Conditions: Chronic Spontaneous Urticaria
Keywords: BTK inhibitor Urticaria Activity Score Angioedema Activity Score CSU
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 311
Healthy volunteers: no

Brief summary:
This was a multicenter, randomized, double-blind and placebo-controlled phase 2b dose-finding study to assess the efficacy and safety of LOU064 in adults chronic spontaneous urticaria (CSU) patients inadequately controlled by H1-antihistamines

Detailed description:
This was a global Phase 2b multicenter, randomized, double-blind, parallel-group, placebo-controlled study investigating the efficacy, safety and tolerability of six dosing groups of oral LOU064 in subjects with inadequately controlled CSU despite treatment with (second generation) H1-antihistamine. The study comprised of the 7 treatment arms: LOU064 10 mg q.d., LOU064 35 mg q.d., LOU064 100 mg q.d., LOU064 10 mg b.i.d, LOU064 25 mg b.i.d., LOU064 100 mg b.i.d. and placebo.

Arms:
arm 1: 10 mg LOU064 qd capsule once daily arm 2: 35 mg capsule qd LOU064 once daily arm 3: 100 mg capsule qd LOU064 once daily arm 4: 10 mg capsule LOU064 bid arm 5: 25 mg capsule LOU064 bid arm 6: 100 mg capsule LOU064 bid arm 7: Participants took matching placebo twice daily

Interventions: intervention 1: LOU064 Arm 1 intervention 2: LOU064 Arm 2 intervention 3: LOU064 Arm 3 intervention 4: LOU064 Arm 4 intervention 5: LOU064 Arm 5 intervention 6: LOU064 Arm 6 intervention 7: Placebo arm
Intervention descriptions: intervention 1: 10 mg LOU064 orally in the morning (once daily) and matching placebo in the evening from Day 1 to 85 intervention 2: 35 mg of LOU064 orally in the morning (once daily) and matching placebo in the evening from Day 1 to 85 intervention 3: 100 mg of LOU064 orally in the morning (once daily) and matching placebo in the evening from Day 1 to 85 intervention 4: 10mg bid of LOU064 orally, twice daily from Day 1 to 85 intervention 5: 25 mg bid of LOU064 orally, twice daily from Day 1 to 85 intervention 6: 100 mg bid of LOU064 orally, twice daily from Day 1 to 85 intervention 7: Matching placebo, orally, twice daily from Day 1 to 85

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
LOU064
Protocol CLOU064A2201
A multicenter, randomized, double-blind, placebo-
controlled Phase 2b dose-finding study to investigate the 
efficacy, safety and tolerability of LOU064 in adult chronic 
spontaneous urticaria patients inadequately controlled by 
H1-antihistamines
Document type:
Clinical Trial Protocol
EUDRACT number:
2018-000993-31
Version number:
00 (Original Protocol)
Clinical Trial Phase:
IIb
Release date:
08-Jan-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 1.0 (01-Dec-2017)
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
2
Objectives and endpoints...................................................................................................16
3
Study design ......................................................................................................................17
4
Rationale............................................................................................................................19
4.1
Rationale for study design .....................................................................................19
4.2
Rationale for choice of background therapy..........................................................20
4.3
Rationale for dose/regimen and duration of treatment ..........................................20
4.4
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................21
21
4.6
Benefits and risks...................................................................................................21
5
Population..........................................................................................................................24
5.1
Inclusion criteria ....................................................................................................24
5.2
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................27
6.1
Study treatment......................................................................................................27
6.1.1
Investigational and control drugs..........................................................27
6.1.2
Additional study treatments ..................................................................28
6.1.3
Treatment arms/group ...........................................................................28
6.2
Other treatment(s)..................................................................................................29
6.2.1
Concomitant therapy.............................................................................29
6.2.2
Prohibited medication ...........................................................................29
6.2.3
Rescue medication ................................................................................30
6.3
Subject numbering, treatment assignment, randomization....................................30
6.3.1
Subject numbering ................................................................................30
6.3.2
Treatment assignment, randomization ..................................................30
6.4
Treatment blinding.................................................................................................31
6.5
Dose escalation and dose modification..................................................................31
6.6
Additional treatment guidance...............................................................................31
 


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6.6.1
Treatment compliance...........................................................................31
6.6.2
Emergency breaking of assigned treatment code..................................32
6.7
Preparation and dispensation.................................................................................32
6.7.1
Handling of study treatment and additional treatment..........................33
6.7.2
Instruction for prescribing and taking study treatment .........................33
7
Informed consent procedures ............................................................................................34
8
Visit schedule and assessments .........................................................................................35
8.1
Screening ...............................................................................................................38
8.2
Subject demographics/other baseline characteristics.............................................39
8.3
Efficacy..................................................................................................................39
8.3.1
eDiary assessments................................................................................39
8.3.2
Other Patient Reported Outcomes (PRO) assessments.........................42
8.3.3
Other assessments: evidence of urticaria ..............................................42
8.3.4
Appropriateness of efficacy assessments..............................................43
8.4
Safety.....................................................................................................................43
8.4.1
Laboratory evaluations..........................................................................44
8.4.2
Electrocardiogram (ECG) .....................................................................45
8.4.3
Pregnancy and assessments of fertility .................................................45
8.4.4
Other safety evaluations........................................................................46
8.4.5
Appropriateness of safety measurements..............................................46
8.5
Additional assessments..........................................................................................46
8.5.1
Pharmacokinetics ..................................................................................46
47
9
Study discontinuation and completion ..............................................................................48
9.1
Discontinuation......................................................................................................48
9.1.1
Discontinuation of study treatment .......................................................48
9.1.2
Withdrawal of informed consent...........................................................49
9.1.3
Lost to follow-up...................................................................................50
9.1.4
Early study termination by the sponsor.................................................50
9.2
Study completion and post-study treatment ..........................................................50
10 Safety monitoring and reporting........................................................................................51
10.1
Definition of adverse events and reporting requirements......................................51
10.1.1
Adverse events (AEs)............................................................................51
10.1.2
Serious adverse events (SAEs)..............................................................52
10.1.3
SAE reporting........................................................................................53
10.1.4
Pregnancy reporting ..............................................................................54
10.1.5
Reporting of study treatment errors including misuse/abuse................54
 


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10.2
Additional safety monitoring.................................................................................55
10.2.1
Liver safety monitoring.........................................................................55
10.2.2
Renal safety monitoring........................................................................56
10.2.3
Data monitoring committee...................................................................56
10.2.4
Steering committee................................................................................56
10.2.5
Adjudication committee........................................................................57
11 Data collection and database management........................................................................57
11.1
Data collection.......................................................................................................57
11.2
Database management and quality control............................................................57
11.3
Site monitoring ......................................................................................................58
12 Data analysis and statistical methods ................................................................................58
12.1
Analysis sets ..........................................................................................................58
12.2
Subject demographics and other baseline characteristics......................................59
12.3
Treatments .............................................................................................................59
12.4
Analysis of the primary endpoint(s) ......................................................................59
12.4.1
Definition of primary endpoint(s).........................................................60
12.4.2
Statistical model, hypothesis, and method of analysis..........................60
12.4.3
Handling of missing values/censoring/discontinuations.......................61
12.5
Analysis of secondary endpoints ...........................................................................62
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................62
12.5.2
Safety endpoints....................................................................................63
12.5.3
Pharmacokinetics ..................................................................................64
12.5.4
PK/PD relationships..............................................................................65
65
67
12.8
Sample size calculation..........................................................................................67
13 Ethical considerations and administrative procedures ......................................................68
13.1
Regulatory and ethical compliance........................................................................68
13.2
Responsibilities of the investigator and IRB/IEC..................................................68
13.3
Publication of study protocol and results...............................................................68
13.4
Quality control and quality assurance....................................................................69
14 Protocol adherence ............................................................................................................69
14.1
Protocol amendments.............................................................................................69
15 References .........................................................................................................................70
16 Appendices ........................................................................................................................72
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................72
 


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16.2
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ..........................................................................................................73
16.3
Appendix 3: Specific renal alert criteria and actions and event follow-up............75
16.4
Appendix 4: Prohibited medications .....................................................................77
78
83
List of tables
Table 2-1
Objectives and related endpoints ..........................................................16
Table 6-1
Investigational and control drug............................................................27
Table 6-2
Treatment regimen per arm...................................................................28
Table 6-3
Prohibited medication ...........................................................................29
Table 8-1
Assessment schedule.............................................................................36
Table 8-2
UPDD....................................................................................................39
Table 8-3
Hives Severity Score.............................................................................40
Table 8-4
Itch Severity Score ................................................................................40
41
41
Table 8-7
DLQI score bands and impact on patient’s life.....................................42
Table 8-8
Physical Assessments............................................................................43
Table 8-9
Laboratory assessments.........................................................................44
Table 8-10
PK sampling schedule...........................................................................47
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 12-1
Non-compartmental pharmacokinetic parameters ................................65
 
68
Table 16-1
Liver event and laboratory trigger definitions ......................................73
Table 16-2
Follow-up requirements for liver events and laboratory triggers..........73
Table 16-3
Specific renal alert criteria and actions.................................................75
Table 16-4
Renal event follow-up...........................................................................76
Table 16-5
Moderate and strong inhibitors of CYP3A4 .........................................77
Table 16-6
Moderate and strong inducers of CYP3A4 ...........................................77
List of figures
Figure 3-1
Study Design .........................................................................................19
61
 


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List of abbreviations
AAS
Angioedema Activity Score
AE
Adverse Event
Alb
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AUCinf
The area under the plasma (or serum or blood) concentration-time 
curve
from time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time 
curve
from time zero to the time of the last quantifiable concentration [mass x 
time / volume]
AUCtau
The area under the plasma (or serum or blood) concentration-time 
curve
from time zero to the end of the dosing interval tau [mass x time / 
volume]
AV block
Atrioventricular block 
BCR
B Cell Receptor
b.i.d.
bis in die / twice a day
BP
Blood Pressure
BTK
Bruton’s Tyrosine Kinase
BTK
Bruton’s Tyrosine Kinase Inhibitor
BUN
Blood Urea Nitrogen
CK
Creatinine Kinase
CL/F
The apparent systemic (or total body) clearance from plasma (or 
serum or blood) following extravascular administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration 
following drug administration [mass / volume]
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
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
CV
Coefficient of Variation
CYP
Cytochrome P
DBP
Diastolic Blood Pressure
DDE
Direct Data Entry
 


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DIN
Drug-Induced Nephrotoxicity
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDC
Electronic Data Capture
ED50
Dose at which 50% of Emax is achieved
EMA
European Medicines Agency
Emax
Maximum Change in Effect over Placebo
eSource
Electronic Source
EU
European Union
E0
Expected Placebo Effect
FAS
Full Analysis Set
FcR
Fc epsilon receptor
FcR
Fc gamma receptor
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
hour
HBcAb
Antibodies against hepatitis B core antigen (anti-HBcAg antibodies)
HBsAb
Antibodies against hepatitis B surface antigen (anti-HBsAg antibodies)
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
HCP
Health Care Professional
HCV
Hepatitis C virus
HCVAb
Hepatitis C virus antibody
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
 


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ISS7
Weekly Itch Severity Score
IUD
Intrauterine device
IUS
Intrauterine system
i.v.
intravenous
LC-MS/MS
Liquid Chromatography–Mass Spectrometry
LDH
lactate dehydrogenase
LDL
Low-Density Lipoprotein
LFT
Liver function test 
LLOQ
lower limit of quantification
MAD
Multiple Ascending Dose
MAR
Missing At Random
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
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)
PK
Pharmacokinetic(s)
PRO
Patient Reported Outcomes
PT
prothrombin time
PTT
Partial Thromboplastin 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
 


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SOP
Standard Operating Procedure
SPT
Skin Prick Test
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TBL
Total Bilirubin
Tmax
The time to reach the maximum concentration after drug 
administration
T1/2
The terminal elimination half-life [time]
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
Vz/F
The apparent volume of distribution during the terminal elimination 
phase following extravascular administration [volume]
WBC
White Blood Cell(s)
WHO
World Health Organization 
WoCBP
Women of Child-Bearing Potential
XLA
X-linked Aggamaglobulinemia
 


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (eg 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 (eg 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 (eg 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.
 


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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 
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Protocol summary
Protocol number
CLOU064A2201
Full Title
A multicenter, randomized, double-blind, placebo- controlled Phase 2b 
dose-finding study to investigate the efficacy, safety and tolerability of 
LOU064 in adult chronic spontaneous urticaria patients inadequately 
controlled by H1-antihistamines
Brief title
A Phase 2b dose-finding study to investigate the efficacy, safety and 
tolerability of LOU064 in adult chronic spontaneous urticaria patients
Sponsor and 
Clinical Phase
Novartis IIb
Investigation type
Drug
Study type
Interventional. 
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy and safety of LOU064 in 
subjects suffering from CSU inadequately controlled by H1-antihistamines
and to select a LOU064 dosing regimen for the subsequent Phase 3 
program.
Primary 
Objective(s) 
The primary objective of this study is to characterize the dose-response 
relationship of LOU064 administered once or twice daily in subjects with CSU 
with respect to change from baseline in UAS7 at Week 4
Secondary 
Objectives
To evaluate the efficacy of LOU064 compared to placebo with respect to 
change from baseline UAS7 at Week 12
To evaluate the efficacy of LOU064 compared to placebo with respect to 
change from baseline UAS7 over time
To evaluate the efficacy of LOU064 compared to placebo with respect to 
achievement of complete clinical response (UAS7= 0) over time
To evaluate the efficacy of LOU064 compared to placebo with respect to 
achievement of disease control (UAS7≤6) over time
To evaluate the effect of LOU064 on angioedema (AAS7) with respect to the 
number of weeks with an AAS7= 0 response from baseline through Week 12
To evaluate the effect of LOU064 on disease-related quality of life with 
respect to achievement of a DLQI score of 0 or 1 at Week 4 and Week 12
To evaluate the effect of LOU064 on CSU-related quality of life with respect 
to change from baseline in DLQI at Week 4 and Week 12
To evaluate the pharmacokinetics (PK) of LOU064 resulting from oral dosing 
(PK sampling will be performed at Week 4 and Week 12)
To evaluate safety and tolerability of LOU064 in subjects with CSU
Study design
This is a global Phase 2b multicenter, randomized, double-blind, placebo-
controlled study. Study duration is 18 weeks (2 weeks screening period; 
12 weeks treatment period; 4 weeks follow-up period). The study comprises 
the 7 following treatment arms:
10 mg LOU064 once daily
35 mg LOU064 once daily
100 mg LOU064 once daily
10 mg LOU064 twice a day
25 mg LOU064 twice a day
100 mg LOU064 twice a day
Placebo
Eligible subjects will be randomly assigned to the treatment arms in a 
1:1:1:1:1:1:1 ratio.
 


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Population
The study population will consist of approximately 308 female and male adult 
patients with at least moderately active chronic spontaneous urticaria 
inadequately controlled by second generation H1-antihistamines.
Key Inclusion 
criteria
Signed informed consent must be obtained prior to participation in the study.
Male and female adult subjects aged ≥18 years of age.
CSU diagnosis for ≥ 6 months prior to screening 
Diagnosis of CSU inadequately controlled by second generation H1-
antihistamines as defined in the following: 
The presence of itch and hives for ≥6 consecutive weeks prior to screening in 
spite of use of non-sedating H1-antihistamines according to local treatment 
guidelines during this time period 
UAS7 score (range 0-42) ≥16 and HSS7 score (range 0-21) ≥ 8 during 7 days 
prior to randomization (Day 1)
Presence of hives must have been documented within three months before 
randomization (either at screening and/or randomization; or documented in 
the subject`s medical history)
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, eg 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, eg
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 (physical exam or 12 lead ECG) < 60 bpm

Resting QTcF ≥450 msec (male) or ≥460 msec (female) at 
pretreatment [screening]  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 (eg tuberculosis, 
atypical mycobacterioses, listeriosis or aspergillosis), HIV, Hepatitis B/C
Study treatment
LOU064 capsules (dose strengths: 10 mg; 25 mg; 50 mg)
Placebo capsules
Efficacy 
assessments
In this study, all efficacy measures are PROs:
Urticaria Patients Daily Diary (UPDD), including 
 


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Urticaria Activity Score (UAS) 
Angioedema Activity Score (AAS)
Assessment of impact of CSU on sleep and daily activity
Dermatology Life Quality Index (DLQI)
Pharmacokinetic 
(PK) assessments 
Assessment of the concentration of LOU064 in blood up to four hours 
following oral administration and before administration at Week 4 and 
Week 12
Key safety 
assessments
Adverse event (AE) monitoring
Physical examinations
Vital signs
Monitoring of laboratory markers in blood and urine
ECG monitoring
Data analysis
The main purpose of this study is to characterize the dose-response
relationship among LOU064 q.d. and b.i.d doses and placebo with respect to 
the change from baseline in UAS7 at Week 4, and select appropriate dose(s) 
to use in Phase 3 studies.
 
 
 
For secondary endpoints, 
summary tables will be presented by treatment group and visit (as applicable) 
using descriptive statistics, which include absolute and relative frequencies 
for categorical variables and arithmetic mean, standard deviation, minimum, 
maximum, median and first and third quartile for continuous variables.
Key words
Chronic spontaneous urticaria
BTK inhibitor
Urticaria activity score
Angioedema activity score
 


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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 has not been studied in larger clinical studies and hence uptitration is 
considered off-label. 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. 
1.1.1.1
Purpose
The purpose of this study is to evaluate the efficacy and safety of LOU064 in subjects suffering 
from CSU inadequately controlled by H1-antihistamines and to select a LOU064 dosing 
regimen for the subsequent Phase 3 program. Key efficacy evaluation criteria are the reduction 
 


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of signs (hives) and symptoms (itch) of CSU measured with the 7-day version of the Urticaria 
Activity Score (UAS7) and the improvement of health-related quality of life as measured by 
the Dermatology Life Quality Index (DLQI).
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 

To characterize the dose-response 
relationship of LOU064 administered once 
or twice daily in subjects with CSU with 
respect to change from baseline in UAS7 at 
Week 4

Change from baseline in UAS7 at Week 4
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the efficacy of LOU064 
compared to placebo with respect to change 
from baseline in UAS7 at Week 12

Change from baseline in UAS7 at Week 12

To evaluate the efficacy of LOU064 
compared to placebo with respect to change 
from baseline in UAS7 over time

Change from baseline in UAS7 over time

To evaluate the efficacy of LOU064 
compared to placebo with respect to 
achievement of complete clinical response 
(UAS7= 0) over time

Complete absence of hives and itch, 
assessed as UAS7= 0 response over time

To evaluate the efficacy of LOU064 
compared to placebo with respect to 
achievement of disease control (UAS7≤6) 
over time

UAS7≤6 response over time

To evaluate the effect of LOU064 on 
angioedema (AAS7) with respect to the 
number of weeks with an AAS7= 0 response 
from baseline through Week 12

Cumulative number of weeks with an 
AAS7= 0 response between baseline and 
Week 12

To evaluate the effect of LOU064 on 
disease-related quality of life with respect to 
achievement of a DLQI score of 0 or 1 at 
Week 4 and Week 12

DLQI score of 0 or 1 at Week 4 and 
Week 12

To evaluate the effect of LOU064 on CSU-
related quality of life with respect to change 
from baseline in DLQI at Week 4 and 
Week 12

Change from baseline in DLQI score at 
Week 4 and Week 12

To evaluate the pharmacokinetics of 
LOU064 resulting from oral dosing at 
Week 4 and Week 12

Concentrations of LOU064 in blood and 
calculation of respective PK parameters at 
Week 4 and Week 12

To evaluate safety and tolerability of 
LOU064 in subjects with CSU

Safety endpoints will include but not be 
limited to:
o
Occurrence of treatment emergent 
adverse events during the study
 


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Objective(s)
Endpoint(s)
o
Occurrence of treatment emergent 
serious adverse events during the 
study
3
Study design
This is a global Phase 2b multicenter, randomized, double-blind, parallel-group, placebo-
controlled study investigating the safety, tolerability, and efficacy of six dosing groups of oral 
LOU064 in subjects with inadequately controlled CSU despite treatment with (second 
generation) H1-antihistamine treatment. 
Throughout the study (i. e. Day -14 until Day 113), subjects must be on a stable treatment 
regimen with a second generation H1-antihistamine at a locally approved licensed posology 
(“background medication”). 
Subjects may take an additional second generation H1-antihistamine that is eliminated primarily 
via renal excretion (eg cetirizine, levocetirizine or bilastine) as rescue medication (see 
Section 6.2.3). The rescue H1-antihistamine must differ from the background H1-antihistamine 
 


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and may only be administered to treat unbearable symptoms (itch) of CSU on a day-to-day basis
throughout the study (from Day -14 until Day 113). 
All other CSU therapies (including H1-antihistamines at higher than approved doses) are 
prohibited (see Table 6-3 in Section 6.6.2). 
An outline of the study design including three periods is presented in Figure 3-1, while a 
detailed visit and assessment schedule can be found in Table 8-1:

Screening period (10-14 days prior to randomization): During the screening period, 
subjects who have provided informed consent will be assessed for study eligibility. 

Treatment period (Day 1 to Day 85): After screening, eligible subjects will be randomly 
assigned to one of the following treatment arms in a 1:1:1:1:1:1:1 ratio:
o
10 mg LOU064 once daily
o
35 mg LOU064 once daily
o
100 mg LOU064 once daily
o
10 mg LOU064 twice a day
o
25 mg LOU064 twice a day
o
100 mg LOU064 twice a day
o
Placebo
 

Follow-up period (Day 86 to Day 113): subjects are followed-up 
 
 to further assess safety.
An extension study is in development. Eligible subjects may roll-over into the extension study 
at Week 12 or at Week 16 (after completing all scheduled assessments planned at these visits), 
following roll-over criteria defined in the extension study protocol. The details of the study 
design and procedures of the extension, if implemented, will be described in a separate protocol.
 


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Figure 3-1
Study Design 
1) Background therapy is 
eneration H1-antihistamine at a locally approved licensed posology that 
must be administered every day with a stable treatment regimen throughout the study (from Day -14 until 
Day 113). 
2) Rescue therapy is a second generation H1-antihistamine at a locally approved licensed posology that is 
eliminated primarily via renal excretion (eg 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 throughout the study (from Day -14 until Day 113). 
3) H1-antihistamines used for background therapy and rescue therapy must not be changed throughout the
study.
4
Rationale
4.1
Rationale for study design
This randomized, double-blind, parallel-group, placebo-controlled design supports dose-range 
finding and assessment of efficacy as well as safety of LOU064 in subjects with CSU 
inadequately controlled by H1-antihistamines. The balanced allocation of subjects to placebo 
and 6 treatment arms receiving LOU064 at doses from 10 to 100 mg either once or twice daily 
aims to establish an accurate dose-response model for the two dosing intervals allowing the 
selection of the treatment regimen with the best benefit-risk profile for patients in the
confirmatory phase of the development program with LOU064 (also see Section 4.3).
The screening period will allow the assessment of eligibility of subjects and the determination 
of baseline disease activity. The assessment of the primary endpoint will be at Week 4 as 
LOU064 is expected to have a fast onset of action. A 12-week treatment period was chosen to 
investigate the maintenance of the expected effect size plateau and to allow historic comparison 
to other treatment options for CSU, eg omalizumab. A 4-weeks follow-up will enable the 
assessment of sustained treatment response or CSU relapse after withdrawal of LOU064.
 


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4.2
Rationale for choice of background therapy
H1-antihistamines were chosen as background medication as it reflects the current treatment 
guidelines to add a second- or third-line therapy to H1-antihistamines in CSU patients who are 
not adequately controlled by H1-antihistamines (Zuberbier et al 2018).
4.3
Rationale for dose/regimen and duration of treatment
In this study, LOU064 will be used in three q.d. arms (10 mg; 35 mg; 100 mg) and three b.i.d. 
arms (10 mg; 25 mg; 100 mg) for 85 days (12 weeks). Treatment duration is covered by 
preclinical data and will allow the assessment of the effect size of LOU064 in CSU, the onset 
of action, and the early maintenance of the effect size plateau. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The proposed study design is expected to enable proper characterization of dose- and exposure-
response relationships for once and twice daily dosing, and thus support determination of the 
 


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optimal dosing regimen for LOU064 for confirmation into Phase 3. For detailed description of 
pre-clinical and clinical study results please refer to the IB.
4.4
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Placebo was chosen as comparator to adjust for the known pronounced placebo effect in CSU 
patients. The use of placebo in this patient population is considered to be appropriate since 
patients will additionally receive a background therapy with H1-antihistamines (see 
Section 6.1.2).
 
 
4.6
Benefits and risks
To date, no CSU patients have been treated with LOU064, and no reports about treatment of 
CSU patients with other BTK inhibitors have been published. However, chronic urticaria is a 
mast cell and basophil driven disease (Ferrer et al 2015) and LOU064 as well as other BTK 
inhibitors have been shown to effectively inhibit mast cell and basophil activation: 
BTK inhibition interferes with the up-regulation of the activation markers CD63 and 
CD203c (LOU064 IB). 
LOU064 and ibrutinib, an approved BTK inhibitor used to treat B cell malignancies, have 
been shown to effectively reduce wheal sizes in skin prick tests (Regan et al 2017; Dispenza 
et al 2018; LOU064 IB). SPT inhibition was shown to be a reliable clinical proxy for 
measuring the effectiveness of a compound to treat CSU (Arm et al 2014). 
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. These patients with a high 
unmet medical need will be part of the eligible patient population for this study.
 
 
 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 IB.
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 
 


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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 (eg: 
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 node 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. In adult patients, BTK inhibition primarily interferes 
with B cell activation but not plasma cell function and is therefore not associated with a 
marked decrease of immunoglobulins (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 symptoms of bleeding while 
in the study. Subjects with a known history of bleeding disorder, subjects taking medication 
that is known to increase the bleeding risk (other than acetylsalicylic acid), and subjects with
an increased thromboembolic risk must be excluded from the study (see details in Section 
5.2). 
Myelomodulation: The role of BTK inhibition in myelomodulation is not fully understood. 
Treatment emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia and anaemia) 
were reported in patients with hematologic malignancies treated with ibrutinib and 
acalabrutinb (see SmPC for ibrutinib and acalabrutinib). Therefore, patients must be closely 
monitored for signs and symptoms of cytopenia while in the study, and those with a history 
of hematological disorders or with markedly altered hematologic parameters at baseline must 
be excluded from the study (see details in Section 5.2).
Risk of cardiovascular origin: LOU064 is an in vitro inhibitor of the hERG channel protein, 
without affecting other ion channels. 
 
 
 
 


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For 
ibrutinib, atrial fibrillation was described for 3% to 6% of subjects across multiple trials 
which might be associated with Na-channel inhibition (see SmPC for ibrutinib). For
acalabrutinib, both atrial fibrillation and atrial flutter of any grade were reported in 3% of 
patients (see SmPC for acalabrutinib). Therefore, an intensive ECG monitoring strategy be 
implemented in this study (see Section 8.4.2). In addition, patients with a known history or 
current diagnosis of ECG abnormalities indicating significant risk of safety will be excluded 
from the study (see details in Section 5.2).
Drug-drug interactions:
 
 
 
 
 
 
 
 
 
 
 
 
 
 Concomitant administration with moderate or strong CYP3A4 inhibitors or 
inducers may possibly cause substantial changes in LOU064 drug exposure, and must be 
avoided while in the study.
Reproductive toxicity: LOU064 is not genotoxic or mutagenic in in vitro or in vivo studies. 
 
 
For ibrutinib and acalabrutinib, embryofetal toxicity in animals is reported 
(see SmPCs). Highly effective methods of contraception must be practiced.
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the 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 
 


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all safety risks are known. Patients and investigators participating in this study will be informed
should important new safety information become available. 
5
Population
The study population will consist of adult patients with at least moderately active CSU
inadequately controlled by second generation H1-antihistamines.
Randomization will be stratified by prior exposure to anti-IgE biologics (including omalizumab 
and ligelizumab) and by geographical region;
 
The goal is to randomize approximately 44 subjects per arm (i.e. a total of 308 subjects) in 
approximately 90 centers worldwide. With an estimated screening failure rate of 30%, 
approximately 440 subjects will be screened.
Subjects who drop out after they have been randomized will not be replaced.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1.
Signed informed consent must be obtained prior to participation in the study
2.
Male and female adult subjects aged ≥18 years of age
3.
CSU diagnosis for ≥ 6 months prior to screening 
4.
Diagnosis of CSU inadequately controlled by second generation H1-antihistamines at the 
time of randomization as defined in the following:
-
The presence of itch and hives for ≥6 consecutive weeks prior to screening in spite of
use of non-sedating H1-antihistamines according to local treatment guidelines during 
this time period
-
UAS7 score (range 0-42) ≥16 and HSS7 score (range 0-21) ≥ 8 during 7 days prior to 
randomization (Day 1)
5.
Presence of hives must have been documented within three months before randomization 
(either at screening and/or at randomization; or documented in the subject`s medical 
history)
6.
Willing and able to complete an Urticaria Participant Daily eDiary (UPDD) for the duration 
of the study and adhere to the study protocol
7.
Subjects must not have had any missing eDiary entries in the 7 days prior to randomization
(Day 1)
 


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5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study:
1.
Use of other investigational drugs within 5 half-lives of Screening, or within 30 days (for 
small molecules) prior to Screening or until the expected pharmacodynamic (PD) effect has 
returned to baseline (for biologics), whichever is longer; or longer if required by local 
regulations.
2.
History of hypersensitivity to any of the study treatments 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, eg. atopic dermatitis, bullous 
pemphigoid, dermatitis herpetiformis, senile pruritus or psoriasis
6. 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, eg 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 (physical exam or 12 lead ECG) < 60 bpm
-
Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pretreatment (screening) 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.
Subjects taking medications prohibited by the protocol (see Section 6.2.2, Table 6-3).
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 while 
taking study treatment 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 (eg calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
 


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-
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. 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 study treatment.
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 
(eg 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. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 7 days after stopping study treatment. A condom is required for all
sexually active male participants to prevent them from fathering a child AND to prevent 
delivery of study treatment via seminal fluid to their partner. In addition, male participants 
must not donate sperm for the time period specified above.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the Informed Consent Form (ICF).
12. Major surgery within 8 weeks prior to screening or surgery planned prior to end of study 
(16 weeks after randomization)
13. History of live attenuated vaccine within 6 weeks prior to randomization 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 screening:
Hemoglobin: < 10 g/dl
Platelets: < 100 000/mm3
White blood cells: <3 000/mm3
Neutrophils: < 1 500/mm3
 


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17. Significant bleeding risk or coagulation disorders 
18. History of gastrointestinal bleeding, eg 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 or International Normalized Ratio (INR) of more 
than 1.5x upper limit of normal (ULN) at screening
22. History of renal disease or creatinine level above 1.5x ULN at screening
23. Known or suspected history of an ongoing, chronic or recurrent infectious disease 
including but not limited to opportunistic infections (eg 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
There will be 3 dispensing visits: Randomization, Week 4 and Week 8.
6.1.1
Investigational and control drugs
Novartis Global Clinical Supply (GCS) will provide the following IMP supplies in 
appropriately blinded labeled bottles (Table 6-1).
Table 6-1
Investigational and control drug
Investigational/Control 
Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply type
Sponsor 
(global or 
local)
LOU064 10 mg
Capsule
Oral use
Double-blind 
supply; bottles
Sponsor 
global 
LOU064 25 mg
Capsule
Oral use
Double-blind 
supply; bottles
Sponsor 
global 
LOU064 50 mg
Capsule
Oral use
Double-blind 
supply; bottles
Sponsor 
global
LOU064 placebo
Capsule
Oral use
Double-blind 
supply; bottles
Sponsor 
global 
 


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6.1.2
Additional study treatments
No other additional treatment beyond investigational treatment (LOU064 and placebo) is 
requested for this trial. Subjects will take background medication (second generation H1-
antihistamines at (locally) approved licensed doses) with a stable regimen during the study
(Section 6.2.1) . For rescue medication, see Section 6.2.3.
6.1.3
Treatment arms/group
Subjects will be assigned at Day 1 to one of the following 7 treatment arms (Table 6-2) in a 
ratio of 1:1:1:1:1:1:1. Each subject will take 2 capsules in the morning and 2 capsules in the 
evening at home (except for Week 4 and Week 12 morning dose, which are to be taken on site 
during the site visit), for a total of 4 capsules daily. Depending on the treatment arm, these 
capsules will contain LOU064 at different dose strengths or placebo. The patient must take one 
capsule from each morning bottle (identified with a sun symbol) in the morning and one capsule 
from each evening bottle (identified with a moon symbol) in the evening.
Table 6-2 Treatment regimen per arm
Number of capsules 
per intake per 
treatment arm
Arm A:
10 mg LOU064 qd
Arm B:
35 mg LOU064 qd
Arm C:
100 mg LOU064 qd
Arm D:
10 mg LOU064 bid
Arm E:
25 mg LOU064 bid
Arm F:
100 mg LOU064 
bid
Arm G:
Placebo
Morning dose
10 mg LOU064 
1
1
0
1
0
0
0
25 mg LOU064 
0
1
0
0
1
0
0
50 mg LOU064 
0
0
2
0
0
2
0
Placebo 
1
0
0
1
1
0
2
Evening dose
10 mg LOU064 
0
0
0
1
0
0
0
25 mg LOU064 
0
0
0
0
1
0
0
50 mg LOU064 
0
0
0
0
0
2
0
Placebo 
2
2
2
1
1
0
2
Treatment duration
All subjects will receive their respective LOU064 or placebo capsules for 12 weeks (from Day 
1 until Week 12). 
 


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6.2
Other treatment(s)
6.2.1
Concomitant therapy
Throughout the study (from Day -14 until Day 113), subjects must take a second generation 
H1-antihistamine at a locally approved licensed dose and posology (background therapy). 
Background therapy must not be changed throughout the study. For detailed information on the 
background medication, refer to the corresponding SmPC.
Prior medication for treatment of CSU will be recorded in the eCRF. In addition, all 
concomitant medication at screening and prior medication that has been terminated within 4 
weeks prior to screening will be recorded. The investigator should instruct the subject to notify 
the study site about any new medications (including medications that are not related to the 
treatment of CSU) he/she takes after the subject was enrolled into the study, ideally before 
initiating a new treatment. All medications, procedures and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the subject was enrolled 
into the study must be recorded on the respective eCRF pages.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical advisor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, Novartis should be contacted to determine if the subject should continue participation 
in the study.
6.2.2
Prohibited medication
Use of the treatments displayed in Table 6-3 are not allowed during the specified time period. 
Table 6-3
Prohibited medication
Medication
Prohibition period
Biologics for treatment of CSU (including omalizumab 
and ligelizumab)
4 months prior to screening until end of 
study
Routine (daily or every other day during 5 or more 
consecutive days) doses of systemic corticosteroids
30 days prior to screening until end of 
study
Note: from Day 1 (baseline) until Week 
12 (end of treatment period) the use of 
systemic corticosteroids is not permitted 
at all.
Leukotriene antagonists (including montelukast and 
zafirlukast)
From screening until end of study
H2-antihistamines
From screening until end of study
First generation antihistamines
From screening until end of study
Second generation antihistamines other than the 
defined background medication and rescue medication
From screening until end of study
Other immunosuppressive medication with or without 
known effect on CSU including but not limited to 
hydroxychloroquine, methotrexate, cyclosporine A, 
cyclophosphamide, tacrolimus and mycophenolate 
mofetil
30 days or 5 half-lives (whichever is 
longer) prior to screening until end of 
study
 


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Medication
Prohibition period
Intravenous (i.v.) immunoglobulins or plasmapheresis 
30 days prior to screening until end of 
study
Regular (daily or every other day) doxepin (oral)
14 days prior to screening until end of 
study
Live attenuated vaccine
6 weeks prior to screening until end of 
study
Moderate and strong inhibitors of CYP3A4 (see Table 
16-5 in Appendix 4), including grapefruit juice
From screening until end of study
Moderate and strong inducers of CYP3A4 (see Table 
16-6 in Appendix 4)
From screening until end of study
Any drug known to prolong QTc interval (see 
https://crediblemeds.org for guidance)
5 half-lives or until pharmacodynamic 
effect has disappeared prior to baseline 
(whichever is longer) until end of study
Anti-platelet or anticoagulant medication (for example, 
warfarin, or clopidogrel or Novel Oral Anti-Coagulant -
NOAC) other than acetylsalicylic acid (up to 100 mg/d)
From screening until end of study
6.2.3
Rescue medication
Second generation H1-antihistamines that are eliminated primarily via renal excretion (eg
cetirizine, levocetirizine or bilastine) are allowed as rescue medication (at a locally approved
licensed posology), used on an as needed basis for subjects with flare-ups of unbearable 
symptoms of their disease during screening, treatment and follow-up periods. The selection of 
the H1-antihistamines rescue medication should be made only once for an individual subject
and documented in the source document. For each individual subject, the H1-antihistamine 
rescue medication used must differ from the H1-antihistamine used for background medication. 
For detailed information on the rescue medication, refer to the corresponding SmPC. A change
of the rescue medication for an individual subject is not permitted. The usage of rescue therapy 
will be recorded in the eDiary (UPDD question 5). Name and dose of rescue medication will be 
reported in the eCRF. Rescue medication will be sourced locally and provided to the patient
during the study.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the ICF, the subject is assigned to the next sequential Subject No. available.
6.3.2
Treatment assignment, randomization
At Day 1, all eligible subjects will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
 


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randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply using a validated system that automates the random assignment of 
medication numbers to packs containing the study treatment.
Randomization will be stratified by geographical region and prior usage of anti-IgE biologics 
(including omalizumab and ligelizumab) for treatment of CSU.
 
 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Subjects, investigator staff, persons performing the assessments will remain blinded to the 
identity of the treatment from the time of randomization until final database lock.
Designated Novartis study team members will remain blinded until the primary endpoint 
analysis (Week 4 analysis).
Blinding will be maintained using the following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study except in the case of subject emergencies 
(see Section 6.6.2) (2) the identity of the treatments will be concealed by the use of study 
treatment that are all identical in packaging, labeling, schedule of administration, appearance, 
taste and odor.
The randomization codes associated with subjects from whom PK samples are taken will be 
disclosed to unblinded PK analysts who will keep PK results confidential until data base lock.
Unblinding will occur in the case of subject emergencies and at the conclusion of the study.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
 


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the validity of the study. It should be emphasized to the patient that the study medication bottles 
are not identical. The patient must take one capsule from each morning bottle (identified with 
a sun symbol) in the morning and one capsule from each evening bottle (identified with a moon 
symbol) in the evening. 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
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
After emergency unblinding the subject will not receive further study treatment and will not be 
able to be enrolled into possible extension studies.
6.7
Preparation and dispensation
Each study site will be supplied with study treatment in packaging as described under 
investigational and control drugs section (6.1.1).
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the 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.
 


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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 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CO Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
The investigator should assess the compliance of each subject in regard to correct use of the 
background H1-antihistamine at every study visit. As with the study treatment, the importance 
of compliance with the background medication needs to be discussed with the subject. The use 
of the rescue H1-antihistamine will be recorded with the eDiary on a daily basis. 
6.7.2
Instruction for prescribing and taking study treatment
Every subject should take 2 capsules of the assigned LOU064 dose or placebo in the morning 
and 2 capsules in the evening with a 12 hour interval at approximately the same time every day. 
Since the study medication bottles are not identical, the patient must take one capsule from each 
morning bottle (identified with a sun symbol) in the morning and one capsule from each evening 
bottle (identified with a moon symbol) in the evening. The study medication may be taken with 
or without a meal but subjects should adhere to their choice throughout the study. If taken 
without food, the study medication should be taken with a glass of water (250 ml) at least 2
hour after the last meal and 1 hour before the next meal. On days of PK assessment, all subjects 
need to take their study medication on site without food (as described above). Subjects should 
be instructed to swallow whole capsules and not to chew or open them. 
If vomiting occurs during the course of treatment, subjects should not take the study treatment 
(LOU064) again before the next scheduled dose. 
Subjects should be instructed not to make up missed doses. A missed dose is defined as a case 
when the full dose is not taken within 4 hours after the approximate time of the usually 
 


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morning/evening dosing. That dose should be omitted and the subject should continue treatment 
with the next scheduled dose. 
Study medication intake will be recorded in the patient’s eDiary. Subjects will be instructed to 
complete eDiary entries after they took their study medication throughout the treatment period.
H1-antihistamines taken as background medication and rescue medication, respectively, should 
be taken according to the local treatment instructions.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC)-
approved informed consent.
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 (eg 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 ICF that complies with 
the ICH Good Clinical Practice (GCP) guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the 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.
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
 


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8
Visit schedule and assessments
Assessment schedule lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the subject’s source documentation.
Subjects should be seen 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 
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Table 8-1
Assessment schedule
Period
Treatment
Follow-up
Visit
Screening
Randomization
End of 
Treatment/
PSW/Study 
Discontinuation
Study 
Completion
Unscheduled
visit14
Day
-14
1
15
29
57
85
113
NA
Week 
-2
0
2
4
8
12
16
NA
Obtain Informed Consent(s)
X
Inclusion/exclusion criteria
X
X
Demographic data
X
Evidence of urticaria1
S
S
Relevant medical history
X
CSU History and prior urticaria 
treatment
X
Cardiovascular History
X
Physical Exam2
S
S
S
S
S
S
S
S
Vital signs
X
X
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
ECG
X3a X3b
X3a
X3c
X3a
X3c
X3a
X
Dispense Subjects’ eDiary
S
Call the subject to check eDiary 
compliance4
S
Prior and Concomitant medication 
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Surgery and procedures
X
X
X
X
X
X
X
X
Re-screening
X
Randomization
X
Study drug dispensation
X
X
X
X
IRT transaction
X
X
X
X
X
X
Rescue medication dispensation and 
usage5
X
X
X
X
X
X
X
X
Subjects’ eDiary  review6
-
UPDD (incl. UAS)
-
AAS
-
Study medication compliance
S
S
S
S
S
S
S
Background medication dispensation 
and compliance assessment
X
X
X
X
X
X
X
X
 


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Period
Treatment
Follow-up
Visit
Screening
Randomization
End of 
Treatment/
PSW/Study 
Discontinuation
Study 
Completion
Unscheduled
visit14
Day
-14
1
15
29
57
85
113
NA
Week 
-2
0
2
4
8
12
16
NA
DLQI (Dermatology Life Quality 
Index)7
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Urine Pregnancy8
S
S
S
S
S
S
BLOOD SAMPLING:
Hematology and Chemistry
X
X
X
X
X
X
X
X
Coagulation
X
X
X
Total IgE
X
X
X
X
X
HBV, HCV testing
X
X
FSH testing9
X
X
Serum pregnancy test10
X
X
PK sampling11
X
X
X
Assessment of how study medication 
was taken (with/without a meal)12
S
S
S
Roll-over criteria for extension study13
S
S
Disposition (End of Treatment and 
Study disposition)
X
S: recorded in the source documents only
X: recorded in the eCRF
1 Before randomization, the presence of hives as sign of urticaria must have been documented. Hives 
can be documented during a study visit (screening/randomization); alternatively, presence of hives 
must have been documented in the medical history (not more than 3 months prior to the screening 
visit) or can be demonstrated using a photograph (not older than 3 months).
2 Detailed description of physical exam: please refer to Table 8-8. A complete physical exam will be 
done at Screening. A short physical exam will be done at all subsequent visits
3a A single ECG measurement 
3b Triplicate ECG measurement pre-dose
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4 To be performed in screening period between day -14 and randomization
5 Rescue medication usage will be assessed by reviewing the patient’s eDiary answer to UPDD 
question 5 
6 UPDD: Urticaria Patient Daily Diary; UAS: Urticaria Activity Score; AAS: Angioedema Activity Score
7 DLQI is completed in the patient’s eDiary during site visit
8Only performed in women of childbearing potential. Serum pregnancy test done by central lab to 
confirm positive urine pregnancy test
9 Only for female subjects with unclear fertility status
10 Only performed in women of childbearing potential
11 Detailed PK sampling schedule is provided in Table 8-10
12 At the PK visits, the subject should be asked how the study medication was usually (≥80%) taken in
the preceding week: with (interval between 1 hour before and 2 hours after the meal) or without a 
meal. This information should be recorded in the source documents.
13 Evaluate roll-over criteria as defined in extension study protocol if implemented
14 Unscheduled visit: the assessment(s) performed at an unscheduled visit are at the investigator’s 
discretion
8.1
Screening
Screening and re-screening
Subjects will have a screening period of 10 to 14 days to establish eligibility for the study. 
If for any reason a subject is a screen failure, the subject may be re-screened. Re-screening is 
only allowed once. There is no restriction on how much time must pass from the date of screen 
failure to the date of re-screening.
IF a subject re-screens for the study, then the subject must sign a new ICF and be issued a new 
subject number prior to any screening assessment being conducted for the subject under the 
new screening subject number. The investigator/qualified site staff will record if the subject 
was re-screened on the re-screening eCRF and any applicable screening numbers the subject 
was issued prior to the current screening number.
The date of the new informed consent signature must be entered on the informed consent eCRF 
to correspond to the new screening subject number. For re-screening, all screening assessments 
must be performed per protocol.
Information to be collected on screening failures
Subjects who sign an ICF and subsequently found to be ineligible prior to randomization will 
be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate eCRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a SAE
during the screening Phase (see SAE section for reporting details). If the subject fails to be 
randomized, the IRT must be notified within 2 days of the screen fail that the subject was not 
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Subjects who are randomized and fail to start treatment, eg subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF. 
8.2
Subject demographics/other baseline characteristics
Baseline CSU activity will be assessed using the eDiary from Day -7 to Day -1. Subject
demographic and baseline characteristic data to be collected on all subjects include age, sex, race
and ethnicity. Relevant medical history (including evaluation of inclusion/exclusion criteria, 
CSU history and cardiovascular history) andcurrent 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), Angioedema Activity Score (AAS), and
Dermatology Life Quality Index (DLQI).
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. 
Assessments will be completed twice daily (UPDD), once daily (AAS, if triggered by opening 
question within the UPDD) or as detailed in the assessment schedule. 
In general, subject complete eDiary questionnaires at home and independent of study visits. 
Subjects will be instructed to complete eDiary entries after they took their study medication 
throughout the treatment period. DLQI questionnaire will be administered during respective 
visits on site and should be completed prior to any other study specific procedure. Site personnel 
must allow subjects to complete the questionnaire on their own without any assistance from the 
site staff. 
8.3.1
eDiary assessments
8.3.1.1
Urticaria Patient Daily Diary (UPDD) 
UPDD includes Urticaria Activity Score (UAS) which assesses twice daily severity of itch and 
number of hives, use of rescue medication, sleep and activity interference, angioedema 
occurrence, its management and records the calls to an healthcare professional (HCP) (see 
Appendix 5). The components are presented in the Table 8-2 and the relevant weekly scores are 
described below.
Table 8-2
UPDD
Diary component
When assessed
Urticaria Activity Score (UAS)

Itch severity
Morning & evening
 


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Diary component
When assessed

Number of hives
8.3.1.1.1 Weekly Hives Severity Score (HSS7)
The hives (wheals) severity score, defined by number of hives, will be recorded by the subject 
twice daily in their eDiary, on a scale of 0 (none) to 3 (> 12 hives/12 hours; Table 8-3). A 
weekly score (HSS7) is derived by adding up the average daily scores of the 7 days preceding 
the visit. The possible range of the weekly score is therefore 0 – 21.
Table 8-3
Hives Severity Score
Score
Hives (Wheals) (every 12 hours)
0
None
1
1-6 hives/12 hours
2
7-12/12 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 8-4). A weekly score (ISS7) is derived by adding up the average 
daily scores of the 7 days preceding the visit. The possible range of the weekly score is therefore 
0 - 21. 
Table 8-4
Itch Severity Score
Score
Pruritus (Itch) (every 12 hours)
0
None
1
Mild (minimal awareness, easily tolerated)
2
Moderate (definite awareness, bothersome but tolerable)
3
Severe (difficult to tolerate)
8.3.1.1.3 Weekly Urticaria Activity Score (UAS7)
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly 
UAS7 score is 0 – 42 (highest activity).
 


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8.3.2
Other Patient Reported Outcomes (PRO) assessments 
8.3.2.1
Dermatology Life Quality Index (DLQI)
The Dermatology Life Quality Index (DLQI) is a 10-item (grouped in 6 domains) dermatology-
specific quality of life (QoL) measure (Finlay et al 1994). The DLQI was validated for patients 
aged 16 and above. Subjects rate their dermatology symptoms as well as the impact of their 
skin condition on various aspects of their lives thinking about the previous 7 days. 
An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-
related QoL). Domain scores are calculated for: Symptoms and Feelings (0-6), Daily Activities 
(0-6), Leisure (0-6), Work and School (0-3), Personal Relationships (0-6), Treatment (0-3). 
The overall DLQI score range was split into score bands (Hongbo et al 2005) and validated in 
terms of their meaning/relevance to patients as follows:
Table 8-7
DLQI score bands and impact on patient’s life
DLQI band
Significance of score
0-1
No effect on patient’s life
2-5
Small effect on patient’s life
6-10
Moderate effect on patient’s life
11-20
Very large effect on patient’s life
21-30
Extremely large effect on patient’s life
A DLQI score of > 10 is relevant for a very large impact on patients’ life and justification for a 
biologic prescription for example in psoriasis (Kaplan et al 2005). The DLQI questionnaires are 
completed at randomization (Day 1), Weeks 4 (Day 29) and Week 12 (Day 85) in the eDiary.
The DLQI should be completed prior to any other assessment and prior to administration of 
investigational medication.
8.3.3
Other assessments: evidence of urticaria
The investigator must confirm the presence of urticaria (i.e. the presence of hives) in each 
subject before randomization by direct physical examination. In the absence of active disease 
at the screening and/or randomization visit, the following will be acceptable: (a) a clearly 
identifiable photograph of the subject that is no older than 3 months showing the presence of 
urticaria, (b) the investigator must have seen the subject with active CSU in the past 3 months, 
 


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or (c) the presence of hives/wheals must have been documented in the medical record of the 
subject by a physician trained in the management of urticaria in the past 3 months.
8.3.4
Appropriateness of efficacy assessments
At the time the omalizumab studies were carried out, the treatment paradigm focused primarily 
on itch (ISS7) as a key symptom of CSU. Over the past several years the goal of therapy has 
evolved and the current target of therapy as described in the current CSU treatment guidelines 
(Zuberbier et al 2018) is to treat the disease until it is gone, i.e. complete control of the disease 
(UAS7= 0). Given the current emphasis on UAS7 in the medical community and as reflected 
in the CSU treatment guidelines, change from baseline in UAS7 will be used to characterize the 
dose-response relationship of LOU064 administered once or twice daily. 
 
 
Data collected during this study will be used to provide information that will support selection 
of doses for further evaluation 
 which may be included 
in future studies.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10, Safety monitoring and reporting.
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 8-8
Physical Assessments
Assessment
Specification
Physical 
examination
A complete physical examination (performed at Screening) will include the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, 
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 all visits except Screening, see Table 8-1) 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).
 


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Assessment
Specification
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, eg 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 Appendix 1.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section (Table 8-
9) unless noted otherwise. Details on the collections, shipment of samples and reporting of 
results by the central laboratory are provided to investigators in the laboratory manual. 
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 8-9
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, Creatinine Kinase (CK), Creatinine, total Bilirubin 
(in case of clinically significant elevation: direct Bilirubin and indirect Bilirubin will 
be assessed)
Only at baseline (Day 1) and Week 12: 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 screening and 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), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time (APTT) 
 


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Test Category
Test Name
Hepatitis 
markers
At Screening only: Hepatitis B surface antigen (HBsAg), anti-HBsAg antibodies
(HBsAb), antibodies against Hepatitis B  core antigen (HBcAb) and Hepatitis B-
Deoxyribonucleic acid (HBV- DNA) as appropriate; Hepatitis C virus antibodies
(HCVAb)  and Hepatitis C-Ribonucleic acid (HCV-RNA) as appropriate
Additional 
tests
IgE, 
; Follicle-stimulating hormone (FSH) (for female subjects with 
unclear fertility status), serum pregnancy test (for WoCBP)
Pregnancy 
Test
Urine pregnancy test for WoCBP
8.4.2
Electrocardiogram (ECG)
Standard 12-lead ECGs must be recorded after 10 minutes rest in the supine position according 
to the ECG investigator manual. The preferred sequence of cardiovascular data collection 
during study visits is ECG collection first, followed by vital signs, and blood sampling. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Triplicate 12 lead ECGs are to be collected for central analysis as follows:

Day 1: before administration of the first dose of study medication

Week 4 and Week 12: before administration of study medication and 1h after 
administration of the study medication (study medication will be taken at the study 
site; ECG recording will be accompanied by taking samples for PK analysis (see 
Section 8.5.1).
Single 12 lead ECGs will be collected for central analysis at Screening, Week 2, Week 8 and 
Week 16. 
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.
In the event that a clinically significant ECG abnormality is identified at the site (eg severe 
arrhythmia, conduction abnormality of QTcF > 500 ms or QTcF prolongation> 60 ms), a copy 
of the assessment is sent to the core laboratory for expedited review if applicable, and the ECG 
is repeated (and a copy sent to the core laboratory) to confirm the diagnosis. If the subject is 
hemodynamically compromised, the investigator or a medically qualified person must initiate 
appropriate safety procedures without delay (for example cardioversion).
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or AEs as appropriate.
8.4.3
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm for the time period specified above.
All pre-menopausal women who are not surgically sterile will have pregnancy testing at 
Screening (on serum), then at randomization (Day 1; BEFORE administration of the study 
 


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medication) and at Weeks 4, 8, 12 and 16 on urine. A positive urine test needs to be confirmed 
with serum test. If positive, the subject must be discontinued from study treatment.
Additional pregnancy testing might be performed if requested by local requirements.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:
1. surgical bilateral oophorectomy without a hysterectomy
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Other safety evaluations
Not applicable.
8.4.5
Appropriateness of safety measurements
Given the mild inhibition of hERG channels and the fact that atrial fibrillation/atrial flutter are 
a known risk for ibrutinib and acalabrutinib, Novartis implements an intensive ECG monitoring 
strategy in this study to allow proper collection of ECG data together with PK sampling to 
detect and analyze any potential effect of LOU064 on cardiac function, in particular QTc 
prolongation. The laboratory evaluation plan will provide sufficient safety information for 
LOU064 in the target population. 
8.5
Additional assessments
8.5.1
Pharmacokinetics
PK samples will be collected at the visits and time points defined in the assessment schedule. 
Instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment should be followed. Residual PK samples may be used to explore 
additional PK aspects such as metabolite formation or plasma protein binding of LOU064.
The PK sampling times selected were based on recent PK data as obtained from 
study CLOU064X2101. In particular due to the high blood clearance, a more dense sampling 
at early time points is required.
 
 
 
 
 


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For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol. The following PK parameters will be determined from the blood concentration time 
data using the actual recorded sampling times and non-compartmental method(s) with Phoenix 
WinNonlin (Version 6.4 or higher): Cmax, Tmax, AUClast, AUCtau, T1/2. Additional PK parameters 
may be added to further characterize the dose/exposure relationship or refine PK/PD analysis.
 
 
 
Therefore and due to the 
limited sampling up to 4 hours these PK parameters may not be determined. 
The PK of LOU064 will be characterized at Week 4 and Week 12 across all cohorts. The latter 
will provide a direct correlation of final safety and efficacy (PK/PD) readouts to exposure in 
term of AUC and Cmax. Likewise the Week 4 readout will be a synchronized assessment with 
cardiovascular safety at the primary endpoint (Week 4). Proposed sampling schedule and 
rationale is given in Table 8-10. Detailed PK samples numbering and schedule is given in 
Appendix 6.
Table 8-10
PK sampling schedule
time
Sample
Comment
Day 1
no PK assessment
the initial exposure and first dose effect of 
LOU064 has been well characterized over a 
wide dose range in study CLOU064X2101
Week 4
Early Steady-state “full” PK profile
baseline PK assessment which allows 
synchronization of parallel cardiovascular 
investigations which may be driven by initial 
high blood exposures (Cmax) at the primary 
endpoint/interim analysis 
Week 12 
(last day, 
last dose)
Assess steady-state + intra-subject variability + 
putative time dependent effects on PK, PK/PD
 


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
Patients may voluntarily discontinue investigational treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian 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, eg 
required surgical interventions associated with a risk for clinically significant bleeding

Following emergency unblinding

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 (eg 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
 


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-
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). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (eg 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

AEs/SAEs
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of assigned treatment code section (6.6.2).
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 allow further collection of personal data
In this situation, the investigator should make a reasonable effort (eg 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. 
 


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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the ICF.
For EU and rest of the world: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
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, eg 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 and treated as a prematurely withdrawn 
subject. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the 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.
Eligible subjects may roll-over into an extension study (which is in development) after
completing investigational treatment (at Week 12) or the follow-up period (at Week 16), 
following roll-over criteria defined in the extension study protocol, in case the study will be 
locally implemented.
 


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events (AEs)
An AE is any untoward medical occurrence (eg, 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 AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs 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.
AEs must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease and 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 AEs must be treated appropriately. Treatment may include one or more of the following:

dose not changed

dose reduced/increased

drug interrupted/withdrawn
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Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued for at least 30 days following the last dose of study 
treatment.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (eg 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 
study drug, 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 AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in 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 (SAEs)
An 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 
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
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, eg 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 SAE irrespective 
if a clinical event has occurred (see details in Section 10.1.5).
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 (eg 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/sponsor 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. A SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety 
(CMO&PS) Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
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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 should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
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. A minimum of 3 months of the newborn must be followed up.
Pregnancy should be recorded and reported by the investigator to the Novartis 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.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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 recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Novartis Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE within 24 
hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in 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
 


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For more information on AE and SAE definition and reporting requirements, please see the
respective sections (10.1.1 and 10.1.2).
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/AEs 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 contributing 
factors are recorded on the appropriate eCRFs
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 in Appendix 2. 

Repeat liver chemistry tests (i.e. ALT, AST, Total Bilirubin (TBL), PT/INR, ALP and GGT) 
to confirm elevation. These liver chemistry repeats will be performed using the central 
laboratory. If results will not be available from the central laboratory, then the repeats can 
also be performed at a local laboratory to monitor the safety of the 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

Obtaining a history of exposure to environmental chemical agents
 


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
Considering gastroenterology or hepatology consultations
All follow-up information, and the procedures performed must be recorded as appropriate in 
the eCRF(s).
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.
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.
10.2.3
Data monitoring committee
There will be no external data monitoring committee for this study. An internal independent 
safety monitoring board will be convened in case of the detection of two or more similar severe 
or serious potentially treatment-related AEs or laboratory abnormalities as described in 
Section 9.1.1 in two or more different subjects. Additional triggers for convening the internal 
independent safety monitoring board may be defined in the respective charter. The internal 
independent safety monitoring board will consist of Novartis designated associates from 
medical, statistical and patient safety departments who are not part of the CLOU064A2201 
study team. 
The internal independent safety monitoring board will review unblinded safety data information 
for the affected subjects and will then decide on appropriate subsequent measures to ensure 
patient safety or to gain more information, if deemed necessary. The review process will follow 
the internal independent safety monitoring board charter. Appropriate subsequent measures 
may include:

unblinded safety review of all enrolled subjects by the internal independent safety 
review board

amendment(s) to the study protocol, which may include discontinuation of treatment 
arms or even stopping the study.
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.
 


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10.2.5
Adjudication committee
Not applicable.
11
Data collection and database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRFs. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements. Designated 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 Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff is required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. 
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.
Randomization codes and 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.
 


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Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. electronic source (eSource) DDE or eCRFs) with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of 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.
12
Data analysis and statistical methods
The analysis will be conducted on all subjects’ data at the time the trial ends. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Randomized Set will consist of all randomized subjects, regardless of whether or not they 
actually received study medication. Subjects will be analyzed according to the treatment 
 


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assigned to at randomization. Unless otherwise specified, mis-randomized subjects (mis-
randomized in IRT) will be excluded from the randomized set. Mis-randomized subjects are 
defined as cases where IRT contacts were made by the site either prematurely or inappropriately 
prior to confirmation of the subject’s final randomization eligibility and no study medication
was administered to the subject.
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least one 
dose of study medication. Following the intent-to-treat principle, subjects will be analyzed 
according to the treatment and strata assigned to at randomization. Mis-randomized subjects 
(mis-randomized in IRT) will be excluded.
The Safety Set will consist of all subjects who received at least one dose of study medication 
whether or not being randomized. Subjects will be analyzed according to treatment received.
12.2
Subject demographics and other baseline characteristics
Demographics and baseline characteristics will be summarized using the safety set and FAS 
including disease characteristics, prior and background medications to treat urticaria, and 
relevant medical histories. Summary statistics will be presented for continuous demographic 
and baseline characteristic variables for each treatment group. The number and percentage of 
subjects in each category will be presented for categorical variables for each treatment group.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term.
12.3
Treatments
Analyses of treatment will be based on the Safety Set.
Study treatment
The duration of exposure to study treatment will be summarized by treatment group. 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.
Prior and concomitant medication
Prior and concomitant medications will be summarized by treatment separated for urticaria 
related background medications and non-urticaria related medications. Urticaria related 
background medications will be summarized by pre-specified categories (including dose) and 
preferred term. Non-urticaria related concomitant medications will be summarized by preferred 
term. Use of rescue medication will be summarized as well.
12.4
Analysis of the primary endpoint(s)
All analyses for efficacy data will be based on the FAS.
 


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The primary objective of this study is to characterize the dose-response relationship among 
LOU064 q.d. and b.i.d. doses (10 mg, 35 mg, 100 mg q.d. and 10 mg, 25 mg, 100 mg b.i.d.) 
and placebo with respect to the change from baseline in UAS7 at Week 4, and to select an 
appropriate dose(s) to use in Phase 3 studies. 
 
 
 
 
12.4.1
Definition of primary endpoint(s)
The primary variable for the study is the change from baseline in UAS7 at Week 4. The UAS7 
is the sum of the average daily UAS over 7 days. Note that the weekly score is derived by using 
the last 7 days prior to the visit.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.4.3
Handling of missing values/censoring/discontinuations
Subjects who discontinue from study treatment early will be encouraged to stay in the study. 
All the available data collected will be used for the primary analysis.
 
 
 


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12.5
Analysis of secondary endpoints
All analyses will be based on the FAS if not specified otherwise. For handling of missing data 
refer to Section 12.4.3.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Summary tables will be presented by treatment group and visit (as applicable) using descriptive 
statistics, which include absolute and relative frequencies for categorical variables and 
arithmetic mean, standard deviation, minimum, maximum, median and first and third quartile 
for continuous variables. For the secondary analysis of UAS7, complete clinical response, 
controlled disease and AAS7= 0, pairwise comparisons of each LOU064 doses to placebo will 
be performed. No adjustment for multiple comparisons will be done due to the exploratory 
nature of this study.
UAS7
Summary statistics of the absolute and percent change from baseline in UAS7 will be presented 
by treatment group and visit in the Treatment and Follow-up periods.
Complete clinical response
The complete clinical response, i.e. absence of hives and itch, is defined as subjects achieving 
UAS7= 0. 
The number of subjects with UAS7= 0 will be summarized by treatment group and visit in the 
Treatment and Follow-up periods.
 
 
Controlled disease (UAS7≤6)
The number of subjects with UAS7≤6 will be summarized by treatment group and visit in the 
Treatment and Follow-up periods.
 
 
 


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Absence of angioedema (AAS7= 0)
The cumulative number of weeks with an AAS7= 0 response between baseline and Week 12 
will be summarized by treatment group.
It will be derived based on AAS eDiary. A weekly AAS7 score will be derived by adding up 
the daily scores of the 7 days preceding the visit, and ranges from 0 to 105. If the AAS7 
assessment is missing, it will be considered as a non-response for the cumulative number of 
weeks that subjects achieve AAS7= 0 response calculation. The cumulative number of weeks 
achieving AAS7= 0 response between baseline and Week 12 will be 
 
 
DLQI
Seven scores will be derived from the DLQI: the score of each of the six dimensions as well as 
the total score of the DLQI will be calculated based on the developers' rules. For each of these 
seven scores the change from baseline and percentage change from baseline will also be derived. 
Summary statistics will be calculated for the absolute values as well as for the change and 
percentage change broken down by visit and treatment group.
Summary tables of the number of subjects with DLQI score of 0 or 1 will be presented by 
treatment group and visit.
12.5.2
Safety endpoints
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG as well as potential risks 
defined in the safety profiling plan) will be summarized by treatment for all subjects of the 
safety set. All data will be included in the analysis regardless of rescue medication use.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent AEs (events started after the 
first dose of study treatment or events present prior to the first dose of study treatment but 
increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term

by treatment, primary system organ class, preferred term and maximum severity

by treatment, Standardized MedDRA Query (SMQ) and preferred term 
All AEs with onset in the follow-up period will be considered as treatment emergent. A subject 
with multiple AEs within a primary system organ class is only counted once towards the total 
of the primary system organ class.
Summaries will also be presented for AEs by severity and for study treatment related AEs. 
If a subject reported more than one AE with the same preferred term, the AE with the greatest 
severity will be presented. If a subject reported more than one AE within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the system 
organ class level, where applicable. All AEs with onset in the follow-up period will also be 
summarized separately.
 


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Separate summaries will be provided for study medication related AEs, deaths, SAEs, and other 
significant AEs leading to discontinuation.
All AEs including the non-treatment emergent AEs will be listed.
Laboratory data
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). Descriptive summary statistics for the change from baseline 
to each study visit will be presented. These descriptive summaries will be presented by test 
group, laboratory test and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post baseline values. 
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged.
Shifts with respect to normal ranges and number and percentage of notable abnormalities will 
also be summarized. For each parameter, the maximum change from baseline will be analyzed 
analogously.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign, treatment group and visit/time. Change from baseline will only be summarized 
for subjects with both baseline and post-baseline values. Shifts with respect to normal ranges 
and number and percentage of notable abnormalities will also be summarized.
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities will be flagged.
ECG
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. Shifts with respect to 
normal ranges and number and percentage of notable abnormalities will also be summarized.
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each subject 
during the study. Frequency tables will be produced for the number and percentage of subjects 
with notable QT and QTcF intervals and with noteworthy PR, QRS and Heart Rate interval or 
changes from baseline. 
 
12.5.3
Pharmacokinetics
LOU064 blood concentration data will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics for PK concentration will be provided by treatment and 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero.
 


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Summary statistics will include mean (arithmetic and geometric), standard deviation (SD), 
coefficient of variation (CV) (arithmetic and geometric), median, minimum and maximum. 
Concentrations below LLOQ will be treated as zero in summary statistics and for PK parameter 
calculations. 
PK parameters will be listed by treatment and subject. Descriptive summary statistics for PK 
parameters will be provided by treatment. An exception to this is Tmax where median, minimum 
and maximum will be presented.
Table 12-1
Non-compartmental pharmacokinetic parameters  
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (ng x 
h/mL)
AUCinf
The AUC from time zero to infinity (ng x h/mL)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (ng x h/mL)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (h)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (1/h) may also be used for 
terminal elimination rate constant (1/h)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (h). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (L/h)
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) (L)
The PK profile of LOU064 will be characterized but not limited to the PK parameters listed 
above. 
 
 
 
 
 
 
 
 
 
 
 


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12.8
Sample size calculation
Primary endpoint(s)
The primary objective of this study is to characterize the dose-response relationship among 
LOU064 q.d. and b.i.d doses (10 mg, 35 mg 100 mg q.d and 10 mg, 25 mg and 100 mg b.i.d) 
and placebo with respect to change from baseline in UAS7 at Week 4. The sample size was 
determined with the software R, version 3.0.3.
 
 
 
 
 
 
 
 
 
 
 


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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, subject recruitment 
procedures (eg advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (eg defined as last subject last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (eg 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. 
 


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


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15
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O'Donnell BF, Lawlor F, Simpson J, et al (1997) The impact of chronic urticaria on the quality 
of life. Br J Dermatol; 136(2): 197-201.
 
Regan JA, Cao Y, Dispenza MC, et al (2017) Ibrutinib, a Bruton's tyrosine kinase inhibitor used 
for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and 
basophil activation test reactivity. J Allergy Clin Immunol; 140(3): 875-9.
Smiljkovic D, Blatt K, Stefanzl G, et al (2017) BTK inhibition is a potent approach to block 
IgE-mediated histamine release in human basophils. Allergy; 72(11):1666-76.
Sun C. Tian X, Lee YS, et al (2015) Partial reconstitution of humoral immunity and fewer 
infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood; 126(19):
2213-9.
Zuberbier T, Aberer W, Asero R, et al (2018) The EAACI/GA(2)LEN/EDF/WAO Guideline 
for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision 
and Update. Allergy; 2018 Jan 15.
 


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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 < 60 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.
 


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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 AE 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
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 (eg 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 (eg 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 (eg 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)
> 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 (eg 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)
 


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN 
accompanied by 
symptomsb
-Discontinue the study treatment immediately
-Hospitalize if clinically appropriate
-Establish causality
-Record the AE and contributing factors (eg 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 
(subject 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 (eg, conmeds, 
med hx, lab) 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 (eg 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 (eg, 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN 
(subject 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 subject
-Establish causality
-Record the AE and contributing factors (eg 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
-Record the AE and contributing factors (eg concomitant 
medication, medical history, laboratory values) in the 
appropriate eCRF
Investigator discretion
a Elevated 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 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.
*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.
 


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16.3
Appendix 3: Specific renal alert criteria and actions and event 
follow-up
Table 16-3
Specific renal alert criteria and actions
Renal Event
Actions
Confirmed serum creatinine increase 25 –
49%

Consider causes and possible interventions 

Follow up within 2-5 days
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 
to make slide specimen available for evaluation by the Renal Safety Group to potentially 
identify project-wide patterns of nephrotoxicity.)
 


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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, eg, 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
 


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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 
 


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SAP_001.pdf: 
 
 
 
 
 
 
Clinical Development 
 
 
LOU064/Generic name/Trade name® 
 
LOU064A2201 
 
A multicenter, randomized, double-blind, placebo- 
controlled Phase 2b dose-finding study to investigate the 
efficacy, safety and tolerability of LOU064 in adult chronic 
spontaneous urticaria patients inadequately controlled by 
H1-antihistamines 
 
 
 
Statistical Analysis Plan (SAP) 
 
 
 
Author: 
Trial Statistician,
 
Document type: 
SAP Documentation 
Document status: 
Amendment v3.0 
Release date: 
17-May-2021 
Number of pages: 
39 
 
 
 
 
 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Protocol CLOU064A2201 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
27- 
May- 
2019 
Prior to 
FPFV 
Creation of 
final 
version 
First version NA 
24- 
Jul- 
2020 
 
 
 
Protocol 
amendment 
v2.0; 
Address the 
comments 
from 
dry- 
run review; 
SAP 
amendment 
Final v2.0 
Section 2.1.1.3 Update the assessment 
window for eDiary assessment (i.e. 
UAS7, AAS); 
 
 
Update the 
analysis 
visit 
window for 
eDairy 
assessment; 
 
 
 
 
Define rule for derive the AAS7= 0 
response; 
Section 2.7.1.1 drop table to define 
adverse event of special interest; 
Section 2.7.3 update the CTCAE grade to 
v5.0; include local lab due to covid-19; 
Section 2.7.4.1 include local ECG due to 
covid-19; 
 
 
 
17- 
Prior to 
Update the 
SAP 
May- final 
offset 
in amendment 
2021 
DBL 
negative 
final v3.0 
binomial 
analysis of 
number of 
weeks with 
AAS7=0 
response 
Update the 
Section 2.7.1 update the treatment 
treatment 
emergent adverse event definition as 
emergent 
“Treatment-emergent events are defined 
adverse 
as any events started on or after the first 
dose of study treatment day or any events 


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Protocol CLOU064A2201 
 
Date 
Time 
point 
Reason for 
update 
Outcome for 
update 
Section and title impacted (Current) 
events 
definition 
presented prior to the first dose of study 
treatment day but increased in severity 
based on preferred term and before end of 
Update the 
censor rule 
for time to 
event 
analysis 
the study.” 
Section 5.4.2 is 
 
 
 
 
 
Update the 
PD code in 
rule 
of 
exclusion 
critieria of 
    analysis set 
Section 5.5 Table 5-1 is updated with 
latest protocol deviation code for inform 
consent not signed or missing as “P- 
INCL01B-ICF not signed”. 


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Protocol CLOU064A2201 
 
 
Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................. 8 
1.2 
Study objectives and endpoints................................................................................ 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 14 
 
 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 15 
2.3.1 
Patient disposition ................................................................................. 15 
2.3.2 
Demographic and baseline characteristics ............................................ 15 
2.3.3 
Medical history ...................................................................................... 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 17 
2.5 
Analysis of the primary objective .......................................................................... 17 
2.5.1 
Primary endpoint ................................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 20 
2.5.4 
Supportive analyses ............................................................................... 20 
2.6 
Analysis of the Secondary objective ...................................................................... 20 
2.6.1 
Secondary endpoint ............................................................................... 20 
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 events (AEs) ............................................................................ 22 
2.7.2 
Deaths .................................................................................................... 23 
2.7.3 
Laboratory data ..................................................................................... 23 
2.7.4 
Other safety data.................................................................................... 26 
2.8 
Pharmacokinetic endpoints .................................................................................... 28 
 
 28 
2.10 
Patient-reported outcomes ..................................................................................... 29 
 
 29 


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Protocol CLOU064A2201 
 
 
 29 
 
 31 
3 
Sample size calculation ..................................................................................................... 31 
4 
Change to protocol specified analyses............................................................................... 32 
5 
Appendix ........................................................................................................................... 32 
5.1 
Imputation rules ..................................................................................................... 32 
5.1.1 
Study drug ............................................................................................. 32 
5.1.2 
AE date imputation ............................................................................... 32 
5.1.3 
Concomitant medication date imputation ............................................. 33 
5.2 
AEs coding/grading ............................................................................................... 35 
5.3 
Laboratory parameters derivations ........................................................................ 35 
 
 35 
 
 35 
 
 37 
5.5 
Rule of exclusion criteria of analysis sets .............................................................. 39 
6 
Reference ........................................................................................................................... 39 
 


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Protocol CLOU064A2201 
 
List of abbreviations 
AAS 
Angioedema Activity Score 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUClast 
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x 
time / volume] 
AUCtau 
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau [mass x time / 
volume] 
b.i.d. 
bis in diem/twice a day 
BP 
Blood Pressure 
Cmax 
The observed maximum plasma (or serum or blood) concentration 
following drug administration [mass / volume] 
CSR 
Clinical Study report 
CSU 
Chronic Spontaneous Urticaria 
CV 
Coefficient of Variation 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLQI 
Dermatology Life Quality Index 
ECG 
Electrocardiogram 
eCRS 
Electronic Case Retrieval Strategy 
ED50 
Dose at which 50% of Emax is achieved 
Emax 
Maximum Change in Effect over Placebo 
EOT 
End of treatment period 
EOS 
End of study period 
E0 
Expected Placebo Effect 
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 
MAR 
Missing at Random 
 
 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
 
 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 


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q.d. 
Qua’que di’e / once a day 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TBL 
Total bilirubin 
Tmax 
The time to reach the maximum concentration after drug administration 
[time] 
ULN 
Upper Limit of Normal 
ULOQ 
Upper Limit Of Quantification 
UPDD 
Urticaria Patient Daily Diary 


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1 
Introduction 
Data will be analyzed by Novartis according to the data analysis section 12 of the study protocol 
which is available in Appendix 16.1.1 of the CSR. Important information is given in the 
following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
This document covers statistical and analytical plans for the 
 
 analysis of all data 
collected up to end of the study for CLOU064A2201 study with reference to the study protocol. 
 
 
 
1.1 
Study design 
This is a global Phase 2b multicenter, randomized, double-blind, parallel-group, placebo- 
controlled study investigating the efficacy, safety and tolerability of six dosing groups of oral 
LOU064 in subjects with inadequately controlled CSU despite treatment with (second 
generation) H1-antihistamine treatment. 
Throughout the study (i. e. Day -14 until Day 113), subjects must be on a stable treatment 
regimen with a second generation H1-antihistamine at a locally approved posology 
(“background medication”). 
The study will consist of three periods: screening (up to 2 weeks), treatment period (12 weeks), 
and follow-up period (4 weeks). 
Approximately 308 patients will be randomized in a 1:1:1:1:1:1:1 ratio stratified by prior 
exposure to anti-IgE biologics (including omalizumab and ligelizumab) and by geographical 
region at randomization visit to the following treatment arms: 
• LOU064 10mg q.d.: 10 mg LOU064 once daily 
• LOU064 35mg q.d.: 35 mg LOU064 once daily 
• LOU064 100mg q.d.:100 mg LOU064 once daily 
• LOU064 10mg b.i.d.: 10 mg LOU064 twice a day 
• LOU064 25mg b.i.d.: 25 mg LOU064 twice a day 
• LOU064 100mg b.i.d.: 100 mg LOU064 twice a day 
• Placebo 
The following study periods will be considered for analysis: 
• Screening period (Screening to Randomization) 
• Treatment period (Randomization to scheduled Week 12 visit including follow-up 
visits for patients prematurely discontinued) 
• Entire study period (Randomization to scheduled Week 16 visit including follow-up 
visits for all patients) 


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Randomization will be stratified by prior exposure to anti-IgE biologics (including omalizumab 
and ligelizumab) and by geographical region (Japan, US, LaCan, and RE).).
 
 
 
 
 
 
 
1.2 
Study objectives and endpoints 
The purpose of this study is to evaluate the efficacy and safety of LOU064 in subjects suffering 
from CSU inadequately controlled by H1-antihistamines and to select a LOU064 dosing 
regimen for the subsequent Phase 3 program. 
Key efficacy evaluation criteria are the reduction of signs (hives) and symptoms (itch) of CSU 
measured with the 7-day version of the Urticaria Activity Score (UAS7) and the improvement 
of health-related quality of life as measured by the Dermatology Life Quality Index (DLQI). 
 
Table 1-1 Objectives and related endpoints 
 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s) 
• 
To characterize the dose-response 
relationship of LOU064 administered once 
or twice daily in subjects with CSU with 
respect to change from baseline in UAS7 
at Week 4 
• 
Change from baseline in UAS7 at Week 4 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the efficacy of LOU064 
compared to placebo with respect to 
change from baseline in UAS7 at Week 12 
• 
Change from baseline in UAS7 at Week 12 
• 
To evaluate the efficacy of LOU064 
compared to placebo with respect to 
change from baseline in UAS7 over time 
• 
Change from baseline in UAS7 over time 
• 
To evaluate the efficacy of LOU064 
compared to placebo with respect to 
achievement of complete clinical response 
(UAS7= 0) over time 
• 
Complete absence of hives and itch, 
assessed as UAS7= 0 response over time 
• 
To evaluate the efficacy of LOU064 
compared to placebo with respect to 
achievement of disease control (UAS7≤ 6) 
over time 
• 
UAS7≤ 6 response over time 
• 
To evaluate the effect of LOU064 on 
angioedema (AAS7) with respect to the 
number of weeks with an AAS7= 0 
• 
Cumulative number of weeks with an 
AAS7= 0 response between baseline and 
Week 12 


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0 Protocol 
 
 
 
response from baseline through Week 12 
• 
To evaluate the effect of LOU064 on 
disease-related quality of life with respect 
to achievement of a DLQI score of 0 or 1 at 
Week 4 and Week 12 
• 
DLQI score of 0 or 1 at Week 4 and 12 
• 
To evaluate the effect of LOU064 on CSU- 
related quality of life with respect to change 
from baseline in DLQI at Week 4 and Week 
12 
• 
Change from baseline in DLQI score at 
Week 4 and 12 
• 
To evaluate the pharmacokinetics of 
LOU064 resulting from oral dosing at Week 
4 and Week 12 
• 
Concentrations of LOU064 in blood and 
calculation of respective PK parameters 
• 
To evaluate safety and tolerability of 
LOU064 in subjects with CSU 
• 
Safety endpoints will include but not be 
limited to: 
o 
Occurrence of treatment emergent 
adverse events during the study 
o 
Occurrence of treatment emergent 
serious adverse events during the 
study 


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2 
Statistical methods 
Novartis will be performing 
 the final analysis. Statistical software R 
version 3.3.3 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. 
The p-values will be presented as one-sided with level of significance 5%. 90% confidence 
intervals will be displayed but not be used for decision making; they will only be used for 
estimation and will therefore always be two-sided. 
 
2.1.1 
General definitions 
 
2.1.1.1 
Study treatment 
The following treatment groups will be presented: 
• LOU064 10 mg q.d. 
• LOU064 35 mg q.d. 
• LOU064 100 mg q.d. 
• LOU064 10 mg b.i.d. 
• LOU064 25 mg b.i.d. 
• LOU064 100 mg b.i.d. 
• Any LOU064 
• Placebo 


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2.1.1.2 
Study Day 1 and Study Day 
For safety analysis, the day of first dose of study treatment is defined as Study Day 1 or Day 1. 
For efficacy analysis, the day of randomization is defined as Study Day 1 or Day 1. 
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for a particular event date is calculated as [Date of event] – [Date of first 
dose/Randomization] + 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/Randomization], 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 
 
2.1.1.3.1 Assessment window for eDiary data 
For completers, the study weeks for assessment completed on eDiary are defined based on the 
study days starting with Day 1 (Randomization Day). The study day for the eDiary date will be 
calculated as [Date of Diary] – [Date of Randomization] + 1 for post-baseline assessment and 
[Date of Diary] – [Date of Randomization] for baseline assessment. The analysis Week 1 
through Week 11 of the treatment period will be derived based on scheduled visit day as defined 
in Table 2-1. The analysis Week 12 score will be derived as Day -7 to Day -1 of actual Week 
12 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 12 visit day). The 
study day for the eDiary date will be calculated as [Date of Diary] – [Date of Week 12 visit day] 
+ 1. The analysis follow-up Week 1 to Week 4 will be derived based on the actual Week 12 
study visit day as defined in Table 2-1. 
 
Table 2-1 
Assessment window for eDiary (for completers) 
 
Analysis visit 
Scheduled 
Visit Day 
eDiary Assessment Window 
Baseline 
1 
Day -7 to Day -1 
Week 1 
- 
Day 1 to Day 7 
Week 2 
15 
Day 8 to Day 14 
Week 3 
- 
Day 15 to Day 21 
Week 4 
29 
Day 22 to Day 28 
Week 5 
- 
Day 29 to Day 35 
Week 6 
- 
Day 36 to Day 42 
Week 7 
- 
Day 43 to Day 49 
Week 8 
57 
Day 50 to Day 56 


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Week 9 
- 
Day 57 to Day 63 
Week 10 
- 
Day 64 to Day 70 
Week 11 
- 
Day 71 to Day 77 
Week 12 
85 
Day -7 to Day -1 of Week 12 study visit 
Follow-up Week 1 
- 
Day 1 to Day 7 of follow-up period 
Follow-up Week 2 
- 
Day 8 to Day 14 of follow-up period 
Follow-up Week 3 
- 
Day 15 to Day 21 of follow-up period 
Follow-up Week 4 
113 
Day 22 to Day 28 of follow-up period 
The baseline week is comprised of the 7 days prior to Day 1 (Day -7 to Day -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. 
The study weeks for assessment completed on eDiary are defined based on the study days 
starting with Day 1 (Randomization Day). The study day for the eDiary date will be calculated 
as [Date of Diary] – [Date of Randomization] + 1 for post-baseline assessment and [Date of 
Diary] – [Date of Randomization] for baseline assessment. 
 
Table 2-2 
Assessment window for eDiary (for early discontinued patients) 
 
Analysis visit 
Scheduled 
Visit Day 
eDiary Assessment Window 
Baseline 
1 
Day -7 to Day -1 
Treatment Week 1 
- 
Day 1 to Day 7 
Treatment Week 2 
15 
Day 8 to Day 14 
Treatment Week 3 
- 
Day 15 to Day 21 
Treatment Week 4 
29 
Day 22 to Day 28 
Treatment Week 5 
- 
Day 29 to Day 35 
Treatment Week 6 
- 
Day 36 to Day 42 
Treatment Week 7 
- 
Day 43 to Day 49 
Treatment Week 8 
57 
Day 50 to Day 56 
Treatment Week 9 
- 
Day 57 to Day 63 
Treatment Week 10 
- 
Day 64 to Day 70 
Treatment Week 11 
- 
Day 71 to Day 77 
Treatment Week 12 
85 
Day 78 to Day 84 


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2.1.1.4 
Baseline 
Baseline for safety is the last assessment (including unscheduled visits) obtained on or before 
the day of the first dose of study treatment. All assessments obtained after the first dose of study 
treatment are considered as post-baseline unless otherwise specified. 
Baseline for efficacy is comprised of the 7 days prior to Day 1 (Randomization Day) for UAS7 
and other assessment on or prior randomization day. 
 
2.1.1.5 
On-treatment 
All safety events happened after first dose of study treatment will be considered on-treatment 
no matter if during treatment period or follow-up period. 
 
2.2 
Analysis sets 
The following analysis sets will be used for the data analysis, details refer to section 5.5. 
The Randomized Set will consist of all randomized subjects, regardless of whether or not they 
actually received study medication. Subjects will be analyzed according to the treatment 
assigned to at randomization. 
The Full Analysis Set (FAS) will consist of all randomized subjects. Following the intent-to- 
treat principle, subjects will be analyzed according to the treatment and strata assigned to at 
randomization. Mis-randomized subjects (mis-randomized in IRT) will be excluded. 
Mis-randomized subjects are defined as cases where IRT contacts were made by the site either 
prematurely or inappropriately prior to confirmation of the subject’s final randomization 
eligibility and no study medication was administered to the subject. 
The Safety Set will consist of all subjects who received at least one dose of study medication 
whether or not being randomized. Subjects will be analyzed according to treatment received. 
If a subject has received the wrong treatment during more than 50% of the time of the entire 
treatment period, the treatment received will be set to this wrong treatment; otherwise it will be 
set to the original assigned treatment. Except for patients assigned to placebo arm, they will be 
summarized under LOU064 in case they took LOU064 during the treatment period independent 
of the time on LOU064. 
 
2.2.1 
Subgroup of interest 
 
 
 
 
 
 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number of screened and screen failure subjects will be shown for all subjects (total). The 
reason for screen failure will be summarized. 
The number of subjects in each analysis set will be presented for each treatment group and all 
subjects (total). The reason for excludedexcluding from any analysis set will be listed. 
The number and percentage of complete Week 4 visits, Week 12 (EOT) visits, Week 16 (EOS) 
visits or early discontinued from treatment/study will be presented by treatment groups and all 
patients (total) based on Randomized Set. 
The number and percentage of patients who have experienced protocol deviations (PD) will be 
tabulated by deviation category, treatment groups and all patients (total). The summary of 
overall important PDs (including COVID-19 related PDs), important PDs excluding COVID- 
19 related PDs, and COVID-19 related PDs will be provided. 
 
2.3.2 
Demographic and baseline characteristics 
Demographics and baseline characteristics will be summarized using the randomized set. 
including disease characteristics, prior and background medications to treat urticaria, and 
relevant medical histories. 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and all patients (total). 
Continuous variables: 
• Age (years) 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) = (body weight in kilograms) / (height in meters)2 
• Baseline UAS7 score 
• Baseline AAS7 score 
• Baseline DLQI score 
• Time since diagnosis of urticaria = (inform consent date – diagnosis date + 1)/365.25 
The number and percentage of subjects in each category will be presented for categorical 
variables for each treatment group and all patients (total). 
Categorical variables: 
• Age categories (< 65, >= 65-<85years , >=85 years) 
• Gender 


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• Race 
• Ethnicity 
• BMI groups (< 25, 25 -<30, >= 30 kg/m2m2) 
• Baseline UAS7 (Mild disease: UAS7 6-<16; Moderate disease: UAS7 16-<28; Severe 
disease UAS7 28-42) 
• Baseline AAS7 = 0 response (Yes, No) 
• Previous exposure to anti-IgE therapy (Yes, No) 
• Geographic region (Japan, US, LaCAN, RE) 
• Previous experience of Angioedema (Yes, No) 
• Baseline CU-index (Positive, Negative) 
• Baseline total IgE level (High, Low) (the median value of all patients at each analysis 
will be used as threshold) 
 
2.3.3 
Medical history 
Any significant prior or current medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. 
Non-urticaria related medical conditions will be summarized by primary system organ class and 
preferred term. 
The urticaria related medical history will be summarized separately. 
Cardiovascular history and family malignancy history will be listed if needed. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The analysis of study treatment data will be based on the safety set. 
 
2.4.1 
Study treatment / compliance 
The duration of exposure to study treatment and duration of study will be summarized by 
treatment group. 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 is defined as last study visit – first dose of study treatment + 1. 
The start date and end date of study treatment will be collected on eCRF and will be used to 
calculate the duration of exposure. In addition, the study treatment taken on each day 
(morning/evening) will be also be entered in the eDiary and will be listed. 


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2.4.2 
Prior, concomitant and post therapies 
Prior urticaria related medication will be summarized by type of therapy and preferred term. 
Prior non-urticaria related medication will be summarized by Anatomical Therapeutic 
Chemical (ATC) code and preferred term for each treatment group. 
Background medications will be summarized by Anatomical Therapeutic Chemical (ATC) code, 
preferred term and dose per administrationfor each treatment group. 
Rescue medications will be summarized by Anatomical Therapeutic Chemical (ATC) code, 
preferred term and dose per administration for each treatment group. 
Concomitant medications other than background or rescue medications will be summarized by 
Anatomical Therapeutic Chemical (ATC) code and preferred term for each treatment group. 
Prior and concomitant significant surgeries and medical procedures will be summarized by 
primary system organ class and MedDRA preferred term for each treatment group. 
Prior medications are defined as treatment taken and stopped prior to first dose of study 
treatment; Concomitant medications are defined as any medication given at least once between 
the day of first dose of randomized study treatment and the date of the last study visit. 
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. 
 
2.5 
Analysis of the primary objective 
All analyses for efficacy data will be based on the FAS. 
The primary objective of this study is to determine a dose response signal and characterize the 
dose-response relationship in either LOU064 q.d. and b.i.d. doses (10 mg, 35 mg, 100 mg q.d. 
and 10 mg, 25 mg, 100 mg b.i.d.) compared to placebo with respect to the change from baseline 
in UAS7 at Week 4, and to select an appropriate dose(s) to use in Phase 3 studies. 
 
 
 
 
 
2.5.1 
Primary endpoint 
The primary variable for the study is the change from baseline in UAS7 at Week 4. The UAS7 
is the sum of the average daily UAS over 7 days (range from 0 to 42). Note that the weekly 
score is derived according to the analysis week defined in Table 2-1 and Table 2-2. 
If one of the morning or evening score for HSS and ISS is missing, then the non-missing score 
for that day (morning or evening) will be used as the daily score. If one or more of the daily 
scores are missing, then the following principles will be applied to handle the missing data: 
• The weekly Urticaria Activity Score is the sum of both the HSS7 score and the ISS7 
score and will be missing if at least one of them is missing. 


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• If a patient has at least 4 non-missing daily scores within the 7 days, then the weekly 
score for HSS or ISS will be calculated as the sum of the available eDiary scores of that 
week, divided by the number of non-missing days multiplied by 7. 
• If there are less than 4 non-missing daily scores within the 7 days, then the weekly score 
for HSS or ISS will be missing for that week. Accordingly, no UAS7 can be calculated. 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 


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2.5.3 
Handling of missing values/censoring/discontinuations 
Subjects who discontinue from study treatment early will be encouraged to stay in the study 
and complete all the scheduled measurements. All the available data collected will be used for 
the primary analysis no matter if they took rescue medication or prohibited medication 
(Treatment policy). 
 
 
 
 
 
2.5.4 
Supportive analyses 
Considering the primary efficacy endpoint is UAS7 score at week 4, the missing data rate is 
expected to be approximately 5%. So no supportive analyses is planned for the primary efficacy 
analysis. 
 
2.6 
Analysis of the Secondary objective 
All analyses for secondary efficacy data will be based on the FAS. 
Summary tables will be presented by treatment group and visit (as applicable) using descriptive 
statistics, which include absolute and relative frequencies for categorical variables and 
arithmetic mean, standard deviation, minimum, maximum, median and first and third quartile 
for continuous variables. 
 
2.6.1 
Secondary endpoint 
UAS7 over time 
Mean estimation and standard error for absolute value, change, and percent change from 
baseline in UAS7 score will be presented by treatment group and visit for entire study period 
 
Summary statistics of the absolute value, change, and percent change from baseline in UAS7 
will be presented by treatment group and visit for entire study period. 
 
 
Summary statistics of the absolute value, change, and percent change from baseline in HSS7 
will be presented by treatment group and visit for entire study period. 
Summary statistics of the absolute value, change, and percent change from baseline in ISS7 will 
be presented by treatment group and visit for entire study period. 
Complete clinical response (UAS7 = 0) 
The complete clinical response, i.e. absence of hives and itch, is defined as subjects achieving 
UAS7= 0. 


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The number of subjects with UAS7= 0 will be summarized by treatment group and visit for 
entire study period. 
 
 
 
 
 
 
 
Controlled disease (UAS7≤ 6) 
The number of subjects with UAS7≤ 6 will be summarized by treatment group and visit for 
entire study period. 
 
 
 
 
 
 
 
Absence of angioedema (AAS7= 0) 
The cumulative number of weeks with an AAS7= 0 response between baseline and Week 12 
will be summarized by treatment group. 
 
 
 
 
 
 
 
 
 
 
 
 
Summary statistics on AAS7 weekly score will be presented by visit and treatment group. 
DLQI 
Seven scores will be derived from the DLQI: the score of each of the six dimensions as well as 
the total score of the DLQI will be calculated based on the developers' rules. 


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For the DLQI subscale and total score derivation, if there is only one missing score per visit, 
then it will be imputed to 0 and then the subscale including this item and the total score will be 
calculated accordingly. If there are two or more missing scores per visit, then the score will be 
missing. 
Summary statistics will be calculated for the absolute values as well as for the change and 
percentage change for DLQI total score broken down by visit and treatment group. 
Summary tables of the number of subjects with DLQI score of 0 or 1 will be presented by 
treatment group and visit for entire study period. 
 
2.6.2 
Statistical hypothesis, model, and method of analysis 
For the secondary analysis of UAS7, complete clinical response, controlled disease and AAS7= 
0, pairwise comparisons of each LOU064 doses to Placebo will be performed. No adjustment 
for multiple comparisons will be done due to the exploratory nature of this study. 
 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing values for binary response like UAS7 = 0 response, UAS7 <=6 response and DLQI 0/1 
of secondary analyses will be imputed by non-responder imputation method regardless of the 
reason for missingness. 
 
 
2.7 
Safety analyses 
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG as well as potential risks 
defined in the safety profiling plan) will be summarized by actual treatment group using the 
safety set. 
All data will be included in the analysis regardless of rescue medication use. 
 
2.7.1 
Adverse events (AEs) 
All information obtained on adverse events will be displayed by treatment group and any 
LOU064 dose. 
Treatment-emergent events are defined as any events started on or after the first dose of study 
treatment day or any events presented prior to the first dose of study treatment day but increased 
in severity based on preferred term and before end of the study. 
The number (and percentage) of subjects with treatment- emergent AEs will be summarized 
in the following ways: 
• by primary system organ class and preferred term 
• by primary system organ class, preferred term and maximum severity 
• by Standardized MedDRA Query (SMQ) and preferred term 
Summaries will also be presented for AEs by severity and for study treatment related AEs. 


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Separate summaries will be provided for deaths, SAEs, and other significant AEs such as 
AEs leading to discontinuation and AEs leading to treatment interruption. 
If a subject reported more than one AE with the same preferred term, the AE with the greatest 
severity will be presented. If a subject reported more than one AE within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the 
system organ class level, where applicable. 
All AEs and SAEs including the non-treatment emergent AEs will be listed. 
 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Crude incidence rate for adverse events of special interest will be provided. The latest project 
eCRS will be used for reporting. 
 
2.7.2 
Deaths 
All deaths will be listed and reason for death will be summarized by SOC and PT. 
 
2.7.3 
Laboratory data 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). 
Descriptive summary statistics for the change from baseline to each study visit will be 
presented. These descriptive summaries will be presented by test group, laboratory test and 
treatment group and any LOU064 dose. Change from baseline will only be summarized for 
subjects with both baseline and post baseline values. 
For each parameter, the maximum change from baseline (maximum decrease and maximum 
increase) will be analyzed analogously. 
Laboratory data will be listed and values outside the normal ranges will be flagged by 
treatment group, subject, and visit/time for patients who have experienced any abnormalities. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the most extreme laboratory test value within a treatment 
period. For the shift tables, the normal laboratory ranges will be used to evaluate whether a 
particular laboratory test value is normal, low, or high (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group. 
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). 
CTCAE grades based on lab results alone will be applied programmatically, Clinical 
assessments (in italic below) will not be considered. In case of missing baseline laboratory 
assessment, it will be assumed as normal. 


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The number and percentage of subjects with CTCAE grade newly occurring or worsening after 
baseline will be presented. Shift tables will be provided on CTCAE grades. These summaries 
will be split into hematology and chemistry. 
 
Table 2-2 
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 
baseline was 
abnormal 
>1.5 - 3.0 x 
ULN if baseline 
was normal; 
>1.5 - 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 10.0 x 
ULN if baseline 
was normal; 
>3.0 - 10.0 x 
baseline if 
baseline was 
abnormal 
>10.0 x ULN 
if baseline 
was normal; 
>10.0 x 
baseline if 
baseline was 
abnormal 
GGT increased 
Gamma- 
glutamyl 
transferase 
(GGT) 
>ULN - 2.5 x 
ULN if baseline 
was normal; 2.0 
- 2.5 x baseline 
if baseline was 
abnormal 
>2.5 - 5.0 x 
ULN if baseline 
was normal; 
>2.5 - 5.0 x 
baseline if 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
>20.0 x ULN 
if baseline 
was normal; 
>20.0 x 
baseline if 


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baseline was 
abnormal 
baseline was 
abnormal 
baseline was 
abnormal 
Alanine 
aminotransferas 
e increased 
Alanine 
aminotransferas 
e (ALT) 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 
- 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN 
if baseline 
was normal; 
>20.0 x 
baseline if 
baseline was 
abnormal 
Aspartate 
aminotransferas 
e increased 
Aspartate 
aminotransferas 
e (AST) 
>ULN - 3.0 x 
ULN if baseline 
was normal; 
1.5 - 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x 
ULN if baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN 
if baseline 
was normal; 
>20.0 x 
baseline if 
baseline was 
abnormal 
Alkaline 
phosphatase 
increased 
Alkaline 
phosphatase 
(ALP) 
>ULN - 2.5 x 
ULN if baseline 
was normal; 
2.0 - 2.5 x 
baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x 
ULN if baseline 
was normal; 
>2.5 - 5.0 x 
baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline was 
abnormal 
>20.0 x ULN 
if baseline 
was normal; 
>20.0 x 
baseline if 
baseline was 
abnormal 
ULN: Upper limit of normal range; LLN: Lower limit of normal range. 
For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. 
Local lab result due to covid-19 situation will only be listed but not include in the summary 
table. 


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Abnormalities in urinalysis result will be summarized by visit separately and listed. 
 
2.7.4 
Other safety data 
 
2.7.4.1 
ECG and cardiac imaging data 
Summary statistics will be provided for ECG parameters by treatment group and any LOU064 
dose, and visit/timepoint (pre-dose or 1 hr post-dose). Shifts with respect to normal ranges and 
number and percentage of notable abnormalities will also be summarized. 
Triplicates measurements on ECG are scheduled for some visits. For numeric measurements, 
the mean of the scheduled measurements will be used. For ECG overall interpretation, most 
common interpretation (normal/abnormal) of the three assessments taken will be used. 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each subject 
during the study. Frequency tables will be produced for the number and percentage of subjects 
with notable QT and QTcF intervals and with noteworthy PR, QRS and Heart Rate interval or 
changes from baseline. 
For ECGs, a notable QT and QTcF interval value is defined as: 
• QT > 500 msec; 
• QTc (Fridericia’s) interval > 450 msec (males), QTc (Fridericia’s) interval > 460 msec 
(females); 
• QTc (Fridericia’s) interval change from baseline > 30 msec, >60 msec; 
• PR > 250 msec. 
All ECG data will be listed by treatment group, subject and visit/time for patients experienced 
and ECG abnormalities. 
Local ECG data will be included in the summary in case central reading was applied. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.7.4.2 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign, treatment group and visit/time. Change from baseline will only be summarized 
for subjects with both baseline and post-baseline values. Shifts with respect to normal ranges 
and number and percentage of notable abnormalities will also be summarized. 
Clinical notable vital sign values: 
• Sitting pulse rate 
o < 50 bpm and 25% decrease from baseline 
o > 100 bpm and 25% increase from baseline 
• systolic blood pressure 
o < 90 
o ≥ 140 mmHg 
• diastolic blood pressure 
o < 60 
o ≥ 90 mmHg 
All vital signs data will be listed by treatment group, subject, and visit/time for patients who 
ever experience any vital sign abnormalities. 
 
2.7.4.3 
Liver events 
To evaluate potential drug-induced liver injury, newly occurring liver enzyme abnormalities 
will also be summarized based on the event criteria given below. For potential Hy’s Law case, 
all the elevations must occur at the same post-baseline timepoint. A case will be considered as 
newly occurring if a criterion is not met or missing at baseline but is met thereafter. 


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Table 2-3 
Liver enzyme abnormalities 
 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
(ALT or AST) & TBL 
>3xULN & (TBL>1.5xULN; >2xULN) 
(ALT or AST) & INR 
>3xULN & INR>1.5 
TBL 
>1xULN; >1.5xULN; >2xULN; 
ALP 
>1.5xULN; >2xULN; >5xULN 
ALP & TBL 
>3xULN; >5xULN & TBL>2xULN 
(ALT or AST) & TBL & ALP 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Potential 
Hy’s Law) 
 
2.8 
Pharmacokinetic endpoints 
Summary statistics for PK analysis will include mean (arithmetic and geometric), standard 
deviation (SD), coefficient of variation (CV) (arithmetic and geometric), median, minimum 
and maximum. 
Concentrations below LLOQ will be treated as zero in summary statistics for PK 
concentration and for PK parameter calculations. 
Descriptive summary statistics will be provided for PK concentration by treatment and 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ. 
LOU064 blood concentration data will be listed by treatment, subject, and visit/sampling 
time point. 
Descriptive summary statistics will be provided for PK parameters listed in Table 2-3 by 
treatment. An exception to this is Tmax where median, minimum and maximum will be 
presented. 
PK parameters will be listed by treatment and subject. 
 
Table 2-4 
pharmacokinetic parameters 
 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (ng x 
h/mL) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (ng x h/mL) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (ng/mL) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (h) 
Other PK parameters will be provided if feasible. 
 
 
 
 
 
 


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2.10 
Patient-reported outcomes 
Please refer to section 2.6.1 for DLQI analysis. 
 
 


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3 
Sample size calculation 
The sample size calculation is based on the primary endpoint. 
The primary objective of this study is to characterize the dose-response relationship among 
LOU064 q.d. and b.i.d doses (10 mg, 35 mg 100 mg q.d and 10 mg, 25 mg and 100 mg b.i.d) 
and placebo with respect to change from baseline in UAS7 at Week 4. The sample size was 
determined with the software R, version 3.0.3. 


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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). 


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


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1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month. 
 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY). 
 
3. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date. 
 
Impute CM start date: 
 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid- 
month point (15MONYYYY). 
 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 
 
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). 


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If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date. 
 
5.1.3.1 
Prior therapies date imputation 
See Section 5.1.3. 
 
5.1.3.2 
Other imputations 
 
First diagnosis date imputation 
 
1. If the first diagnosis day/ month are missing and the year is non-missing: 
 
a. If the year part of the first diagnosis date is equal to the year part of the inform 
consent date, then the imputed first diagnosis date is set to the year start point 
(01JanYYYY). 
 
b. Otherwise the imputed first diagnosis date is set to the mid-year point 
(01JulYYYY). 
 
2. If the first diagnosis day is missing and the month/year are non-missing: 
 
a. If the month and year part of the first diagnosis date is equal to the month and year 
part of the inform consent date, then the imputed first diagnosis date is set to the 
month start point (01MONYYYY). 
 
b. Otherwise the imputed first diagnosis date is set to the mid-month point 
(15MONYYYY). 
 
5.2 
AEs coding/grading 
Not applicable. 
 
5.3 
Laboratory parameters derivations 
Not applicable. 


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5.5 
Rule of exclusion criteria of analysis sets 
Table 5-1 
Subject classification rule 
 
Analysis Set 
PD categories codes that 
cause subject to be excluded 
Non-PD criteria that cause subjects to 
be excluded 
Randomized set 
(RAN) 
DVSPID: P-INCL01B-ICF not 
signed; 
Not randomized; 
Full analysis set 
(FAS) 
DVSPID: P-INCL01B-ICF not 
signed; OTH11-ICH-GCP 
Not in RAN; Mis randomized 
Safety analysis set 
(SAF) 
DVSPID: P-INCL01B-ICF not 
signed; OTH11-ICH-GCP; M- 
TRT04 
NA. 
P-INCL01B-ICF not signed: ICF missing or not obtained. 
OTH11-ICH-GCP: Severe ICH-GCP non-compliance of study site 
TRT04: Subject randomized but no study treatment was taken. 
 
6 
Reference 
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics, 61(3): 738-48. 
 
 
 
Newcombe, R. G. (1998). "Two-sided confidence intervals for the single proportion: 
comparison of seven methods". Statistics in Medicine. 17 (8): 857–872. 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Stat Med; 33(10): 1646-61.