipstick and sediment microscopy evidence of Drug-Induced Nephrotoxicity 
(DIN): crystals, red blood cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), 
white blood cells, tubular epithelial cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event


Novartis
Confidential
Page 79
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1
16.4
Appendix 4: Prohibited medications
The lists provided in the table below are non-exhaustive. In case of any doubt, the corresponding 
SmPC should be checked.
Table 16-5
Moderate and strong inhibitors of CYP3A4
Strong inhibitors of 
CYP3A4
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir,darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, 
idelalisib,indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
LCL161,lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole,ritonavir, saquinavir, saquinavir/ritonavir, telaprevir, 
telithromycin,tipranavir/ritonavir,troleandomycin, Viekira pack, voriconazole
Moderate inhibitors 
of CYP3A4
ACT-178882, amprenavir, aprepitant, atazanavir, casopitant,
cimetidine,ciprofloxacin, crizotinib, cyclosporine, darunavir, diltiazem, 
dronedarone,erythromycin, faldaprevir, ferula asafetida resin (herbal 
product), FK1706,fluconazole, imatinib, isavuconazole, netupitant, nilotinib, 
schisandra,sphenanthera, tofisopam, verapamil
Table 16-6
Moderate and strong inducers of CYP3A4
Strong inducers of 
CYP3A4
avasimibe, carbamazepine, enzalutamide, ifampin, mitotane, 
phenobarbital,phenytoin, rifabutin, St. John’s wort (herbal product)
Moderate inducers of 
CYP3A4
bosentan, efavirenz, etravirine, lersivirine, lopinavir, modafinil, 
nafcillin,ritonavir/tipranavir, semagacestat, talviraline, thioridazine


Novartis
Confidential
Page 80
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1


Novartis
Confidential
Page 81
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1


Novartis
Confidential
Page 82
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1


Novartis
Confidential
Page 83
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1


Novartis
Confidential
Page 84
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1


Novartis
Confidential
Page 85
Amended Protocol Version v03 Clean
Protocol No. CLOU064A2201E1

SAP_001.pdf: 






Novartis
For business use only
Page 4
SAP final v2.0
CLOU064A2201E1
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions..................................................................................9
2.2
Analysis sets ..........................................................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................12
2.3.1
Patient disposition.................................................................................12
2.3.2
Demographic and baseline characteristics ............................................13
2.3.3
Medical history......................................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment / compliance................................................................14
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................21
2.5.3
Handling of missing values/censoring/discontinuations.......................21
2.5.4
Supportive analyses...............................................................................21
2.6
Analysis of the Secondary objective......................................................................21
2.6.1
Secondary endpoint...............................................................................21
2.6.2
Statistical hypothesis, model, and method of analysis..........................22
2.6.3
Handling of missing values/censoring/discontinuations.......................22
2.7
Safety analyses.......................................................................................................22
2.7.1
Adverse event during observational period...........................................22
2.7.2
Laboratory data .....................................................................................22
2.7.3
Liver events...........................................................................................23
23
24
24
24
24


Novartis
For business use only
Page 5
SAP final v2.0
CLOU064A2201E1
25
3
Sample size calculation .....................................................................................................25
4
Change to protocol specified analyses ..............................................................................26
5
Appendix ...........................................................................................................................26
5.1
Imputation rules.....................................................................................................26
5.1.1
Study drug.............................................................................................26
5.1.2
AE date imputation ...............................................................................26
5.1.3
Concomitant medication date imputation .............................................27
5.1.4
Prior therapies date imputation .............................................................28
5.1.5
Other imputations..................................................................................28
5.2
AEs coding/grading ...............................................................................................29
5.3
Laboratory parameters derivations ........................................................................29
29
5.5
Rule of exclusion criteria of analysis sets..............................................................30
6
Reference...........................................................................................................................30


Novartis
For business use only
Page 6
SAP final v2.0
CLOU064A2201E1
List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
b.i.d.
bis in diem/twice a day
BP
Blood Pressure
CSR
Clinical Study report
CSU
Chronic Spontaneous Urticaria
CV
Coefficient of Variation
CTCAE
Common Terminology Criteria for Adverse Events
ECG
Electrocardiogram
EOT
End of treatment period
EOS
End of study period
FAS
Full Analysis Set
GCP
Good Clinical Practice
HSS7
Weekly Hives Severity Score
Ig
Immunoglobulin
INR
International Normalized Ratio
IRT
Interactive Response Technology
ISS7
Weekly Itch Severity Score
LLN
Lower Limit of Normal 
LLOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Drug Regulatory Affairs
QTcF
QT interval corrected by Fridericia’s formula
SAE
Serious Adverse Event
SAF
Safety Analysis set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TBL
Total bilirubin
ULN
Upper Limit of Normal
ULOQ
Upper Limit Of Quantification
UPDD
Urticaria Patient Daily Diary




Novartis
For business use only
Page 8
SAP final v2.0
CLOU064A2201E1
Primary Objective(s)
Endpoint(s) for primary objective(s)

To assess the long-term safety and 
tolerability of LOU064 in patients with CSU 
who have participated in preceding studies 
with LOU064.

Safety endpoints will include but not be 
limited to: occurrence of treatment 
emergent (serious and non-serious) 
adverse events during the extension study
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the efficacy of LOU064 when 
given without H1-antihistamines in patients 
with CSU with respect to change from 
baseline in UAS7, achieving controlled 
disease (defined by a UAS7≤6), and 
achieving complete response (defined by a 
UAS7=0) at Week 4 of treatment

Change from baseline in UAS7 at Week 4

UAS7≤6 response at Week 4

UAS7=0 response at Week 4

To evaluate the long-term efficacy of 
LOU064 in patients with CSU who have 
participated in previous studies with 
LOU064 with respect to maintaining or 
achieving controlled disease (defined by a 
UAS7≤6) over time

UAS7≤6 response over time

To evaluate the long-term efficacy of 
LOU064 in patients with CSU who have 
participated in preceding studies with 
LOU064 with respect to change from 
baseline in UAS7 over time

Change from baseline in UAS7 over time


Novartis
For business use only
Page 9
SAP final v2.0
CLOU064A2201E1
2
Statistical methods
Novartis will be performing 
 the final analysis. Statistical software 
R version 3.4.3 and SAS version 9.4 or later will be used.
2.1
Data analysis general information
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. 
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies.
2.1.1
General definitions 
2.1.1.1
Study treatment
The following treatment groups will be presented:

LOU064 100 mg b.i.d.

Treatment free
2.1.1.2
Study Day 1 and Study Day for treatment period
For safety analysis, the day of first dose of study treatment is defined as Study Day 1 or Day 1. 


Novartis
For business use only
Page 10
SAP final v2.0
CLOU064A2201E1
For efficacy analysis, the day of enrollment in treatment period (visit 101) is defined as Study 
Day 1 or Day 1.
Study days will be labeled relative to Day 1 for treatment period. 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/Enrollment] + 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/Enrollment], i.e., Day -1, Day -2, etc., will be one day, two days, etc., before Day 
1, respectively. Duration of an event will be calculated as (Event end date – Event start date + 
1). The descriptor “Day 0” will not be used.
2.1.1.3
Assessment window for Study Week (eDiary)
The study weeks for assessment completed on eDiary are defined based on the study days 
starting with Day 1 (Enrollment in observational/treatment period Day). 
For completers of treatment period, the study day for eDiary date will be calculated as [Date of 
Diary] – [Date of Enrollment] + 1 for post-baseline assessment and [Date of Diary] – [Date of 
Enrollment] for baseline assessment. The analysis Week 1 through Week 51 of the treatment 
period will be derived based on scheduled visit day as defined in Table 2-1. The analysis Week 
52 score will be derived  as Day -7 to Day -1 of actual Week 52 study visit day. 
During the follow-up period, the study weeks for assessment completed on eDiary are defined 
based on the study days starting with Day 1 of follow-up period (actual Week 52 visit day). The 
study day for the eDiary date will be calculated as [Date of Diary] – [Date of Week 52 visit day] 
+ 1. The analysis follow-up Week 1 to Week 16 will be derived based on the actual Week 52 
study visit day as defined in Table 2-1.
For early discontinued patients, it is suggested to collect the eDiary data even after the patient 
discontinued from treatment per “Treatment policy strategy” (this part of data is named as 
“retrieved drop-out data”). The retrieved drop-out data will be included in the weekly score 
derivation per assessment window defined in Table 2-1.
Table 2-1
Assessment window for eDiary
Period
Analysis visit
Scheduled Visit 
Day
eDiary Assessment Window
Observational
OEnrollment
1
Day -7 to Day -1
OWeek 1
-
Day 1 to Day 7
OWeek 2
-
Day 8 to Day 14
OWeek 3
-
Day 15 to Day 21
OWeek 4
29
Day 22 to Day 28


Novartis
For business use only
Page 11
SAP final v2.0
CLOU064A2201E1
OWeek 5
-
Day 29 to Day 35
OWeek 6
-
Day 36 to Day 42
OWeek 7
-
Day 43 to Day 49
OWeek 8
57
Day 50 to Day 56
OWeek 9
-
Day 57 to Day 63
OWeek 10
-
Day 64 to Day 70
OWeek 11
-
Day 71 to Day 77
OWeek 12
85
Day 78 to Day 84
Treatment
Baseline
1
Day -7 to Day -1
Similar as in observational period.
Week 12
85
Day 78 to Day 84
...
Week 16
113
Day 106 to Day 112
...
Week 20 
141
Day 134 to Day 140
...
Week 28
197
Day 190 to Day 196
...
Week 40
281
Day 274 to Day 280
...
Week 52
365
Day 358 to Day 364
For completers, Day -7 to Day 
-1 of Week 52 study visit
Follow-up
Follow-up Week 1
393
Day 1 to Day 7 of Week 52 
study visit
...
Follow-up Week 4
421
Day 22 to Day 28 of Week 
52 study visit
...
Follow-up Week 12
477
Day 78 to Day 84 of Week 52 
study visit
The baseline week is comprised of the 7 days prior to Day 1 (Day -7 to Day -1). The baseline 
UAS7 score for observational period could be different from the UAS7 score of the last visit 
for core study. The baseline UAS7 score for treatment period could be different from the UAS7 
score of the last visit for observational period. 


Novartis
For business use only
Page 12
SAP final v2.0
CLOU064A2201E1
2.1.1.4
Baseline
Baseline for safety in treatment period is the last assessment (including unscheduled visits) 
obtained on or before the first dose day of study treatment. All assessments obtained after the 
first dose of study treatment are considered as post-baseline unless otherwise specified.
Baseline for efficacy in treatment period is comprised of the 7 days prior to Day 1 (Enrollment 
in treatment period Day) for UAS7 and other assessment on or prior enrollment in treatment 
period day. 
For observational period, only baseline UAS7 score is applicable and defined in section 2.1.1.3.
2.1.1.5
On-treatment
All safety events happened after first dose of study treatment and before minimum(last dose +
28days, end of study visit) will be considered on-treatment no matter during treatment period 
or follow-up period.
For AE summary for observational period, all adverse event happened after enrollment in 
observational period and before roll over to treatment period will be summarized.
2.2
Analysis sets
The following analysis sets will be used for the data analysis, details refer to section 5.5.
The Safety Analysis Set includes all subjects who received at least one dose of study 
treatment during the treatment period of this extension study.
For the observational period, the observational Full Analysis Set (oFAS) includes all subjects 
who enrolled in the observational period.
All enrolled subjects includes all subjects who enrolled in this extension study.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number of screened and screen failures subjects will also be shown for all enrolled subjects. 
The reason for screen failure will be summarized. 
The number of subjects in each analysis set will be presented by observational period based on 
oFAS and treatment period based on Safety set. The reason for excluded from any analysis set 
will be listed.




Novartis
For business use only
Page 14
SAP final v2.0
CLOU064A2201E1

Race (from core study A2201)

Ethnicity (from core study A2201)

BMI groups (< 25, 25 - 30, >= 30 kg/m**2)

Baseline UAS7 category (Mild disease: UAS7 6-<16; Moderate disease: UAS7 16-<28; 
Severe disease UAS7 28-42)/Enrollment UAS7 category
2.3.3
Medical history
Relevant medical histories and current medical conditions before first dose of study treatment 
in the treatment period will be summarized by system organ class and preferred term according 
to MedDRA dictionary for SAF. Urticaria related medical history will be summarized 
separately for SAF.
All relevant medical histories and current medical conditions will be listed for all subjects 
enrolled. Cardiovascular history and family malignancy history for subjects developed 
malignancy during the treatment period will be listed for SAF
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The analysis of study treatment data will be based on SAF.
2.4.1
Study treatment / compliance
The duration of exposure to study treatment and duration of study will be summarized for SAF. 
In addition, the number of subjects with exposure of at least certain thresholds (eg, any exposure, 
≥1 week, ≥2 weeks, ≥4 weeks, ≥8 weeks, etc.) will be displayed. 
Duration of exposure is defined as last dose of study treatment – first dose of study treatment 
+ 1.
Duration of study for entire study period is defined as last study visit – enrollment in 
treatment period + 1.
Duration of exposure (weeks) = duration of exposure (days) / 7
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 subject years) = duration of exposure (years) / 100
The start date and end date of study treatment will be collected on eCRF and will be used to 
calculate the duration of exposure. 


Novartis
For business use only
Page 15
SAP final v2.0
CLOU064A2201E1
2.4.2
Prior, concomitant and post therapies
Prior, non-urticaria related concomitant medications and urticaria related concomitant 
medication or rescue medications during treatment period will be summarized by Anatomical 
Therapeutic Chemical (ATC) code and preferred term for SAF. Additionally, concomitant 
surgeries, medical procedures and non-drug therapies by primary system organ class and 
preferred term will be preseted.


Novartis
For business use only
Page 16
SAP final v2.0
CLOU064A2201E1
Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the date of the last study visit. 
Background medications and rescue medications during treatment period will be sumairzed 
separately by Anatomical Therapeutic Chemical (ATC) code and preferred term for SAF.
Medications will be identified using the Novartis Drug and Therapy Dictionary (NovDTD) 
including the Anatomical Therapeutic Chemical (ATC) code. Medications will be presented in 
alphabetical order, by ATC code. 
All relevant listings will be provided based on SAF for concomitant medication; concomitant 
surgeries, medical procedures and non-drug therapies.
2.5
Analysis of the primary objective
The primary objective of this study is to investigate the long-term safety and tolerability of 
LOU064 in subjects with CSU. The primary safety analysis will be analyzed using SAF.
2.5.1
Primary endpoint
2.5.1.1
Adverse events
All adverse events which newly start on the same day or after the first dose of study medication 
in the treatment period of this extension study OR  worsen on the same day or after the first 
dose of study medication and within min(last dose + 28 days, end of study visit) will be 
considered as treatment emergent adverse event for this extension study.
Number and percentage of subjects having any treatment emergent adverse events during entire 
study period of the extension study, by system organ class and preferred term will be provided 
for:

All adverse events

Adverse events by maximum severity

Drug related adverse events

Serious Adverse events

Adverse events leading to treatment discontinuation
Adverse events by standardized MedDRA Query (SMQ), System organ class (SOC) and 
preferred term will be provided. Separate summaries will be provided for deaths, SAEs, and 
other significant AEs leading to discontinuation.
If a subject reported more than one AE with the same preferred term, the AE with the greatest 
severity will be presented. 
All adverse events will be listed for SAF.
Safety topic of special interest




Novartis
For business use only
Page 18
SAP final v2.0
CLOU064A2201E1
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Event (CTCAE) grades (version 5.0), given in Table 2-3: 
hemoglobin, platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total 
bilirubin (TBL), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP).
The number and percentage of subjects with CTCAE grade newly occurring or worsening after 
baseline will be presented.
Table 2-3
CTCAE grades for laboratory parameters to be analyzed
CTCAE term
Laboratory 
assessment
Grade 1
Grade 2
Grade 3
Grade 4
Anemia 
Hemoglobin 
(Hgb) 
<LLN-10.0 
g/dL; 
<10.0- 8.0 g/dL; 
<8.0 g/dL; 
Life-
threatening 
consequences; 
Platelet 
count 
decreased 
Platelet
<LLN-
75,000/mm; 
<75,000-
50,000/mm3; 
<50,000-
25,000/mm3; 
<25,000/mm3
; 
White blood cell 
decreased 
White blood cell
<LLN-
3000/mm3; 
<3000-
2000/mm3; 
<2000-
1000/mm3; 
<1000/mm3; 
Neutrophil 
count decreased 
Neutrophils
<LLN-
1500/mm3; 
<1500-
1000/mm3; 
<1000-
500/mm3; 
<500/mm3; 
Lymphocyte 
count decreased 
lymphocytes 
<LLN-
800/mm3; 
<800-
500/mm3; 
<500-200/mm3; 
<200/mm3; 
INR increased 
INR
>1.2 - 1.5; 
>1 - 1.5 x 
baseline if on 
anticoagulation
; monitoring 
only indicated
>1.5 - 2.5; 
>1.5 - 2.5 x 
baseline if on 
anticoagulation
; dose 
adjustment 
indicated 
>2.5; 
>2.5 x baseline 
if on 
anticoagulation
; bleeding
-
Creatinine 
increased 
Serum 
creatinine
>1-1.5 x ULN 
>1.5 - 3.0 x 
baseline; 
>1.5 - 3.0 x 
ULN 
>3.0 x baseline; 
>3.0 - 6.0 x 
ULN 
>6.0 x ULN 
Blood urea 
Nitrogen (BUN) 
increased
Urea
>1- 1.5xULN
>1.5 - 3.0 x 
baseline; 
>1.5 - 3.0 x 
ULN 
>3.0 x baseline; 
>3.0 - 6.0 x 
ULN 
>6.0xULN
Blood bilirubin 
increased
Total bilirubin 
(TBL)
>ULN - 1.5 x 
ULN if baseline 
was normal; 
> 1.0 - 1.5 x 
baseline if 
>1.5 - 3.0 x 
ULN if baseline 
was normal; 
>1.5 - 3.0 x 
baseline if 
>3.0 - 10.0 x 
ULN if baseline 
was normal; 
>3.0 - 10.0 x 
baseline if 
>10.0 x ULN 
if baseline 
was normal; 
>10.0 x 
baseline if 
















Novartis
For business use only
Page 26
SAP final v2.0
CLOU064A2201E1
4
Change to protocol specified analyses
Not applicable. 
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: 


Novartis
For business use only
Page 27
SAP final v2.0
CLOU064A2201E1
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:


Novartis
For business use only
Page 28
SAP final v2.0
CLOU064A2201E1
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). 
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date. 
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date. 
5.1.4
Prior therapies date imputation
See Section 5.1.3.
5.1.5
Other imputations
Diagnosis date imputation
1. If the first diagnosis day/ month are missing and the year is non-missing:


Novartis
For business use only
Page 29
SAP final v2.0
CLOU064A2201E1
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
Not applicable.
5.3
Laboratory parameters derivations
Not applicable.