A Multi-center, Randomized, Double-blind, Active and Placebo-controlled Study to Investigate the Safety and Efficacy of Ligelizumab (QGE031) in the Treatment of Chronic Spontaneous Urticaria (CSU) in Adolescents and Adults Inadequately Controlled With H1-antihistamines
Phase: PHASE3
Conditions: Chronic Spontaneous Urticaria
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
QGE031/Ligelizumab 
Clinical Trial Protocol CQGE031C2302 / NCT03580369 
A multi-center, randomized, double-blind, active and 
placebo-controlled study to investigate the efficacy and 
safety of ligelizumab (QGE031) in the treatment of Chronic 
Spontaneous Urticaria (CSU) in adolescents and adults 
inadequately controlled with H1-antihistamines 
Document type: 
Amended Protocol Version 
EUDRACT 
number: 
2018-000839-28 (PIP number: EMEA – 001811-PIP02-15-
M03) 
Version number: 
v02 (Clean) 
Clinical Trial 
Phase: 
III 
Release date: 
07-Jan-2021
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 ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
 12 
 15 
 15 
Protocol summary .............................................................................................................. 19 
1 
Introduction ....................................................................................................................... 21 
1.1 
Background ............................................................................................................ 21 
1.2 
Purpose .................................................................................................................. 22 
2 
Objectives and endpoints ................................................................................................... 22 
3 
Study design ...................................................................................................................... 24 
4 
Rationale ............................................................................................................................ 25 
4.1 
Rationale for study design ..................................................................................... 25 
4.1.1 
Rationale for choice of background therapy ......................................... 27 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 27 
4.3 
Rationale for choice of control drugs (comparator/placebo) and combination 
drugs ...................................................................................................................... 29 
4.4 
Purpose and timing of interim analysis ................................................................. 30 
4.5 
Risks and benefits .................................................................................................. 30 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 32 
5 
Population .......................................................................................................................... 32 
5.1 
Inclusion criteria .................................................................................................... 32 
5.2 
Exclusion criteria ................................................................................................... 33 
6 
Treatment ........................................................................................................................... 36 
6.1 
Study treatment ...................................................................................................... 36 
6.1.1 
Investigational and control drugs .......................................................... 36 
6.1.2 
Additional study treatments .................................................................. 36 
6.1.3 
Treatment arms...................................................................................... 36 
6.2 
Other treatment(s) .................................................................................................. 37 
6.2.1 
Concomitant therapy ............................................................................. 37 
6.2.2 
Prohibited medication ........................................................................... 37 
6.2.3 
Rescue medication ................................................................................ 38 
6.3 
Subject numbering, treatment assignment, randomization .................................... 39 

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6.3.1 
Subject numbering ................................................................................ 39 
6.3.2 
Treatment assignment and randomization ............................................ 39 
6.4 
Treatment blinding ................................................................................................ 39 
6.5 
Dose escalation and dose modification.................................................................. 42 
6.6 
Additional treatment guidance ............................................................................... 43 
6.6.1 
Treatment compliance ........................................................................... 43 
6.6.2 
Emergency breaking of assigned treatment code .................................. 43 
6.7 
Preparation and dispensation ................................................................................. 43 
6.7.1 
Handling of study treatment and additional treatment .......................... 44 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 44 
7 
Informed consent procedures ............................................................................................ 45 
8 
Visit schedule and assessments ......................................................................................... 46 
8.1 
Screening ............................................................................................................... 56 
8.1.1 
Information to be collected on screening failures ................................. 56 
8.2 
Subject demographics/other baseline characteristics............................................. 56 
8.3 
Efficacy .................................................................................................................. 56 
8.3.1 
eDiary assessments................................................................................ 57 
8.3.2 
Other PRO assessments......................................................................... 60 
8.3.3 
Other assessments: Evidence of urticaria .............................................. 62 
8.3.4 
Appropriateness of efficacy assessments .............................................. 62 
8.4 
Safety ..................................................................................................................... 62 
8.4.1 
Laboratory evaluations .......................................................................... 63 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 64 
8.4.3 
Assessment of parasitic infections ........................................................ 64 
8.4.4 
Pregnancy and assessments of fertility ................................................. 65 
8.4.5 
Anaphylaxis assessment ........................................................................ 66 
8.4.6 
Assessment of cardio-cerebrovascular events ....................................... 66 
8.4.7 
Assessment of neoplastic events ........................................................... 66 
8.4.8 
Appropriateness of safety measurements .............................................. 66 
8.5 
Additional assessments .......................................................................................... 66 
 
 66 
8.5.2 
Pharmacokinetics and pharmacodynamics ........................................... 66 
 
 67 
 
 67 
9 
Study discontinuation and completion .............................................................................. 69 
9.1 
Discontinuation ...................................................................................................... 69 
9.1.1 
Discontinuation of study treatment ....................................................... 69 

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9.1.2 
Withdrawal of informed consent ........................................................... 70 
9.1.3 
Lost to follow-up ................................................................................... 71 
9.1.4 
Early study termination by the sponsor ................................................. 71 
9.2 
Study completion and post-study treatment .......................................................... 71 
10 Safety monitoring and reporting ........................................................................................ 71 
10.1 
Definition of adverse events and reporting requirements ...................................... 71 
10.1.1 
Adverse events ...................................................................................... 71 
10.1.2 
Serious adverse events .......................................................................... 73 
10.1.3 
SAE reporting........................................................................................ 74 
10.1.4 
Pregnancy reporting .............................................................................. 75 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 75 
10.2 
Additional Safety Monitoring ................................................................................ 76 
10.2.1 
Liver safety monitoring ......................................................................... 76 
10.2.2 
Renal safety monitoring ........................................................................ 77 
10.2.3 
Data Monitoring Committee ................................................................. 77 
10.2.4 
Adjudication Committee ....................................................................... 77 
11 Data collection and database management ........................................................................ 78 
11.1 
Data collection ....................................................................................................... 78 
11.2 
Database management and quality control ............................................................ 78 
11.3 
Site monitoring ...................................................................................................... 79 
12 Data analysis and statistical methods ................................................................................ 79 
12.1 
Analysis sets .......................................................................................................... 80 
12.2 
Subject demographics and other baseline characteristics ...................................... 80 
12.3 
Treatments ............................................................................................................. 80 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 81 
12.4.1 
Definition of primary endpoint(s) ......................................................... 81 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 82 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 85 
 
 85 
12.5 
Analysis of secondary endpoints ........................................................................... 86 
12.5.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 86 
12.5.2 
Safety endpoints .................................................................................... 90 
 
 91 
 
 91 
 
 91 
 
 92 
12.7 
Interim analysis (primary efficacy analysis).......................................................... 94 

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12.8 
Sample size calculation.......................................................................................... 94 
13 Ethical considerations and administrative procedures ...................................................... 96 
13.1 
Regulatory and ethical compliance ........................................................................ 96 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 96 
13.3 
Publication of study protocol and results............................................................... 97 
13.4 
Quality control and quality assurance.................................................................... 97 
14 Protocol adherence ............................................................................................................ 97 
14.1 
Protocol amendments............................................................................................. 97 
15 References ......................................................................................................................... 99 
16 Appendices ...................................................................................................................... 102 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 102 
16.1.1 
Appendix 1.1: Clinically notable vital signs – adolescent subjects .... 103 
16.1.2 
Appendix 1.1.2 : Notable values for adolescents’ vital signs ............. 104 
16.2 
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ........................................................................................................ 105 
16.3 
Appendix 3: Specific renal alert criteria and actions and event follow-up .......... 108 
16.4 
Appendix 4: PRO tools ........................................................................................ 109 
 
 121 
16.6 
Appendix 6: World allergy organization grading system .................................... 122 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Investigational and control drugs .......................................................... 36 
Table 6-2 
Prohibited medication ........................................................................... 37 
Table 6-3 
Drug administration .............................................................................. 41 
Table 6-4 
Blinding and unblinding plan ................................................................ 41 
Table 8-1 
Assessment schedule ............................................................................. 48 
Table 8-2 
UPDD .................................................................................................... 57 
Table 8-3 
Hives Severity Score ............................................................................. 57 
Table 8-4 
Itch Severity Score ................................................................................ 58 
Table 8-5 
Sleep interference score ........................................................................ 58 
Table 8-6 
Activity interference score .................................................................... 59 
Table 8-7 
Actions/treatments for Angioedema ..................................................... 59 
Table 8-8 
DLQI/CDLQI score bands and impact on patient’s life ....................... 60 
Table 8-9 
Physical Assessments ............................................................................ 63 
Table 8-10 
Laboratory Assessments ........................................................................ 64 

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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 76 
Table 10-2 
Base Renal Monitoring ......................................................................... 77 
Table 12-1 
Summary of annual prevalence of CSU in pediatric population ........... 96 
Table 16-1 
Best BP Measurement Practices - Pediatrics ...................................... 103 
Table 16-2 
Upper and lower limits for adolescents’ vital signs that may be 
considered of concern if newly identified may be identified using 
the following table for guidance1: ....................................................... 104 
Table 16-3 
Liver event and laboratory trigger definitions .................................... 105 
Table 16-4 
Follow-up requirements for liver laboratory triggers with liver 
symptoms ............................................................................................ 105 
Table 16-5 
Follow up requirements for liver laboratory triggers .......................... 106 
Table 16-6 
Specific renal alert criteria and actions ............................................... 108 
Table 16-7 
Renal event follow-up ......................................................................... 109 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 24 
Figure 4-1 
Change from baseline in HSS7, ISS7, and UAS7 by visit .................... 27 
 
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List of abbreviations 
AC 
Adjudication Committee 
 
 
AE 
Adverse Event 
AH 
Anti-histamine 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AAS 
Angioedema Activity Score 
ASS7 
Weekly Angioedemy Activiy Score 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CDLQI 
Children’s Dermatology Life Quality Index 
CU 
Chronic Urticaria 
CIU 
Chronic Idiopathic Urticaria 
CMO&PS 
Chief Medical Office and Patient Safety 
CO 
Country Organization 
COVID-19 
Corona Virus Disease 2019 
CRF 
CS 
Case Report/Record Form  
Corticosteroids 
CSU 
Chronic Spontaneous Urticaria 
CT 
Computerized Tomography 
CTC 
Common Toxicity Criteria 
DLQI 
Dermatology Life Quality Index 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eDiary 
Electronic Diary 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EoT 
End of treatment 
EoS 
End of study 
eSource 
Electronic Source 
EU 
European Union 
FAS 
Full Analysis Set 
FcεRI 
IgE receptor 
FcεRII 
IgE receptor 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
β-hCG 
Beta-Human Chorionic Gonadotropin 
HCP 
Health care practitioner 
HRQoL 
Health-Related Quality of Life 
HSS 
Hives Severity Score 

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HSS7 
H1-AH 
IA 
Weekly Hives Severity Score 
H1-antihistamines 
Interim Analysis 
IB 
Investigator’s Brochure 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
IM 
Independent Ethics Committee 
Intra-muscular 
IN 
Investigator notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISS 
Itch Severity Score 
ISS7 
Weekly Itch Severity Score 
IUD 
Intrauterine device 
IUS 
IV 
Intrauterine system 
Intra-venous 
LFT 
Liver function test  
LDH 
Lactate Dehydrogenase 
LLOQ 
LPLV 
Lower limit of quantification 
Last patient last visit 
LoE 
Lack of efficacy 
LTRA 
Leukotriene Receptor Antagonist 
MAR 
Missing at random 
MCP-mod 
Multiple comparison procedure modeling 
MedDRA 
Medical dictionary for regulatory activities 
MERS 
Middle Eastern respiratory syndrome 
MMRM 
Mixed model with repeated measures 
MoA 
Mechanism of action 
MRI 
Magnetic Resonance Imaging 
NYHA 
New York Heart Association 
Oma 
Omalizumab 
PBO 
Placebo 
 
 
PK 
Pharmacokinetic(s) 
p.o. 
Oral(ly) 
PRO 
Patient Reported Outcomes 
PSD 
Premature subject discontinuation 
PT 
Prothrombin time 
QALYS 
Quality-adjusted life-years 
q4w 
Every 4 weeks 
QMS 
Quality Management System 
QoL 
Quality of life 
QTcF 
QT interval corrected by Fridericia’s formula 
RAN 
Randomized set 
RBC 
Red blood cell(s) 

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RDO 
RoW 
Retrieved Drop Out 
Rest of world 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
sc 
Subcutaneous 
sCr 
Serum creatinine 
SOP 
Standard Operating Procedure 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TBL 
Total bilirubin 
TD 
Study Treatment Discontinuation 
UAS7 
Weekly Urticaria Activity Score 
ULN 
Upper limit of normal 
UPDD 
UPV 
US 
Urticaria patient daily device 
Unplanned visit 
United States 
VAS 
Visual Analog Scale 
WBC 
White blood cell(s) 
WHO 
World Health Organization  
 
 
 

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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 (eCRFs) into one 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, 1 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 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
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 

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Run-in Failure 
A subject who is screened but not randomized/treated after the run-in period (where 
run-in period requires adjustment to subject’s intervention or treatment) 
UAS7 
Weekly Urticaria Activity Score 
Screen Failure 
A subject who did not meet 1 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. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body 
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 
Victim drug  
The drug that is affected by the drug-drug interaction 
Withdrawal of study 
consent  
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of personal 
data.  
 
 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amendment protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation.  
 
 

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Protocol summary 
Protocol 
number 
CQGE031C2302 
Full Title 
A multi-center, randomized, double-blind, active and placebo-controlled study to investigate 
the efficacy and safety of ligelizumab (QGE031) in the treatment of Chronic Spontaneous 
Urticaria (CSU) in adolescents and adults inadequately controlled with H1-antihistamines 
Brief title 
A Phase III study of efficacy and safety of ligelizumab in the treatment of CSU in 
adolescents and adults inadequately controlled with H1-antihistamines 
Sponsor and 
Clinical Phase 
Novartis Phase III 
Investigation 
type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
The purpose of this study is to establish efficacy and safety of ligelizumab in adolescent and 
adult subjects with CSU who remain symptomatic despite standard of care treatment by 
demonstrating better efficacy over omalizumab. 
Primary 
Objective(s)  
The primary objective of the study is to demonstrate that ligelizumab (72 mg q4w and/or      
120 mg q4w) is superior to placebo and superior to omalizumab 300 mg q4w in change from 
baseline in UAS7 at Week 12. 
Secondary 
Objectives 
Objective 1: To demonstrate that a greater proportion of subjects achieve UAS7 = 0 at Week 
12 who are treated with ligelizumab 72 mg q4w and/or 120 mg q4w compared to placebo-
treated subjects and compared with omalizumab 300 mg q4w treated subjects. 
Objective 2: To demonstrate the superiority of ligelizumab 72 mg q4w and/or 120 mg q4w 
treated subjects with respect to a reduction from baseline in the weekly itch severity score at 
Week 12 compared to placebo-treated subjects and omalizumab 300 mg q4w treated 
subjects. 
Study design 
This is a Phase III multi-center, randomized, double-blind, active- and placebo-controlled, 
parallel-group study. There is a screening period of up to 28 days, a 52 week double-blind 
treatment period, and a 12 week post-treatment follow-up period. 
Population 
The study population will consist of approximately 1050 male and female subjects aged 
≥ 12 years who have been diagnosed with CSU and who remain symptomatic despite the 
use of H1-AH. Of these, approximately 1000 adults and 50 adolescents are planned for 
inclusion in the study. 
Key Inclusion 
criteria 
● Signed informed consent must be obtained prior to participation in the study. The 
subject’s’, parent’s or legal guardian’s signed written informed consent and child’s assent, if 
appropriate, must be obtained before any assessment is performed. Of note, if the subject 
reaches age of consent (age as per local law) during the study, they will also need to sign 
the corresponding study Informed Consent Form (ICF) at the next study visit. 
● Male and female subjects ≥ 12 years of age at the time of screening. 
(NOTE: Recruitment of adolescent subjects, ≥ 12 to < 18 years of age, will be in accordance 
with local regulatory/ethics committee requirements). 
● CSU diagnosis for ≥ 6 months (defined as onset of CSU with supporting documentation). 
● Diagnosis of CSU refractory to H1-AH at locally label approved doses at the time of 
randomization, as defined by all of the following: 
 
● The presence of itch and hives for ≥ 6 consecutive weeks at any time prior to Visit 1   
(Day - 28 to Day -14) despite current use of non-sedating H1-AH 
 
● UAS7 score (range 0-42) ≥ 16 and Weekly hives severity score (HSS7) (range 0-21) ≥ 
8 during the 7 days prior to randomization (Visit 110, Day 1) 
 
● Subjects must be on H1-AH at only local label approved doses for treatment of CSU 
starting at Visit 1 (Day -28 to Day -14) 
● Willing and able to complete a daily symptom eDiary for the duration of the study and 
adhere to the study visit schedules. 

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Key Exclusion 
criteria 
● History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar 
chemical classes (i.e. to murine, chimeric or human antibodies). 
● Subjects having a clearly defined cause of their chronic urticaria, other than CSU. This 
includes, but is not limited to, the following: symptomatic dermographism (urticaria factitia), 
cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic- or contact-
urticaria. 
● Diseases, other than chronic urticaria, with urticarial or angioedema symptoms such as 
urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and 
hereditary or acquired angioedema (eg, due to C1 inhibitor deficiency). 
● Subjects with evidence of helminthic parasitic infection as evidenced by stools being 
positive for a pathogenic organism according to local guidelines. All subjects will be 
screened at Visit 1. If stool testing is positive for pathogenic organism, the subject will not be 
randomized and will not be allowed to rescreen. 
● Any other skin disease associated with chronic itching that might influence in the 
investigators opinion the study evaluations and results (e.g. atopic dermatitis, bullous 
pemphigoid, dermatitis herpetiformis, senile pruritus, etc.). 
● Prior exposure to ligelizumab or omalizumab and other IgE therapies. 
● Any H2 antihistamine, LTRA (montelukast or zafirlukast) or H1 antihistamines use at 
greater than approved doses after Visit 1. 
Study 
treatment 
● Ligelizumab 120 mg sc q4w 
● Ligelizumab 72 mg sc q4w 
● Omalizumab 300 mg sc q4w 
● Placebo 0 mg sc q4w 
Efficacy 
assessments 
● Weekly urticaria activity score (UAS7) 
● Weekly hives severity score (HSS7) 
● Weekly itch severity score (ISS7) 
Key safety 
assessments 
Safety evaluations include adverse events (AEs), laboratory values, vital signs and 
electrocardiogram (ECG). 
Other 
assessments  
● Patient reported outcomes (AAS7, Dermatology Life Quality Index( DLQI)/ Children 
Dermatology Life Quality Index (CDLQI),
 
Data analysis 
The primary endpoint is the absolute change from baseline in UAS7 score at Week 12, 
which is the UAS7 score at Week 12 minus the UAS7 score at baseline. The statistical 
hypotheses test for the primary endpoint being tested is that the absolute change from 
baseline in UAS7 score at Week 12 in any of the ligelizumab groups (low or high dose) is not 
superior to the omalizumab group and placebo group. A linear mixed model with repeated 
measures (MMRM) will be used to estimate treatment differences for change from baseline 
in UAS7 score at Week 12. 
The analysis of primary endpoint and the secondary endpoints included in the testing 
strategy will focus on the adult subjects. Due to the relatively low number of adolescent 
subjects for this study, the data collected for adolescent subjects will be provided in a 
descriptive manner separately. The adolescent subject data will be forwarded to a separate 
cross-study extrapolation analysis to support determination of the final posology for the 
treatment of adolescent patients. 
Key words 
Anti-IgE, chronic spontaneous urticaria, hives severity score, itch severity score, urticaria 
activity score 

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1 
Introduction 
1.1 
Background  
Chronic Spontaneous Urticaria (CSU), also known as Chronic Idiopathic Urticaria (CIU) is 
defined as the spontaneous occurrence of itchy wheals (hives), angioedema or both lasting for 
at least 6 weeks (Zuberbier et al 2014, Kaplan et al 2016, 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, 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, Powell et al 2007). The symptoms of 
urticaria and urticaria associated angioedema adversely affect daily activities and sleep 
(O'Donnell et al 1997). The overall burden of CSU is substantial; CSU has a negative impact 
on patients’ lives and health related quality of life (HRQoL) and work productivity (Maurer et 
al 2017). 
A majority of CSU patients can be treated with H1-antihistamine (H1-AH) monotherapy (Kozel 
and Sabroe 2004), which is frequently used at doses up to 4 fold the approved dose (Zuberbier 
et al 2014, Zuberbier et al 2018). The use of H2 antihistamines and Leukotriene Receptor 
Antagonists (LTRAs) has in the past been recommended in treatment guidelines for patients 
who remained symptomatic despite treatment with H1-AH (Zuberbier et al 2009, Bernstein et 
al 2014), although their use has not been as well supported by clinical studies. In the latest 
version of the treatment guidelines (Zuberbier et al 2018), neither H2-antihistamines nor 
LTRAs are now perceived to have evidence to maintain them as recommendable in the 
algorithm. Systemic corticosteroids are sometimes added to the treatment regimens, however 
they are not recommended in treatment guidelines for long term treatment as patients are then 
at risk of adverse effects associated with chronic systemic corticosteroid exposure. 
More recently omalizumab, a less potent monoclonal antibody than ligelizumab that also targets 
immunoglobulin E (IgE), has been approved in several countries including those in the 
European Union, the United States, Japan and Switzerland as add-on therapy in patients with 
CSU with symptoms despite treatment with antihistamines. Omalizumab improved the signs 
and symptoms of urticaria (i.e. hives and itch) in patients who failed treatment with H1-AH as 
well as in those who failed treatment with a combination of H1- and H2-antihistamines and a 
LTRA (Gober et al 2008, Kaplan et al 2008, Maurer et al 2013, Kaplan et al 2013). 
Ligelizumab (QGE031) is a humanized IgG-type monoclonal antibody that binds to human IgE 
with higher affinity than omalizumab. Upon binding to specific epitopes in the C3 region of 
IgE, ligelizumab is able to block the interaction of IgE with both the high and low affinity IgE 
receptors (FcεRI and FcεRII). Ligelizumab does not mediate IgE receptor cross-linking and 
consequent histamine release (i.e. is non-activating). This overall mechanism of action (MoA) 
is shared with omalizumab (Chang et al 2015). 
When subjects are treated with ligelizumab, circulating IgE is rapidly bound by the anti-IgE 
antibody and becomes inaccessible to IgE receptors on mast cells and basophils (Arm et al 2014, 
Gauvreau et al 2016). Ligelizumab has demonstrated dose- and time-dependent suppression of 
free IgE, reduction in basophil FcεRI expression and thus basophil surface IgE, and inhibition 
of skin prick test responses to allergens, superior in extent and duration to those observed with 

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omalizumab (Arm et al 2014, Gauvreau et al 2016). IgE is necessary for the enhanced 
expression 
of 
the 
FcεRI 
seen 
in 
atopic 
subjects 
(MacGlashan 
et 
al 
1997, 
MacGlashan et al 1998), and thus a decrease in FcεRI expression on circulating basophils 
accompanies ligelizumab treatment. Other potentially beneficial effects from anti-IgE therapy 
include decreased IgE production (Lowe and Renard 2011), reduced IgE+ B cell numbers 
(Ota et al 2009) and reduced cytokine production by T cells (Coyle et al 1996). 
1.2 
Purpose 
The purpose of this study is to establish efficacy and safety of ligelizumab in adult and 
adolescent subjects with CSU, who remain symptomatic despite standard of care treatment by 
demonstrating better efficacy over Xolair® (omalizumab) when added to H1-AH at approved 
doses, over 12 months of treatment and a follow-up period of 12 weeks. 
Due to the relatively low number of adolescent subjects expected to enroll in this study,
 
 
 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Objectives 
Endpoints 
Primary objective 
Endpoint for primary objective 
● The primary objective of the study is to 
demonstrate that ligelizumab (72 mg q4w and/or 
120 mg q4w) is superior to placebo and superior 
to omalizumab 300 mg q4w in change from 
baseline in UAS7 at Week 12 
● Absolute change from baseline in UAS7 at Week 12 
Secondary objectives  
Endpoints for secondary objectives  
● To demonstrate that a greater proportion of 
subjects achieve UAS7 = 0 at Week 12 who are 
treated with ligelizumab 72 mg q4w and/or 120 mg 
q4w compared to placebo-treated subjects and 
compared with omalizumab 300 mg q4w treated 
subjects 
● Complete absence of hives and itch at Week 12, 
assessed as percentage of subjects achieving UAS7 = 0  
● To demonstrate the superiority of ligelizumab 72 
mg q4w and/or 120 mg q4w treated subjects with 
respect to a reduction from baseline in the weekly 
itch severity score at Week 12 compared to 
placebo-treated subjects and omalizumab 300 mg 
q4w treated subjects 
● Improvement of severity of itch, assessed as absolute 
change from baseline in ISS7 score at Week 12 
● To demonstrate that a greater proportion of 
subjects who are treated with ligelizumab 72 mg 
q4w and/or 120 mg q4w achieve DLQI = 0-1 at 
Week 12 compared to placebo-treated subjects 
and omalizumab 300 mg q4w treated subjects 
● No impact on subjects quality of life at Week 12, 
assessed as % of subjects achieving DLQI = 0-1* 
● To demonstrate that the ligelizumab 72 mg q4w 
and/or 120 mg q4w treated subjects have a longer 
angioedema occurrence-free period compared 
with placebo-treated subjects and omalizumab 
300 mg q4w treated subjects. 
● Cumulative number of weeks that subjects achieve 
AAS7 = 0 responses between baseline and Week 12 

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Objectives 
Endpoints 
● To demonstrate the safety and tolerability of 
ligelizumab 72 mg q4w and 120 mg q4w 
● Occurrence of treatment emergent adverse events 
during the study 
● Occurrence of treatment emergent serious adverse 
events during the study 

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 *For the adolescents subgroup analyses, CDLQI will be used for the objective/endpoint assessments. 
3 
Study design 
This is a Phase III multi-center, randomized, double-blind, active- and placebo-controlled, 
parallel-group study. The study consists of 3 distinct periods: 
• Screening period (Day - 28 to Day 1): Duration of up to 4 weeks in which subjects who have 
given informed consent are assessed for eligibility. 
• Double-blind treatment period (52 weeks): The subjects will be seen in the clinic every 
4 weeks. 
• Post-treatment follow-up period (12 weeks): This period consists of 3 visits (every 4 weeks) 
with the final visit occurring 16 weeks after the last dose at Week 48.   
Figure 3-1 
Study design 
 
 
Screening period 
Subjects will have a screening period of up to 4 weeks to establish eligibility for the study. 
Subjects will be required to attend 2 visits during screening period: Visit 1 (Day -28 to Day - 14) 
and Visit 20 (Day -7). An extended screening period will be permitted only in exceptional 
circumstances when information concerning eligibility is outstanding (eg, pending laboratory 
data).  
Rescreening may be allowed for subjects who failed initial screening. Only 1 rescreening will 
be allowed (see Section 5.1 and Section 5.2). If a subject is rescreened for the study, the subject 
must sign a new informed consent and will be issued a new subject number. Informed consent 

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for a rescreened subject must be obtained prior to performing any study-related assessments or 
collecting any data for the Screening visit. 
Double-blind treatment period 
On Day 1, eligible subjects will be randomly assigned to receive ligelizumab 72 mg or 120 mg 
sc q4w, omalizumab 300 mg sc q4w or placebo sc q4w. During the double blind treatment 
period the first dose of study drug will be administered on Day 1 (Visit 110). The last dose in 
the ligelizumab 72 mg or 120 mg or omalizumab 300 mg group will be administered on Day 
337 (Week 48, Visit 230) study visit. 
Subjects randomized to the placebo group will receive the first dose of placebo on Day 1 (Visit 
110) and the last dose of placebo on Day 141 (Week 20, Visit 160) study visit. From Week 24 
to Week 48 these subjects will receive ligelizumab 120 mg sc q4w. 
Approximately 315 subjects will be allocated to each of the ligelizumab 72 mg q4w, 120 mg 
q4w and omalizumab 300 mg q4w arms, respectively. Approximately 105 subjects will be 
allocated to the placebo/ligelizumab 120 mg q4w arm. Subjects are expected to attend all site 
visits based on the assessment schedule (Table 8-1). 
Follow-up period 
The follow-up period is 12 weeks with the last follow-up visit (Visit 1999) corresponding to 
16 weeks after the last treatment dose. No investigational treatment will be given during the 
post-treatment follow-up period. Subjects will be allowed to take their rescue medication on an 
as needed basis, assessed on a daily basis by the subjects. Subjects will be required to visit the 
study center every 4 weeks during post-treatment / follow-up period. 
Eligible subjects may roll-over into an extension study (CQGE031C2302E1), once the study is 
locally approved and implemented. Subjects will be eligible to enroll in the extension study, 
after succesfully completing the current study and fulfilling the enrollment criteria defined in 
the extension study protocol. 
4 
Rationale  
4.1 
Rationale for study design 
Data from the dose-range finding Study CQGE031C2201 suggest that ligelizumab treatment 
improves itch and hives in adult subjects with CSU who have failed treatment with H1-AH and 
those who failed treatment with a combination of H1 and H2 antihistamines and LTRA. This 
Phase III study is designed to further evaluate the efficacy and safety of ligelizumab in adult 
and adolescent CSU subject’s refractory to antihistamines.  
The target population for this study consists of CSU subjects who remain symptomatic despite 
treatment with H1-AHs at locally approved doses. 
Only ligelizumab- and omalizumab-naïve subjects will be enrolled. This avoids any potential 
issue of a prior treatment with an anti-IgE antibody having an unknown persistent influence in 
the study population, and avoids potential selection bias based on results of prior exposure.  

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Although the signs and symptoms of CSU are burdensome to subjects, placebo controlled trials 
have been safely and successfully conducted in this indication (Kaplan et al 2013, Maurer et al 
2013). Subjects have been allocated across the treatment arms according to statistical 
consideration and sample size requirements. Comparison to placebo will provide a background 
incidence in the study population for possible safety findings. 
As CSU appears to be the same condition with the same unmet need in both adult and pediatric 
populations, adolescents will be included in this study. The symptoms, natural course and the 
various subtypes of CSU are very similar in both age groups. Furthermore, the disease 
classification is the same for both adult and adolescent subjects, with an autoimmune etiology 
as the main identifiable cause of CSU in both adolescents and adults. 
 
 
 
 
All subjects in the placebo arm will receive ligelizumab 120 mg q4w from Week 24 onwards. 
A switch to ligelizumab before Week 24 is not allowed. In addition to continuing their 
background medication (locally approved doses of H1-AH), subjects in the placebo group may 
receive rescue therapy (for details, see Section 6.2.3). The drop-out rate in the placebo arm of 
the CQGE031C2201 study over a 6-month treatment duration was 
 
Therefore, with a similar expected drop-out rate, a 6-month placebo duration in the current 
study is anticipated to be feasible. 
The number of subjects receiving placebo has been limited as far as possible while still allowing 
statistical comparison and maintenance of blinding to active versus placebo treatment.  
This study will use ligelizumab placebo only.
 
 
 
 
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 emphasis and target 
of therapy as described in the CSU treatment guidelines (Zuberbier et al 2014, Zuberbier et al 
2018) have evolved and focus on UAS7 which is a composite of ISS7 and HSS7 rather than 
only ISS7. In addition to the current emphasis on UAS7 in the medical community, as reflected 
in the CSU treatment guidelines, data from the Phase II study CQGE031C2201 also support the 
change from baseline in UAS7 at week 12 being assessed as the primary endpoint. Change from 
baseline in ISS7 and achievement of UAS7 = 0 will be evaluated as secondary endpoints 
included in the testing strategy. 
After the completion of the double-blind treatment period, subjects will enter a post-treatment 
follow-up period
 
 
 

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4.1.1 
Rationale for choice of background therapy 
This study requires concurrent use of one second generation-H1-AH at doses approved by the 
local Health Authority as background medication. All subjects, regardless of what treatment 
arm they are randomized to, will receive standard of care therapy (H1-AH at (locally label 
approved doses) as background medication. Subjects must remain on a stable treatment regimen 
(type and dose of H1-AH) throughout the study.  If a subject must switch to another background 
H1-AH (at approved dose) as a result of an AE, the subject will be considered to have remained 
on stable treatment. 
4.2 
Rationale for dose/regimen and duration of treatment 
Rationale for dose/regimen 
Two ligelizumab doses, 72 and 120 mg, will be tested in this Phase III study. These doses are 
selected based on the totality of observed clinical data in the Phase IIb CQGE031C2201 study, 
the lack of any safety concerns across the doses tested and modeling and simulation data. 
Overview of Phase II clinical data 
The following ligelizumab doses were tested in the CQGE031C2201 study: 24, 72 and 240 mg 
q4w over 20 weeks, as well as 120 mg in a single administration. Data for the 120 mg single 
dose was collected to enable further exposure response analysis, to support dose selection and 
frequency, based on duration of effect. 
The treatment responses for UAS7 change from baseline, the primary endpoint (Week 12) for 
the Phase III program, and for HSS7 and ISS7 are shown in Figure 4-1. 
Figure 4-1 
Change from baseline in HSS7, ISS7, and UAS7 by visit 
 
The strongest treatment responses across all 3 endpoints at Week 4 were seen with 72 mg and 
120 mg and appeared to be comparable. Beyond Week 4, data is available for 24 mg, 72 mg 
and 240 mg. The response for the 72 mg and 240 mg doses appear to be similar up to Week 20. 

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With doses of 24 or 72 mg q4w a partial relapse of symptoms towards the end of the dosing 
interval can be observed. These data imply that the 72 mg q4w dose achieves rapid and good 
control of symptoms and a dose higher than 72 mg q4w can provide enough drug exposure 
throughout the dosing interval such that relapse of symptoms is minimal. These data also imply 
that treating subjects at a monthly interval is more beneficial in achieving a meaningful 
sustained clinical response. 
During the phase II study there was no evidence of dose related safety signals up to Week 20 
except for a trend in injection site reactions, which were mostly non-serious, mild to moderate 
in severity, reversible and did not lead to treatment discontinuations. This observation is further 
supported by data from adult asthma trials where doses up to 240 mg q2w were administered. 
Furthermore, in the CQGE031C2201E1 study 240mg q4w did not result in any new safety 
signals. 
Doses of 72 and 120 mg are considered safe dose levels for phase III with a substantial safety 
window. There have been no new or unexpected safety findings in the CQGE031C2201 study, 
across all the doses assessed. 

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Rationale for route of administration 
In the CQGE031C2201 study, ligelizumab was administered subcutaneously. The 
subcutaneous (s.c.) route of administration will continue to be used, due to the favorable 
bioavailability demonstrated with ligelizumab in previous studies and because of its ease of 
administration. 
Rationale for duration of treatment 
The double blind treatment period will be 52 weeks in duration, with the primary endpoint 
assessed at Week 12. Current treatment guidelines recommend re-evaluating the necessity for 
continued or alternative drug treatment every 3–6 months (Zuberbier et al 2014, Zuberbier et al 
2018). However, it is recognized that patients with a longer history of CSU are more likely to 
have persistence of disease and therefore, in clinical practice, often require many months to 
years of treatment. The planned 52 week treatment period is not only consistent with such actual 
clinical practice; it will also be more likely to allow effective treatment of subjects who have 
both a shorter and longer history of CSU. 
The study will evaluate the efficacy of ligelizumab in controlling angioedema as well as 
evaluate the burden of angioedema. While many patients with CSU suffer from angioedema, 
the episodes may be infrequent and are unpredictable. Thus a 1 year period of time provides a 
greater probability of observing its clinical course and the potential reduction in the occurrence 
of angioedema as a result of treatment 
. 
4.3 
Rationale for choice of control drugs (comparator/placebo) and 
combination drugs 
Omalizumab has been selected as an active comparator for the following reasons: 
• it is the only drug in the same class as ligelizumab currently approved as add-on therapy in 
CSU subjects with inadequate response to H1-AH. 
• it is recommended as a third line option in the current treatment algorithm for 
management of CSU (Zuberbier et al 2018) after failure of higher dose antihistamines. 
• to confirm the efficacy and safety of ligelizumab versus omalizumab that was noted in the 
CQGE031C2201 study. 
Placebo is used in this study for the following reasons: 
• to allow blinding of investigators and subjects to treatment and thereby minimize bias in 
the evaluation of safety and efficacy assessments, 
• to allow assessment of the improvement in terms of CSU control for subjects with disease 
not controlled by background medication who are treated with ligelizumab, in comparison 
to those continuing solely on background medication, and 

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• to allow the assessment of safety of ligelizumab on top of background medication 
compared to background medication alone. 
The use of combination drugs is not applicable to this trial. 
4.4 
Purpose and timing of interim analysis 
An interim analysis will be performed after all adult subjects have completed the treatment 
period (Week 52 visit). The interim analysis at the time of this Week 52 database lock would 
be utilized for the primary efficacy analysis for this study.
 
 
An unblinded study team will conduct the Week 52 primary efficacy 
analysis and a separate blinded study team will oversee the conduct of the study until the final 
database lock, after all the subjects have completed end of study participation. All investigators, 
site personnel, subjects, and the blinded study team will remain blinded until the final database 
lock has occurred. No access to patient level data will be provided to the investigators, site 
personnel, subjects, and blinded study team.  
 
4.5 
Risks and benefits 
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 basic (acceptable 
effective) contraception requirements outlined in the exclusion criteria. If there is any question 
that the subject will not reliably comply, they should not be entered or continue in the study. 
In the overall ligelizumab clinical program, approximately 923 subjects have been exposed 
across 12 studies, covering the indications of CSU, asthma, atopic dermatitis, and bullous 
pemphigoid  The longest individual continuous exposure to ligelizumab is 12 months 
(CQGE031C2201E1 and CQGE031B2201E1). Cumulative (continuous and interrupted) 
human duration of exposure to ligelizumab is approximately 16 and 20 months (across the 
CQGE031B2201/CQGE031B2201E1 
asthma 
studies 
and 
the 
CQGE031C2201/ 
CQGE031C2201E1 CSU studies, respectively). The following doses have been tested in the 
clinical programs: 12 mg, 24 mg, 36 mg, 72 mg, 180 mg and 240 mg s.c. q4w, 280 mg q2w and 
120 mg s.c. single dose. To date in the CSU program alone, 254 subjects have been exposed to 
ligelizumab at doses up to 240 mg s.c. q4w. 
Overall, no apparent dose-dependent safety signals (except for a trend in injection site reactions, 
which can be easily managed clinically) have been observed to date, although the number of 
subjects studied is relatively small, in line with the development phase of the CSU program. In 
the asthma clinical study CQGE031B2201, there appeared to be a dose dependency of injection 
site reactions between ligelizumab high dose group (28.6% of 199 subjects) and ligelizumab 
low dose group (12.5% of 40 subjects), which was comparable to omalizumab (14.5% of 131 
subjects). The incidence of injection site reactions was higher among all the active treatment 
groups compared to that of placebo (5.2% of 96 subjects). Similarly, in the CSU dose-finding 
study (CQGE031C2201), the overall safety profile was comparable between different doses of 
ligelizumab (24 mg, 72 mg and 240 mg q4w or 120 mg single dose), omalizumab and placebo. 

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The exceptions were AEs related to injection site reactions, where a possible trend of dose 
dependency for ligelizumab was observed. All cases of injection site reactions (except 1 case 
of medical significance) regardless of treatment group or doses were non-serious, mild to 
moderate in severity, reversible, and did not lead to discontinuation of study treatment. 
With regards to Serious Adverse Events (SAEs), the incidence of SAEs was comparable 
between subjects treated with ligelizumab and those receiving placebo in both asthma and CSU 
indications. There has been no dose dependency in SAEs observed among subjects treated with 
different doses of ligelizumab (CQGE031B2201 in asthma and CQGE031C2201 in CSU). 
Risk associated with omalizumab is well characterized. Potential risks to omalizumab are 
hypersensitivity-type allergic reactions (i.e., anaphylaxis, angioedema and urticaria), immune 
complex associated allergic reactions (i.e., serum sickness), Churg-Strauss syndrome, and hyper 
eosinophilia. In clinical trials, the most commonly reported adverse reactions are injection site 
reactions (including injection site pain, swelling, erythema and pruritus) and headaches. 
Additional information on risks associated with omalizumab is found in the local health 
authority approved product information. Severe thrombocytopenia has been reported in 
preclinical studies in cynomolgus monkeys with high doses of omalizumab. Although 
thrombocytopenia has not been observed with ligelizumab in the toxicology studies in non-
human primates or in the clinical program conducted so far, the current protocols include 
monitoring of platelets as part of the hematology assessment. Ligelizumab is in the class as 
omalizumab and therefore, in theory, carries the same risks as omalizumab. 
IgE is an antibody that may have an adaptive role in immunity to parasitosis, particularly 
helminthic infections. Thus, blocking the interaction of IgE and its receptors with ligelizumab 
may alter immunologic responsiveness to parasites. Bearing this in mind, monitoring for the 
occurrence of infection and response to therapy is recommended for subjects at high risk of 
geohelminth infection who receive ligelizumab. Insufficient data are available to determine the 
length of monitoring required for geohelminth infections after stopping ligelizumab. However, 
it is expected that ligelizumab will not interfere with a polyclonal reaction triggered by exposure 
to parasites. The resulting increase of IgE production would decrease, through target mediated 
disposition, the half-life of ligelizumab hence restoring normal IgE levels more rapidly. 
Based on currently available data from the ligelizumab clinical program, there is no evidence 
of an increased risk of infections/viral infections. At this time there are no specific data to 
inform on incidence or severity of Corona Virus Disease 2019 (COVID-19) (due to severe acute 
respiratory syndrome coronavirus 2) or Middle Eastern respiratory syndrome (MERS) in 
patients receiving omalizumab or ligelizumab.  
Therefore, based on the cumulative data available across all clinical studies in different patient 
populations for ligelizumab, the current evidence demonstrates that ligelizumab is safe and 
well-tolerated and thus appropriate for further development. 
The non-clinical safety evaluation for ligelizumab supports a clinical treatment of children 
down to the age of 2 years. There is no evidence to suggest that ligelizumab will have a different 
mode of action or will be cleared differently in pediatric versus adult subjects. No new or 
unexpected safety signals were identified in the CQGE031C2201 study in adults. 
The data from CQGE031C2201 demonstrates that ligelizumab administration results in 
significant improvement of CSU symptoms including itch, hives, angioedema and quality of 

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life (QoL) 
. Hence the potential benefit to the subject from 
participation in the current study is that treatment with ligelizumab could improve their CSU 
symptoms, leading to a better QoL.  
Regarding the choice of omalizumab as an active comparator, the Phase III studies for 
omalizumab included adolescents, based on which omalizumab is approved for use in 
adolescents. It is safe and well-tolerated for use in this population. 
The inclusion and exclusion criteria are selected to enroll subjects with CSU likely to benefit 
from participating in the study. The overall risk will be minimized by compliance with the 
inclusion/exclusion criteria, close clinical monitoring including periodic review of data by an 
independent Data Monitoring Committee (DMC), the use of an electronic diary at home to 
monitor symptoms 
. 
Investigators will be instructed on acceptable treatments for managing worsening of disease 
with rescue medication during the course of this study (see Section 6.2.3), thereby allowing 
subjects to continue in the study as long as possible. The investigator will provide the subject 
with written instructions to contact them if symptoms of CSU worsen. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities, i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial  
integrity are listed in relevant sections. Notification of the Public Health emergency should be 
discussed with Novartis prior to implementation of mitigation procedures and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate. 
5 
Population 
The study population will consist of approximately 1050 male and female subjects aged ≥ 12 
years who have been diagnosed with CSU and who remain symptomatic despite the use of H1-
AH. Of these, approximately 1000 adults and 50 adolescents are planned for inclusion in the 
study. 
It is anticipated that approximately 1616 subjects will need to be screened (an estimated 
screening failure rate of 35%) in order to randomize approximately 1050 subjects into the 52 
week treatment period (see Figure 3-1). 
Since both adults and adolescent subjects will be enrolled into this study, randomization will be 
stratified by age group. In addition, randomization for adults will be stratified by region and/or 
country to ensure a balanced assignment to each treatment group. Considering the relative small 
sample size of adolescent subjects, there will be no additional stratification for adolescent 
subjects. 
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. 

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2. Subject’s, parent’s or legal guardian’s signed written informed consent and child’s assent, 
if appropriate, must be obtained before any assessment is performed. Of note, if the 
subject reaches age of consent (age as per local law) during the study, they will also need 
to sign the corresponding study Informed Consent Form (ICF) at the next study visit. 
3. Male and female subjects ≥ 12 years of age at the time of screening. 
(NOTE: Recruitment of adolescent subjects, ≥ 12 to <18 years of age, will be in 
accordance with local regulatory/ethics committee requirements). 
4. CSU diagnosis for ≥ 6 months (defined as onset of CSU with supporting documentation). 
5. Diagnosis of CSU refractory to H1-AH at locally label approved doses at the time of 
randomization, as defined by all of the following: 
a. The presence of itch and hives for ≥ 6 consecutive weeks at any time prior to Visit 1 
(Day -28 to Day -14) despite current use of non-sedating H1-AH 
b. UAS7 score (range 0−42) ≥ 16 and HSS7 score (range 0−21) ≥ 8 during the 7 days 
prior to randomization (Visit 110, Day 1) 
c. Subjects must be on H1-AH at only locally label approved doses for treatment of 
CSU starting at Visit 1 (Day -28 to Day -14) 
6. Willing and able to complete a daily symptom eDiary for the duration of the study and 
adhere to the study visit schedules. 
7. Subjects must not have had any missing eDiary entries in the 7 days (twice a day) prior to 
randomization (Day 1, Visit 110), i.e. 14 eDiary entries required. Rescreening may be 
considered only once. 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects. 
1. Use of other investigational drugs within 5 half-lives, or within 30 days (for small 
molecules) prior to Visit 1 or until the expected pharmacodynamic effect has returned to 
baseline (for biologics), whichever is longer. 
2. History of hypersensitivity to any of the study drugs or their excipients or to drugs of 
similar chemical classes (i.e. to murine, chimeric or human antibodies). 
3. Subjects having a clearly defined cause of their chronic urticaria, other than CSU. This 
includes, but is not limited to, the following: symptomatic dermographism (urticaria 
factitia), cold-, heat-, solar-, pressure-, delayed pressure-, aquagenic-, cholinergic- or 
contact-urticaria. 
4. Diseases, other than chronic urticaria, with urticarial or angioedema symptoms such as 
urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) 
and hereditary or acquired angioedema (eg, due to C1 inhibitor deficiency). 
5. Subjects with evidence of helminthic parasitic infection as evidenced by stools being 
positive for a pathogenic organism according to local guidelines. All subjects will be 
screened at Visit 1 (see Section 8.4.3). If stool testing is positive for pathogenic 
organisms, the subject will not be randomized and will not be allowed to rescreen. 

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6. Any other skin disease associated with chronic itching that might influence, in the 
investigator’s opinion, the study evaluations and results (eg, atopic dermatitis, bullous 
pemphigoid, dermatitis herpetiformis, senile pruritus, etc.). 
7. Prior exposure to ligelizumab, omalizumab and other IgE therapies. 
8. Any H2 antihistamine use after Visit 1. 
9. Any LTRA (montelukast or zafirlukast) use after Visit 1. 
10. Any H1-AH used as background medication at greater than local label approved doses 
after Visit 1. 
11. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to 
randomization. 
12. Inability to comply with study and follow-up procedures. 
13. Use of prohibited treatment detailed in protocol (Table 6-2). 
14. Contraindications to or hypersensitivity to study drugs including but not limited to 
fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine, rupatadine, epinephrine 
or any of their ingredients. 
15. Documented history of anaphylaxis. 
16. History of malignancy of any organ system within the past 5 years (except for basal cell 
carcinoma or actinic keratoses or Bowen disease (carcinoma in situ) that have been 
treated, with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the 
cervix or non-invasive malignant colon polyps that have been removed). 
17. Presence of clinically significant cardiovascular (such as but not limited to myocardial 
infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, 
arrhythmia and uncontrolled hypertension within 12 months prior to Visit 1), neurological, 
psychiatric, metabolic or other pathological conditions (such as but not limited to 
cerebrovascular disease, neurodegenerative or other neurological diseases, uncontrolled 
hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic 
state or ophthalmologic disorder) that could interfere with or compromise the safety of the 
subjects, interfere with evaluation or interpretation of the study results, or preclude 
completion of the study. 
18. Medical examination or laboratory findings that suggest the possibility of decompensation 
of co-existing conditions for the duration of the study. Any items that are cause for 
uncertainty will be reviewed with the investigator. 
19. History of, or current treatment for, hepatic disease including but not limited to acute or 
chronic hepatitis, cirrhosis or hepatic failure or Aspartate Aminotransferase (AST)/ 
Alanine Aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN)  
or International Normalized Ratio (INR) of more than 1.5 at Visit 1. 
20. History of renal disease or creatinine level above 1.5x ULN at Visit 1. 
21. Platelets < 100 000/μL at Visit 1. 
22. History of long QT syndrome or whose QTcF (Fridericia) measured at Visit 1 is 
prolonged (> 450 ms for males or > 460 ms for females) and confirmed by a central 
assessor (these subjects should not be rescreened). 
23. Pregnant or nursing (lactating) women. 

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24. Female subjects, including adolescent females of 12 to less than 18 years of age, of child-
bearing potential, defined as all women physiologically capable of becoming pregnant, 
unless they are using basic (acceptable effective) methods of contraception for the 
duration of the study (approx. 4 months, i.e. 5 half-lives, after last dose of ligelizumab or 
omalizumab). Basic (acceptable effective) contraception methods include: 
a. 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 effective methods of contraception 
b. Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), 
total hysterectomy or tubal ligation at least 6 weeks before taking investigational 
drug. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow-up hormone level assessment 
c. 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 
d. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository  
e. Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow-up hormone level assessment is she considered not of child bearing potential. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF. 

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6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drugs 
Investigational/ 
Control Drug 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply type 
Sponsor 
(global or 
local) 
Ligelizumab 120 mg 
per 1 mL 
Liquid in vial  
s.c. 
Open label subject 
packs; vials 
Sponsor 
global 
Omalizumab 150 mg 
per 1.2mL 
Lyophilized powder for 
solution in vial 
s.c. 
Open label subject 
packs; vials 
Sponsor 
global 
Ligelizumab Placebo 0 
mg per 1 mL 
Liquid in vial 
s.c. 
Open label subject 
packs; vials 
Sponsor 
global 
6.1.2 
Additional study treatments 
No other additional treatment beyond investigational treatment (ligelizumab, omalizumab, 
placebo to ligelizumab) is requested for this trial. Subjects will continue to use their background 
medication H1-AH at (locally approved doses) with a stable regimen during the study. For 
rescue medication, see Section 6.2.3. 
6.1.3 
Treatment arms 
Subjects will be assigned at Visit 110 to one of the following 4 treatment arms. Each subject 
will receive a total of 2 injections every 4 weeks: 
a. Ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab + 1 injection of 1.0 mL 
ligelizumab placebo 
b. Ligelizumab 72 mg arm: 1 injection of 0.6 mL ligelizumab + 1 injection of 1.0 mL 
ligelizumab placebo 
c. Omalizumab 300 mg arm: 2 injections of 1.2 mL omalizumab 
d. Placebo / ligelizumab arm: 2 injections of 1.0 mL ligelizumab placebo from Week 0 
through Week 20; 1 injection of 1.0 mL ligelizumab + 1 injection of 1.0 mL ligelizumab 
placebo from Week 24 through Week 48 
During the double-blind treatment period, study drug will be administered for 13 visits as per 
Table 6-3 and Table 8-1. Due to the specifics of the blinding procedure in this trial, the 
dispensing and administration of the study treatments must be performed by suitable authorized 
site personnel who are otherwise not involved in study conduct. Further details are provided in 
Section 6.3.2, Section 6.4 and Section 6.7. 

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6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
This study requires concurrent use of one second generation H1-AH at locally approved doses 
as background medication. Subjects must remain on a stable treatment regimen (type and dose 
of H1-AH) throughout the study. 
If a subject must switch to another background H1-AH (at approved dose) as a result of an AE, 
the subject will be considered to have remained on stable treatment. 
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. 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 appropriate Case Report 
Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. 
6.2.2 
Prohibited medication 
Use of the class of treatments displayed in Table 6-2 is NOT allowed after start of screening. 
The minimum required period without prohibited treatment before Visit 1 is also listed in Table 
6-2. Each concomitant drug must be individually assessed against all exclusion criteria and the 
table below to see if it is allowed. If in doubt, the investigator should contact Novartis or 
delegate before randomizing a subject or allowing a new medication to be started.  
Table 6-2 
Prohibited medication 
Medication 
Minimum required period 
without medications 
Omalizumab 
No prior use allowed 
Ligelizumab 
No prior use allowed 
Routine (more than 3 doses over a 5 day period) oral corticosteroids * 
30 days prior to Visit 1 
IV/IM/Intra-Articular corticosteroids 
30 days prior to Visit 1 
Beta-blocker therapy 
7 days prior to Visit 1 
Leukotriene antagonists 
Stop at Visit 1 
H2-antihistamines 
Stop at Visit 1 
First generation H1-antihistamines  
Stop at Visit 1 
Hydroxychloroquine or chloroquine 
30 days prior to Visit 1 
Other immunosuppressive medication with or without 
known effect on CSU including but not limited to Methotrexate, 
cyclosporine A, cyclophosphamide, tacrolimus and mycophenolate 
mofetil 
30 days prior to Visit 1 
Intravenous immunoglobulin G 
30 days prior to Visit 1 
Plasmapheresis 
30 days prior to Visit 1 
Regular (daily or every other day) doxepin (oral) 
14 days prior to Visit 1 
Vaccination with inactivated viruses 
48 hours prior to each dosing 
visit (i.e. Visit 110 to Visit 230)  

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Medication 
Minimum required period 
without medications 
Live attenuated vaccine 
30 days prior to Visit 1 
* Allowed only as rescue therapy only after Week 12, on an as-needed basis for unbearable symptoms as per 
Section 6.2.3. Other preparations of corticosteroids (CS) with limited systemic exposure for non-CSU indications 
can be used (e.g. Intra nasal or any topical CS) as-needed basis. 
If the prohibited treatment was used during the study for any indication, the subject must 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. If the 
subject received a live virus vaccination during the study, the subject must discontinue study 
treatment. 
If a subject takes concomitant omalizumab (outside of study assigned treatment) in the follow-
up phase, the subject must discontinue from the study, in which case, 
 samples 
should not be collected at the End of Study (EoS) visit. 
The table is not considered all inclusive. Medication should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. 
6.2.3 
Rescue medication 
In addition to being used as background medication (see Section 6.2.1), the non-sedating H1-
AH fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine and rupatadine, will also 
be allowed as rescue medication 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 a H1-AH rescue medication should be made only once for an individual subject. 
For each individual subject, the AH rescue medication used must differ from the AH used for 
background medication (see Section 6.2.1), in order to avoid AHs at non-approved doses. A 
switch of the H1-AH rescue medication for an individual subject is not permitted except due to 
an AE. 
Prior to Week 12, any corticosteroid use for CSU is prohibited.  After the Week 12 primary 
endpoint, subjects will be permitted to use oral corticosteroids such as prednisone or its 
equivalent, as rescue medication if needed. The selection of the oral corticosteroid to be used 
as rescue medication after Week 12, should be made only once for an individual subject. A 
switch of oral corticosteroids as rescue medication for an individual is not permitted except due 
to an AE. The CSU treatment guidelines suggest that systemic corticosteroids may be used for 
up to 10 consecutive days to manage flare-ups in clinical practice. However in this clinical study, 
corticosteroid use will be limited to 3 days in a 30 day period and a maximum of 9 doses in 
total (i.e. a maximum of 9 days of corticosteroids in total) after Week 12 to avoid any 
confounding suppression of signs and symptoms of CSU. If a subject uses more than 3 doses 
of corticosteroid in a 30 day period or more than 9 doses of corticosteroid in total during the 
study period (including the follow-up period), the subject will be discontinued from study 
treatment. 
Rescue medication will be sourced locally. Use of H1-AH and oral corticosteroids rescue 
medication (number of tablets taken and name of rescue medication) only for CSU will be 
recorded on the eDiary by the subject. The rescue medication information will be captured on 
the appropriate electronic Case Report Form (eCRF). 

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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 patient is first enrolled for screening (Interactive Response Technology (IRT) to be 
contacted at screening Visit 1) 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 
informed consent form, the patient is assigned to the next sequential Subject No. available. 
6.3.2 
Treatment assignment and randomization 
At Visit 110 all eligible subjects will be randomized via IRT to one of the treatment arms. The 
investigator or his/her delegate will inform the independent unblinded site personnel 
(pharmacist or authorized delegate) to contact the IRT after confirming that the subject fulfills 
all the inclusion/exclusion criteria. The IRT will assign a 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 package of investigational treatment to be dispensed to the subject and will 
specify the volume of dose. The randomization number will not be communicated to the caller. 
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, or by a delegate under 
Novartis/sponsor supervision, 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 Drug Supply Management using 
a validated system that automates the random assignment of medication numbers to packs 
containing the investigational drug(s). 
Since both adults and adolescent subjects will be enrolled into this study, randomization will be 
stratified by age group. In addition, randomization for adults will be stratified by region and/or 
country to ensure a balanced assignment to each treatment group. Considering the relative small 
sample size of adolescent subjects, there will be no additional stratification for adolescent 
subjects. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
Subjects, investigator staff and personnel performing the study assessments will remain blinded 
to the identity of the treatment from the time of randomization until final database lock. An 
unblinded study monitor will visit the study site to monitor study drug related administration 
(see Section 11.3). 
Blinding will be maintained using the following methods: 

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1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions: 
• Bioanalyst (PK): to enable identification of samples from the ligelizumab treatment 
arms of the study to facilitate bioanalysis; 
• Independent personnel (external to Novartis) involved in monitoring anaphylaxis, 
neoplastic and cerebro-cardiovascular events (Adjudication Committee members), if 
needed; and  
• An independent Data Monitoring Committee (DMC; see Section 10.2.3) and the 
independent statistician supporting the DMC activities (Table 6-4). 
2. The following measures will be applied to keep the subject and study personnel blinded 
despite differences of the investigational treatments in appearance, viscosity and volume: 
• The study drug must be prepared by an independent unblinded pharmacist (or 
authorized delegate) and administered by an independent unblinded administrator 
who are both not involved in any of the study assessments. If an unblinded pharmacist 
is not available, preparation and administration of drug may also be performed by a 
single independent unblinded site person if he/she is authorized to do both. 
• Preparation of the investigational drug must be done in a separate space/room where 
subjects and study personnel have no access during time of preparation. 
• To blind the liquid volume in the syringe, the syringe must be covered by a strip of 
opaque tape. The differences in length of the syringe plunger, related to the 
differences in the volume, should also be covered by the way of administration (see 
Pharmacist Manual). 
• The prepared syringes must be placed on a tray which is covered by an opaque towel 
to ensure the syringes are not visible to the subject at any time. 
• The independent unblinded authorized site persons (pharmacist/administrator) should 
not communicate the appearance, the volume and any perceived sensation associated 
with the administration of the investigational drug. 
• The subject will be instructed to look away, from the tray of prepared syringes 
(whenever the tray is uncovered) and from the injection site. 
The procedural details relating to treatment blinding and unblinded drug administration will be 
described in the Pharmacist Manual, which is provided separately. 
In each treatment group, subjects receive 2 injections at every visit (Table 6-3). Subjects in the 
placebo arm will have placebo administered for 6 visits, then will be switched to ligelizumab 
120 mg for rest of the treatment period. All subjects will be observed following the 
recommendation by the National Heart, Lung, and Blood Institute and by the American 
Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma 
and Immunology Executive Committees Joint Task Force (Cox et al 2007) for the anti-IgE 
therapy currently available (omalizumab). All subjects in all treatment arms will need to remain 
at the site for a 2 hour observation at randomization and Weeks 4, 8, 24, 28 and 32 and for a 30 
minute observation period for the remaining treatment visits. This approach will help maintain 
the blind for subjects and site staff. 
After the Week 52 database lock for the interim analysis, an unblinded study team will perform 
the primary efficacy analysis. Treatment assignment will remain blinded to all investigators, 

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site personnel, subjects and blinded study team until all patients have completed the entire study 
participation and the final database lock has occurred. 
Interim analysis data will not be shared with the blinded study team overseeing the conduct of 
the ongoing study until all subjects have completed the entire study and the final database lock 
has occurred. Interim analysis results and reports  generated prior to the final database lock that 
would reveal subject-level data will be kept in a secure and restricted area until the end of the 
study. 
Unblinding of investigator, site personnnel and patients will only occur in the case of subject 
emergencies and at the conclusion of the study. 
Health authorities will be granted access to unblinded data if needed. 
Table 6-3 
Drug administration 
Treatment 
Ligelizumab 
120 mg arm 
Ligelizumab 
72 mg arm 
Omalizumab 
300 mg arm 
Placebo/ligelizumab arm 
Placebo 
period 
Ligelizumab 
period 
Ligelizumab 
120 mg/mL liquid in 
vial 
1 x 1.0 mL 
1 x 0.6 mL 
0 
0 
1 x 1.0 mL 
Omalizumab 
150 mg/1.2mL 
Lyophilized powder 
for reconstitution 
0 
0 
2 x 1.2 mL 
0 
0 
Ligelizumab Placebo1 
0 mg/mL liquid in vial 
1 x 1.0 mL 
1 x 1.0 mL 
0 
2 x 1.0 
mL 
1 x 1.0 mL 
Total # of injections 
2 
2 
2 
2 
2 
Total volume injected 
2.0 mL 
1.6 mL 
2.4 mL 
2.0 mL 
2.0 mL 
1 Placebo for blinding between ligelizumab doses. 
Table 6-4 
Blinding and unblinding plan  
Role 
Time or Event 
DMC 
Analysis 
 
 
 
Week 52 
Interim 
Analysis (IA) 
Randomization 
list generated 
Treatment 
allocation 
& dosing 
Safety 
event 
(single 
subject 
unblinded) 
Subjects 
B 
B 
B 
B 
B 
Investigator and Site 
staff 
B 
B 
UI 
B 
B 
Unblinded site staff 
eg, pharmacy staff 
and study drug 
administrator  
B 
UI 
NA 
B 
B 
Global Clinical 
Supply and 
Randomization 
Office 
UI 
UI 
UI 
UI 
UI 

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Role 
Time or Event 
DMC 
Analysis 
 
 
 
Week 52 
Interim 
Analysis (IA) 
Randomization 
list generated 
Treatment 
allocation 
& dosing 
Safety 
event 
(single 
subject 
unblinded) 
Unblinded sponsor 
staff eg, for study 
treatment re-supply, 
unblinded monitor(s) 
B 
UI 
NA 
B 
B 
Unblinded 
Pharmacovigilance 
sponsor staff 
B 
B 
UI 
B 
B 
Trial 
Statistician/statistical 
programmer 
B 
B 
B 
B 
B 
Independent 
Statistician/statistical 
programmer 
B 
B 
B 
UI 
NA 
Independent 
committees used for 
assessing interim 
results, if required 
(eg, DMC) 
B 
UI 
UI 
UI 
B 
Adjudication 
committee 
B 
B 
B* 
B 
B 
Bioanalyst (PK) 
B 
UI 
B 
B 
B 
All other sponsor 
staff not identified 
above (trial team, 
project team, 
management & 
decision boards, 
support functions) 
B 
B 
B 
B 
B 
Unblinded sponsor 
team for week 52 IA 
as defined in the 
Charter for 
maintaining data 
integrity for interim 
lock 
B 
B 
B 
B 
UI 
UI : Allowed to be unblinded on individual subject level 
B : Remains blinded 
NA : Not applicable to role 
*Unblinded if needed 
6.5 
Dose escalation and dose modification 
Study drug dose adjustments are not permitted. Any interruption of study drug administration 
should be discussed with Novartis or delegate regarding the subject’s eligibility to continue 
investigational treatment. 

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Any missed or altered study drug administration must be recorded on the appropriate eCRF in 
order to reconstruct an accurate dosing history for each subject. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Subjects will receive 2 subcutaneous injections every 4 weeks at 13 visits during the double-
blind treatment period. Compliance is assured as study drug must / will be administered by 
independent unblinded study personnel via subcutaneous injection at the site. Administration 
of study drug must be recorded in the source documents and the corresponding eCRF for each 
administration. 
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. If the IRT system is 
not available for technical reasons, the IRT help desk can facilitate emergency code break 
requests. 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 at any time in case of 
emergency. The investigator will provide: 
• protocol number 
• study drug name 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact the 
investigator’s backup in cases of emergency, or when he/she is unavailable, the local Novartis 
Country Organization (CO) (or any entity to which it has delegated responsibility for emergency 
code breaks) to ensure that un-blinding can be performed at any time. 
The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason. 
Study treatment must be discontinued after emergency unblinding. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under Section 6.7.1.1. 
For drug preparation of omalizumab prior to administration, please refer to the Pharmacy 
Manual. 

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A unique medication number is printed on the study medication label. 
An independent unblinded pharmacist (or authorized delegate) will identify the study 
medication kits to dispense to the subject by contacting the IRT and obtaining the medication 
number(s) and volume of dose. The study medication has a 2-part label (base plus peel-off label). 
Immediately before preparing study treatment, the unblinded pharmacist (or authorized 
delegate) will detach the outer part of the label from the packaging and affix it to the source 
document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by the independent unblinded study pharmacist or designated 
person at the study site, handled and stored safely and properly and kept in a secured location 
to which only the independent unblinded site personnel has access. Upon receipt, all study 
treatment must be stored according to the instructions specified on the labels and in the 
Investigator’s Brochure (IB). Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization (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 other information 
except for the medication number. 
The independent unblinded site personnel 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 unblinded monitors during site visits or remotely and at the completion of 
the trial. 
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  
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
The independent study drug administrator will administer the study treatment to the subject 
during the study visit without engaging in any unnecessary interactions that may have the 
potential to unblind the subject or any of the study site personnel. 
The injections can be administered in the deltoid region on the right and/or left arm, and/or in 
the right and/or left thigh, or the abdomen as preferred by subject and/or site. The injections are 
administered subcutaneously after aspiration of the plunger of the syringe. If blood appears at 
the needle hub or blood is drawn into the syringe upon aspiration, the needle must be withdrawn 
without administration of the dose and the injection site changed. Each injection must be 
administered at a different site (eg, right arm and left thigh). 

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The guidelines for the preparation and administration of study medication are described in the 
pharmacist manual. 
Subjects will remain on-site for observation for a period of 2 h post-dose for the first 3 study 
drug administrations at Visits 110, 120 and 130 and the 3 study drug administrations at Visits 
170, 180 and 190 and 30 min post-dose for all other drug administrations. These observation 
periods follow the recommendation suggested by the National Heart, Lung, and Blood Institute 
and by the American Academy of Allergy, Asthma & Immunology and the American College 
of Allergy, Asthma and Immunology Executive Committees Joint Task Force (Cox et al 2007) 
for the anti-IgE therapy currently available (omalizumab). As described in the Investigator 
Brochure (IB), the site needs to ensure readiness to react to anaphylactic events (eg, have 
available injectable epinephrine, antihistamine, corticosteroids, intravenous supplies, oxygen, 
an oral airway, Ambu bag and the ability to transport a subject rapidly to an emergency 
department/hospital). 
The dose for individual subjects will be the same within a treatment arm and will be assigned 
at randomization (Visit 110). 
All study drug dosages prescribed and dispensed to the subject and all dosing errors or missed 
administrations during the study must be recorded on the appropriate eCRF. 
All kits of study treatment assigned by the IRT will be recorded in the IRT. 
The investigator must promote compliance by instructing the subject to ensure scheduled visits 
are made to the site in order to take the study treatment as prescribed and by stating that 
compliance is necessary for the subject’s safety and the validity of the study. 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. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC)-approved informed consent (witnessed, 
where required by law or regulation). 
If applicable, and if allowed according to local regulatory/ethics committee requirements, in 
cases where the subject's representative(s) gives consent , 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’s source documents. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit,  Investigator may 
conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Health Authority.  

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Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).  
Novartis will provide to investigators in a separate document a proposed informed consent form 
and child’s assent form that complies with the ICH GCP guidelines and regulatory requirements 
and is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the basic (acceptable effective) contraception 
requirements. 
After IRB/IEC approval, a copy of the approved version of all consent forms must be provided 
to Novartis. 
8 
Visit schedule and assessments 
Table 8-1 lists all of the assessments. All data obtained from the assessments listed in Table 8-1 
must be supported in the subject’s source documentation. The table indicates which data are 
entered into the eCRF from the source data (X), remain in the source documents only (S) or are 
loaded into the database from separate source documents, i.e. outside vendors (XS). 
Subjects must be seen for all visits on the designated day, or as close to it as possible. The 
subject should be instructed to contact the investigator if he/she is unable for any reason to 
attend the visit as planned and the visit should be rescheduled as close as possible to the original 
date. Missed or rescheduled visits should not lead to automatic treatment or study 
discontinuation. 
All subjects who complete the treatment period will be expected to attend all follow-up visits 
(Visit 310 to 1999). 
Subjects who discontinue treatment early will be expected to perform the Week 52 assessment 
(last visit in the double blinded treatment period) 4 weeks after they receive their last dose. For 
subjects who wish to prematurely discontinue treatment prior to the primary endpoint for any 
reason, every effort should be made to have them continue study visits as per the assessment 
schedule, at least until Visit 140 (Week 12). At the final visit, all dispensed investigational 
product should be reconciled and the AE and concomitant medications reconciled on the eCRF. 
 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 

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alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls or virtual contacts (e.g., tele consult), can replace on-site study visits, 
for the duration of the disruption until it is safe for the participant to visit the site again.  

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Table 8-1 
Assessment schedule 
Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Obtain Informed 
Consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history 
(including CSU 
history) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evidence of urticaria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior urticaria 
treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family malignancy 
history (CRF to be 
completed if subject 
develops malignancy 
during the study) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
medication usage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Surgery and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rescreening 
(rescreening eCRF 
should be recorded if 
the subject is 
rescreened) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense H1-AH 
rescue medication 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
Dispense oral 
corticosteroid rescue 
medication4 
 
 
 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
Study drug/placebo 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Randomization 
 
 
XS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
XS 
 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
 
 
 
 
 
ePROs should be 
completed prior to 
any other 
assessment and 
prior to 
administration of any 
medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Dispense Subjects’ 
eDiary 
S  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Subjects’ 
eDiary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
 
Subjects’ eDiary 
(review compliance) 
Includes the urticaria 
subject daily diary 
(UPDD) and AAS 
(Angioedema activity 
score)  
 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
XS 
 
DLQI (Dermatology 
Life Quality 
Index)/CDLQI 
(Children’s DLQI) 
 
 
XS 
XS7 
XS7 
XS7 
 
 
XS7 
 
 
 
 
 
 
XS7 
XS7 
XS7 
XS7 
 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool ova and 
parasite evaluation 
If diarrhea, or any 
other symptoms 
suggestive of 
parasitic infection, 
develops at any time 
between visits before 
end of study, 
additional stool 
sampling for 
assessment of 
parasitic conditions 
should be done as 
soon as possible 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
X 
Hematology  
(*INR at Visit 1, 
V110 and UPV) 
XS* 
 
XS* 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8
* 
Clinical chemistry 
(FSH to be done 
only if indicated as 
per Section 8.4.4) 
 
XS 
 
XS 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 
XS8 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Urine dipstick (local)  
(When a dipstick 
evaluation is 
abnormal, eg 
positive for WBC 
and/or blood, a urine 
sample must be sent 
for microscopic 
examination to the 
central lab) 
 
X 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
X 
 
 
X 
X 
Serum β-hCG (for all 
pre-menopausal 
women who are not 
surgically sterile) 
Section 8.4.4 
XS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test (local) 
(If positive, 
confirmation by 
serum β-hCG test 
should be done by 
central lab) 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Physical Exam 
(Physical exam on 
Screening Visit 1 is 
comprehensive but 
subsequent physical 
exams maybe 
limited) 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height  
(For adolescents, 
height to be 
collected at each 
visit. For adults 
height will be 
collected at 
screening only) 
X 
 
S 
S 
S 
S 
S 
S 
X 
S 
S 
S 
S 
S 
S 
X 
S 
S 
X 
S 
Weight 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
ECG (single ECG to 
be taken at Visits 1 
and 240/EoT/TD) 
XS10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XS10 
 
 
 
XS1
0 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver safety 
monitoring 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Renal safety 
monitoring 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 

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Period 
Screening 
Double-blind treatment 
Post-treatment 
follow-up  
 
Visit 
1 
20 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240/ 
EoT/ 
TD 
310 
320 
1999/ 
EoS/
PSD 
UPV6 
Day  
-28 to 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
393 
421 
449 
 
Week (R = 
randomization 
week) 
-4 to   
-2 
-1 
R 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
 
Others 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
completion/ 
discontinuation form 
 
 
X 
 
 
 
 
Study completion/ 
discontinuation form 
X 
 
TD = Study treatment discontinuation; PSD = Premature subject discontinuation 
X = assessment to be recorded on eCRF 
S = assessment to be recorded on source documentation only 
XS = assessment data to be received in loaded format from separate source documents i.e. external vendors 
UPV = Unplanned visit (NOTE – assessments as listed should be done only at the discretion of the investigator, according to the reason for the unplanned visit) 
1 IC obtained prior to all study specific screening procedures during or as close to the start of the screening period as possible 
  
 
3 Samples to be taken pre-dose
samples should not be collected at the End of Study (EoS) visit, if the subject takes omalizumab (outside of the study 
assigned treatment). 
4 A subject must not have access to more than 3 doses of corticosteroids at any 30 day period. 
5 At Visit 320, dispense 3 stool collection kits. Patients should collect samples prior to Visit 1999/EoS/PSD (no later than 7 days after Visit 1999/EoS in unavoidable 
circumstances).  
6 Assessments listed under unplanned visit column can be chosen as required 
7 Remote PROs collection is possible in case the patient cannot attend the visit at site due to a Public Health emergency 
8 Samples can be collected & analyzed in a certified local laboratory due to a Public Health emergency 
9 If V170 has already occurred prior to the amendment 1 approval & the urine dipstick was not collected, it should be collected as an unscheduled assessment at the 
patient’s next scheduled visit. 
10 For any ECG with subject safety concern, 2 additional ECGs must be performed to confirm the finding. 

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8.1 
Screening 
Subjects will have up to 4 week screening period to establish eligibility for the study. Subjects 
will be required to attend 2 visits during screening period: Visit 1 (Day -28 to Day -14) and 
Visit 20 (Day -7). An extended screening period will be permitted only in exceptional 
circumstances when information concerning eligibility is outstanding (eg, pending laboratory 
data). 
Rescreening may be allowed for subjects who failed initial screening. Only 1 rescreening will 
be allowed (Section 5.1 and Section 5.2). If a subject rescreens for the study, the subject must 
sign a new informed consent and will be issued a new subject number. Informed consent for a 
rescreened subject must be obtained prior to performing any study-related assessments or 
collecting any data for the Screening visit. 
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent form 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 Section 10.1.3 for reporting details). 
Adverse events that are not SAEs will be followed by the investigator and collected only in the 
source data. If the subject fails to be randomized, the IRT must be notified within 2 days of the 
screen failure that the subject was not randomized. 
Subjects who are randomized and fail to start treatment, eg, subjects randomized in error, will 
be excluded from the analysis sets, both Full Analysis Set (FAS) and Safety Analysis Set (SAF)  
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data to be collected on all subjects include age, 
sex, race and ethnicity. Participant race and ethnicity, as required by some Health Authorities, 
are collected to assess the diversity of the study population and to evaluate their impact on the 
safety and efficacy parameters in the study. Relevant medical history (including CSU 
history)/current medical condition present before signing the informed consent will be captured. 
Where possible, diagnoses, and not symptoms, will be recorded. Data on subjects’ family 
history of malignancies will be collected on the respective eCRF page, only when a subject has 
a malignancy event, to assess possible risk factors related to any malignancies. 
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), 
(Children’s) Dermatology Life Quality Index ((C)DLQI), Work
 
 
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. 

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Assessments will be completed once or twice daily or monthly depending on the questions.  
Site must allow subjects to complete the eDiary questionnaires on their own without any 
assistance from the site staff. 
The eDiary assessment should be completed prior to any other assessment (except at Visit 1 
and 20) and prior to administration of any investigational medication. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, patient reported outcome assessments (DLQI/CDLQI, 
) may be 
collected remotely at Weeks 4, 8, 12, 24, 52 or any visit(s) in the follow-up period. 
8.3.1 
eDiary assessments 
8.3.1.1 
Urticaria Patient Daily Diary (UPDD) 
UPDD includes Urticaria Activity Score (UAS) which assesses twice daily the severity of itch 
and number of hives, use of rescue medication once daily, sleep and activity interference, 
angioedema occurrence and its management and records the calls to a health care practitioner 
(HCP) (Appendix 4, Patient Diary: Urticaria Patient Daily Diary (UPDD)). The components 
are presented in the Table 8-2 and the relevant weekly scores are described below. 
Table 8-2 
UPDD 
Diary component 
When assessed 
Urticaria Activity Score (UAS) 
● Itch severity 
● Number of hives 
Morning & evening 
Sleep interference 
Morning 
Daily activity interference 
Evening 
Rescue medication use 
Evening 
Angioedema 
● Whether patient had an episode 
● If patient had an episode, how did they manage it 
Evening 
Contact health care provider 
Evening 
8.3.1.1.1 Weekly Hives Severity Score (HSS7), 
The hives severity score, defined by number of hives (wheals), will be recorded by the subject 
twice daily in their eDiary, on a scale of 0 (none) to 3 (see 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. 
Complete hives response is defined as HSS7 = 0. 
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 

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When either the morning or evening score is missing, the non-missing score for that day 
(morning or evening) will be used as the daily score. When 1 or more of the daily scores are 
missing, the following principles will be applied to handle the missing data: 
The weekly HSS score will be derived based on the sum of the available eDiary score during 
that week. It will be considered calculable with at least 4 daily scores provided in that week, 
otherwise, the weekly score will be left missing. 
Note that for the screening assessments, 14 of 14 consecutive eDiary entries are required in the 
7 days prior to randomization as per inclusion criteria. 
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 (intense/severe) (see 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 (maximum itch). Partially missing diary entries will be handled in the 
same way as described for the weekly HSS. 
Complete itch response is defined as ISS7 = 0. 
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). 
Complete UAS7 response is defined as UAS7 = 0. 
8.3.1.1.4 Weekly Sleep interference score  
Sleep interference will be assessed by the subject, once daily in the morning in the eDiary. It is 
scored on a scale from 0 to 3 (see Table 8-5). The possible range of the weekly sleep interference 
score is therefore 0-21 (maximum interference). 
Table 8-5 
Sleep interference score 
Score 
Sleep interference 
0 
No interference 
1 
Mild, little interference with sleep 
2 
Moderate, awoke occasionally, some interference with sleep 
3 
Substantial, woke up often, severe interference with sleep 

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8.3.1.1.5 Weekly Activity interference score 
Activity interference will be assessed by the subjects on a scale of 0 to 3 (Table 8-6), once daily 
in the evening in the eDiary. Daily activities could include, school, sports, hobbies and activities 
with friends and family. The possible range of the weekly activity interference score is therefore 
0-21 (maximum interference). 
Table 8-6 
Activity interference score 
Score 
Activity interference 
0 
No interference 
1 
Mild, little interference with daily activities 
2 
Moderate, some interference with daily activities 
3 
Substantial, severe interference with daily activities 
8.3.1.1.6 H1-AH rescue medication use 
The number of tablets of rescue medication used over the past 24 hours to control conditions 
such as itch or hives is recorded once daily in the eDiary by the subject. The dose per day of 
rescue medication will be calculated as the daily number of tablets times the dose of each tablet 
and then the dose per week of rescue medication will be calculated as the sum of the dose per 
day, over 7 days. 
8.3.1.1.7 Angioedema occurrence 
Angioedema occurrence is recorded once daily in the evening in the eDiary by the subject. 
Angioedema will be reported as number of days with angioedema. Actions and/or treatments 
related to those angioedema occurrences will be also recorded in the eDiary (Table 8-7). 
Table 8-7 
Actions/treatments for Angioedema 
Actions/treatments 
Did nothing 
Took some prescription or non-prescription medication 
Called my doctor, nurse or nurse practitioner 
Went to see my doctor, nurse or nurse practitioner 
Went to the emergency room at the hospital 
Was hospitalized 
8.3.1.1.8 Number of calls to doctor or nurse 
The number of calls to doctor, nurse or nurse practitioner because of the subject’s skin condition 
will be recorded once daily in the eDiary by the subject. 
8.3.1.2 
Angioedema Activity Score (AAS) 
Angioedema activity score is recorded once daily in the evening in the eDiary by the subject. 
This validated tool assesses occurrence of episodes of angioedema by an opening question. If 
“yes” is the answer to the opening question the subject will continue to answer questions about 
the duration, severity and impact on daily functioning and appearance of the angioedema 
(Appendix 4, Patient Diary: Angioedema Activity Score (AAS)). A score between 0 and 3 is 

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assigned to every answer field. The AAS score in this study will be reported as weekly AAS 
(AAS7). The possible range of the AAS7 score is 0−105. Higher score means higher severity. 
The opening question will be used to count the number of angioedema affected days during the 
AAS documentation period but has no score. 
8.3.2 
Other PRO assessments 
8.3.2.1 
Dermatology Life Quality Index (DLQI) 
The Dermatology Life Quality Index (DLQI) is a 10-item (grouped in 6 domains) dermatology-
specific quality of life (QoL) measure (Finlay and Khan 1994). The DLQI was validated for 
patients aged 16 and above.  
In this study, DLQI will be administered only in adult subjects (18 years and older). These 
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.  
In this study, subjects of age 17 at the time of consenting are considered in the adolescent group 
and therefore they, along with the subjects aged 12 through 16, will be administered the CDLQI, 
which was designed initially for use in children from age 4 to age 16 (Lewis-Jones and Finlay 
AY 1995). The rationale of this approach relies on the following reasons: 
• As a good practice rule, the same PRO should be administered to the same subjects 
consistently over a study period; 
• The data will be analyzed separately for adults (≥ 18 years old) and adolescents (≥ 12 to < 
18 years old) and the same analysis group of subjects needs to have the same PRO (Patient 
Reported Outcomes) in the study; 
• There is no mapping possible between DLQI and CDLQI and the developers do not 
recommend changing between the 2 versions during a study; and  
• Published data show a good correlation between DLQI and CDLQI scores in the group of 
patients 16-17 years old. (van Geel et al 2016). 
An overall score is calculated and ranges from 0 to 30 for both instruments (higher score 
meaning worse dermatology QoL). For DLQI, the 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) and Treatment (0-3). For CDLQI, the domain scores are calculated for: 
Symptoms and Feelings (0-6), Leisure (0-9), School and holidays (0-3), Personal Relationships 
(0-6), Sleep (0-3) and Treatment (0-3). 
The scores were split into score bands (Hongbo et al 2005, Waters et al 2010) and validated in 
terms of their meaning/relevance to patients as follows: 
Table 8-8 
DLQI/CDLQI score bands and impact on patient’s life 
DLQI band 
CDLQI band 
Significance of score 
0-1 
0-1 
No effect on patients life 
2-5 
2-6 
Small effect on patients life 
6-10 
7-12 
Moderate effect on patients life 
11-20 
13-18 
Very large effect on patients life 
21-30 
19-30 
Extremely large effect on patients life 

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A DLQI/CDLQI score of > 10 is relevant for a very large impact on patients’ life and 
justification for a biologic prescription for example in psoriasis (Finlay 2005). The DLQI and 
CDLQI questionnaires are administered at randomization and at Weeks 4, 8, 12, 24, 52 and 
every visit in the follow-up period.  
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the DLQI and CDLQI questionnaires may be collected remotely at Weeks 4, 8, 12, 24, 
52 or any visit(s) in the follow-up period. 

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8.3.3 
Other assessments: Evidence of urticaria 
The investigator must confirm the presence of urticaria in each subject, at one of the Screening 
visits (Visit 1 or Visit 20) by direct physical examination. In the absence of active disease being 
visible at Visit 1 or Visit 20, the following will be acceptable: (a) a clearly identifiable 
photograph of the subject showing the presence of urticaria, or (b) the investigator must have 
seen the subject with active CSU in the past 6 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, data from the Phase II study CQGE031C2201 support the 
change from baseline in UAS7 (which is a composite of ISS7 and HSS7) at Week 12 being 
assessed as the primary endpoint. Change from baseline in ISS7 and achievement of UAS7 = 0 
will be assessed as secondary endpoints included in the testing strategy. 
Disease recurrence after study drug is withdrawn will be measured during the post-treatment 
follow-up period. For all subjects, symptom scores will be measured during both the treatment 
and post-treatment follow-up periods. 
Data collected during this study will be used to provide information that will support selection 
of doses for further evaluation and subject reported outcome (PRO) tools 
 
which may be included in future studies. 
8.4 
Safety 
Main safety and tolerability assessments include: 
• AEs and SAEs, including AEs leading to treatment discontinuation and events of 
interest such as injection site reactions, anaphylaxis, pre-malignancy/malignancy, 
cardio-cerebrovascular events 
• Physical examination 
• Vital signs 
• Laboratory evaluations 
• ECG (Electrocardiogram) 

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Table 8-9 
Physical Assessments 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities and vascular and neurological systems. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will include the examination of general appearance and vital signs. A 
short physical exam will be conducted at all visits starting from Visit 1 except where a 
complete physical examination is required (see Table 8-1). 
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 blood pressure and pulse measurements. After the subject has been sitting 
for 5 minutes, with back supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured 3 times using an automated validated device with an 
appropriately sized cuff. The repeat sitting measurements will be made at 1 – 2 minute 
intervals and the mean of the 3 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. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for 
safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again.  
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens detailed in this section 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.  In case of lab abnormalities, 
an additional re-draw for central laboratory assessment is allowed during the screening period 
to confirm eligibility criteria. 
Clinically significant abnormalities must be recorded on the relevant section of the CRFs (Case 
report/Record Forms) capturing medical history/Current medical conditions/AEs. 
A serum β-hCG will be collected at screening Visit 1 for all pre-menopausal women who are 
not surgically sterile. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits,  an alternative lab (local) collection site may be used for protocol specified safety lab 
assessments. 
It is recommended to use certified local laboratories, if feasible. If a local laboratory is used 
during a Public Health emergency, local laboratory reports need to be collected, reviewed, 
filed in the patient medical record or chart at the site, and entered into the CRF. 

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Table 8-10 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured.  
Coagulation 
At Visits 1 and 110,coagulation will be assessed by International Normalized Ratio (INR).   
Chemistry 
Albumin, total bilirubin, alkaline phosphatase, AST, ALT, LDH, GGT, chloride, sodium, 
potassium, magnesium, calcium, inorganic phosphorus, creatinine, urea/BUN and uric 
acid will be measured. If the total bilirubin concentration is increased above 1.5 times the 
upper limit of normal, direct and indirect reacting bilirubin should be differentiated. 
Urinalysis 
A midstream urine sample (approximately 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. Semi-
quantitative “dipstick” evaluation for specific gravity, glucose, pH, protein, bilirubin, 
ketones, leukocytes and blood will be performed at site. When a dipstick evaluation is 
abnormal, eg, positive for WBC and/or blood, a urine sample must be sent to the Central 
Lab for microscopic examination including RBC and WBC. (Details on collection of urine 
for analysis by central laboratory are provided to investigators in the laboratory manual.) 
Parasite 
screening 
Assessment of stool samples for parasitic infections (refer to Assessment of parasitic 
infections Section 8.4.3 
Pregnancy Test 
Serum / Urine pregnancy test (refer to Pregnancy and assessments of fertility Section 
8.4.4) 
8.4.2 
Electrocardiogram (ECG) 
Standard 12 lead ECGs must be recorded after 10 minutes rest in the supine position to ensure 
a stable baseline. 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. 
Single ECGs will be collected at Visits 1 and Visit 240/EoT/TD. 
The original ECG will be sent electronically to the Clinical Research Organization (CRO) 
directly from the provided ECG machine. Two “identical” duplicate print-outs will be generated 
on non-heat sensitive paper and kept at the investigator site as source documentation and as 
back-up for submission to the vendor in case of problems with the electronic transmission. The 
“identical” duplicates must be labeled with study number, subject initials, subject number, date 
and time, and signed and archived in the study site source documents. 
For any ECGs with subject safety concerns, 2 additional ECGs must be performed to confirm 
the safety finding.  
Clinically significant ECG findings prior to dosing with investigational treatment must be 
discussed with the sponsor. Clinically significant abnormalities must be recorded on the 
relevant section of the CRFs capturing Medical history/Current medical conditions/AE as 
appropriate. 
Full details of all procedures relating to the ECG collection and reporting will be contained in 
a technical manual to be provided by the CRO to each investigator site. 
 
8.4.3 
Assessment of parasitic infections 
Reduction in IgE levels may confer increased susceptibility to parasitic infections. The risk of 
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therapy such as ligelizumab and omalizumab is suspected to be low. Data from the Phase II 
CQGE031C2201 study in this regard was unremarkable but limited due to study sample size.  
All subjects will be given three stool sample collection kits at screening Visit 1 and Visit 320 
by the site or site’s local laboratory. Subjects will take the stool sample kits home and collect 
stool samples from three different bowel movements, ideally on three different days, within 
seven days of Visit 1 and in the week prior to Visit 1999. Subjects will return the three stool 
samples to the site or local laboratory as soon as possible after Visit 1 (in order to allow 
processing within the screening period) and at Visit 1999 (no later than 7 days after Visit 
1999/EoS in unavoidable circumstances). 
Stool samples for parasitic disease will be examined for ova and parasites by the local laboratory. 
The identification of organisms in positive stools will be made by local laboratory. If stool 
testing is positive for pathogenic organisms (pathogenic as defined by the local laboratory), the 
result must be recorded in the source document and the subject will not be randomized and will 
not be allowed to rescreen. Stool samples negative for pathogenic organisms must be recorded 
in the source document before Visit 110. 
Subjects must be advised that if diarrhea, or any other symptoms suggestive of parasitic 
infection, develops at any time before the end of study, three additional stool samples must be 
collected at the next visit or sooner and sent to local laboratory for analysis.  
8.4.4 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have serum β-hCG collected at 
screening Visit 1. Post-menopausal status should be recorded in the CRF. 
At Visit 110 and subsequent study visits until Visit 1999/EoS/PSD, all pre-menopausal women 
who are not surgically sterile will have urine pregnancy testing performed BEFORE 
administration of the study medication.  A positive urine test needs to be confirmed with a 
central lab serum test prior to study drug administration. If positive, the subject must be 
discontinued from study treatment. 
Additional pregnancy testing might be performed if requested by local regulatory/ethics 
committee 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, Follicle Stimulating Hormone (FSH) 
testing is required at screening/baseline. 

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8.4.5 
Anaphylaxis assessment 
An adjudication committee (AC) will be put in place to determine whether cases of 
hypersensitivity identified through a search algorithm based on the Standardized MedDRA 
Queries may represent cases of anaphylaxis. Further details regarding the AC will be 
documented in the AC charter. See Section 10.2.4 for details. 
8.4.6 
Assessment of cardio-cerebrovascular events 
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of cardio-cerebrovascular events. The clinical presentation 
and association of these events with pre-existing risk factors will be part of the assessment. See 
Section 10.2.4 for details 
8.4.7 
Assessment of neoplastic events 
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of neoplastic events. The clinical presentation and 
association of these events with pre-existing risk factors will be part of the assessment. See 
Section 10.2.4 for details. 
8.4.8 
Appropriateness of safety measurements 
In addition to safety assessments that are standard in this population, 
 
will be evaluated for monitoring subjects’ safety. Events of special interest such as 
anaphylaxis, malignancies, and cardio-cerebrovascular events will be monitored and will be 
adjudicated by expert ACs. 
8.5 
Additional assessments 
 
 
 
 
 
8.5.2 
Pharmacokinetics and pharmacodynamics 
 
 
 
8.5.2.1 
Blood collection and processing 
All blood samples will be taken from the contra-lateral arm of the injection by either direct 
venipuncture or an indwelling cannula inserted in a forearm vein. 
 
 

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All samples will be given a unique sample number. The actual sample collection date and time 
will be entered on the appropriate eCRF page. Sampling problems will be noted in the Notes 
field of the eCRFs.  
Detailed instructions for blood sample collection, processing, storage and shipment are 
provided in the blood log (Section 16.5), lab manual and flow charts prepared by the Central 
Laboratory. 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of investigational treatment for a subject occurs when investigational treatment 
is stopped earlier than the protocol planned duration, and can be initiated by either the subject 
or the investigator. 
The investigator must discontinue investigational treatment for a given subject if he/she 
believes that continuation would negatively impact the subject's well-being. 
Investigational treatment must be discontinued under the following circumstances: 
• Subject/guardian decision 
• AEs for which continued exposure to the study drug would be detrimental 
• Abnormal renal laboratory results requiring discontinuation (see Appendix 3) 
• Abnormal liver laboratory results requiring discontinuation (see Appendix 2) 
• Platelets < 75000/µL 
• Pregnancy (see Section 8.4.4 and Section 10.1.4) 
• Unblinding of study treatment other than to authorized personnel (see Section 6.4) for any 
reason 
• Subject develops a medical condition that requires use of prohibited treatment as per 
Section Section 6.2.2, or if subject exhibits a behavior of non-compliance regarding 
prohibited medications 
• Subject received a live virus vaccination during the study 
• Subject experiences an unexpected hypersensitivity reaction of grade 5, as defined by the 
World Allergy Organization Grading System (Cox et al 2017), see Appendix 6: 
• Lower or upper respiratory: Respiratory failure with or without loss of consciousness; 
or  
• Cardiovascular: Hypotension with or without loss of consciousness 
• Emergency use of epinephrine due to anaphylactic or anaphylactoid reaction 
• Any other protocol deviation that results in a significant risk to the subject’s safety 
• Any situation in which study participation might result in a safety risk to the subject 
• Following emergency unblinding 
• If a subject uses rescue corticosteroids for CSU more than 3 doses in a 30 day period or 
more than 9 doses of in total after week 12  during the study period (including the follow-
up period). 
• If a subject misses 3 consecutive doses. 
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. Always consider reasons which are related to safety and efficacy 
first. 

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Subjects who discontinue investigational 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 Section 9.1.2, withdrawal of informed consent). They will be 
expected to perform the Wk 52/Visit 240/EoT/TD assessments 4 weeks after their last dose and 
will be expected to perform all follow-up assessments (Visits 310-1999). 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. 
For subjects who wish to prematurely discontinue treatment prior to the primary endpoint (Visit 
140/Wk 12) for any reason, every effort should be made to have them continue study visits as 
per the assessment schedule, at least until Visit 140 (Week 12). At the final visit, all dispensed 
investigational product should be reconciled and the AE and concomitant medications 
reconciled on the appropriate eCRF. 
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 treatment code section. 
If subjects discontinue from investigational treatment and are administered Xolair® 
(omalizumab) in the follow-up period, the subject should be discontinued from the study and 
no efficacy or safety assessments should be collected from the subject at the EoS visit. 
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. The data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to 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. 

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For United States (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 informed consent form. 
For EU and Rest of World (RoW): 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. Follow-up is recommended 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’s 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. 
Patients may be eligible to roll-over into an extension study (CQGE031C2302E1) after 
completion of the study. 
 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (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 

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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. Adverse events also may be detected when they are volunteered by the subject 
during or between visits or through physical examination findings, laboratory test findings or 
other assessments. 
Adverse events must be recorded 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 Common Toxicity Criteria (CTC) AE grade (version 5 or higher)];  
2. its relationship to the study treatment and other investigational treatment. If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug. They happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject; 
3. its duration (start and end dates), or if the event is ongoing, an outcome of not 
recovered/not resolved, must be reported; 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met; 
5. action taken regarding with study treatment 
All AEs must be treated appropriately. Treatment may include 1 or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn; and 
6. its outcome i.e., its recovery status or whether it was fatal. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment or end of study visit, whichever is longer. 
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 

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(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB). 
Abnormal laboratory values or test results constitute AE 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 for alert ranges for laboratory and other test 
abnormalities. 
For lab values provided without related clinical information, the CTCAE scale must be used 
to determine the seriousness. Any value of Grade 4 and above on this CTCAE scale must be 
considered serious. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event, eg, appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
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• 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 (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective of whether a clinical event has occurred or not.  
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 after the last patient last visit (LPLV) must be 
reported to Novartis Safety within 24 hours of learning of its occurrence. 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. Any SAEs reported up to the subject’s last 
visit will be reported in the eCRF. SAEs beyond that date will only be recorded in the Novartis 
Safety database. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess the relationship of each SAE to each specific 
component of the study treatment (if the study treatment consists of several components) 
complete the SAE Report Form in English and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each reoccurrence, 
compilation, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 

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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the investigational 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 investigational 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.  
Consider the following 3 categories (as applicable) to determine SAE reporting timeframes:  
1. To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence.  
2. Any SAEs experienced after the 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment. 
3. Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An 
SAE that is considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
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.  
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. The follow-up should be for up to 12 months following the birth of the 
baby. Any SAE experienced during pregnancy must also be reported.  
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. 

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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in 
Dosing CRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring  
10.2.1 
Liver safety monitoring 
To ensure 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 must be followed. 
The following 2 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 CRFs 
Please refer to Table 16-3 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver event defined in Table 16-3 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 16-4 and Table 16-5. Repeat liver chemistry tests (ALT, 
AST, TBL, PT/INR, ALP and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the 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 CRF.  

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• 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  
• A thorough follow-up of the liver event should include (based on investigator’s 
discretion) serology tests, imaging and pathology assessments, gastroenterologist or 
hepatologist’s consultancy, obtaining more detailed history of symptoms and prior or 
concurrent diseases, history of concomitant drug use, exclusion of underlying liver 
disease, imaging such as abdominal ultrasound, CT or MRI scans and obtaining a 
history of exposure to environmental chemical agents 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
10.2.2 
Renal safety monitoring  
The following base monitoring for renal laboratory values, as per the Novartis Drug-Induce 
Nephrotoxicity Guidelines (Nov-2017; Table 10-2 below) of abnormal renal laboratory values, 
will be carried out as part of the assessment schedule (Table 8-1) during the course of the study: 
Table 10-2 
Base Renal Monitoring 
Assessments  
Assessment Frequency  
Serum  
Creatinine, Electrolytes (Na, Ca, K)  
1. Single baseline  
2. Steady State assessment  
3. 6-monthly during study  
4. Final visit ≥ 48h after last dose  
Urine  
Dipstick (Spot urine sample) 
Every renal laboratory trigger or renal event as defined in Table 16-6 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-7. 
10.2.3 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess safety data and critical efficacy 
variables at defined intervals during the course of this study and recommend to the sponsor 
whether to continue, modify or terminate the study. 
Specific details regarding composition, responsibilities, data monitoring, meeting frequency 
and documentation of DMC reports, minutes and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC. 
10.2.4 
Adjudication Committee 
To enhance the safety assessment, more specifically relative to 1) anaphylactic events, 2) 
neoplastic events, and 3) major cardio-cerebrovascular events, 3 Adjudication Committees, 

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independent panels of experts external to Novartis, will provide reviews of identified potential 
events in a blinded manner. Adjudication will be performed on a regular basis. 
All the details of the adjudication processes including the committee members are included in 
the adjudication committee charters. 
11 
Data collection and database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US Code of Federal 
regulations (CFR) 21 Part 11 requirements. Designated investigator site staff will not be given 
access to the Electronic Data Capture (EDC) system until they have been trained. Automatic 
validation programs check for data discrepancies and, by generating appropriate error messages, 
allow the data to be confirmed or corrected before transfer of the data to the CRO working on 
behalf of Novartis. After final database lock, the investigator will receive copies of the patient 
data for archiving at the investigational site. 
The investigator/designee is responsible for assuring that the data entered into eCRF is complete 
and accurate, and that entry and updates are performed in a timely manner.  
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 staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff are required to respond to the query and confirm 
or correct the data. 
Concomitant medications entered into the database will be coded using the WHO (World Health 
Organization) Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Concomitant procedures, non-drug therapies 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. Stool samples will be processed by local labs and the results will be collected by 
Novartis via eCRFs. 
ECG readings will be processed centrally and results will be sent electronically to Novartis. 
Patients will fill in their daily diary data on a smart phone device at home. PROs will be 
completed by patients on site on the day of applicable visits. The system will be supplied by a 
vendor(s) who will also manage the database. The database will be sent electronically to 
Novartis personnel. 

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Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied to Novartis who will also manage the database. The database will be sent electronically.  
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. 
The occurrence of relevant protocol deviations will be determined. After these 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 or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
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. 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, electrocardiograms and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form 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 CRFs 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 subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation. 

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Due to the relatively low number of adolescent subjects for this study, the data collected for 
adolescent subjects will be provided in a descriptive manner separately.  
12.1 
Analysis sets 
The following analysis sets will be used in this trial: 
Randomized set (RAN): The RAN set will include all randomized subjects, regardless of 
whether or not they receive a dose of study drug. Subjects will be analyzed according to the 
treatment they are assigned. 
Full analysis set (FAS): The FAS set will include all randomized subjects who received at least 
1 dose of study drug. Subjects will be analyzed according to the treatment to which they are 
assigned at randomization. FAS will be used for all efficacy variables, unless otherwise stated. 
Safety analysis set (SAF): The SAF set will include all subjects who received at least 1 dose of 
study drug whether or not being randomized. Subjects will be analyzed according to the 
treatment they received. The safety set will be used in the analysis of all safety variables. The 
actual treatment will be defined as the treatment received over the study. In case of error in 
dispensation, the actual treatment will correspond to the treatment which was given most often. 
12.2 
Subject demographics and other baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects in the randomized set (RAN). The number 
and percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects. 
Medical history 
Any condition entered as medical history or current medical conditions at baseline will be coded 
using the MedDRA dictionary. They will be summarized by system organ class and preferred 
term of the MedDRA dictionary for RAN. Summaries for cardiovascular and urticaria specific 
medical history will also be provided. 
12.3 
Treatments 
Study Treatment 
The analysis of study treatment data will be based on the safety set.  
The number of patients and the length of time (in weeks) exposed to each study drug and dose 
will be summarized by treatment. In addition, the number of doses, total cumulative dose, and 
number of missed doses will be presented. Categorical data will be summarized as frequencies 
and percentages. For continuous data, mean, SD, median, 25th and 75th percentiles, minimum, 
and maximum will be presented. 
Prior and concomitant medications 
Prior medications are defined as medications taken and stopped prior to first dose of study 
treatment. Prior medications will be summarized based on RAN. Prior medications for CSU 
will be summarized by type of therapy, preferred term and treatment group. Prior medications 

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non-related to CSU will be summarized by Anatomical Therapeutic Chemical (ATC) code and 
preferred term. 
Concomitant medications will be summarized by treatment for the safety set separated for 
urticaria related background medications and non-urticaria related medications. Urticaria 
related background medications will be summarized by type of therapy, preferred term and 
treatment group. Non-urticaria related concomitant medications will be summarized by 
preferred term. 
12.4 
Analysis of the primary endpoint(s) 
This section will detail the statistical analysis of the primary endpoint. Details of the hypothesis 
testing strategy including primary and secondary endpoints to handle multiplicity are provided 
in Section 12.5.1. 
The analysis of primary endpoint and the secondary endpoints included in the testing strategy 
will focus on the adult subjects.  
The aim is to estimate the treatment effect of the investigational drug (ligelizumab) compared 
to omalizumab and placebo, for the target population of adults on the primary endpoint. The 
detailed definition of the primary estimand is provided in Section 12.4.1 and the justification of 
the corresponding primary estimand, as well as the definition of the supplementary estimands 
will be provided in the statistical analysis plan. 
The efficacy information for adolescents will be presented descriptively for this study. The 
adolescent subject data will be forwarded to a separate cross-study extrapolation analysis to 
support determination of the final posology for the treatment of adolescent patients. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is the absolute change from baseline in UAS7 score at Week 12, which 
is the UAS7 score at Week 12 minus the UAS7 score at baseline. 
The UAS7 is the sum of the HSS7 score and the ISS7 score, and ranges from 0-42. Weekly 
scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 7 
days preceding the visit.  
The primary estimand will account for two categories of intercurrent events which will be 
treated in  different ways. We will distinguish between intercurrent events unrelated to the 
COVID-19 pandemic and intercurrent events that happened due to operational complications 
caused by the COVID-19 pandemic, e.g. patients missed their dose as they were not able to 
receive their study medication due to regional lockdowns. Intercurrent events due to non-
operational reasons during the COVID-19 pandemic will be treated analogously to intercurrent 
events unrelated to the COVID-19 pandemic and will therefore be classified as intercurrent 
events unrelated to the COVID-19 pandemic for the primary efficacy analysis. In order to 
distinguish between these two categories, protocol deviations arising due to the COVID-19 
pandemic will be collected in addition to the original list of protocol deviations. Hence, the 
COVID-19 pandemic related protocol deviations complete the set of protocol deviations already 
in place and will coexist with those. The COVID-19 pandemic related protocol deviations will 
identify intercurrent events due to COVID-19, which will then be split into operational 
complications due to COVID-19 (e.g., a missed dose because the patient was not able to reach 

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the site because of a local lockdown due to COVID-19, etc.) and non-operational complications 
due to COVID-19 (e.g., lack of efficacy and adverse events).  
Subjects who discontinue from study treatment early will be encouraged to stay in the study 
following the procedures described in Section 9.1.1. These are considered as retrieved drop-out 
(RDO) subjects. The definition of primary estimand is described by the following attributes, 
and the detail handling of intercurrent events descriptions will be provided in Section 12.4.2.  
• Population: Adult participants receiving H1-antihistamines therapy at local-approved 
dose level as background medication suffering from chronic spontaneous urticaria and 
meeting study inclusion/exclusion criteria (as listed in Section 5.1 and Section 
5.2). Further details about the population are provided in Section 5. 
• Endpoint: absolute change from baseline in UAS7 score at Week 12 
• Treatment of interest: ligelizumab or the placebo or omalizumab treatment with stable 
H1-antihistamines (H1-AH) at local-approved doses as background medication + allowed 
rescue medication if needed.   
• Handling of remaining intercurrent events: 
Intercurrent events unrelated to the COVID-19 pandemic : 
1. Discontinuation of initially assigned study treatment prior to Week 12 due to adverse 
events (AE) or lack of efficacy (LoE) or any other reasons unrelated to the COVID-19 
pandemic:  Participants who discontinue from study treatment early will be encouraged to 
stay in the study as detailed in Section 9.1.1. Retrieved drop out (RDO) data collected 
after study treatment discontinuation will be used for analysis. (treatment policy strategy). 
2. Use of rescue medication prior to Week 12 unrelated to the COVID-19 pandemic: ignore 
(treatment policy strategy). 
Intercurrent events related to the COVID-19 pandemic due to operational complications: 
1. Discontinuation of study treatment prior to Week 12 due to the COVID-19 pandemic: had 
participants not discontinued study treatment prior to Week 12 due to the COVID-19 
pandemic (hypothetical strategy). 
2. Missed treatment prior to Week 12 due to the COVID-19 pandemic: had participants not 
missed treatment prior to Week 12 due to the COVID-19 pandemic (hypothetical strategy) 
• The summary measure: difference in mean absolute change from baseline in UAS7 
score at Week 12 between treatments (ligelizumab 72 mg q4w vs placebo/omalizumab 
and ligelizumab 120 mg q4w vs placebo/omalizumab) 
For all the intercurrent events occurred during the COVID-19 pandemic period which are not 
due to operational complications, they will be classified as intercurrent events unrelated to 
COVID-19 pandemic and handled by the treatment policy strategy. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypotheses test for the primary endpoint being tested is that the absolute change 
from baseline in UAS7 score at Week 12 in any of the ligelizumab groups (low or high dose) is 
not superior to the omalizumab group and placebo group. i.e.  
H01: µligelizumab ≥ µPlacebo versus HA1: µligelizumab < µPlacebo  
H01': µligelizumab ≥ µomalizumab versus HA1': µligelizumab < µomalizumab 

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where µ is the mean change from baseline of UAS7 at Week 12. 
Stating these formulae in another way gives the following: 
H1l, H1h: Ligelizumab low or high dose is not superior to placebo with respect to absolute change 
from baseline at Week 12; 
 
H1l', H1h': Ligelizumab low or high dose is not superior to omalizumab with respect to absolute 
UAS7 change from baseline at Week 12. 
 
A linear mixed model with repeated measures (MMRM) will be used to estimate treatment 
differences for change from baseline in UAS7 score at Week 12, based on the FAS. 
 
 
 
epeated measures within subject are modeled using an unstructured covariance 
of the error terms. Additional important covariates may be added to the model.  
The detailed testing strategy including the primary endpoint analysis is provided in Section 12.5. 

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Multiple intercurrent events occuring prior to Week 12 
In general, if there are multiple intercurrent events occurring prior to Week 12 with different 
relations to the COVID-19 pandemic, that is, at least one of the intercurrent event is classified 
as being unrelated to COVID-19 and one is classified as being related to COVID-19 operational 
complications, the treatment policy strategy will be applied. That is, multiple intercurrent events 
occurring prior to Week 12 will be handled by the hypothetical strategy only if all of them are 
classified as being due to COVID-19 operational complications. 
 

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12.4.3 
Handling of missing values/censoring/discontinuations 
The UAS7 score is derived from the sum of the HSS7 score and the ISS7 score, as noted above. 
The HSS7 and ISS7 score will be derived by adding up the daily HSS and ISS scores of the 7 
days preceding the visit, respectively. The daily score (HSS and ISS) will be calculated by 
averaging the morning and evening HSS and ISS score, respectively. If one of the morning or 
evening scores is missing, the non-missing score for that day (morning or evening) will then be 
used as the daily score. 
For each weekly score from UPDD (i.e. HSS7, ISS7 and UAS7 score), if one or more of the 
daily scores are missing, the following principles will be applied to handle the missing daily 
data: 
• If a patient has at least 4 non-missing daily scores within the 7 days prior to the study visit, 
the weekly score will be calculated as the sum of the available eDiary scores of that week, 
divided by the number of non-missing days, multiplied by 7. 
• If there are less than 4 non-missing daily scores within the prior 7 days, then the weekly 
score will be considered as missing for that week. 
 
 
 
 

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12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy and/or pharmacodynamic endpoint(s) 
• Complete absence of hives and itch at Week 12, assessed as % of subjects achieving 
UAS7 = 0.  
The proportion of subjects with UAS7 = 0 at Week 12 will be analyzed using a logistic 
regression model including treatment group, region and baseline UAS7 score. Missing data will 
be considered as non-responder in the analysis. 
• Improvement of severity of itch, assessed as absolute change from baseline in ISS7 score 
at Week 12. 
The absolute change from baseline in ISS7 score at Week 12 will be analyzed analogously to 
absolute change from baseline in UAS7 score at Week 12, i.e. using MMRM modeling. 
• No impact on subjects’ quality of life at Week 12, assessed as % of subjects achieving 
DLQI = 0-1. 
An overall score will be calculated according to the scoring manual. The proportion of subjects 
with overall DLQI scores ≤ 1 at Week 12 will be analyzed using a logistic regression model 
which includes treatment group, region and baseline UAS7 score. Missing data will be 
considered as non-responder in the analysis. 
• Cumulative number of weeks that subjects achieve AAS7 = 0 responses between baseline 
and Week 12. 
The cumulative number of weeks achieving AAS7 = 0 response between baseline and Week 12 
will be derived based on the AAS eDiary. 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 modelled using a negative binomial regression model with log link, using treatment 
group, region and baseline AAS7 = 0 status. 
Testing strategy 
The efficacy analysis of secondary variables listed in the testing strategy will focus on adult 
subjects. The efficacy information for adolescent subjects will be provided in a descriptive 
manner over time. 
The following null hypotheses (H0) will be tested against the respective alternative hypotheses 
(HA) in a closed testing procedure (Bretz et al 2009), thus controlling the family-wise type I 
error which is set to 0.025 (one-sided) at the level of the individual studies, and for the pooled 
dataset of both studies as listed in Figure 12-1 Multiple testing strategy: 
Primary endpoint 
UAS7 change from baseline at Week 12 
H01: µligelizumab ≥µPlacebo versus HA1: µligelizumab < µPlacebo 

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H01': µligelizumab ≥ µomalizumab versus HA1': µligelizumab < µomalizumab 
where µ is the mean change from baseline in UAS7 at Week 12, as described in Section 12.4.2. 
Secondary endpoints 
UAS7 = 0 at Week 12 
 
H02: πligelizumab ≤ πPlacebo versus HA2: πligelizumab > πPlacebo 
H02': πligelizumab ≤ πomalizumab versus HA2': πligelizumab > πomalizumab 
where π is the proportion of subjects achieving UAS7 = 0 at Week 12. 
Stating these formulae in another way gives the following: 
 
H2l, H2h: Ligelizumab low or high dose is not superior to placebo with respect to UAS7 = 0 
response at Week 12; 
H2l', H2h': Ligelizumab low or high dose is not superior to omalizumab with respect to UAS7 = 
0 response at Week 12. 
ISS7 change from baseline at Week 12 
 
H03: µligelizumab ≥ µPlacebo versus HA3: µligelizumab < µPlacebo 
H03': µligelizumab ≥ µomalizumab versus HA3': µligelizumab < µomalizumab 
where µ is the mean change from baseline in ISS7 to Week 12. 
Stating these formulae in another way gives the following: 
 
H3l, H3h: Ligelizumab low or high dose is not superior to placebo with respect to the absolute 
change from baseline to Week 12 of ISS7; 
H3l', H3h': Ligelizumab low or high dose is not superior to omalizumab with respect to the 
absolute change from baseline to Week 12 of ISS7. 
DLQI = 0-1 at Week 12 
 
H04: πligelizumab ≤ πPlacebo versus HA04: πligelizumab > πPlacebo 
H04': πligelizumab ≤ πomalizumab versus HA4': πligelizumab > πomalizumab 
where π is the proportion of subjects achieving DLQI = 0 or 1 at Week 12. 
Stating these formulae in another way gives the following: 
 
H4l, H4h: Ligelizumab low or high dose is not superior to placebo with respect to the DLQI = 0 
or 1 response at Week 12; 
H4l', H4h': Ligelizumab low or high dose is not superior to omalizumab with respect to the DLQI 
= 0 or 1 response at Week 12. 
Cumulative number of weeks that subjects achieve AAS7=0 responses between baseline 
and Week 12 
 
H05: µligelizumab ≤ µPlacebo versus HA5: µligelizumab > µPlacebo 

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H05': µligelizumab ≤ µomalizumab versus HA5': µligelizumab > µomalizumab 
where µ is the mean cumulative number of weeks achieving AAS7 = 0 during 12 weeks. 
Stating these formulae in another way gives the following: 
 
H5l, H5h: Ligelizumab low or high dose is not superior to placebo with respect to the cumulative 
number of weeks achieving AAS7 = 0 during 12 weeks; 
H5l', H5h': Ligelizumab low or high dose is not superior to omalizumab with respect to the 
cumulative number of weeks achieving AAS7 = 0 during 12 weeks. 
 
                   
A testing procedure is proposed with type-I-error control in the planned submission package 
which consists of studies C2302 and C2303 (both with identical design). Hypotheses can only 
be tested in the order as indicated by the arrows for alpha propagation for each individual study 
as listed in Figure 12-1. If the primary endpoint has demonstrated the superiority versus placebo 
and versus omalizumab, the alpha could be passed to the tests for all of the secondary endpoints. 
For the secondary endpoints, if an endpoint demonstrates superiority versus placebo based on 
each of the individual studies, the same endpoint can be tested based on the pooled dataset as 
pre-specified. 
For the comparison versus placebo based on each individual study, the initial alpha level for 
each branch is set to α/2 = 0.0125 (one-sided). The first hypothesis (H1h and H1l) is tested with 

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α/2 = 0.0125 (one-sided) of high/low dose ligelizumab versus placebo regarding the primary 
endpoint. If either of the hypotheses is rejected, the corresponding second hypothesis (H1h' 
and/or H2l') of high/low dose ligelizumab versus omalizumab is tested with α/2. The same 
principle applies for moving from the second to the third hypothesis. If either H3h and/or H3l is 
rejected, α/4 is passed to the other dose on primary endpoint testing together with the initial α/2. 
The rest α/4 is passed to test H4h and/or H4l for the same ligelizumab dose versus placebo. The 
testing within each sequence is strictly hierarchical, so that null hypotheses can be tested along 
the pre-defined order at the level assigned to the respective sequence until a null hypothesis 
cannot be rejected, at which point the testing in that sequence stops. If all null hypotheses in 
either of the sequence can be rejected, the “unused” type I error is transferred to the other 
sequence, so that the initial level in the other sequence is increased. Thus, the family-wise type 
I is controlled at α = 0.025 (one-sided). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.5.2 
Safety endpoints 
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG) 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. In addition safety endpoints for adults and adolescents will each be 
presented separately. 
Adverse events 
Treatment emergent adverse events (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. AEs will be summarized by presenting, for each treatment 
group, the number and percentage of subjects having any AE, having an AE in each primary 
system organ class and having each individual AE (preferred term). Summaries will also be 
presented for AEs by severity and for study treatment related AEs. If a subject reported more 
than 1 AE with the same preferred term, the AE with the greatest severity will be presented. If 
a subject reported more than 1 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. 
Serious adverse events will also be summarized. Separate summaries will be provided for death, 
SAE, and other significant AEs leading to discontinuation. 
All AEs with onset in the follow-up period will be considered as treatment emergent. Only AEs 
occurring in the follow-up period will be included in the follow-up report. Data from the placebo 
arm after switching to ligelizumab will be summarized separately.  
Adverse events of special interest for ligelizumab treatment will also be summarized. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Subjects with notable vital signs as defined below 
will be listed. 
For adults: 
• Hypertension (systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure of ≥ 
90 mmHg) or hypotension (systolic blood pressure of < 90 mmHg and/or diastolic blood 
pressure of < 60 mmHg). 
• Pulse rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia). 
For adolescents: 
• See Appendix 1 for upper and lower limits for children’s vital signs that may be 
considered of concern if newly identified. 
12-lead 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. 

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Clinical laboratory evaluations 
The summary of laboratory evaluations will be presented for 2 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. 
 
 
 
 
 
 
 
 
 
 
Resource utilization 
Data relating to resource utilization is collected and reported by the subject in the daily eDiary 
and may be used for the purpose of economic evaluation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.7 
Interim analysis (primary efficacy analysis) 
An interim analysis is planned when all adult subjects have completed the treatment period 
(Week 52 visit). The interim analysis at the time of this Week 52 database lock would be utilized 
for the primary efficacy analysis for this study. A separate unblinded study team will perform 
the interim analysis.
  
 A blinded study team 
will oversee the study conduct until all subjects have completed the entire study participation 
and the final database lock has occurred. All investigators, study personnel, subjects, and the 
blinded study team will remain blinded to the interim results and to the individual treatment 
assignment until all subjects have completed the entire study participation and the final database 
lock has occurred. 
 
12.8 
Sample size calculation 
Sample size justification for adult subjects 
The sample size justification is based on UAS7 change from baseline and achievement of UAS7 
= 0. Due to the much larger effect sizes versus placebo, the sample sizes are driven by the 
assumptions underlying the comparisons of ligelizumab versus omalizumab 300 mg. To avoid 
assigning an unnecessary large number of subjects to placebo, subjects will be randomized in a 
3:3:3:1 ratio to ligelizumab high dose, ligelizumab low dose, omalizumab and placebo, 
respectively. 
All calculations were performed with nQuery Advisor 7.0. 
UAS7 change from baseline at Week 12 

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Based on interim results from CQGE031C2201, it is assumed that the difference between 
ligelizumab and omalizumab 300 mg mean change of UAS7 from baseline to Week 12 is at 
least 3.5 in favor of ligelizumab, with common standard deviation of approximately 13 based 
on the Phase IIb study. Although it is planned to use a repeated measures model for the analysis, 
an approximate sample size can be based on a simple t-test, assuming type I error 0.025 (one-
sided) and power 90%, which results in 291 per group. This will give > 99% power for the same 
comparison versus placebo, if the placebo sample size is only 97 and the assumed difference is 
8.  
Achievement of UAS7 = 0 at Week 12 
A sample size of 291 per group, which is required for the UAS7 change from baseline, will 
provide more than 90% power based upon a 2 group continuity corrected χ2 test with a 0.025 
one-sided significance level to detect the difference between a proportion of 0.30 (omalizumab 
300 mg) and a proportion of 0.45 (ligelizumab, odds ratio of 1.909). As for the change from 
baseline, the power for the comparison versus placebo is > 99% even if the placebo sample size 
is only 97 and the proportion of placebo treated subjects achieving UAS7 = 0 responses is 
around 10%. These power calculations are an approximation of the power achieved with the 
logistic regression approach. 
Despite the intention of convincing study subjects to stay in the study and providing eDiary 
information even if they will be discontinued early from the study treatment, the early 
discontinuation rate from study at Week 12 is only assumed to be around 5% based on the phase 
II study data.  
In summary, the required adult sample size in each of the ligelizumab and omalizumab 300 mg 
arms is approximately 300, while the placebo sample size can be reduced to approximately 100 
for efficacy comparisons.  
It was also confirmed that the assigned sample size calculated above is sufficient to maintain 
the power of the overall multiple testing strategy (at least 90%) for the primary endpoint (UAS7 
change from baseline at Week 12) and the key secondary endpoint (UAS7=0 response rate at 
Week 12) through the recycled alpha based on the simulations. The detail simulation results are 
provided in the statistical analysis plan. 
The analysis strategy has been adjusted to mitigate the potential COVID-19 impact  on the study. 
The original proposed sample size will be still sufficient to maintain the statistical power of the 
overall multiple testing strategy (at least 90%) for the primary endpoint (UAS7 change from 
baseline at Week 12) based on individual study data. The power of the key secondary endpoint 
(UAS7=0 response rate at Week 12) will be maintained (at least 90%) through the pooled data 
set as well. Detailed simulation results of the statistical power for the updated testing strategy 
will be provided in a separate document (e.g., statistical analysis plan). 
 
Sample size justification for adolescent subjects 
The target sample size of 50 adolescent subjects receiving ligelizumab treatment and 
completing the treatment period is based upon the expected prevalence of adolescent CSU 
patients in a representative patient population (see Table 12-1 for details). The annual 
prevalence of CSU in the pediatric population is low and comparable with adults (< 1%). 

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Although the age-related prevalence of CSU for adolescent patients is similar to adults, the 
overall target for enrollment is impacted by the fact that 11 to 17 year old patients only comprise 
about 10% of the total population (9.5% of the population in the US Census Bureau). 
Table 12-1 
Summary of annual prevalence of CSU in pediatric population 
Region 
Source (year) 
Annual prevalence (%) 
0-51 or 0-62 years 
6-11 years 
12-17 years 
UK 
IMS LifeLink (2010) 
0.01-0.03 
0.07 
0.07 
UK 
CPRD (2013) 
0.003-0.092 
0.006-0.098 
0.006-0.081 
USA 
IMS LifeLink (2010) 
0.25-0.33 
0.18 
0.16 
USA 
MarketScan (2014) 
0.01-0.13 
0.01-0.06 
- 
1 Age category for IMS LifeLink and MarketScan analyses 
2 Age category for CPRD (UK) and Study CQGE031C5001 analyses 
In order to satisfy Health Authority requirements to provide pediatric patients with new 
treatment options, a total of 100 adolescent subjects are planned to be enrolled equally across 
the CQGE031C2302 and CQGE031C2303 studies taking into consideration the prevalence of 
adolescent CSU patients and the uncertainty of completing their enrollment. Ninety adolescent 
subjects are planned to be randomized equally across the 2 ligelizumab and omalizumab 
treatment arms, and 10 adolescent subjects into the placebo arms. Assuming an approximately 
20% drop out rate for the adolescent subjects, this is anticipated to provide approximately 25 
adolescent subjects in each of the 2 ligelizumab and the omalizumab arms, and 8 adolescent 
subjects in the placebo arms at the end of the studies. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, 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. 

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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, Last Patient Last Visit) and 
finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (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 at the trial investigator 
meetings. 
13.4 
Quality control and quality assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal 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, 
or observations are 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. 

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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 
References 
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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Refer to Appendix 1.1 for clinically notable vital sign values for adolescents.  
Refer to Appendix 2 for clinically notable laboratory values for hepatotoxicity.  
Refer to Appendix 3 for clinically notable laboratory values for nephrotoxicity.  
The following other specific criteria have been identified for this study: 
Platelets < 75,000/μL 
• Any patient who have platelets < 75 000/μL after being randomized should discontinue 
study treatment. 
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 CRF. 
Notable values for vital signs and change from baseline will be summarized.  
Notable values for adults 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 QTcF (Fridericia’s) interval of greater than 450 
ms for males or greater than 460 ms for females – all such ECGs will be flagged by the Central 
CRO’s cardiologist and require assessment for clinical relevance by the investigator. For 
adolescent subjects, the Central CRO will use age-and gender-specific reference values. 

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16.1.1 
Appendix 1.1: Clinically notable vital signs – adolescent subjects 
16.1.1.1 Guideline for pediatric blood pressure measurements: 
Table 16-1 
Best BP Measurement Practices - Pediatrics 
1. The child should be seated in a quiet room for 3–5 min before measurement, with the back 
supported and feet uncrossed on the floor. 
2. BP should be measured in the right arm for consistency, for comparison with standard tables, 
and to avoid a falsely low reading from the left arm in the case of coarctation of the aorta. 
The arm should be at heart level, supported, and uncovered above the cuff. The patient and 
observer should not speak while the measurement is being taken. 
3. The correct cuff size should be used. The bladder length should be 80%–100% of the 
circumference of the arm, and the width should be at least 40%. 
4. For an auscultatory BP, the bell of the stethoscope should be placed over the brachial artery in 
the antecubital fossa, and the lower end of the cuff should be 2–3 cm above the antecubital 
fossa. The cuff should be inflated to 20–30 mm Hg above the point at which the radial pulse 
disappears. Overinflation should be avoided. The cuff should be deflated at a rate of 2–3 mm 
Hg per second. The first (phase I Korotkoff) and last (phase V Korotkoff) audible sounds 
should be taken as SBP and DBP. If the Korotkoff sounds are heard to 0 mm Hg, the point at 
which the sound is muffled (phase IV Korotkoff) should be taken as the DBP, or the 
measurement repeated with less pressure applied over the brachial artery. The measurement 
should be read to the nearest 2 mm Hg. 
5. To measure BP in the legs, the patient should be in the prone position, if possible. An 
appropriately sized cuff should be placed mid-thigh and the stethoscope placed over the 
popliteal artery. The SBP in the legs is usually 10%–20% higher than the brachial artery 
pressure. 
Adapted from Pickering et al 2005.  

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16.1.2 
Appendix 1.1.2 : Notable values for adolescents’ vital signs 
Table 16-2 
Upper and lower limits for adolescents’ vital signs that may be 
considered of concern if newly identified may be identified using the 
following table for guidance1: 
Age 
Systolic BP2,3 
Diastolic BP2,3 
HR3 
12 yrs 
101-135 
59-91 
60-110 
13 yrs 
104-137 
60-91 
60-110 
14 yrs 
106-140 
60-92 
60-110 
15 yrs 
107-142 
61-93 
60-110 
16 yrs 
108-145 
63-94 
60-110 
17 yrs 
108-147 
64-97 
60-100 
18 yrs 
 - 
 - 
60-100 
1 The table above was developed from multiple resources listed below. The normal values for 
vital signs in children vary greatly with age, growth and development. The purpose of these 
values is to guide investigators to identify or screen for values of concern in pediatric patients 
by age. These are not normal values, which can be found in sources such as the Harriet Lane 
Pediatric Handbook but rather are upper and lower limits for children’s vital signs that may be 
considered of concern if newly identified. The significance of these findings must be considered 
in view of the patient’s disease, time course and overall clinical condition. 
2 Based on percentiles by height (50th - 99th) 
3 Arcara K, Tschudy M. The Harriet Lane Handbook 
who.int/childgrowth/standards/w_f_a_tables_p_girls/en/index.html 
who.int/childgrowth/standards/second_set/hcfa_girls_p_exp.txt 
who.int/childgrowth/standards/second_set/hcfa_boys_p_exp.txt 

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16.2 
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements 
Table 16-3 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline:  
• ALT or AST > 5 × ULN 
• ALP > 2 × ULN (in the absence of known 
bone pathology) 
• Total bilirubin > 3 × ULN (in the absence 
of known Gilbert syndrome) 
• ALT or AST > 3 × ULN and INR > 1.5 
• Potential Hy’s Law cases (defined as ALT 
or AST > 3 × ULN and Total bilirubin > 2 
× ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 × 
ULN) 
• Any clinical event of jaundice (or 
equivalent term) 
• ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal 
pain, nausea, or vomiting, or rash with 
eosinophilia 
• Any adverse event potentially indicative 
of a liver toxicity* 
If ALT or AST abnormal at baseline: 
• ALT or AST > 2x baseline or > 300 U/L 
(whichever occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage-related conditions; non-infectious hepatitis; benign, malignant and unspecified 
liver neoplasms ULN: upper limit of normal 
 
Table 16-4 
Follow-up requirements for liver laboratory triggers with liver 
symptoms  
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
No change 
to study 
treatment 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
If elevated at 
baseline: 
ALT > 2 x 
baseline 

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ALT 
TBL 
Liver Symptoms 
Action 
or > 300 U/L 
(whichever 
occurs ﬁrst) 
and GLDH in 
48-72 hours. 
• 
Follow-up for 
symptoms. 
  
If normal at 
baseline: 
ALT > 5 x ULN 
for more than two 
weeks 
Normal 
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt 
study drug 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring 
and workup 
for competing 
etiologies. 
• 
Study drug 
can be 
restarted only 
if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline. 
If elevated at 
baseline: 
ALT > 3 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) for 
more than two 
weeks 
  
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
  
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For patients with 
Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or 
elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 
 
Table 16-5 
Follow up requirements for liver laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Total Biliruin (isolated) 
  
  

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Criteria 
Actions required 
Follow-up monitoring 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
Monitor LFTs weekly until 
resolution** to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution** (frequency at 
investigator discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF 
Investigator discretion 
**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 
Refer to Section 10.2.2 
Table 16-6 
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% + OR if <18 years 
old, eGFR < 35mL/min/1.73 m2 
• 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+ 
OR 
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 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 
+ Corresponds to KDIGO criteria for Acute Kidney Injury 
 
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:  
o Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)  
o Signs and symptoms like fever, headache, shortness of breath, back or 
abdominal pain, dysuria or hematuria, dependent or periorbital edema  
o Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine 
output  
o Concomitant events or procedures such as trauma, surgical procedures, cardiac 
or hepatic failure, contrast media or other known nephrotoxin administration, or 
other diseases or causes, e.g., dehydration due to delirium, tumor lysis  
 

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Table 16-7 
Renal event follow-up 
FOLLOW-UP OF RENAL EVENTS 
Assess+, document and record in CRF  
• Urine dipstick and sediment microscopy evidence of 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 protein-creatinine ratio < 1 g/g Cr, or ACR <300 mg/g Cr of 
baseline) 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 
16.4 
Appendix 4: PRO tools 
Samples of questionnaire provided here are for illustrative purpose only. The text format and 
wording might slightly vary. 
Patient Diary: Urticaria Patient Daily Diary (UPDD) 
 

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Patient Diary: Angioedema Activity Score (AAS) 
 

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Dermatology Life Quality Index (DLQI): 
 

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Children Dermatology Life Quality Index (CDLQI): 
 

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16.6 
Appendix 6: World allergy organization grading system 
World allergy organization subcutaneous immunotherapy systemic reaction 
grading system