Clinical trial NCT05024058
Conditions: Chronic Inducible Urticaria
Keywords: ligelizumab anti-IgE CINDU chronic inducible urticaria symptomatic dermographism cold urticaria cholinergic urticaria urticaria itch hives
Sponsor: Novartis Pharmaceuticals
Start date: 2021-11-16; Completion date: 2022-08-09
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a placebo controlled, phase 3 study designed to evaluate the efficacy and safety of ligelizumab in participants with chronic inducible urticaria who are inadequately controlled with H1-antihistamines

Detailed description:
There are currently no approved therapies for patients with CINDU who remain symptomatic despite treatment with H1-antihistamines. The purpose of this study was to establish efficacy and safety of ligelizumab (QGE031) over placebo in participants with chronic inducible urticaria (CINDU) who remain symptomatic despite treatment with H1 antihistamine.

Arms: arm 1: Ligelizumab low dose subcutaneous injection every 4 weeks in participants with symptomatic dermographism arm 2: Ligelizumab high dose subcutaneous injection every 4 weeks in participants with symptomatic dermographism arm 3: Placebo subcutaneous injection every 4 weeks in participants with symptomatic dermographism arm 4: Ligelizumab low dose subcutaneous injection every 4 weeks in participants with cold urticaria arm 5: Ligelizumab high dose subcutaneous injections every 4 weeks in participants with cold urticaria arm 6: Placebo subcutaneous injection every 4 weeks in participants with cold urticaria arm 7: Ligelizumab high dose subcutaneous injections every 4 weeks in participants with cholinergic urticaria arm 8: Placebo subcutaneous injections every 4 weeks in participants with cholinergic urticaria
Interventions: intervention 1: Ligelizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Ligelizumab treated groups and arms intervention 2: Placebo treated groups and arms

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
QGE031/Ligelizumab / NCT05024058
Clinical Trial Protocol 
A multi-center, randomized, double-blind, placebo 
controlled study to investigate the efficacy and safety of 
ligelizumab (QGE031) in the treatment of Chronic Inducible 
Urticaria (CINDU) in adolescents and adults inadequately 
controlled with H1-antihistamines 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2020-003018-11 
Version number: 
00 (Original Protocol) 
Clinical Trial Phase: 
III 
Release date: 
07-Jul-2021 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Purpose .................................................................................................................. 19 
2 
Objectives, endpoints and estimands ................................................................................. 19 
2.1 
Primary estimands ................................................................................................. 21 
2.2 
Secondary estimands ............................................................................................. 22 
3 
Study design ...................................................................................................................... 23 
3.1 
Study design........................................................................................................... 23 
3.2 
Provocation tests .................................................................................................... 26 
4 
Rationale ............................................................................................................................ 27 
4.1 
Rationale for study design ..................................................................................... 27 
4.1.1 
Rationale for choice of background therapy ......................................... 28 
4.1.2 
Rationale for use of provocation testing to elicit urticaria .................... 28 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 29 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 29 
4.4 
Purpose and timing of interim futility analyses ..................................................... 30 
4.5 
Risks and benefits .................................................................................................. 30 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 34 
5 
Study Population ............................................................................................................... 34 
5.1 
Inclusion criteria .................................................................................................... 34 
5.2 
Exclusion criteria ................................................................................................... 35 
6 
Treatment ........................................................................................................................... 37 
6.1 
Study treatment ...................................................................................................... 37 
6.1.1 
Investigational and control drugs .......................................................... 37 
6.1.2 
Additional study treatments .................................................................. 38 
6.1.3 
Supply of study treatment ..................................................................... 38 
6.1.4 
Treatment arms/group ........................................................................... 38 
6.1.5 
Treatment duration ................................................................................ 38 
6.2 
Other treatment(s) .................................................................................................. 39 




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8.5.6 
Exit interviews (optional at selected sites) ............................................ 74 
9 
Discontinuation and completion ........................................................................................ 74 
9.1 
Discontinuation from study treatment and from study .......................................... 74 
9.1.1 
Discontinuation from study treatment ................................................... 74 
9.1.2 
Discontinuation from study ................................................................... 76 
9.1.3 
Lost to follow-up ................................................................................... 76 
9.2 
Withdrawal of informed consent/Opposition to data/biological samples .............. 76 
9.3 
Study completion and post-study treatment .......................................................... 77 
9.4 
Early study termination by the sponsor ................................................................. 77 
10 Safety monitoring, reporting and committees ................................................................... 77 
10.1 
Definition of adverse events and reporting requirements ...................................... 77 
10.1.1 
Adverse events ...................................................................................... 77 
10.1.2 
Serious adverse events .......................................................................... 79 
10.1.3 
SAE reporting........................................................................................ 80 
10.1.4 
Pregnancy reporting .............................................................................. 81 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 81 
10.2 
Additional Safety Monitoring ................................................................................ 82 
10.2.1 
Liver safety monitoring ......................................................................... 82 
10.2.2 
Renal safety monitoring ........................................................................ 83 
10.3 
Committees ............................................................................................................ 83 
10.3.1 
Data Monitoring Committee ................................................................. 83 
10.3.2 
Steering Committee ............................................................................... 83 
10.3.3 
Adjudication committee ........................................................................ 84 
11 Data Collection and Database management ...................................................................... 84 
11.1 
Data collection ....................................................................................................... 84 
11.2 
Database management and quality control ............................................................ 84 
11.3 
Site monitoring ...................................................................................................... 85 
12 Data analysis and statistical methods ................................................................................ 86 
12.1 
Analysis sets .......................................................................................................... 86 
12.2 
Participant demographics and other baseline characteristics ................................. 86 
12.3 
Treatments ............................................................................................................. 87 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 87 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 87 


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12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 87 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 88 
12.4.4 
Handling of missing values not related to intercurrent event ............... 89 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 89 
12.4.6 
Supplementary analysis ......................................................................... 90 
12.5 
Analysis supporting secondary objectives ............................................................. 90 
12.5.1 
Efficacy
endpoint(s) .................................... 93 
12.5.2 
Safety endpoints .................................................................................... 93 
 
 96 
 
 96 
 
 96 
 
96 
 
 96 
12.7 
Interim analyses (Futility analysis) ........................................................................ 97 
12.8 
Sample size calculation .......................................................................................... 97 
12.8.1 
Primary endpoint(s) ............................................................................... 98 
12.8.2 
Secondary endpoint(s) ......................................................................... 100 
13 Ethical considerations and administrative procedures .................................................... 101 
13.1 
Regulatory and ethical compliance ...................................................................... 101 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 101 
13.3 
Publication of study protocol and results............................................................. 101 
13.4 
Quality Control and Quality Assurance ............................................................... 101 
14 Protocol adherence .......................................................................................................... 102 
14.1 
Protocol amendments ........................................................................................... 102 
15 References ....................................................................................................................... 103 
16 Appendices ...................................................................................................................... 106 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 106 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................ 108 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up .... 111 
16.4 
Appendix 4 Sampson Criteria for anaphylaxis .................................................... 112 
 
 113 
 
 113 
 
 125 
16.7 
Appendix 7: World allergy organization grading system .................................... 127 
 


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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 19 
Table 4-1 
Rationale for study design ..................................................................... 27 
Table 6-1 
Investigational and control drug ............................................................ 37 
Table 6-2 
Prohibited medication ........................................................................... 39 
Table 6-3 
Dose and Treatment schedule ............................................................... 42 
Table 6-4 
Blinding and unblinding plan ................................................................ 46 
Table 8-1 
Assessment Schedule ............................................................................ 51 
Table 8-2 
Efficacy variables .................................................................................. 59 
 
 64 
Table 8-4 
Safety assessments ................................................................................ 66 
Table 8-5 
Laboratory assessments ......................................................................... 67 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 82 
Table 10-2 
Base Renal Monitoring ......................................................................... 83 
Table 12-1 
Sensitivity of power to changes in assumptions (Symptomatic 
Dermographism) ................................................................................... 98 
Table 12-2 
Sensitivity of power to changes in assumptions (cold urticaria) ........... 99 
Table 12-3 
Sensitivity of power to changes in assumptions (cholinergic 
urticaria) ................................................................................................ 99 
Table 12-4 
Sensitivity of required sample size (per arm) to changes in 
assumptions for different targeted statistical power (cholinergic 
urticaria) ................................................................................................ 99 
Table 16-1 
Best Blood Pressure (BP) Measurement Practices - Pediatrics .......... 106 
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 guidance ......................................................... 107 
Table 16-3 
Liver event and laboratory trigger definitions .................................... 108 
Table 16-4 
Follow up requirements for liver laboratory triggers – ALT, AST, 
TBL ..................................................................................................... 108 
Table 16-5 
Follow up requirements for liver events and laboratory triggers – 
Isolated Hyperbilirubinemia ................................................................ 110 
Table 16-6 
Specific renal alert criteria and actions ............................................... 111 
Table 16-7 
Renal event follow-up ......................................................................... 111 
 
 125 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 26 


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Figure 12-1 
Testing strategy for symptomatic dermographism and cold urticaria ... 91 
Figure 12-2 
Testing strategy for cholinergic urticaria .............................................. 93 
Figure 16-1 
World allergy organization subcutaneous immunotherapy systemic 
reaction grading system ....................................................................... 127 
 


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List of abbreviations 
AC 
Adjudication Committee 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
ATE 
Arterial Thromboembolic Event 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
 
CFR 
Code of Federal Regulations 
 
CINDU 
Chronic Inducible Urticaria 
ClinRO 
Clinician Reported Outcomes 
CMO&PS 
Chief Medical Office and Patient Safety  
COA 
Clinical Outcome Assessment 
COVID-19 
Corona Virus Disease of 2019 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CS 
Corticosteroids 
CSR 
Clinical Study Report 
CSU 
Chronic Spontaneous Urticaria 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Critical Temperature Threshold 
DIN 
Drug Inducted Nephrotoxicity 
 
DMC 
Data Monitoring Committee 
EC 
European Community 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medical Association 
EOS 
End of Study 
EOT 
End of Treatment 
 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trial Database 
FAS 
Full Analysis Set 


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FcεRI 
High Affinity Immunoglobulin E Receptor 
FcεRII 
Low Affinity Immunoglobulin E Receptor 
FDA 
Food and Drug Administration 
Fric 
Friction 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
H1-AH 
H1 antihistamines 
HA 
Health Authorities 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin  
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
HLT 
High Level Term 
 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection Site Reaction 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LLOQ 
lower limit of quantification 
LT 
Life Threatening 
MAR 
Missing at Random 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MRCT 
Multi Regional Clinical Trial 
MRI 
Magnetic Resonance Imaging 
NRS 
Numeric Rating Scale 
NYHA 
New York Heart Association 
PCE 
Pulse Controlled Ergometry 
PD 
Pharmacodynamic(s) 
PDCO 
Pediatric Committee at the European Medicines Agency 


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PGA 
Physician Global Assessment 
 
 
PK 
Pharmacokinetic(s) 
POCT 
Point Of Care Tests 
PSD 
Premature Subject Discontinuation 
PSDS 
Post Study Drug Supply 
PT 
Prothrombin Time 
PTA 
Post Trial Access 
QMS 
Quality Management System  
QoL 
Quality of Life 
QTcF 
QT interval corrected by Fridericia’s formula 
RBC 
red blood cell(s) 
RDO 
Retrieved Drop-out 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SAR-CoV-2 
Severe Acute Respiratory syndrome CoronaVirus 2 
SAS 
Statistical Analysis System  
SC 
Subcutaneous 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Query  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Events 
TFS 
Total Fric Score 
TNF 
Tumor Necrosis Factor 
 
ULN 
upper limit of normal 
UPV 
Unplanned Visit 
US 
United States 
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Biologic 
Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study participant. 
Clinical 
Outcome 
Assessment 
(COA) 
A measure that describes or reflects how a participant feels, functions, or survives. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by replacing 
personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, or a 
group of individuals followed up or traced over time.  
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug. 
Discontinuation 
from study 
Point/time when the participant permanently stops receiving the study treatment and further 
protocol required assessments or follow-up, for any reason. No specific request is made to 
stop the use of their samples or data. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study treatment for any 
reason (prior to the planned completion of study drug administration, if any). Participant 
agrees to the other protocol required assessments including follow-up. No specific request 
is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a day, 
75 mg twice a day). 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using data 
collection systems, such as Web-based applications, interactive voice response systems 
and clinical laboratory interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from  source data/documents used at 
the point of care. 
End of the 
clinical trial 
The end of the clinical trial is defined as the last visit of the last participant or modify if 
different  as defined by the protocol.  
Enrollment 
Point/time of participant entry into the study at which informed consent must be obtained.  
The action of enrolling one or more participants. 
Estimand  
As defined in the ICH E9 (R1) addendum, estimand is a precise description of the treatment 
effect reflecting the clinical question posed by the trial objective. It summarizes at a 
population-level what the outcomes would be in the same participants under different 
treatment conditions being compared. Attributes of an estimand include the population, 
variable (or endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary for the 
variable. 
Healthy 
volunteer 
A person with no known significant health problems who volunteers to be a study 
participant.  
Intercurrent 
events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study. 
Medication 
number 
A unique identifier on the label of medication kits. 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study or the 
participant allocated to an invalid stratification factor. 
Off-site 
Describes trial activities that are performed at remote location by an off-site healthcare 
professional, such as procedures performed at the participant's home. 




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Withdrawal of 
study consent 
(WoC) / 
Opposition to 
use of data 
/biological 
samples 
Withdrawal of consent from the study occurs when the participant explicitly requests to stop 
use of their data and biological samples (opposition to use data and biological samples) 
AND no longer wishes to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local regulations) 
and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where collection and 
processing of personal data is justified by a different legal reason than consent. 


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Protocol summary 
Protocol 
number 
CQGE031E12301 
Full Title 
A multi-center, randomized, double-blind, placebo controlled study study to investigate the 
efficacy and safety of ligelizumab (QGE031) in the treatment of Chronic Inducible Urticaria 
(CINDU) in adolescents and adults inadequately controlled with H1-antihistamines 
Brief title 
Study of efficacy and safety of ligelizumab in adolescents and adults  with chronic inducible 
urticaria who remain symptomatic despite treatment with H1- antihistamines 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to establish efficacy and safety of ligelizumab (QGE031) over 
placebo in participants with chronic inducible urticaria (CINDU) who remain symptomatic 
despite treatment with H1 antihistamine. There are currently no approved therapies for 
patients with CINDU who remain symptomatic despite treatment with H1-antihistamines. 
Primary 
Objective(s) 
The primary objective is to demonstrate superiority of ligelizumab versus placebo with 
regards to the change from baseline in response to a standardized provocation test at Week 
12 for each CINDU subtype. 
For each subtype of CINDU, the primary clinical question of interest is: what is the treatment 
effect of the ligelizumab treatment versus placebo on the primary endpoint in participants 
with H1-AH as background medication, regardless of use of rescue medications and/or 
prohibited medications and treatment discontinuations due to either adverse events, or use 
of prohibited medications, or lack of efficacy, assuming that participants had never 
discontinued treatment due to other reasons or missed any treatment prior to Week 12 due 
to other non-human controlled emergency situations (e.g. COVID-19)?. 
Secondary 
Objectives 
To demonstrate superiority of ligelizumab versus placebo with regard to proportion of 
participants with a complete response after standardized provocation test at Week 12 for 
each CINDU. To demonstrate superiority of ligelizumab versus placebo in itch NRS 
(numerical rating scale) following the provocation test at week 12 for each CINDU. 
To assess the safety of ligelizumab during the study. 
For each subtype of CINDU the secondary clinical question of interest is: what is the 
treatment effect of the ligelizumab treatment versus placebo on the secondary endpoints in 
participants with H1-AH as background medication, regardless of use of rescue medications 
and/or prohibited medications, and considering treatment discontinuations due to either AE, 
or use of prohibited medications, or lack of efficacy as non-responders, assuming that 
participants had never discontinued treatment due to other reasons or missed any treatment 
prior to Week 12 due to other non-human controlled emergency situations (e.g. COVID-
19)?. 
Study design 
This is a Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study. There is a screening period of up to 28 days, a 24 week double-blind treatment 
period, and a 12 week post-treatment follow-up period. 
Study 
population 
The study population will consist of approximately 428 male and female participants aged ≥ 
12 years who have been diagnosed with symptomatic dermographism, cold urticaria or 
cholinergic urticaria and who remain symptomatic despite the use of H1-AH at the approved 
dose level. Of these, approximately 168, 102 and 158 participants with symptomatic 
dermographism, cold urticaria and cholinergic urticaria, respectively, are planned for 
inclusion in the study.  


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Key Inclusion 
criteria 
• Signed informed consent must be obtained before any assessment is performed. 
• Participant’s parent’s or legal guardian’s signed informed consent and child’s assent, if 
appropriate, must be obtained before any assessment is performed. Of note, if the 
participant 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 participants ≥ 12 years of age at the time of screening. (NOTE: 
Recruitment of adolescent participants, ≥ 12 to <18 years of age, will be in accordance with 
local regulatory/ethics committee requirements). 
• Confirmed CINDU diagnosis (as per guidelines) for symptomatic dermographism, cold 
urticaria or cholinergic urticaria for ≥ 4 months (defined as onset of CINDU with supporting 
documentation (e.g medical record, clinical history, photographs)). 
• Diagnosis of CINDU (symptomatic dermographism, cold urticaria or cholinergic urticaria) 
inadequately controlled with H1-AH at local label approved doses at the time of 
randomization, as defined by all of the following: 
 
• Positive response (i.e development of symptoms) to triggers despite treatment with 
H1-AH 
 
• Positive response (i.e. development of symptoms, see Section 8.3.1) to provocation 
test on day of randomization 
• Participants must be able to physically perform the protocol defined provocation test 
specific to the participant's CINDU. 
• Cholinergic urticaria participants must show sweating in performing the pulse-controlled 
ergometry test on day of randomization. Participants with anhidrosis must not be included. 
• Willing and able to complete a daily symptom eDiary as per protocol requirement and 
adhere to the study visit schedules. 
Key Exclusion 
criteria 
• History of hypersensitivity to any of the study drugs or its components or to drugs of 
similar classes (i.e. to murine, chimeric or human antibodies) or to the provocation test or 
items used in provocation tests 
• Participants who have concomitant CSU at screening 
• Participants who have a familial form (e.g familial cold autoinflammatory syndrome, 
familial cold urticaria)  of the target CINDU that is being considered for the participant's 
inclusion in this study 
• Participants having a more defined other form of inducible urticaria than the target CINDU 
that is being considered for the participant's inclusion in this study 
• Diseases, other than chronic inducible urticaria, with urticaria or angioedema symptoms 
such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria 
pigmentosa) and hereditary or acquired angioedema (eg, due to C1 inhibitor deficiency). 
• 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.) or skin diseases associated with 
only wheals and no itch e.g asymptomatic dermographism 
• Prior exposure to ligelizumab, omalizumab or other anti-IgE therapies. 
Study 
treatment 
• Ligelizumab 120 mg sc 
• Ligelizumab 72 mg sc 
• Placebo 0 mg sc 
Treatment of 
interest 
The randomized treatment which is ligelizumab or the placebo treatment (no further 
treatment for participants who discontinue treatment due to AE, lack of efficacy or intake of 
prohibited medications) with stable H1-antihistamines at local-approved doses as 
background medication + allowed rescue medication. The dose of the allowed background 
medication for CINDU must remain stable during the trial. Further details about the 
investigational treatment and control treatment are provided in Section 6. 




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1 
Introduction 
1.1 
Background 
Urticaria lasting for greater than 6 weeks is defined as chronic urticaria (Bernstein et al 2014). 
Chronic urticaria, characterized by the recurrence of itchy hives (also known as wheals) and/or 
angioedema, is further divided into two sub-types: chronic spontaneous urticaria (CSU) and 
chronic inducible urticaria (CINDU) or physical urticaria. As the name suggests, symptoms of 
CINDU are induced by exposure to a particular non-physical stimuli or by physical triggers 
such as heat, cold, or pressure (Bernstein et al 2014, Zuberbier et al 2018). CINDUs triggered 
by external physical stimuli include symptomatic dermographism, cold contact urticaria, 
delayed pressure urticaria, solar urticaria, vibratory urticaria, while those induced by non-
physical stimuli include cholinergic urticaria, aquagenic urticaria, and exercise induced 
anaphylaxis/urticaria (Maurer et al 2018). Among these various CINDUs, symptomatic 
dermographism, cold and cholinergic urticaria are reported to be the most prevalent forms 
globally (Maurer et al 2017, Maurer et al 2018). 
There are no reliable population based estimates available on the prevalence and incidence of 
CINDU in the general population. Only treatment center-based or burden of disease studies 
have reported frequency of CINDU among patients with chronic urticaria or frequency of co-
existing CINDU in patients with CSU. An observational study reported that 1 in every 4 patients 
with chronic urticaria had co-existing CINDU (Maurer et al 2017, Maurer et al 2018). 
CINDU can be a debilitating disease with a severe impact on the quality of life. Management 
of CINDU typically involves threshold testing and avoidance of relevant triggers (Zuberbier et 
al 2018). Where this is not feasible or possible, symptomatic treatment follows a stepwise 
approach (Metz et al 2011, Dressler et al 2018), similar to that for CSU. The first line of 
treatment is with standard doses of non-sedating H1-anti-histamines (H1-AH) followed by 
updosing in case of non-responsiveness to standard doses (Maurer et al 2018). Higher than 
standard doses are usually required for symptom control, and up to half the participants do not 
achieve complete symptom control despite use of H1-antihistamines. Therefore, there is a 
considerable unmet medical need for treatment options for anti-histamine refractory CINDU. 
Although the exact pathophysiology of CINDU is still under investigation, IgE mediated 
degranulation of tissue resident mast cells, and subsequent release of histamine has been 
postulated to play an important role Maurer et al 2018). In this context, there is a growing body 
of evidence demonstrating that omalizumab, a humanized anti-IgE monoclonal antibody, may 
be efficacious in anti-histamine refractory CINDU patients. A recent systematic literature 
review evaluated 43 studies, including case reports or case studies of omalizumab treatment 
across 9 CINDU subtypes, and reported substantial treatment benefits in CINDU patients with 
the strongest evidence of benefit in symptomatic dermographism, cold urticaria and solar 
urticaria (Maurer et al 2018). Two randomized, placebo controlled investigator initiated trials 
with omalizumab, one in symptomatic dermographism and another in cold urticaria, 
demonstrated clinically meaningful improvements in provocation threshold (FricTest®) and 
change in critical temperature, respectively (Maurer et al 2017, Metz et al 2017). 
Ligelizumab is a humanized, IgG1-subtype monoclonal antibody, which is a highly potent 
inhibitor of human IgE. Overall, the mode of action of ligelizumab is closely related to the one 


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of omalizumab. However, ligelizumab binds to a different epitope on IgE than omalizumab. 
This differential epitope recognition translates into a qualitatively different IgE inhibition 
profile with ligelizumab showing a significantly enhanced blockade of high-affinity IgE 
receptor FcεRI (predominantly found on the surface of mast cells and basophils) compared to 
omalizumab. Conversely, omalizumab more potently blocks IgE binding to FcεRII/CD23 
(Gasser et al 2020). These data suggest that ligelizumab may have higher clinical efficacy than 
omalizumab in diseases in which engagement of the IgE/FcεRI axis on mast cells and basophils 
is the more prominent driver of disease pathology than FcεRII/CD23. 
In completed human studies CQGE031A2102, CQGE031A2103, CQGE031A1101 and 
CQGE031B2203, ligelizumab showed higher potency compared to omalizumab, evidenced by 
enhanced suppression of free IgE, FcεRI and surface IgE expression of basophils, allergen skin 
prick test and bronchial allergen challenge responses. These studies consistently support the 
scientific rationale for the development of ligelizumab in IgE driven diseases. 
Ligelizumab is currently being developed in the CSU indication. Data from CQGE031C2201, 
the first clinical study in CSU, demonstrated that ligelizumab (72 and 240 mg q4w SC) was 
efficacious i.e. achievement of complete hives response when added to standard of care 
treatment in patients with moderate to severe CSU (Maurer et al 2019). Data from the 
CQGE031C2201E1 study (an open-label extension study for participants who complete 
CQGE031C2201 study and present with active disease) showed that 1- year treatment with 
ligelizumab 240 mg q4w resulted in a high rate of early onset, sustained and complete control 
of hives and itch (UAS7=0), and angioedema. There were no newly identified or unexpected 
safety concerns. 
Two pivotal Phase 3, randomized, placebo- and omalizumab-controlled studies 
(CQGE031C2302 and CQGE031C2303) are currently ongoing. The purpose of these studies is 
to establish the efficacy and safety of ligelizumab (72 mg and 120 mg q4w) in adult and 
adolescent participants with CSU, who remain symptomatic despite standard of care treatment. 
Dose selection for these studies was based on the observed efficacy, supported by a model based 
exposure response analysis, from the Phase 2b CQGE031C2201 study. 
Based on pediatric plan agreements with the Pediatric Committee at the European Medicines 
Agency (PDCO) and with the US Food and Drug Administration (FDA), a randomized, double 
blind, placebo-controlled Phase 2b dose-finding study in adolescents has been completed 
(CQGE031C2202). The purpose of the study was to evaluate pharmacokinetics, safety and 
efficacy of ligelizumab (24 mg and 120 mg q4w) in children from 12 to <18 years of age with 
CSU. A descriptive analysis of efficacy results showed that ligelizumab was effective for 
treatment of CSU in adolescents. Dose dependent changes from baseline in weekly UAS were 
observed at Week 12. The proportion of subjects with complete UAS7 response (UAS7=0) was 
higher in the ligelizumab 120 mg q4w arm compared to the ligelizumab 24 mg q4w and placebo. 
Ligelizumab exposure was generally in line with data from the previous study in adult CSU 
patients considering PK variability. Ligelizumab was safe and well tolerated by the adolescent 
patients with no newly identified safety signals. 
In summary, the available data on omalizumab use in CINDU (Maurer et al 2017, Metz et al 
2017, Maurer et al 2018 ), its approved use for the treatment of CSU and the promising efficacy 


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data for ligelizumab in CSU, together support the potential for ligelizumab to be an effective 
therapy for the treatment of CINDU. 
1.2 
Purpose 
The purpose of this study is to establish efficacy and safety of ligelizumab (QGE031) versus 
placebo in adolescents and adults with chronic inducible urticaria who remain symptomatic 
despite treatment with H1 antihistamine. 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
To demonstrate superiority of ligelizumab versus 
placebo with regards to the change from baseline in 
response to a standardized provocation test for each 
CINDU subtype 
Symptomatic Dermographism 
Change from baseline in Total Fric Score (TFS) at Week 12 
in response to FricTest® 4.0 
Cold Urticaria 
Change from baseline in critical temperature threshold 
(CTT) at Week 12 in response to the TempTest® 4.0 
Cholinergic Urticaria 
Change from baseline in itch numerical rating scale (NRS) 
at Week 12 in response to the pulse-controlled ergometry 
test. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
To demonstrate superiority of ligelizumab versus 
placebo with regard to proportion of participants with a 
complete response after standardized provocation test 
To demonstrate superiority of ligelizumab versus 
placebo in itch NRS following the provocation test. 
Symptomatic Dermographism 
Proportion of participants with complete response in 
FricTest® at Week 12 
Change from baseline in itch NRS following provocation test 
at Week 12, in participants with itch NRS > 0 at baseline 
Cold Urticaria 
Proportion of participants with complete response in 
TempTest® at Week 12 
Change from baseline in itch NRS following provocation test 
at Week 12, in participants with itch NRS > 0 at baseline 
Cholinergic Urticaria 
Proportion of participants with itch NRS=0 following the 
pulse-controlled ergometry test at Week 12 
Proportion of participants with physician global assessment 
of severity of hives=0 following the pulse-controlled 
ergometry test at Week 12 
To assess the safety of ligelizumab  
Safety endpoints will include but not be limited to: 
• Occurrence of treatment emergent adverse events 
(serious and non-serious) during the study 
• Occurrence of treatment emergent adverse events during 
the study leading to discontinuation of study treatment 
• Occurrence of treatment emergent adverse events of 
interest listed as either identified or potential risks, during 
the study 
• Changes in safety parameters  


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2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g premature discontinuation of treatment). 
For each subtype of CINDU, the primary clinical question of interest is: what is the treatment 
effect of the ligelizumab treatment versus placebo on the primary endpoint in participants with 
H1-AH as background medication, regardless of use of rescue medications and/or prohibited 
medications and treatment discontinuations due to either AE, or use of prohibited medications, 
or lack of efficacy, assuming that participants had never discontinued treatment due to other 
reasons or missed any treatment prior to Week 12 due to other non-human controlled emergency 
situations (e.g. COVID-19)? 
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of additional background and rescue medications, mirroring the conditions in 
clinical practice. This will also enable an estimation of the effect of study drug for the full 
duration of the study. Further details can be found in Section 5. 
The primary estimand for each of the CINDU cohort is described by the following attributes: 
• Population: participants receiving H1-antihistamines therapy at local-approved dose level 
as background medication suffering from symptomatic dermographism, cold urticaria, or 
cholinergic 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: 
1. Symptomatic Dermographism: change from baseline to Week 12 in Total Fric Score 
(score derived based on results from the Fric Test 4.0, see Section 8.3.1.1 for detail) 
2. Cold urticaria: change from baseline to Week 12 in critical temperature thresholds 
(CTT, i.e. the highest temperature hives are triggered, see Section 8.3.1.2 for details) 
in response to the TempTest® 
3. Cholinergic urticaria: change from baseline to Week 12 in itch numerical rating scale 
(NRS) in response to the pulse-controlled ergometry (see Section 8.3.1.3 for details). 
• Treatment of interest: ligelizumab or the placebo treatment (no further treatment for 
patients who discontinue treatment due to AE, lack of efficacy or intake of prohibited 
medications) with stable H1-antihistamines at local-approved doses as background 
medication + allowed rescue medication. The dose of the allowed background medication 
for CINDU must remain stable during the trial. Further details about the investigational 
treatment and control treatment are provided in Section 6. 
• Handling of remaining intercurrent events: 
1. Discontinuation of initial assigned study treatment prior to Week 12 due to adverse 
events (AE), use of prohibited medications or lack of efficacy (LoE): 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). 
2. Discontinuation of initial assigned study treatment prior to Week 12 due to reasons 
other than adverse events (AE), use of prohibited medications, or lack of efficacy 


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(LoE): had participants taken the assigned treatment up to Week 12 (hypothetical 
strategy). 
3. Use of prohibited medications prior to Week 12 and not result in treatment 
discontinuation: ignore (treatment policy). 
4. Missed treatment prior to Week 12 due to other non-human controlled emergency 
situations (e.g. COVID-19): had participants not missed treatment prior to Week 12 
(hypothetical strategy). 
• The summary measure: 
1. Symptomatic Dermographism: difference in mean change from baseline in Total Fric 
Score at Week 12 between treatments (ligelizumab 72 mg q4w vs placebo and 
ligelizumab 120 mg q4w vs placebo) 
2. Cold urticaria: difference in mean change from baseline of CTT at Week 12 between 
treatments (ligelizumab 72 mg q4w vs placebo and ligelizumab 120 mg q4w vs 
placebo) 
3. Cholinergic urticaria: difference in mean change from baseline in itch NRS in 
response to the pulse-controlled ergometry test at Week 12 between treatments 
(ligelizumab 120 mg q4w vs placebo) 
2.2 
Secondary estimands 
For each subtype of CINDU, the secondary clinical questions of interest are similar as the 
primary clinical questions of interest and are based on the secondary endpoints. The only 
difference is that, for the endpoint of complete responder status, participants with 
discontinuation of initially assigned study treatment prior to Week 12 due to either AEs, or use 
of prohibited medications or lack of efficacy (LoE) will be considered as non-responders (i.e. 
composite strategy). 
The secondary estimand for each of the CINDU cohort is described by the following attributes: 
• Population: participants receiving H1-antihistamines therapy at local-approved dose level 
as background medication suffering from symptomatic dermographism, cold urticaria, or 
cholinergic urticaria and meeting study inclusion/exclusion criteria (as listed in Section 
5.1and Section 5.2). 
• Endpoints: 
• Symptomatic dermographism: 
proportion of participants achieving complete response (i.e. Total Fric score = 0) in 
the FricTest®4.0 at week 12. Participants with discontinuation of initially 
assigned study treatment prior to Week 12 due to AEs, use of prohibited 
medications or lack of efficacy (LoE) will be considered as non-responders. 
change from baseline to Week 12 in itch numeric rating scale (NRS) following the 
FricTest ®4.0. 
• Cold urticaria: 
proportion of participants achieving complete response (a negative provocation test 
result for the lowest temperature (4°C) in TempTest®4.0 at week 12. 
Participants with discontinuation of initially assigned study treatment prior to 


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Week 12 due to AEs, use of prohibited medications or lack of efficacy (LoE) 
will be considered as non-responders. 
change from baseline to Week 12 in itch numeric rating scale (NRS) following the 
TempTest®4.0 
• Cholinergic urticaria: 
proportion of participants achieving complete response in itch NRS (itch NRS =0) 
following the pulse-controlled ergometry test at Week 12. Participants with 
discontinuation of initially assigned study treatment prior to Week 12 due to 
AEs, use of prohibited medications or lack of efficacy (LoE) will be considered 
as non-responders. 
proportion of participants achieving complete response in physician global 
assessment of severity of hives (i.e. PGA hive score=0) following the pulse-
controlled ergometry test at week 12. 
Participants with discontinuation of initially assigned study treatment prior to Week 12 due to 
AEs, use of prohibited medications or lack of efficacy (LoE) will be considered as non-
responders. 
• The summary measure: 
Symptomatic dermographism and cold urticaria: 
1. difference in complete response rates at Week 12 between treatments (ligelizumab 72 mg 
q4w vs placebo and ligelizumab 120 mg q4w vs placebo) 
2. difference in mean change from baseline of itch NRS following provocation tests (i.e. 
FricTest® 4.0 and TempTest®4.0 for symptomatic dermographism and cold urticaria) at 
Week 12 between treatments (ligelizumab 72 mg q4w vs placebo and ligelizumab 120 mg 
q4w vs placebo) 
Cholinergic urticaria: 
1. difference in proportion of participants achieving itch NRS=0 at week 12 between 
treatments (ligelizumab 120 mg q4w vs placebo) 
2. difference in proportion of participants achieving PGA hive score=0 at week 12 between 
treatments (ligelizumab 120 mg q4w vs placebo) 
3 
Study design 
3.1 
Study design 
This is a Phase III multicenter, randomized, double-blind, placebo-controlled study to 
demonstrate superiority of ligelizumab 72 mg and/or 120 mg sc q4w over placebo as an add-on 
therapy to H1-antihistamines at local-approved doses in adolescents and adults for the treatment 
of Chronic Inducible Urticaria (CINDU). The study will be approximately 40 weeks in duration 
with the primary endpoint assessed at Week 12. There are 3 subtypes of CINDU populations 
being assessed in three parallel cohorts; symptomatic dermographism, cold urticaria and 
cholinergic urticaria. The study consists of 3 distinct periods: 


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Screening period (Day - 28 to Day 0): Duration of up to 4 weeks in which participants who 
have given informed consent are assessed for eligibility. 
Treatment period (24 weeks): There are 8 visits during this period. Participants will receive 
treatment at 6 visits (Week 0, Week 4, Week 8, Week 12, Week 16 and Week 20). No treatment 
will be given at Week 1 and Week 24 (End of Treatment visit). Provocation testing will be done 
at Week 0, Week 4, Week 8, Week 12 and Week 24. 
Follow-up period (12 weeks): The participants should be seen in the clinic every 4 weeks until 
Week 36. There will be no study treatment administered at these visits; provocation testing will 
be done at Week 36 only. 
Screening 
Participants will have up to 4 weeks for screening to establish eligibility for the study. The 
screening period can be shortened depending on the availability of the laboratory results and 
adherence to wash-outs related to non-allowed medication. Only in exceptional circumstances, 
when information concerning eligibility is outstanding (e.g pending laboratory data), will an 
extended period be permitted. Along with the participant's background medication, participants 
will also be allowed to take rescue medication (non sedating H1-AH) on an as needed basis for 
unbearable symptoms from screening up to the end of the study (Section 6.2.3). 
Rescreening may be allowed for participants who failed initial screening. Only 1 rescreening 
will be allowed (Section 5.1 and Section 5.2). If a participant is rescreened for the study, the 
participant must sign a new informed consent and will be issued a new participant number. 
Informed consent for a rescreened participant must be obtained prior to performing any study-
related assessments or collecting any data for the Screening visit. 
Double-blinded treatment period 
Symptomatic dermographism and cold urticaria cohorts: On Day 1, participants will be 
randomized equally into ligelizumab 120mg vs ligelizumab 72 mg vs placebo, with participants 
in the placebo arm being randomly re-allocated to ligelizumab 120 mg and ligelizumab 72 mg 
at week 12. Randomization will only be performed once at Day 1, in a 2:2:1:1 fashion into 4 
arms: ligelizumab 120 mg, ligelizumab 72 mg, placebo to ligelizumab 120 mg and placebo to 
ligelizumab 72 mg. 
During the treatment period, doses are administered at 6 visits; Week 0, Week 4, Week, 8, Week 
12, Week 16 and Week 20. No dose is administered at Week 1 (Day 8) visit. Participants 
randomized to the placebo arm will receive placebo for the first three treatment visits; Week 0, 
Week 4 and Week 8 and will then switch to ligelizumab 120 mg q4w or ligelizumab 72 mg q4w 
(1:1 ratio) for the remaining 3 treatment visits; Week 12, Week 16 and Week 20. Participants 
will continue to use their stable background therapy (H1-AH) at stable doses during the study. 
Cholinergic urticaria cohort: On Day 1, participants will be randomized into a 1:1 fashion to 
ligelizumab 120 mg q4w vs. placebo. Participants of the placebo arm will be allocated to 
ligelizumab 120 mg at Week 12. Participants of the cholinergic urticaria cohort will not receive 
the ligelizumab 72 mg dose (see rationale in Table 4.1). During the treatment period, doses are 
administered at 6 visits; Week 0, Week 4, Week, 8, Week 12, Week 16 and Week 20. No dose 
is administered at Week 1 (Day 8) visit. Participants randomized to the placebo arm will receive 
placebo for the first three treatment visits; Week 0, Week 4 and Week 8 and will then switch to 


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ligelizumab 120 mg q4w for the remaining 3 treatment visits; Week 12, Week 16 and Week 20. 
Participants will continue to use their stable background therapy (H1-AH) at stable doses during 
the study. 
At weeks 0, 4, 8, 12, 24 and 36 participants from all cohorts will be subjected to provocation 
tests in order to elicit symptoms. A positive response at Week 0 (Day 1) (see Section 8.3.1) to 
the FricTest®4.0, TempTest®4.0 or Pulse Controlled Ergometry is required to be randomized to 
the symptomatic dermographism, cold urticaria or cholinergic urticaria cohorts, respectively. 
Based on medical history, if a participant has more than one form of inducible urticaria 
(example: symptomatic dermographism and cold urticaria) then the participant must be 
considered for randomization into the group that is most bothersome to the participant. Since 
thresholds are not defined in CINDU, it is left to the investigator's judgement to enroll only 
those participants with moderate or severe disease burden. 
For the symptomatic dermographism cohort, it is planned to allocate approximately 168 
participants so that each treatment arm has 56 participants. For the cold urticaria cohort, it is 
planned to allocate approximately 102 participants so that each treatment arm has 34 patients. 
For the cholinergic urticaria, it is planned to allocate approximately 158 participants so that 
each treatment arm has 79 participants. For details on the calculation of the sample size for each 
of the three cohorts, see Section 12.8. 
Due to the low prevalence of this indication among the three cohorts, it is plausible that not all 
cohorts will be able reach their planned sample size, requiring modification of the sample size 
and modification to the statistical analysis with different data cut-offs for the different cohorts. 
Follow-up period 
The follow-up period is 12 weeks with the last follow-up visit (Week 36) corresponding to 16 
weeks after the last treatment dose. No study treatment will be given during the post-treatment 
follow-up period. Participants will continue with the background medication and will be 
allowed to take their rescue medication on an as needed basis,
 
 Participants will be required to visit the study center every 4 weeks during post-
treatment / follow-up period. 
Remote procedures 
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  ensure 
participant safety and trial integrity, the option of conducting the entire visit 105, 170 and visit 
180 remotely may be offered to participants. For any other visit it may also be possible to 
conduct certain assessments for safety and efficacy remotely as described within Section 8. Any 
assessment performed remotely will be performed under the oversight of the Investigator, who 
retains accountability for the oversight and all efficacy and safety decisions with delegation of 
tasks to an off-site healthcare professional (OHP). The remote procedures will be offered in 
certain countries and sites as determined by Novartis based on national and local regulations. 
The OHPs whether provided by Novartis or by the site must be agreed with Novartis before use.  


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Figure 3-1 
Study design 
 
3.2 
Provocation tests 
Important: Study treatment must NOT be administered before any provocation test.  
The procedure to perform the provocation tests are outlined in detail in the provocation test 
manual and should be followed.  
Participants from the three subtypes should avoid exposure to triggers 24 hours before their 
provocation test.  
For symptomatic dermographism and cold urticaria, participants must not have any CINDU 
related symptoms at the provocation test site for at least 24 hours prior to the provocation test. 
For cholinergic urticaria, participants with cholinergic urticaria are required to be symptom free 
before the start of the provocation test. 
All participants must avoid taking any rescue medication in the 24 hours prior to the provocation 
test. It is recommended to keep at least 30 minutes between provocation test and drug 
administration.  
For both cold urticaria and symptomatic dermographism participants, the provocation test will 
be applied to specific areas on the body e.g left volar forearm, upper back. The body area will 
be recorded in the eCRF (Electronic case report form). The body area must be free from 
inflammation, injuries, broken or infected skin and it is recommended that the same body part 
be used throughout the study. For cholinergic urticaria as the whole body is involved in the 


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provocation test, the different body areas where the hives appear will also be recorded in the 
eCRF. 
In certain situations, the provocation test may be repeated as long as the participant has refrained 
from taking rescue medication in the 24 hours preceding the repeat provocation test. 
For all three subtypes, if the provocation test was not performed correctly as per user 
instructions or if there were technical issues encountered during the provocation test or if the 
investigator suspects a false negative and the participant did not experience any symptoms, the 
test may be repeated. In this case, a minimum of 30 minutes is required between tests. 
For symptomatic dermographism and cold urticaria, if the participant did experience symptoms 
from the provocation test that was incorrectly performed, the test can be repeated at a different 
area on the skin that has been 24 hours symptom free. There has to be a minimum of 30 minutes 
between provocation tests. For cholinergic urticaria, if the participant did experience symptoms 
from the provocation test that was incorrectly performed, the test can be repeated after all 
symptoms have subsided. 
The results of the last repeat test are to be recorded in the eCRF. 
The number of times the test is repeated is left to the discretion of the investigator, taking the 
participant's safety and well-being into consideration. 
It should be noted, the provocation tests are considered to be completed correctly even if the 
test is stopped early due to participants reaching their maximum symptoms, results of which are 
to be recorded in the eCRF.  
4 
Rationale 
4.1 
Rationale for study design 
Table 4-1 
Rationale for study design 
Overall 
This is a Phase 3, parallel group, placebo-controlled, confirmatory study to 
evaluate efficacy of ligelizumab over placebo in chronic inducible urticaria. There 
are currently no approved therapies for patients with CINDU who remain 
symptomatic despite treatment with H1-antihistamines. Hence, even though the 
signs and symptoms of the disease can be burdensome, this study is designed as 
a placebo-controlled study, with a background therapy of H1-antihistamines. 
Additionally, comparison to placebo will provide an estimate of background 
incidence of possible safety findings in this rarely studied population. Among the 
various CINDUs, symptomatic dermographism, cold and cholinergic urticaria are 
reported to be the most prevalent forms globally (Maurer et al 2017, Maurer et al 
2018). Further, specific tools have been developed for these CINDUs to elicit 
disease symptoms in a reproducible manner. Based on these considerations, 
symptomatic dermographism, cold and cholinergic urticaria were selected for this 
proposed study. 
Randomization (strata, 
allocation ratio) 
On Day 1, using Interactive Response Technology (IRT), all eligible participants 
from the symptomatic dermographism and cold urticaria cohort will be randomized 
in a 2:2:1:1 ratio to ligelizumab 120 mg q4w, ligelizumab 72 mg q4w or placebo to 
ligelizumab 120 mg and placebo to ligelizumab 72 mg while all eligible participants 
from the cholinergic urticaria cohort will be randomized in a 1:1 ratio to ligelizumab 
120 mg q4w or placebo to ligelizumab 120 mg. The data from the completed 
Phase 2 dose range finding study - CQGE031C2201 suggest that the 72 mg q4w 
dose can achieve rapid and good control of symptoms and a dose higher than 72 


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mg q4w can provide enough drug exposure throughout the dosing interval such 
that relapse of symptoms is minimal. These data coupled with the overall low 
prevalence for cholinergic urticaria compared to symptomatic dermographism and 
cold urticaria are reasons for evaluating only the higher dose of 120 mg q4w in the 
cholinergic urticaria subtype. Since both adults and adolescent participants will be 
enrolled into this study, randomization will be stratified by age group (adolescent 
12-17 years old and adult ≥ 18 years old). Randomization of adults will be further 
stratified by region to ensure a balanced assignment to each treatment group. 
Blinding 
Blinding participants to the treatment they have received in a controlled trial is 
particularly important when the response criteria are subjective such as assessing 
severity of itch. Double-blinding is used in this study up to week 12 to minimize 
bias in the evaluation of safety and efficacy assessments. It will allow for unbiased 
assessment of the improvement in terms of CINDU control for participants with 
disease not controlled by background medication who are treated with ligelizumab, 
in comparison to those continuing solely on background medication. 
Duration of study 
periods 
Data from the completed CQGE031C2201 and CQGE031C2201E1 studies shows 
a rapid onset and sustained efficacy beyond 12 weeks of treatment. A treatment 
period of 24 weeks is more than the 12- week treatment period in the omalizumab 
studies (Maurer et al 2018) in symptomatic dermographism and cold urticaria and 
is considered sufficient to demonstrate the efficacy of ligelizumab in the three 
subtypes of CINDU. The ongoing pivotal Phase 3 studies with ligelizumab in CSU 
consist of 1-year treatment with 72 and 120 mg s.c. q4w doses of ligelizumab with 
a primary endpoint at week 12. The similarities between CSU and CINDU allow for 
further inference of sustained efficacy and safety following longer ligelizumab 
treatment duration from the Phase 3 studies in CSU. The 12 week follow-up period 
is consistent with the ongoing Phase 3 CSU trials and was selected based on the 
half-life of ligelizumab. 
Study population 
The symptoms and natural course of disease, burden of disease and unmet 
medical need for CINDU appear to be similar in both adult and pediatric 
populations.therefore, adolescents are also being included in this study. This is 
similar to the approach taken for the pivotal Phase 3 CSU studies. 
To prevent any confounding effect of CSU symptoms, the study population will 
consist of participants with only CINDU and no concomitant CSU. 
Only ligelizumab- and omalizumab-naïve participants will be enrolled. This is done 
to avoid any potential influence of prior treatment with an anti-IgE antibody on the 
disease outcome, and avoids potential selection bias based on results of prior 
exposure in the study population. 
4.1.1 
Rationale for choice of background therapy 
The choice for background medication in this study is based on the current standard of care for 
treatment of CINDU. The study requires that all participants, regardless of the treatment arm 
they get randomized to, must use one second generation-H1-AH at local-approved doses 
(approved by the local Health Authority) as background medication. Participants must remain 
on a stable treatment regimen (type and dose of H1-AH) throughout the study. If a participant 
must switch to another background H1-AH (at approved dose) as a result of an AE or due to 
unavailability of medication in the country, the participant will be considered to have remained 
on stable treatment. 
4.1.2 
Rationale for use of provocation testing to elicit urticaria 
Since the symptoms can occur upon exposure to commonly used items such as clothing, belts, 
etc. or common daily activities, self-reporting by patients can be high in CINDU. In a recent 
study by Sánchez et al, the authors reported that 76% of patients with CSU reported a physical 
trigger to their symptoms although only 36.3% had a positive response to a challenge test 


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(Sánchez et al 2017). The outcome of a challenge test i.e., eliciting urticaria in a clinical setting 
substantiates the diagnosis and also allows quantification of the symptoms. The results from the 
test also serve as a guide to both the patient and physician to help inform appropriate avoidance 
measures and potential treatment options. Methods and specific devices that have been 
developed to elicit urticaria allow for a systematic approach to study CINDU thus 
circumventing the uncertainty created by a patient’s avoidance of triggers, and allowing for a 
true estimation of treatment effect. Hence, in the proposed clinical study, FricTest®4.0, the 
TempTest®4.0 and pulse-controlled ergometry will be used to elicit symptoms caused by 
symptomatic dermographism, cold urticaria and cholinergic urticaria, respectively. In order to 
keep participant burden at a minimum, provocation testing will be done only at randomization, 
Week 4, 8, 12, 24 and 36. 
4.2 
Rationale for dose/regimen and duration of treatment 
Ligelizumab 72 and 120 mg s.c. q4w will be evaluated in symptomatic dermographism and 
cold urticaria cohorts for treatment of CINDU.  Given the overall low prevalence of cholinergic 
urticaria and the modeling and simulation data from CSU suggesting sustained efficacy 
throughout the dosing interval with the 120 mg dose, only the 120 mg dose is being evaluated 
in cholinergic urticaria. There is no evidence to suggest that ligelizumab will have a different 
mode of action or cleared differently in adolescents versus adults. Hence, the same doses of 
ligelizumab are being evaluated in both adolescents and adults. 
The rationale for selection of ligelizumab doses is as follows: 
• A robust phase 2b dose range finding study with ligelizumab in CSU which led to the 
choice of 72 and 120 mg s.c. q4w for the ongoing Phase 3 pivotal CSU studies. 
• Approximately 2100 patients enrolled in the ongoing Phase 3 pivotal CSU studies, with no 
overt safety events observed so far. 
• Clinical and pathophysiological similarities between CSU and CINDU resulting in similar 
manifestation of the disease i.e. hives and/or angioedema (Maurer et al 2018). 
• An efficacy signal for omalizumab, another anti-IgE in CINDU at the same doses as those 
approved for CSU (Maurer et al 2018, Dressler et al 2018). 
• A similar safety profile between CSU and CINDU is anticipated. 
Rationale for route of administration 
In the ongoing and completed CSU studies, ligelizumab has been administered subcutaneously. 
The subcutaneous (s.c.) route of administration will continue to be used in this study, based on 
the favorable bioavailability and tolerability demonstrated with s.c. administration of 
ligelizumab in previous studies and the ease of administration via this route. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Placebo is used as a comparator in this study for the following reasons: 
• to allow blinding of investigators and participants to treatment and thereby minimizing 
bias in the evaluation of safety and efficacy assessments, 


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• to allow assessment of the improvement of disease in participants with CINDU not 
controlled by background medication who are treated with ligelizumab, in comparison to 
those continuing solely on background medication, and 
• to allow the assessment of safety of ligelizumab on top of background medication 
compared to background medication alone. 
To minimize exposure to placebo, all participants in the placebo arm will receive either 
ligelizumab 72 or 120 mg s.c. q4w, at Week 12 of study participation. 
4.4 
Purpose and timing of interim futility analyses 
Due to the low prevalence of cholinergic urticaria, an interim analysis may be conducted in case 
there is an obvious difference in recruitment speed between the three cohorts. The interim 
futility analysis may be triggered when approximately 50% of randomized participants in the 
cholinergic urticaria cohort have completed the Week 12 visit and all randomized participants 
in the symptomatic dermographism and cold urticaria cohorts have completed the Week 12 visit. 
Depending on the outcome of the futility analysis, further recruitment in cholinergic urticaria 
subtype may be stopped or continued as planned. Participants who have already been enrolled 
in the study prior to the futility analysis will continue to remain the study. 
4.5 
Risks and benefits 
This study investigates the efficacy and safety of ligelizumab in participants with CINDU 
inadequately controlled with H1-AH, and seeks to address a significant unmet treatment need 
in this patient population. In all the clinical studies thus far, the highest single dose of 
ligelizumab administered to participants intravenously (iv) was 10 mg/kg (CQGE031A2102 
study) and subcutaneously (s.c) was 420 mg (CQGE031B2101 study). The highest multiple 
dose of ligelizumab administered to participants was up to six s.c administrations of 280 mg 
once every 2 weeks (CQGE031X2201 study). The longest exposure to ligelizumab is 
approximately 
17 
months 
(across 
studies 
CQGE031B2201, 
CQGE031B2201E1, 
CQGE031C2201 and CQGE031C2201E1). 
Potential risks related to study treatment for study participants 
The most common AEs reported at a greater frequency after s.c. administration of ligelizumab 
as compared to placebo were upper respiratory tract infections (including nasopharyngitis), 
injection site reactions and headache. A brief summary of identified and potential risks with 
ligelizumab that require close monitoring during the study is listed below. Please refer to the 
Ligelizumab Investigator Brochure for more details on each of these risks. 
Injection site reactions 
Majority of the injection site reactions (ISR) events reported in ligelizumab clinical studies were 
mild (94%) in severity. No ISRs were reported as severe or serious adverse events (SAEs) in 
the CQGE031C2201 and CQGE031C2201E1. Majority of ISRs resolved spontaneously 
without treatment either on the same day or next day of study drug administration and did not 
require discontinuation of study drug.  
 


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Hypersensitivity reactions (including anaphylaxis) 
Hypersensitivity reactions are anticipated AEs to biologics class of drugs. For all the completed 
and prematurely terminated studies (non-CSU), hypersensitivity events were comparable 
amongst the ligelizumab and the placebo groups (7.6% on ligelizumab treatment and 6.1% on 
placebo treatment). In the completed CSU studies, hypersensitivity events were noted in 30.2% 
on ligelizumab treatment and 20.9% on placebo treatment. 
An adjudication committee (AC) was put in place after the start of CQGE031B2201 study 
(Phase IIa in asthma) to assess events that could potentially represent anaphylactic reactions. In 
the completed studies, in asthma and CSU indications, four patients in ligelizumab arm 
experienced anaphylaxis, positively adjudicated. Three cases have been positively adjudicated 
as anaphylaxis in the ongoing blinded studies. 
Investigators should be alert to the occurrence of hypersensitivity events. Investigators should 
be familiar with the diagnosis and treatment of allergic and anaphylactic reactions and have on 
hand injectable epinephrine, antihistamine, corticosteroids, IV supplies, oxygen, an oral airway, 
Ambu bag, etc. when administering the study treatment. Appendix 4 includes the diagnostic 
criteria for anaphylaxis (Sampson et al 2014) and Appendix 7 includes the grading guidance for 
allergic reactions. In the clinical studies with ligelizumab, patients are required to be monitored 
on site for two hours during the first three administrations and for a 30-minute observation 
period for the remaining treatment visits. In this trial as there is a switch from placebo to 
ligelizumab, to maintain blinding, all participants will be required to be monitored onsite for 
two hours during all six treatment visits. Participants who experience severe hypersensitivity 
reactions should be immediately discontinued and not allowed to participate in future 
ligelizumab studies. Please note additional discontinuation criteria related to anaphylaxis or 
severe hypersensitivity reactions in Section 9.1.1 
Participants with conditions or medications that would complicate the diagnosis and treatment 
of anaphylaxis should not be enrolled in this trial. 
Treatment should be immediately employed for any signs or symptoms suggesting anaphylaxis 
(e.g. decrease in systolic or diastolic blood pressure and/or bronchospasm requiring emergency 
treatment). Prior to discharge, participants should be counseled by site personnel to watch for 
symptoms of anaphylaxis such as bronchospasm, urticaria, angioedema or hypotension. As an 
additional safety precaution, participants will be instructed on the management of suspected 
anaphylactic events (e.g. the use of epinephrine, seeking urgent medical care) should they 
suspect they are having such an event. 
Further, the ligelizumab program has an AC that independently assesses events that could 
potentially represent anaphylactic events. 
Immunogenicity (anti-drug antibodies) 
All biologics have the potential to induce anti-drug antibodies (ADAs). Across all studies and 
in all different populations (including but not limited to patients with bullous pemphigoid, 
atopic dermatitis, asthma and CSU) so far, ADAs against ligelizumab were formed in 
approximately 15% of subjects. The occurrence of ADAs was only noted after prolonged 
treatment (i.e. after 3rd or 4th monthly dose of ligelizumab. For majority of the ADAs the titres 
were low and transient in nature. In only a few ADA positive subjects the occurrence of ADAs 


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appeared to correlate with loss of exposure. The variability in the data set on total IgE did not 
allow to draw conclusions on the impact of ADA formation on target engagement in the absence 
of a neutralizing Ab assay. When correlating the timing and incidence of occurrence of ADAs 
with AEs, there was no clear correlation between ADA formation and AEs, because the AEs 
were either equally distributed between ADA positive and ADA negative subjects or the 
occurrence of ADAs was separated in time from the AEs. Given the trend for similar rates 
across different populations, and similar pathophysiology between CSU and CINDU, we can 
anticipate that the rate of ADA formation to be similar to that noted in the completed CSU 
studies. 
Serum sickness: While to date no such events have been reported in the ligelizumab database, 
immune complex formation triggering serum sickness or vasculitis is a potential risk of 
monoclonal antibody administration. 
Thrombocytopenia 
No effects on platelets or signs of thrombocytopenia have been observed with ligelizumab in 
the nonclinical safety studies in adult and juvenile cynomologous monkeys. Severe 
thromobocytopenia was reported in preclinical studies in cynomolgous monkeys with high 
doses of omalizumab but has not been seen in humans. The current ligelizumab protocols 
include monitoring of platelets as part of the hematology assessment and participants with 
counts below 75,000 /µL should be discontinued. 
Parasitic infections 
IgE is an antibody that may have role in adaptive immune response 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 participants at high risk of 
geohelminth infection who receive ligelizumab. 
Potential risks due to study procedures to study participants: 
• Provocation tests 
The provocation tests used in the study (FricTest®4.0, TempTest®4.0 and pulse-controlled 
ergometry) are commonly used, are highly sensitive and specific for diagnosing and inducing 
symptoms associated with CINDU. Specific to cholinergic urticaria, the provocation test 
involves physical exercise to induce symptoms of CINDU. Since the ergometry is pulse-
controlled, the provocation is gentle (Altrichter et al 2014). Mild increases in body temperature 
following physical exercise are likely. In the study by Altrichter et al, the maximum increase in 
body temperature from baseline noted in cholinergic urticaria patients was 2.52 °C versus 2.31° 
C in healthy volunteers. The provocation test allows for recording of time to occurrence of hives. 
In the same study by Altrichter et al, the authors noted that while the median time to hives was 
27 minutes, 19 minutes was the earliest time to occurrence of hives. The investigator will be 
instructed to keep patient safety as a priority and if participants experience uncontrolled hives 
or any discomfort within a short timeframe of initiation of provocation, the test may be stopped. 
Management of the reactions should be first considered, following with the administration of 
study treatment once the participants recover. 
 


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Risk management 
A Data Monitoring Committee (DMC) was established in 2018 to review the data from all 
ongoing Chronic Urticaria studies (CQGE031C2202, CQGE031C2302E1, CQGE031C2302 
and CQGE031C2303). To date, after review of all the data the DMC has recommended no 
change to the conduct of these ongoing studies. 
The non-clinical safety evaluation for ligelizumab supports the development of ligelizumab in 
the pediatric population. There is no evidence to suggest that ligelizumab will have a different 
mode of action or will be cleared differently in pediatric versus adult participants. 
No new or unexpected safety signals have been identified in the completed or ongoing studies 
thus far, including the recently completed Phase 2b study (CQGE031C2202) in adolescent 
patients with CSU as well two ongoing Phase 3 studies (CQGE031C2302 and CQGE031C2303) 
in adult and adolescent patients with CSU. The inclusion and exclusion criteria are selected to 
enroll participants with CINDU who are likely to benefit from participating in the study. The 
overall risk will be minimized by compliance with the inclusion/exclusion criteria, protocol 
guidance on managing side effects, discontinuation criteria, close clinical monitoring, 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 
participants to continue in the study as long as possible. 
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. 
Women of child-bearing potential 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
Potential benefits to study participants 
There is evidence that CINDU is an IgE-mediated disease similar to CSU. Literature evidence 
shows that omalizumab, an anti-IgE antibody, is effective in the treatment of refractory 
CINDUs, further substantiates the role of IgE in CINDU. The data from CQGE031C2201 
demonstrated significant improvement of CSU symptoms including itch, hives, angioedema 
and quality of life (QoL), with ligelizumab treatment. In the same study, at Week 12, a 
statistically significantly higher proportion of ligelizumab treated patients (72 and 240 mg q4w) 
achieved complete hives response (Hive Severity Score7=0) compared to omalizumab 300 mg 
q4w. Considering the evidence of treatment benefit with IgE suppression in CINDU, and a 
superior suppression of IgE with ligelizumab compared to omalizumab, it is anticipated that 
ligelizumab treatment in patients participating in the current study could result in significant 
improvement in their disease symptoms and overall quality of life. 


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4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
The study population will consist of both adolescents and adults. Approximately 428 male and 
female participants aged ≥ 12 years who have been diagnosed with symptomatic 
dermographism, cold urticaria or cholinergic urticaria and who remain symptomatic despite the 
use of H1-AH at the approved dose level. Of these, approximately 168, 102 and 158 adolescent 
and adult participants with symptomatic dermographism, cold urticaria and cholinergic urticaria, 
respectively, are planned for inclusion in the study. An approximate 10% study drop-out rate is 
included in estimating the sample size. As recruitment of adolescents is expected to be low due 
to the very low prevalence of CINDU in the pediatric population, no minimum number of 
adolescents is defined as required neither for any of the CINDU subtypes nor for the overall 
study population.  
It is anticipated that approximately 612 participants will need to be screened in order to 
randomize approximately 428 participants into the 24 week treatment period due to an estimated 
screening failure rate of approximately 30%. Participants that drop out of the trial will not be 
replaced. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained before any assessment is performed. 
2. Participant’s parent’s or legal guardian’s signed informed consent and child’s assent, if 
appropriate, must be obtained before any assessment is performed. Of note, if the 
participant 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 participants ≥ 12 years of age at the time of screening (NOTE: 
Recruitment of adolescent participants, ≥ 12 to <18 years of age, will be in accordance 
with local regulatory/ethics committee requirements).  
4. Confirmed CINDU diagnosis (as per guidelines) for symptomatic dermographism, cold 
urticaria or cholinergic urticaria for ≥ 4 months (defined as onset of CINDU with 
supporting documentation (e.g medical record, clinical history, photographs)). 
5. Diagnosis of CINDU (symptomatic dermographism, cold urticaria or cholinergic urticaria) 
inadequately controlled with H1-AH at local label approved doses at the time of 
randomization, as defined by all of the following: 
a. Positive response (i.e., development of symptoms) to triggers despite treatment with 
H1-AH 


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b. Positive response (i.e., development of symptoms, see Section 8.3.1) to provocation 
test on day of randomization 
 
6. Participants must be able to physically perform the protocol defined provocation test 
specific to the participant's CINDU. 
7. Cholinergic urticaria participants must show sweating in performing the pulse-controlled 
ergometry test on day of randomization. Participants with anhidrosis must not be included. 
8. Willing and able to complete a daily symptom eDiary as per protocol requirement and 
adhere to the study visit schedules. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days for 
small molecules prior to the screening visit 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 its components or to drugs of 
similar classes (i.e. to murine, chimeric or human antibodies) or to the provocation test or 
items used in provocation tests 
3. Participants who have concomitant CSU at screening 
4. Participants who have a familial form (e.g familial cold autoinflammatory syndrome, 
familial cold urticaria) of the target CINDU that is being considered for the participant's 
inclusion in this study 
5. Participants having a more defined other form of inducible urticaria than the target 
CINDU that is being considered for the participant's inclusion in this study 
6. Diseases, other than chronic inducible 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). 
7. 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.) or skin diseases associated with 
only wheals and no itch e.g asymptomatic dermographism 
8. Participants with evidence of helminthic parasitic infection as evidenced by stools being 
positive for a pathogenic organism according to local guidelines. All participants will be 
screened at Visit 1 (see Section 8.4). If stool testing is positive for pathogenic organisms, 
the participant will not be randomized and will not be allowed to rescreen. 
9. Prior exposure to ligelizumab, omalizumab or other anti-IgE therapies. 
10. Any H1-AH used as stable background medication at greater than local label approved 
doses after screening visit (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). 


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14. Contraindications to or hypersensitivity to drugs used in the study including but not 
limited to fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine, rupatadine, 
epinephrine or any of their ingredients. 
15. Documented history of anaphylaxis including exercise induced anaphylaxis (not related to 
anaphylactoid-like reaction associated with CINDU). 
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 screening visit (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 participants, 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. Participants with history of HIV (Human immunodeficiency virus) infection. 
20. Participants with evidence of or history of chronic hepatitis B virus (HBV) infection 
and/or hepatitis C virus (HCV) infection. 
21. History of, or current treatment for, hepatic disease including but not limited to cirrhosis 
or hepatic failure or AST (aspartate aminotransferase)/ALT (alanine 
aminotransferase)/albumin/TBL (total bilirubin )/ levels of more than 1.5x upper limit of 
normal (ULN) at screening visit (Visit 1). 
22. History of renal disease or creatinine level above 1.5x ULN at screening visit (Visit 1). 
23. Platelets < 100 000/μL at screening visit (Visit 1). 
24. History of long QT syndrome or whose QTcF (Fridericia) measured at screening visit 
(Visit 1) is prolonged (> 450 ms for males or > 460 ms for females). 
25. Pregnant or nursing (lactating) women. 
26. Female participants, 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 effective methods of contraception during dosing of study 
treatment. Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable effective methods of 
contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 


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taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository 
• 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 study treatment. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms). Women are considered not of child bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
6 
Treatment 
6.1 
Study treatment 
Study treatment includes investigational drug and placebo. Novartis Global Clinical Supply 
(GCS) will provide these investigational products in an open-label fashion. Unblinded 
pharmacists are responsible at sites towards IMP accountability. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ Control 
Drug 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor 
(global or local) 
Ligelizumab 120 mg per 
1 mL 
Liquid in vial (solution 
for injection) 
s.c 
Open label kits; 
vials 
Novartis Pharma 
AG 
Ligelizumab Placebo 0 
mg per 1 mL 
Liquid in vial (solution 
for injection) 
s.c 
Open label kits; 
vials 
Novartis Pharma 
AG 
For 72 mg arm, 0.6 mL of 1mg/mL solution will be administered 


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6.1.2 
Additional study treatments 
No other treatment beyond investigational drug (ligelizumab) and control drug (placebo to 
ligelizumab) are included in this trial. Participants will continue to use their background 
medication H1-AH (at local-approved doses) with a stable regimen during the study. For rescue 
medication, see Section 6.2.3. 
6.1.3 
Supply of study treatment 
Novartis Global Clinical Supply (GCS) will supply the investigational drug and the placebo. 
GCS will not supply other treatment that are listed in Section 6.2. 
6.1.4 
Treatment arms/group 
Participants in the symptomatic dermographism and cold urticaria cohorts will be assigned at 
Week 0 to one of the following 4 treatment arms in a ratio of 2:2:1:1. Each participant will 
receive 1 injection every 4 weeks at the clinic: 
• Ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab 
• Ligelizumab 72 mg arm: 1 injection of 0.6 mL ligelizumab 
• Placebo / ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab placebo from Week 
0 through Week 8; 1 injection of 1.0 mL ligelizumab from Week 12 through Week 20 
• Placebo / ligelizumab 72 mg arm: 1 injection of 0.6 mL ligelizumab placebo from Week 0 
through Week 8; 1 injection of 0.6 mL ligelizumab from Week 12 through Week 20 
Participants in the cholinergic urticaria cohort will be assigned at Week 0 to one of the following 
2 treatment arms in a ratio of 1:1. Each participant will receive 1 injection every 4 weeks: 
• Ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab 
• Placebo / ligelizumab arm: 1 injection of 1.0 mL ligelizumab placebo from Week 0 
through Week 8; 1 injection of 1.0 mL ligelizumab from Week 12 through Week 20 
During the double-blind treatment period, study drug will be administered at 6 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. All study treatment dispensing visits will occur at 
the clinic. 
6.1.5 
Treatment duration 
The planned duration of treatment is 24 weeks, with the last planned dispensing visit for every 
participant at week 20. Discontinuation of the study drug treatment can be initiated by either 
the participant or the investigator (Section 9.1.1). 
Participants who complete participation in this trial prior to the investigational treatment 
becoming available in the country of the participant and continues to derive clinical benefit 
from the treatment based on the investigator’s evaluation may receive post-trial access. Post 
Trial Access (PTA) means the provision of treatment to trial participants following their 
completion of trial participation. PTA will be provided until one of the following is met: 
participant no longer derives clinical benefit, investigator discontinues treatment, launch or 


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reimbursement (where applicable), treatment fails to achieve registration in the trial 
participant’s country, or the clinical program is discontinued for any other reason. 
Mechanisms for provision of PTA may include an extension phase to this study, a separate 
extension protocol, a rollover protocol, a registry trial, provision of the Novartis investigational 
product in a non-trial setting (known as post-study drug supply (PSDS)) when no further safety 
or efficacy data are required, or any other mechanism appropriate for the country. 
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition patients onto locally available alternative treatment, or standard of care. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
This study requires concurrent use of one second generation H1-AH at local approved doses as 
background medication. Participants must remain on a stable treatment regimen (type and dose 
of H1-AH) throughout the study. If a participant must switch to another background H1-AH (at 
approved dose) as a result of an AE or it being no longer available in the country, the participant 
will be considered to have remained on stable treatment. 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate 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 participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
6.2.2 
Prohibited medication 
Use of the class of treatments displayed in Table 6-2 is NOT allowed after start of screening 
(Visit 1) and up until after the end of the follow-up period. The minimum required period 
without prohibited treatment before screening visit (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 participant or allowing a new medication to be started. 
Table 6-2 
Prohibited medication 
Medication 
Prohibition period 
prior to Screening visit 
(Visit 1) 
Action taken if prohibited 
medication is administered 
Omalizumab 
No prior use allowed 
Discontinue from study 
Ligelizumab 
No prior use allowed 
Discontinue from study 
Routine (daily or every other day during 
more than one consecutive day /month) 
doses of systemic corticosteroids* 
30 days prior to Visit 1 
Stop prohibited treatment 


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Medication 
Prohibition period 
prior to Screening visit 
(Visit 1) 
Action taken if prohibited 
medication is administered 
IV/IM/IA corticosteroids 
30 days prior to Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
Beta-blocker therapy 
7 days prior to Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
Leukotriene antagonists 
Stop at Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
H2-antihistamines 
Stop at Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
First generation H1-antihistamines 
Stop at Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
Hydroxychloroquine or chloroquine 
30 days prior to Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
Other immunosuppressive and 
immunomodulatory medication with or 
without known effect on CINDU 
including but not limited to 
Methotrexate, cyclosporine A, 
cyclophosphamide, tacrolimus and 
mycophenolate mofetil, anti-IL-1, anti-
TNF-alpha 
30 days prior to Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
Intravenous immunoglobulin G 
30 days prior to Visit 1 
Discontinue study treatment 
Plasmapheresis 
30 days prior to Visit 1 
Discontinue study treatment 
Regular (daily or every other day) 
doxepin (oral) 
14 days prior to Visit 1 
Stop prohibited treatment or 
discontinue from study treatment 
Vaccination with inactivated viruses 
48 hours prior to each dosing 
visit (i.e. Week 0 to Week 20) 
Stop prohibited treatment 
Live attenuated vaccine 
30 days prior to Visit 1 
Discontinue study treatment 
*Corticosteroids (CS) with limited systemic exposure for non-CINDU indications can be used (e.g. Intra nasal or 
any topical CS) on an as-needed basis. 
If the prohibited treatment was used during the study for any indication, the participant must 
discontinue use of the prohibited treatment if the participant wishes to continue in the study. If 
the participant must continue a prohibited medication during the study, the participant must 
discontinue study treatment. If the participant receives a live virus vaccination during the study, 
the participant must discontinue study treatment. 
Table 6-2 is not considered all inclusive. Medication should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. 
6.2.3 
Rescue medication 
If unbearable symptoms occur during the study, investigators must instruct participants on the 
acceptable treatment for managing their disease with the use of rescue medication, thereby 
allowing participants to continue in the study as long as possible. Investigators must instruct 
participants to assess the need for rescue medication on a day-by-day basis, following the 
limitations for H1-AH rescue medications and adhering to local regulations. It is only during 
the 24 hours prior to the provocation visit, participants must avoid taking any rescue medication 
(see Section 3.2). 




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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
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. 
6.3.1.2 
Handling of additional treatment 
Not applicable. 
6.3.2 
Instruction for prescribing and taking study treatment 
Table 6-3 
Dose and Treatment schedule 
Investigational / Control Drug (Name and Strength) 
Dose 
Frequency and/or Regimen 
QGE031 120 mg per 1 mL  
1 mL  
Every 4 weeks 
QGE031 120 mg per 1 mL 
0.6 mL  
Every 4 weeks 
Ligelizumab Placebo 0 mg per 1 mL 
1 mL 
Every 4 weeks 
Ligelizumab Placebo 0 mg per 1 mL 
0.6 mL 
Every 4 weeks 
The independent study drug administrator will administer the study treatment to the participant 
during the study visit without engaging in any unnecessary interactions that may have the 
potential to unblind the participant or any of the study site personnel. 
The injection 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 participant and/or site. The injection 
is 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. The injections 
should not be administered on damaged skin and the injections sites should be rotated. 
The guidelines for the preparation and administration of study medication are described in the 
Pharmacist Manual. 
Participants will remain on-site for observation for a period of 2 h post-dose for all visits where 
study drug treatment is administered. 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 2011) 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 participant rapidly to an emergency department/hospital). Prior to 
discharge, participants should be counseled by site personnel to watch for symptoms of 
anaphylaxis such as bronchospasm, urticaria, angioedema or hypotension. As an additional 
safety precaution, participants will be instructed on the management of suspected anaphylactic 
events should they suspect they are having such an event. 


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Except for participants on placebo, the participant will receive the same dose at all treatment 
administration visits. Participants on placebo will be switched at week 12 to ligelizumab and 
will receive the same dose at subsequent treatment visits. 
All study drug dosages prescribed and dispensed to the participant 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 participant 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 participant’s safety and the validity of the study. The participant 
must also be instructed to contact the investigator if he/she is unable for any reason to take the 
study treatment as prescribed. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment. The Participant No. consists of the Center Number (Center No.) (as 
assigned by Novartis to the investigative site) with a sequential participant number suffixed to 
it, so that each participant’s participation is numbered uniquely across the entire database. Upon 
signing the informed consent form, the participant is assigned to the next sequential Participant 
No. available in the EDC system. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. Only 
one rescreening will be allowed per participant. 
6.4.2 
Treatment assignment, randomization 
At Week 0 (Day 1/Visit 100), all eligible participants in the symptomatic dermographism and 
cold urticaria cohorts will be randomized into 4 arms via IRT in a 2:2:1:1 ratio to ligelizumab 
120 mg, ligelizumab 72 mg, placebo to ligelizumab 120 mg or placebo to ligelizumab 72 mg 
while all eligible participants in the cholinergic urticaria cohort will be randomized in a 1:1 ratio 
to ligelizumab 120 mg or placebo to ligelizumab 120 mg. The investigator or his/her delegate 
will contact the IRT system after confirming that the participant fulfills all the 
inclusion/exclusion criteria. The IRT call must be made only after provocation test results are 
available. 
The IRT system will assign a randomization number to the participant, which will be used to 
link the participant to a treatment arm and will specify a unique medication number for the 
package of study drug treatment to be dispensed to the participant. This information will not be 
provided to the blinded site user. Only the unblinded pharmacist or delegate can access the 
participant treatment details and is provided with the kit details. All kits of study treatment 
assigned by the IRT will be recorded in the IRT system. 






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Table 6-4 
Blinding and unblinding plan 
 
Time or Event 
Role 
Randomization 
list generated 
Treatment 
allocation 
& dosing 
Safety 
event 
(single 
participant 
unblinded) 
DMC 
Interim 
Futility 
Analysis 
Participants 
B 
B 
B 
B 
Site staff 
B 
B 
UI 
B 
Novartis CTT 
B 
B 
B 
B 
Global Clinical Supply 
B 
UI 
UI 
UI 
Randomization office 
UI 
UI 
UI 
UI 
Unblinded site staff e.g. pharmacy staff and 
study drug administrator 
Unblinded sponsor staff e.g. for study treatment 
re-supply, unblinded monitor(s), sample 
analyst(s) 
B 
UI 
B 
B 
Unblinded Pharmacovigilance sponsor staff 
B 
B 
UI 
B 
{Independent}Statistician/ statistical 
programmer/data analysts 
 
 
B 
UI 
B 
UI 
Independent committees used for assessing 
interim results, if required (e.g. DMC) 
B 
UI 
UI 
UI 
Adjudication committee 
B 
B 
B 
B 
Steering committee 
B 
B 
B 
B 
All other Sponsor staff not identified above(i.e 
project team, support functions) 
B 
B 
B 
B 
UI: Allowed to be unblinded on individual participant level  
B: Complete blinded 
6.6 
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 participant’s eligibility to continue 
study treatment. 
The decision to interrupt or defer study treatment in case of a suspected and symptomatic 
COVID-19 or similar type of disease should be based on investigator judgment and should take 
into account factors such as severity of symptoms, comorbidities, and the course of the infection. 
E.g., very mild symptoms in an otherwise healthy participant or resolving symptoms at the time 
of notification to the investigator may not necessarily require treatment interruption. 
Any missed or altered study drug administration must be recorded on the appropriate eCRF in 
order to reconstruct an accurate dosing history for each participant. 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
Participants will receive 1 subcutaneous injection every 4 weeks at 6 visits during the double-
blind treatment period. Compliance of the study drug is assured as study drug must / will be 


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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. 
The investigator must promote compliance by instructing the participant to take the background 
and rescue medication exactly as prescribed and by stating that compliance is necessary for the 
participant’s safety and the validity of the study. The participant must also be instructed to 
contact the investigator if he/she is unable for any reason to take the background and rescue 
medication as prescribed. 
6.7.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to treat the participant 
safely. Most often, discontinuation from study treatment and knowledge of the possible 
treatment assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT by the investigator 
or delegate. When the investigator or delegate contacts the system to break a treatment code for 
a participant, he/she must provide the requested participant identifying information and confirm 
the necessity to break the treatment code for the participant. The investigator will then receive 
details of the study drug treatment for the specified participant and a fax or email confirming 
this information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
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 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
the investigator's backup in cases of emergency, or when he/she is unavailable, to ensure that 
un-blinding can be performed at any time. 
Study treatment must be discontinued after emergency unblinding. After an emergency break, 
the participants may not be eligible for post-trial access. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local regulatory/ethics committee requirements), the participant must be informed 
about the study to the extent possible given his/her level of understanding. If the participant is 
capable of doing so, he/she must indicate agreement by personally signing and dating the 
written informed consent document. 






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the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 


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Table 8-1 
Assessment Schedule 
Period 
Screening 
Treatment 
Follow-Up 
USV 
Visit Name 
Screening 
Randomization 
Treatment 
EOT/TD 
Follow-Up 
EOS/PSD 
UPV 
Visit Numbers1 
1 
100 
105 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-28 to -1 
1 
8 
29 
57 
85 
113 
141 
169 
197 
225 
253 
- 
Weeks 
-4 to -1 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
- 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for 
optional exit interview for 
adults only (at selected 
sites/countries)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history 
(including CINDU history) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Evidence of urticaria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior urticaria treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Family malignancy history 
(eCRF to be completed if 
participant develops 
malignancy during the 
study) 
 
X 
Prior and Concomitant 
medication usage 
X 
Surgery and Procedures 
X 


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Period 
Screening 
Treatment 
Follow-Up 
USV 
Visit Name 
Screening 
Randomization 
Treatment 
EOT/TD 
Follow-Up 
EOS/PSD 
UPV 
Visit Numbers1 
1 
100 
105 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-28 to -1 
1 
8 
29 
57 
85 
113 
141 
169 
197 
225 
253 
- 
Weeks 
-4 to -1 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
- 
Rescreening (rescreening 
eCRF should be recorded 
if the participant is 
rescreened) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IRT registration 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Participants’ 
eDiary 
S 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Participants’ eDiary  
 
 
 
 
 
 
 
 
 
 
S 
 


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Period 
Screening 
Treatment 
Follow-Up 
USV 
Visit Name 
Screening 
Randomization 
Treatment 
EOT/TD 
Follow-Up 
EOS/PSD 
UPV 
Visit Numbers1 
1 
100 
105 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-28 to -1 
1 
8 
29 
57 
85 
113 
141 
169 
197 
225 
253 
- 
Weeks 
-4 to -1 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
- 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry (FSH to 
be done only if required as 
per Section 8.4.3) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum β-hCG (for all pre-
menopausal women who 
are not surgically sterile) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test 
(local) (If positive, 
confirmation by serum β-
hCG test should be done 
by central lab)5 
 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 


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Period 
Screening 
Treatment 
Follow-Up 
USV 
Visit Name 
Screening 
Randomization 
Treatment 
EOT/TD 
Follow-Up 
EOS/PSD 
UPV 
Visit Numbers1 
1 
100 
105 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-28 to -1 
1 
8 
29 
57 
85 
113 
141 
169 
197 
225 
253 
- 
Weeks 
-4 to -1 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
- 
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)5 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Stool ova and parasite 
evaluation if clinical signs 
or symptoms of parasitosis 
develop at any time prior to 
the last study drug 
administration, additional 
assessments for parasitic 
conditions will be 
performed7 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Background Medication 
Usage 
X 
Dispense H1-AH rescue 
medication 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
S 
Physical Exam (physical 
exam at screening visit 
(Visit 1) is comprehensive 
but subsequent physical 
 
S 


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Period 
Screening 
Treatment 
Follow-Up 
USV 
Visit Name 
Screening 
Randomization 
Treatment 
EOT/TD 
Follow-Up 
EOS/PSD 
UPV 
Visit Numbers1 
1 
100 
105 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-28 to -1 
1 
8 
29 
57 
85 
113 
141 
169 
197 
225 
253 
- 
Weeks 
-4 to -1 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
- 
exams can be limited to a 
short exam) 
Body Weight 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Body Height (for adult 
participants body height 
will be collected only at 
screening visit) 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs 
X 
ECG (single ECG to be 
taken at Visits 1 and 
160/EoT/TD) 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Adverse Events 
X 
Liver Safety Monitoring 
S 
Renal Safety Monitoring5 
S 
Sweat detection test 
(cholinergic urticaria only) 
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
Provocation Test (FricTest 
for symptomatic 
dermographism, TempTest 
for cold urticaria or Pulse-
Controlled Ergometry test 
for cholinergic urticaria)  
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
Itch (NRS) post-
provocation test for 
symptomatic 
dermographism, cold 
urticaria and cholinergic 
urticaria 
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 


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Period 
Screening 
Treatment 
Follow-Up 
USV 
Visit Name 
Screening 
Randomization 
Treatment 
EOT/TD 
Follow-Up 
EOS/PSD 
UPV 
Visit Numbers1 
1 
100 
105 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
Days 
-28 to -1 
1 
8 
29 
57 
85 
113 
141 
169 
197 
225 
253 
- 
Weeks 
-4 to -1 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
- 
Total Fric Score 
(symptomatic 
dermographism), Critical 
Temperature Threshold 
(cold urticaria), Physician 
global assessment of 
severity of hives 
(cholinergic urticaria )  
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
Study drug/placebo 
administration8 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Treatment completion or 
Discontinuation Form 
 
X 
 
 
 
 
Provide participant contact 
details for exit interview (if 
applicable)3 Interview is to 
be performed after end of 
 
 
 
 
 
 
 
 
S 
 
 
 
S 




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8.1 
Screening 
Screening 
Participants will have up to 4 week screening period to establish eligibility for the study. 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 participants who failed initial screening. Only 1 rescreening 
will be allowed. If a participant rescreens for the study, the participant must sign a new informed 
consent and will be issued a new participant number. Informed consent for a rescreened 
participant must be obtained prior to performing any study-related assessments or collecting 
any data for the screening visit (Visit 1). 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to randomization will be considered a screen failure. The reason for screen failure should 
be recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and inclusion/exclusion pages must also be completed for screen failure participants. 
No other data should be entered into the clinical database for participants who are screen failures, 
unless the participant experienced an SAE during the screening phase (see SAE Section 10.1.2 
for reporting details). If the participant fails to be randomized, the IRT must be notified within 
2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographic and baseline characteristic data to be collected on all participants 
include age, sex, race and ethnicity. As this trial is conducted in more than one region, this trial 
is considered to be a multi-regional clinical trial (MRCT) and in line with ICH guideline E17, 
participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by Health Authorities. 
Relevant medical history (including CINDU history, cardio-vascular history)/current medical 
condition present before signing the informed consent will be captured. Where possible, 
diagnoses, and not symptoms, will be recorded. Data on participants’ family history of 
malignancies will be collected on the respective eCRF page, only when a participant has a 
malignancy event, to assess possible risk factors related to any malignancies. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the Section 6.2.1 Concomitant Therapy for 
further details on what information must be recorded on the appropriate page of the eCRF 




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for a distance of approximately 60 mm (Magerl et al 2016). Each pin is responsible for 
producing a linear hive depending on the severity of the participant's symptomatic 
dermographism. An itchy palpable clearly visible hive with a width of ≥ 3mm is considered as 
a positive response. 10 minutes after the test, the participant is asked to evaluate the severity of 
their itch, pain and burning where the FricTest® 4.0 was applied using a 11 point numerical 
rating scale ranging from no symptom (scored 0) to worst possible symptom (scored 10). The 
higher the number of linear hives, the more severe the disease is. The total number of linear 
hives with a width of ≥ 3mm is the Total Fric Score (TFS) and is recorded in the eCRF. 
The following scoring method for Total Fric Score is used: 
0= no linear hive ≥ 3mm in width, 1= one linear hive ≥ 3mm in width, 2= two linear hives ≥ 
3mm in width, 3= three linear hives ≥ 3mm in width and 4 = four linear hives ≥ 3mm in width 
8.3.1.2 
TempTest 4.0 
To elicit symptoms of cold urticaria, the TempTest® will be used. The TempTest® 4.0 has a 
single 2 mm wide 350 mm U-shaped Peltier element generating a temperature gradient from 
4 °C to 44 °C along its length. The device is applied to the participant’s skin. The test skin area 
chosen must be an area where it is comfortable for the participant to remain immobile for at 
least 5 minutes. Usually the test skin area chosen is the participant’s volar forearm. The 
participant places the inner forearm or other test skin area on the aluminum stencil on the device 
for up to approximately 5 minutes. The stencil produces the temperature range continuously. 
With this procedure it is determined at which threshold temperature (highest temperature for 
cold urticaria) hives are triggered. A palpable clearly visible itchy hive is considered a positive 
response. 
10 minutes after the provocation time is up, the hives on the skin are compared to the foil stencil 
and the threshold temperature is determined. The hives can be marked on the foil and it can be 
saved in the participant’s file for medical documentation of the therapy. The threshold 
temperature at which hives are triggered will be recorded in the eCRF. The participant is asked 
to evaluate the severity of their itch, pain and burning where the TempTest 4.0 was applied 
using a 11 point numerical rating scale ranging from no symptom (scored 0) to worst possible 
symptom (scored 10) and is to be recorded in the eCRF. 
8.3.1.3 
Pulse-controlled ergometry test 
To elicit symptoms of cholinergic urticaria in a clinical setting, pulse-controlled ergometry will 
be used. If a participant has risk factors for coronary artery disease, it is up to the discretion of 
the investigator to decide whether the patient needs cardiac clearance prior to undergoing the 
pulse controlled ergometry provocation test. In general, participants must be feeling well to 
perform this test. In this procedure, participants undergo pulse-controlled incremental 
ergometry for 30 min (stationary bicycle ride) increasing their pulse rate by 15 beats every 5 
min to a final maximum increase of 90 beats per minute above the starting level at 30 min 
(Altrichter et al 2014). A pulse oximeter is fitted to the participant to monitor pulse rate. Only 
participants that are able to sweat should be included in the cholinergic urticaria cohort, hence, 
to detect sweating on day of randomization, starch-iodine powder or similar is applied to the 
lower back or other area that shows sweating. This sweat detection test must be performed on 
all provocation test days and is described in the provocation test manual for cholinergic urticaria. 














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Height and weight 
Height in cm and Body weight (to the nearest 0.1 kg in indoor clothing, but without shoes) 
will be measured as specified in Table 8-1. 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens detailed in this section unless 
noted otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the Laboratory Manual. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, if participants cannot visit the site for 
protocol specified safety lab assessments, or if the central lab cannot be used, an alternative lab 
(local) collection site may be used. Safety samples that can be collected remotely will be 
collected and analyzed in line with the study laboratory manual. Where samples are collected 
and analyzed at a local laboratory instead of the central laboratory, the local laboratory reports 
need to be reviewed by the investigator, collected and filed in the medical record or chart. The 
local laboratory report should be available for review at request of Novartis. 
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 eCRFs 
capturing medical history/Current medical conditions/AEs. 
A serum β-hCG will be collected at the screening visit for all pre-menopausal women who are 
not surgically sterile. 
Table 8-5 
Laboratory assessments 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets count, Leukocytes, , Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, ),  
Chemistry 
Albumin, Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aminotransferase 
(AST), Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphate, Sodium, 
Potassium, Creatinine, total bilirublin, Urea Nitrogen or Urea, Uric acid, Glucose (non-
fasting) 
Urinalysis* 
Semi-quantitative “dipstick” evaluation for specific gravity, pH, glucose, protein, bilirubin, 
ketones, leukocytes and blood will be performed at site. When a dipstick evaluation is 
abnormal, e.g., positive for White blood cells (WBC) and/or blood, a urine sample must be 
sent to the Central Lab for microscopic examination including Red blood cells (RBC) and 
WBC. (Details on collection of urine for analysis by central laboratory are provided to 
investigators in the Laboratory Manual.) 
Coagulation 
At screening visit (Visit 1) and Day 1 (Visit 100), coagulation will be assessed by 
International Normalized Ratio (INR), Activated partial thromboplastin time (APTT) 
Parasite 
screening 
Local laboratory assessment of stool samples for parasitic infections (Section 8.4.4)  
Pregnancy Test* 
Serum / Urine pregnancy test (Section 8.4.3)  
* For point of care tests (POCT), the clinical sites in China will be allowed to analyze several parameters such 
as urine/serum for pregnancy test and urinalysis as per clinical site practice (refer to China laboratory manual 
for further details) 


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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 local 12 lead ECGs will be collected at Screening (Visit 1), Week 24 (Visit 160) and 
unscheduled as required. 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions, e.g., at the 
Screening (as applicable) to assess eligibility. The investigator must calculate QTcF if it is not 
auto-calculated by the ECG machine. 
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, participant initials, participant 
number, date and time, and signed and archived in the study site source documents. 
Clinically significant ECG findings prior to dosing with study drug treatment must be discussed 
with the sponsor. Additional, unscheduled, safety ECGs may be repeated at the discretion of 
the investigator at any time during the study as clinically indicated. For any ECGs with 
participant safety concerns or clinically significant abnormalities, two additional ECGs must be 
performed to confirm the safety finding. ECG safety monitoring, or a review process, should 
be in place for clinically significant ECG findings at baseline before administration of study 
treatment and during the study. 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or AEs 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 
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 eCRF. 
All pre-menopausal women who are not surgically sterile will have urine pregnancy testing 
during the treatment and follow-up period. Urine pregnancy tests must be performed before 
study drug administration. A positive urine pregnancy test needs to be confirmed with a central 
lab serum pregnancy test during all study periods. If positive, the participant must be 
discontinued from study treatment. 
If participants cannot visit the site to perform the urine pregnancy tests, urine pregnancy test 
kits may be used to perform the urine pregnancy test at home and report the result to the site. It 
is important that participants be instructed to perform the urine pregnancy test first and only if 
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A communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g. following country specific measures). 
Additional pregnancy testing might be performed if requested by local 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 (Visit 1) or Day 1 (Visit 100). 
8.4.4 
Assessment of parasitic infections 
Reduction in IgE levels may confer increased susceptibility to parasitic helminth infections. 
The risk of acquiring or activating infections with helminths during or after treatment with anti-
IgE therapy such as ligelizumab and omalizumab is suspected to be low. Data from the Phase 
2 CQGE031C2201 study in this regard was unremarkable but limited due to the small study 
sample size. 
All participants will be given three stool sample collection kits at screening visit (Visit 1) and 
Week 32 by the site or site’s local laboratory. Participants will take the stool sample kits home 
and collect stool samples from three different bowel movements, ideally on three different days, 
within seven days after Visit 1 and in the week prior to Week 36(EOS/PSD). Participants will 
return the three stool samples to the site or local laboratory as soon as possible after the 
screening visit (in order to allow processing within the screening period) and at Week 
36(EOS/PSD). 
Stool samples for parasitic disease will be examined by microscopy 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 helminthic parasites (pathogenic as defined 
by the local laboratory), the result must be recorded in the source document and the participant 
will not be randomized and will not be allowed to rescreen. Stool samples negative for 
pathogenic parasites must be recorded in the source document before Day 1 (Visit 100). 
Participants 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. 
8.4.5 
Anaphylaxis assessment 
An Adjudication Committee (AC) will be put in place to determine whether cases of 
hypersensitivity reactions identified through a search algorithm based on the Standardized 












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The investigator must discontinue study treatment for a given participant if the investigator 
believes that continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/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 8.4.3 and Section 10.1.4) 
• Unblinding of study treatment other than to authorized personnel (see  Section 6.5) for any 
reason 
• Participant develops a medical condition that requires use of prohibited treatment as per 
Section 6.2.2, or if participant exhibits a behavior of non-compliance regarding prohibited 
medications 
• Participant received a live virus vaccination during the study 
• Participant experiences an unexpected hypersensitivity reaction of grade 5, as defined by 
the World Allergy Organization Grading System (Cox et al 2017), see Appendix 7: 
• Emergency use of epinephrine due to anaphylactic or anaphylactoid reaction. 
• Any other protocol deviation that results in a significant risk to the participant’s safety 
• Any situation in which study participation might result in a safety risk to the participant 
• Following emergency unblinding 
If 3 consecutive doses are missed (i.e a 12 week gap from last dose) a significant drop in drug 
exposure may be expected which can lead to aggravation of disease symptoms. Hence for the 
benefit of the participant, it is recommended that the participant be discontinued from the study 
treatment and avail of other alternative treatment options either in the follow up period or 
outside the study, as appropriate with participant condition. 
If discontinuation from study treatment by the participant occurs, the investigator should make 
a reasonable effort to understand the primary reason for the participant’s discontinuation from 
study treatment and record this information. Always consider reasons which are related to safety 
and efficacy first. 
Participants who discontinue from study treatment will be expected to perform the Week 
24/EoT/TD assessments 4 weeks after their last dose and will be expected to perform all follow-
up assessments (Week 28 to 36).  
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
For participants who wish to prematurely discontinue treatment prior to the primary endpoint 
(Week 12) for any reason, every effort should be made to have them continue study visits as 
per the assessment schedule, at least until Week 12.  


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After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 
9.2 
Withdrawal of informed consent/Opposition to data/biological 
samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 


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Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. Participants may be eligible for post-trial access after completion of the study. 
9.4 
Early study termination by the sponsor 
The study or any of the subtypes can be terminated by Novartis at any time for any reason. This 
may include reasons related to  
• Benefit/risk assessment of participating in the study 
• Practical reasons (including slow enrollment)  
• Regulatory or medical reasons 
• Decision based on recommendations following interim futility analysis  
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider the participant’s welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor, depending on the local 
regulation, will be responsible for informing IRBs/IECs of the early termination of the trial. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 


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Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (study treatment) product. 
For medical devices, an adverse event (AE) is any untoward medical, unintended disease or 
injury or untoward clinical signs, including an abnormal laboratory finding, in participants, 
users or other persons, in the context of a clinical investigation, whether or not related to the 
device. 
The investigator has the responsibility for managing the safety of individual participant 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 participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (version 5 or higher) 
2. Its relationship to the investigational study treatment and other study treatment. If the 
event is due to lack of efficacy or progression of underlying illness (i.e. progression of the 
study indication) the assessment of causality will usually be ‘Not suspected.’ The rationale 
for this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single participant. 
More specific, worsening of urticaria (progression of the underlying condition) or 
reactions to the provocation tests or reactions following accidental exposure to CINDU 
triggering factors, such as exposure to cold, physical exercise should be considered "not 
suspected". 
3. Its duration (start and end dates) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken with regard to study treatment. 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Drug interrupted/permanently discontinued 
6. Its outcome (i.e. recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 


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AE monitoring should be continued for at least 30 days following the last dose of study 
treatment. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute 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 participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Appendix 1. 
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 AE [appearance of (or worsening of any pre-existing)], undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
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• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered as a serious 
adverse event irrespective if a clinical event has occurred (see Section 10.1.5). 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after last study visit must be reported to 
Novartis Safety immediately, without undue delay, under no circumstances later than within 24 
hours of learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 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.  
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 unless otherwise specified by local 
law/regulations. Any SAEs reported up to the participant’s last visit will be reported in the 
eCRF and the Novartis Safety database. SAEs beyond that date will only be recorded in the 
Novartis Safety database. 
All follow-up information for the SAE including recurrent episodes, information on 
complications, progression of the initial SAE and recurrent episodes must be reported as follow-
up to the original episode immediately, without undue delay, and under no circumstances later 
than within 24 hours of the investigator receiving the follow-up information. An SAE occurring 
at a different time interval or otherwise considered completely unrelated to a previously 
reported one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the 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 


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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 participant 
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 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment for 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported. After 
consent is provided, the pregnancy reporting will occur up to one year after the estimated date 
of delivery.  
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 


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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to 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 
eCRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-3 in Appendix 2 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, 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 (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation. 
•  These liver chemistry repeats will be performed using the central laboratory. If results 
will not be available from the central laboratory, then the repeats can also be performed at 
a local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate eCRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the study treatment (Section 9.1.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 


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• Thorough follow-up of the liver event should include 
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Renal safety monitoring 
The following base monitoring for renal laboratory values, as per the Novartis Drug-Induced 
Nephrotoxicity (DIN) Guidelines (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 for 
those participants who have received study drug: 
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) 
*For point of care tests (POCT), the clinical sites in China will be allowed to analyze these tests as per clinical 
site practice (refer to China laboratory manual for further details) 
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. 
10.3 
Committees 
10.3.1 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will evaluate the results of the futility analysis. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.3.2 
Steering Committee 
The Steering Committee (SC) consists of a limited number of investigators drawn from the pool 
of investigators participating in the trial, i.e., not being members of the DMC, AC or Novartis 
representatives from the Clinical Trial Team. 
The SC will help to conduct the study with highest scientific and ethical standards by providing 
input to the study protocol and/or potential amendments as required. Together with the clinical 
trial team, the SC will also develop recommendations for publications of study results including 
authorship rules. The details of the role of the steering committee will be defined in the steering 
committee charter. 


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10.3.3 
Adjudication committee 
To enhance the safety assessment, more specifically relative to 1) anaphylactic events, 2) 
neoplastic events, and 3) major cardio-cerebrovascular events, 3 ACs, independent panels of 
experts external to Novartis, will provide reviews of identified potential events in a blinded 
manner. 
All the details of the adjudication processes including the committee members are included in 
the AC 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 (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the 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 captured by 
Novartis via eCRFs. 
ECG readings will be processed centrally and results will be sent electronically to Novartis. 




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documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Inferential efficacy comparisons with placebo will be focus on the placebo-controlled period 
(i.e. up to Week 12). 
Data analyses will be presented by treatment group. For symptomatic dermographism and cold 
urticaria, efficacy and safety data for the placebo-controlled period will be presented by the 3 
treatment groups of ligelizumab 120 mg q4w, ligelizumab 72 mg q4w, and placebo. For 
cholinergic urticaria, efficacy and safety data for the placebo-controlled period will be presented 
by the 2 treatment groups of ligelizumab 120 mg q4w and placebo. 
These treatment groups represent the treatment participants will be assigned to during the 
placebo-controlled period. 
For the entire treatment period or study period, data will be presented by a combination of the 
"original" and "after switch" treatment groups (e.g. placebo - ligelizumab 120 mg q4w), as 
appropriate. 
12.1 
Analysis sets 
For each CINDU cohort, the following analysis sets will be used in this trial: 
The Randomized Analysis Set (RAS) consists of all randomized participants, regardless of 
whether or not they receive a dose of study drug. Participants will be analyzed according to the 
treatment they are assigned. 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment. Participants will be analyzed 
according to the treatment they have been assigned to. 
The Safety Set (SAF) includes all participants who received any study treatment. Participants 
will be analyzed according to the study treatment(s) received. The actual treatment will be 
defined as the treatment received over the study. In case of error in dispensation, the actual 
treatment will correspond to the treatment which was given most often. 
12.2 
Participant demographics and other baseline characteristics 
For each CINDU cohort, demographic and other baseline data including disease characteristics 
will be listed and summarized descriptively by treatment group for the Safety set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 


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Relevant medical histories and 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, by treatment group. 
Summaries for cardiovascular and urticaria specific medical history will also be provided. 
12.3 
Treatments 
For each CINDU cohort, the Safety set will be used for the analyses below. Categorical data 
will be summarized as frequencies and percentages. For continuous data, mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented. 
Number of participants and the duration of exposure (in weeks) to each treatment and dose will 
be summarized by means of descriptive statistics using the safety set. In addition, the number 
of doses, total cumulative dose, and number of missed doses will be presented. 
Prior medications are defined as medications taken and stopped prior to first dose of study 
treatment. Prior medications will be summarized based on Safety set. Prior medications for 
CINDU will be summarized by type of therapy, preferred term and treatment group. Prior 
medications non-related to CINDU will be summarized by Anatomical Therapeutic Chemical 
(ATC) code and preferred term. 
Concomitant medications prior to and after the start of the study treatment will be summarized 
by treatment for the safety set separated for urticaria related background medications and non-
CINDU related medications. CINDU related background medications will be summarized by 
type of therapy, preferred term and treatment group. Non-CINDU related concomitant 
medications will be summarized by preferred term. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
This section will detail the statistical analysis of the primary estimand. Details of the hypothesis 
testing strategy including primary and secondary endpoints to handle multiplicity are provided 
in Section 12.5. 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The primary estimand for the three CINDU cohorts are provided in Section 2.1. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Symptomatic Dermographism: 
The aim is to estimate the treatment effect of ligelizumab compared to placebo, for the target 
population on the primary endpoint (i.e. change from baseline to week 12 in Total Fric Score). 
The justification of the corresponding primary estimand is detailed in Section 2.1. 
The primary analysis method is based on a two-sample t-test. 
The null hypothesis test (H0) for the primary endpoint is that the change from baseline at Week 
12 in Total Fric Score in any of the ligelizumab groups (low or high dose) is not superior to the 
placebo group: 
H01.SDerm: μligelizumab ≥ μPlacebo versus HA1.SDerm: μligelizumab < μPlacebo 


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where μ is the mean change from baseline of Total Fric Score at week 12, negative value 
indicates improvement. 
Cold Urticaria: 
The aim is to estimate the treatment effect of ligelizumab compared to placebo, for the target 
population on the primary endpoint (i.e. change from baseline to week 12 in CTT). The 
justification of the corresponding primary estimand is detailed in Section 2.1. 
The primary analysis method is based on a two-sample t-test. 
The null hypothesis (H0 ) for the primary endpoint is that the change from baseline at Week 12 
in CTT in any of the ligelizumab groups (low or high dose) is not superior to the placebo group: 
H01.Cold: μligelizumab ≥ μPlacebo versus HA1.Cold: μligelizumab < μPlacebo 
where μ is the mean change from baseline of CTT at week 12, negative value indicates 
improvement. 
Cholinergic Urticaria: 
The aim is to estimate the treatment effect of ligelizumab compared to placebo, for the target 
population on the primary endpoint (i.e. change from baseline to week 12 in itch NRS following 
the pulse-controlled ergometry test). The justification of the corresponding primary estimand is 
detailed in Section 2.1. 
The primary analysis method is based on a two-sampe t-test. 
The null hypothesis (H0) for the primary endpoint is that the change from baseline at Week 12 
in itch NRS in the ligelizumab 120 mg q4w group is not superior to the placebo group: 
H01.Chol: μligelizumab ≥ μPlacebo versus HA1.Chol: μligelizumab < μPlacebo 
where μ is the mean change from baseline in itch NRS following the pulse controlled ergometry 
test at week 12, negative value indicates improvement. 
All primary and secondary endpoints will be tested against the respective alternative hypotheses 
in a closed testing procedure (Bretz et al 2009), so that the family-wise type I error will be 
controlled at 0.025 (one-sided) for each sub-type. The detailed testing strategy is provided in 
Section 12.5. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
Participants who discontinue from study treatment early will be encouraged to stay in the study 
following the procedure described in Section 9.1.1. These are considered as retrieved drop-out 
(RDO) participants. 
For all three CINDU subtypes, symptomatic dermographism, cold urticaria, and cholinergic 
urticaria, the primary analysis will account for different intercurrent events as explained in the 
following: 
• Discontinuation of assigned study treatment either due to AE or lack of efficacy or 
use of prohibited medications: Retrieved drop out (RDO) data collected after study 
treatment discontinuation will be used for analysis. If no RDO data was collected after 
study treatment permanent discontinuation, missing data for ligelizumab groups will be 


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multiply imputed based on information from the placebo, and under the MAR assumption 
for the placebo group. 
• Discontinuation of study treatment for the reasons other than AE or lack of efficacy 
or use of prohibited medications: primary variable will be treated as missing and 
multiply imputed under the MAR assumption for all the groups. 
• Use of prohibited medications prior to Week 12 and not resulting in treatment 
discontinuation: handled by treatment policy, data collected after the intercurrent event 
will be used as it is. 
• Missed treatment prior to Week 12 due to other non-human controlled emergency 
situations (e.g. COVID-19): primary variable will be treated as missing and multiply 
imputed under the MAR assumption for all the groups. 
12.4.4 
Handling of missing values not related to intercurrent event 
If the provocation testing is stopped due to any reason e.g participant discomfort, technical 
issues the data will be considered as missing. 
Symptomatic dermographism 
Handling of missing or incomplete results in the FricTest 4.0: 
· The missing Total Fric Scores will be multiply imputed under the MAR assumption for all the 
groups. 
Cold urticaria 
Handling of missing or incomplete results in response to the TempTest®: 
· The missing CTT will be multiply imputed under the MAR assumption for all the groups. 
Cholinergic urticaria 
Handling of missing or incomplete itch NRS results following the pulse-controlled ergometry 
test: 
· The missing itch NRS will be multiply imputed under the MAR assumption for both treatment 
groups. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
For all three CINDU cohorts, the following sensitivity analysis will be performed for the 
primary estimand, to assess the robustness of the estimation in the presence of deviations from 
the assumptions specified in the primary analysis. 
• The ANCOVA (Analysis of covariance) model with treatment group, baseline scores, 
region/country as covariates will be performed. Intercurrent events will be handled in the 
same way as in the primary analysis. 
• To account for uncertainty in the imputations, the tipping point analyses will be 
considered, if needed.  


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12.4.6 
Supplementary analysis 
In addition to the primary analysis, change from baseline at week 12 on Total Fric 
Score/CTT/itch NRS will be tested using Wilcoxon rank sum test for symptomatic 
dermographism, cold urticaria, and cholinergic urticaria respectively. 
For each CINDU cohort, if the primary analysis is statistically significant, subgroup analyses 
to assess the homogeneity of the treatment effect across demographic and baseline disease 
characteristics may be performed. 
Other supplementary analysis will be described in the SAP (Statistical Analysis Plan) as needed. 
12.5 
Analysis supporting secondary objectives 
For detailed definitions of secondary estimands, please refer to Section 2.2 The following 
secondary endpoints will be assessed and included into the testing strategy for the three CINDU 
cohorts: 
• Symptomatic dermographism 
1. proportion of participants achieving complete response in response to the FricTest 4.0 
(Total Fric Score=0) at Week 12 
2. absolute change from baseline to Week 12 on itch NRS following the FricTest 4.0. 
• Cold urticaria 
1. proportion of participants achieving complete response in response to the TempTest at 
Week 12 
2. change from baseline to Week 12 on itch NRS following the TempTest. 
• Cholinergic urticaria 
1. proportion of participants achieving complete response in itch NRS following the 
pulse-controlled ergometry test, assessed as itch NRS=0 at Week 12. 
2. proportion of participants achieving complete response in physician global assessment 
(PGA) of severity of hives following the pulse-controlled ergometry test, assessed as 
PGA hive score=0 at Week 12. 
The proportion of participants with complete response at Week 12 will be compared by the 
Fisher's Exact test between each of the ligelizumab dose group and the placebo group. In case 
of missing data caused by discontinuation due to reasons other than AE, lack of efficacy, or 
intake of prohibited medication, or missing data not related to intercurrent events, raw scores 
in corresponding provocation test (i.e. Total Fric Score, CTT, and itch NRS) will be first 
imputed as described in Section 12.4.3 and Section 12.4.4, respectively, then the missing 
responder status will be derived based on the imputed raw score. As sensitivity analysis, 
proportion of complete responders will be analyzed using a logistic regression model including 
treatment group, region/country and baseline score. 
Change from baseline to Week 12 on itch NRS in response to provocation tests will be analyzed 
based on participants who have baseline scores greater than zero by two-sample t-test. In case 
of missing data caused by discontinuation due to reasons other than AE, lack of efficacy, or 
intake of prohibited medication, or missing data not related to intercurrent events, itch NRS will 
be imputed in a same manner as described in Section 12.4.3 and Section 12.4.4, respectively. 


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Testing strategy for symptomatic dermographism and cold urticaria 
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) for each CINDU cohort. 
Primary endpoint 
Total Fric Score/CTT change from baseline at Week 12 
H01: μligelizumab ≥ μPlacebo versus HA1: μligelizumab < μPlacebo 
where μ is the mean change from baseline in Total Fric Score/CTT at Week 12, as described in 
Section 2.1. 
Secondary endpoints 
• proportion of participants achieving complete response in response to FricTest 4.0 and 
TempTest at Week 12 
H02:πligelizumab ≤ πPlacebo versus HA2: πligelizumab > πPlacebo 
where π is the proportion of participants achieving complete response status at Week 12, as 
described in Section 2.2. 
• itch NRS following provocation tests change from baseline at Week 12 
H03: μligelizumab ≥ μPlacebo versus HA3: μligelizumab < μPlacebo 
where μ is the mean change from baseline in itch NRS following the FricTest 4.0 and TempTest 
at Week 12, as described in Section 2.2. 
Figure 12-1 
Testing strategy for symptomatic dermographism and cold urticaria 
 


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For symptomatic dermographism and cold urticaria CINDU cohort, the hypotheses are mapped 
into two families. 
The first family consists of four hypotheses: H11, H12, H21, and H22. These four hypotheses form 
two branches such that hypotheses within a same branch correspond to the same ligelizumab 
dose regimen (72 mg q4w or 120 mg q4w). In essence, the type-I-error probability will be 
equally split for both branches of hypotheses and within each branch the hypotheses are tested 
sequentially as follows: 
The initial alpha level for each branch is set to α/2=0.0125 (one-sided). The first hypothesis 
(H11 and H12) is tested with 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 hypotheses (H21 and/or H22) of high/low dose ligelizumab versus placebo 
regarding the secondary endpoint on complete response is tested with α/2. 
In the first family, the testing within each dose is strictly hierarchical: the secondary endpoint 
on complete response will only be assessed if efficacy was shown previously for the primary 
endpoint. If efficacy is shown for both the primary and the secondary endpoint for one of the 
doses, the associated weight is passed on to the other dose. 
The second family consists of H31 and H32, will only be tested if all four hypotheses in the first 
family are rejected. The initial alpha level will be equally split (i.e. is set to α/2=0.0125, one-
sided) for each hypothesis. If either of the hypotheses is rejected, the associated weight is passed 
on to the other dose, so that other hypothesis is tested with α. 
Testing strategy for cholinergic urticaria 
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) for cholinergic urticaria. 
Primary endpoint 
Itch NRS change from baseline at Week 12 
H01: μligelizumab ≥ μPlacebo versus HA1: μligelizumab < μPlacebo 
where μ is the mean change from baseline in itch NRS following the pulse-controlled ergometry 
test at Week 12, as described in Section 2.1. 
Secondary endpoints 
• proportion of participants achieving complete response in itch NRS (itch NRS=0 ) 
following the pulse-controlled ergometry test at Week 12 
H02:πitchligelizumab ≤ πitchPlacebo versus HA2: πitchligelizumab >πitchPlacebo 
where πitch is the proportion of participants achieving complete response in itch NRS at Week 
12, as described in Section 2.2. 
• proportion of participants achieving complete response in physician global assessment of 
severity of hives (PGA hive score =0) following the pulse-controlled ergometry test at 
Week 12 


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H03:πhiveligelizumab ≤ πhivePlacebo versus HA3: πhiveligelizumab > πhivePlacebo 
where πhive is the proportion of participants achieving complete response in PGA hive score=0 
at Week 12, as described in Section 2.2. 
Figure 12-2 
Testing strategy for cholinergic urticaria 
 
For cholinergic urticaria, the hypotheses are tested sequentially in a fix order as follows: 
The initial alpha level is set to α=0.025 (one-sided) for the first hypothesis (H1) of ligelizumab 
120 mg q4w versus placebo regarding the primary endpoint. If H1 is rejected, the second 
hypothesis (H2) of ligelizumab versus placebo regarding the secondary endpoint on complete 
response in itch NRS is tested with α. If H2 is rejected, the third hypothesis (H3) of ligelizumab 
versus placebo regarding the secondary endpoint on complete response in physician global 
assessment of severity of hives is tested with α. 
12.5.1 
Efficacy 
 endpoint(s) 
Efficacy endpoints other than the primary and secondary endpoints are detailed in 
Section 12.6. 
12.5.2 
Safety endpoints 
The following applies to all three subtypes of CINDU (i.e. symptomatic dermographism, cold 
urticaria, and cholinergic urticaria). 


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For all safety analyses (i.e. AEs, laboratory data, vital signs, and ECG), the safety set will be 
used. All data will be included in the analysis regardless of rescue medication use. All listings 
and tables will be presented by treatment group.  
Adverse events 
All information obtained on AEs will be displayed by treatment group (or sequence) and 
participant. 
Treatment emergent AEs will be summarized by actually received treatment. 
Treatment emergent AEs (TEAE) are defined as: 
• Events started after the first dose of study treatment (ligelizumab) in this study and within 
16 weeks of last dose of study treatment 
• Events present prior to the first dose of study treatment (ligelizumab) in this study but: 
1. increased in severity based on preferred term (e.g. worsening of headache), 
2. same PT but increased severity (e.g. from mild to moderate), 
3. same PT but increase in seriousness (from non-serious AE to SAE; if already a SAE 
from medical significant to LT/fatal) 
and within 16 weeks after the last dose of the study treatment. 
The number (and percentage) of participants with treatment emergent AEs will be summarized 
in the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant adverse events leading to treatment discontinuation. 
The number (and proportion) of participants with treatment emergent AEs of special interest 
(AESI) will be summarized by treatment. 
The number (and proportion) of participants with treatment emergent AEs related to other safety 
topics such as events related to “liver toxicity” will be summarized by treatment. 
A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
For the placebo-ligelizumab treatment group, treatment-emergent AEs will be counted 
separately for the placebo treatment and ligelizumab treatment. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged. Summary statistics will be provided by treatment, 
and visit/time and separately in adults and adolescents. 
 




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12.7 
Interim analyses (Futility analysis) 
A final analysis will be performed after all participants have completed Week 36 (or 
discontinued prior to Week 36). Formal testing of the primary endpoint with full level alpha 
will be performed at the primary analysis time point. 
Due to the low prevalence of cholinergic urticaria, an interim futility analysis may be conducted 
in case there is an obvious difference in recruitment speed in the three cohorts. In other words, 
this interim futility analysis would be triggered when approximately 50% of randomized 
participants in the cholinergic urticaria cohort have completed the Week 12 visit while 100% 
of randomized participants in the symptomatic dermographism and cold urticaria cohorts have 
completed the Week 12 visit. During this analysis, there will be no decision rules applied for 
the symptomatic dermographism and cold urticaria cohort. This analysis will be conducted to 
assess whether efficacy met a pre-specified level only for the cholinergic urticaria cohort. 
Depending on the outcome of the futility analysis, further recruitment in cholinergic urticaria 
subtype may be stopped or continued as planned. Participants who have already been enrolled 
in the study prior to the futility analysis will continue to remain in the study. 
Futility analysis results will be evaluated by the DMC based on calculated predictive 
probabilities of the primary estimand (see Section 2) for cholinergic urticaria. Details of the 
calculations and the associated thresholds will be described in the DMC Charter and its 
associated analysis plan. Additional analyses on the secondary estimand (see section 2) and 
safety will also be performed to assist in the futility evaluation, as planned in the DMC charter. 
12.8 
Sample size calculation 
Symptomatic dermographism 
The sample size justification is based on change from baseline in Total Fric Score and 
achievement of complete response in FricTest®4.0 at Week 12. 
Cold urticaria 
The sample size justification is based on change from baseline in CTT (in response to 
TempTest®4.0) and achievement of complete response in TempTest®4.0 at Week 12. 
Cholinergic Urticaria 
The sample size justification is based on change from baseline in itch NRS in response to the 
pulse-controlled ergometry test and achievement of complete response in itch NRS (itch NRS=0) 
at Week 12. 
For symptomatic dermographism and cold urticaria, participants will be randomized in a 2:2:1:1 
ratio to ligelizumab 72 mg q4w, ligelizumab 120 mg q4w, placebo - ligelizumab 120 mg q4w, 
and placebo - ligelizumab 72 mg q4w, respectively. In other words, participants are randomly 
assigned to ligelizumab 72 mg q4w, ligelizumab 120 mg q4w, and placebo group with a 1:1:1 
ratio in the placebo-controlled period (i.e. up to Week 12). For cholinergic urticaria, participants 
will be randomized in a 1:1 ratio to ligelizumab 120 mg q4w and placebo - ligelizumab 120 mg 
q4w. 
All sample size calculations were performed with SAS 9.4 PROC POWER. 


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Based on simulation studies, the sample sizes calculated below for each of the three CINDU 
cohorts are sufficient to maintain the power of overall multiple testing strategy (at least 90%) 
for the primary endpoint (see Section 2.1) and the first secondary endpoint (i.e. complete 
response rate following the FricTest®4.0 for symptomatic dermographism, complete response 
rate following the TempTest®4.0 for cold urticaria, and complete response rate in itch NRS 
following the pulse-controlled ergometry test for cholinergic urticaria) through the recycled 
alpha. Detailed simulation results on power with all endpoints in the testing strategy (see 
Section 12.5) are provided in the statistical analysis plan. 
Data from each subtype is analyzed separately. Hence if sample size is not achieved for one of 
the subtypes, this will not impact the analysis for the other subtypes. The overall population 
(adolescent and adult participants) will be considered for the primary and secondary analyses. 
12.8.1 
Primary endpoint(s) 
Symptomatic Dermographism 
Since two ligelizumab dose regimens will be tested versus placebo with respect to the primary 
endpoints (change from baseline in Total Fric Score at Week 12), the type-I-error will be split 
to 1.25% one-sided for each comparison. 
Assuming the treatment difference in change from baseline to Week 12 in Total Fric Score is 
at least 1.3 in favor of the ligelizumab group, and a standard deviation of approximately 1.7, a 
sample size of approximate 56 participants per group and a drop-out rate of 10% provides 93.7% 
power to show that the primary analysis based on a two-sample t-test will be statistically 
significant at the one-sided 1.25% significance level (SAS 9.4, PROC POWER, difference in 
two sample means). 
Mean changes from baseline in Total Fric Score of -0.6 (standard deviation: 1.4) in placebo 
group, -1.78 (standard deviation: 1.66) in omalizumab 150 mg group, and - 2.0 (standard 
deviation: 1.67) in omalizumab 300 mg group have been reported in Maurer et al 2017. 
Table 12-1 
Sensitivity of power to changes in assumptions (Symptomatic 
Dermographism) 
True treatment difference 
ligelizumab vs placebo 
(Total Fric Score) 
SD (Total 
Fric Score) 
Power for primary endpoint (one-sided α =1.25%), for N= 56 
per arm 
With 5% drop-out 
rate 
With 10% drop-out 
rate 
With 15% drop-out 
rate 
1.5 
1.3 
1.3 
1 
2 
2 
1.7 
1.3 
94.2% 
85.6% 
95.0% 
95.3% 
92.8% 
83.3% 
93.7% 
94.0% 
91.1% 
80.7% 
92.1% 
92.5% 
SD=Standard Deviations 
Cold Urticaria 
Since two ligelizumab dose regimens will be tested versus placebo with respect to the primary 
endpoints (change from baseline in critical temperature thresholds (CTT) at Week 12), the type-
I-error will be split to 1.25% one-sided for each comparison. 


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Assuming the treatment difference in change from baseline to Week 12 in CTTs is at least 10°C 
in favor of the ligelizumab group, and a standard deviation of approximately 8°C, a sample size 
of approximate 34 participants per group a drop-out rate of 10% provides >99% power to show 
that the primary analysis based on a t-test will be statistically significant at the one-sided 1.25% 
significance level (SAS 9.4, PROC POWER, difference in two sample means). 
Mean changes from baseline in CTT of -0.3°C (standard deviation: 3.9°C) in placebo group, 
CTT of -10.6°C (standard deviation: 7.6°C) in omalizumab 150 mg group, and CTT of -10.4°C 
(standard deviation: 9.4°C) in omalizumab 300 mg group have been reported in Metz et al 2017. 
Table 12-2 
Sensitivity of power to changes in assumptions (cold urticaria) 
True treatment difference 
ligelizumab vs placebo (°C) 
SD (°C) 
Power for primary endpoint (one-sided α =1.25%) for N= 34 
per arm 
With 5% drop-out 
rate 
With 10% drop-out 
rate 
With 15% drop-out 
rate 
11 
10 
10 
8 
10 
10 
9 
8 
98.1% 
95.3% 
98.3% 
95.3% 
97.3% 
93.9% 
97.5% 
93.9% 
96.2% 
92.1% 
96.5% 
92.1% 
SD=Standard Deviation 
Cholinergic Urticaria 
Assuming the treatment difference in change from baseline to Week 12 in itch NRS following 
the pulse-controlled ergometry test is at least 1.65 in favor of the ligelizumab 120 mg q4w group, 
and a standard deviation of approximately 3.0, a sample size of approximate 79 participants per 
group and a drop-out rate of 10% provides 90.2% power to show that the primary analysis based 
on a two-sample t-test will be statistically significant at the one-sided 2.5% significance level 
(SAS 9.4, PROC POWER, difference in two sample means). 
Median pre-treatment itch VAS of 60 (25th percentile=40, 75th percentile=80) and median 
post-treatment itch VAS of 30 (25th percentile=20, 75th percentile=70) in the overall 
population after 4 doses of omalizumab 300 mg have been reported in Gastaminza et al.  
Table 12-3 
Sensitivity of power to changes in assumptions (cholinergic urticaria) 
True treatment difference 
ligelizumab vs placebo 
(itch NRS) 
SD (itch 
NRS) 
Power for primary endpoint (one-sided α =2.5%) for N= 79 
per arm 
With 5% drop-out 
rate 
With 10% drop-out 
rate 
With 15% drop-out 
rate 
1.5 
1.5 
1.65 
1.8 
2.5 
3.0 
3 
2.5 
95.5% 
86.0% 
91.7% 
99.2% 
94.4% 
84.1% 
90.2% 
98.9% 
93.2% 
81.9% 
88.5% 
98.5% 
SD= Standard Deviation 
Table 12-4 
Sensitivity of required sample size (per arm) to changes in 
assumptions for different targeted statistical power (cholinergic 
urticaria) 
Sample size required 


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True treatment 
difference ligelizumab 
vs placebo (itch NRS) 
SD (itch 
NRS) 
Targeted statistical power 
for primary endpoint (one-
sided α=2.5%) 
with 5% 
drop-out 
rate 
with 10% 
drop-out 
rate 
with 15% 
drop-out 
rate 
1.65 
3.0 
90% 
75% 
79% 
84% 
1.65 
3.0 
80% 
56% 
59% 
63% 
SD=Standard Deviation 
12.8.2 
Secondary endpoint(s) 
Symptomatic dermographism 
• Complete response rate 
Assuming a type-I-error of 2.5% two-sided and a complete response (negative outcome in the 
FricTest®4.0) rate of 11% in the placebo group. With approximate 56 participants per group 
and a drop-out rate of 10%, the power to show a complete response rate of 44% in the 
ligelizumab groups based on Fisher’s exact test (SAS 9.4, two group Fisher’s-exact test of equal 
proportions) is 91.5%. 
Placebo-response rates of 11% (2 out of 18) have been reported in Maurer et al 2017. 
The power of the all the endpoints included in the testing strategy is confirmed based on the 
simulation through the recycled alpha as planned. The detail simulation results will be provided 
in the statistical analysis plan. 
Cold urticaria 
• Complete response rate 
Assuming a type-I-error of 2.5% two-sided and a complete response (negative outcome in the 
TempTest®4.0) rate of 5% in the placebo group. With approximate 34 participants per group 
and a drop-out rate of 8%, the power to show a complete response rate of 40% in the ligelizumab 
groups based on Fisher’s exact test (SAS 9.4, two group Fisher’s-exact test of equal proportions) 
is 81.8%. 
Placebo-response rates of 0% (0 out of 12) and 5% (1 out of 20) have been reported in 
Metz et al 2017 and Krause et al 2013, respectively. 
The power of the all the endpoints included in the testing strategy is confirmed based on the 
simulation through the recycled alpha as planned. The detail simulation results will be provided 
in the statistical analysis plan. 
Cholinergic urticaria 
• Complete response rate in itch NRS 
For complete response in itch NRS, assuming a type-I-error of 5% two-sided and a complete 
response (see Section 2.2) rate of 13% in the placebo group. With approximate 79 participants 
per group and a drop-out rate of 10%, the power to show a complete response rate of 38% in 
the ligelizumab groups based on Fisher’s exact test (SAS 9.4, two group Fisher’s-exact test of 
equal proportions) is 91.1%. 
In Gastaminza et al, complete response rates of 22% (2 out of 9) and 8% (1 out of 13) have been 
reported for placebo and omalizumab 300 mg group during the blinded treatment period, and 
37.5% (6 out of 16) in the overall population in the open label treatment period. 


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The power of the all the endpoints included in the testing strategy is confirmed based on the 
simulation. The detail simulation results will be provided in the statistical analysis plan. 
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, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 


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Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any study treatment drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 








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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
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 eCRF. 
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 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 
participants, the Central CRO will use age-and gender-specific reference values. 
Appendix 1.1: Clinically notable vital signs - adolescent participants 
Guideline for pediatric blood pressure measurements: 
Table 16-1 
Best Blood Pressure (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 systolic blood pressure and diastolic blood pressure. 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 diastolic BP, 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 midthigh and the stethoscope placed over the popliteal artery. The systolic BP in the legs 
is usually 10%-20% higher than the brachial artery pressure. 
Adapted from Pickering TG et al 2005 
 


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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 guidance 
Age (Years) 
Boys1 
 
Girls1 
 
Heart Rate2 
SBP (mm Hg) 
DBP (mm Hg) 
SBP (mm Hg) 
DBP (mm Hg) 
12  
>117 
<75 
>118 
<75 
62-96 
13  
>121 
<75 
>121 
<76 
14  
>126 
<77 
>122 
<76 
15  
>128 
<79 
>122 
<77 
60-92 
16  
>129 
<80 
>123 
<77 
17  
>131 
<81 
>124 
<77 
The blood pressure values in the table above were adapted from Flynn et al 2017 by modifying 5% of 
height (in table 6 of the publication) with 50% height to represent ‘average’ child height per age/sex. The 
normal values for vital signs in children vary greatly with age, growth and development. Selected BP 
threshold values serve as a representative guide of ‘elevated BP’ for a child of ‘average’ size.  
The purpose of the values listed in this table is to guide investigators to identify or screen for values of 
concern in pediatric participants by age. The significance of these findings must be considered in view of 
the participant’s disease, time course and overall clinical condition. 
1 Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical practice guideline for screening and management 
of high blood pressure in children and adolescents 
2 Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children 
from birth to 18 years of age: a systematic review of observational studies. Lancet 2011; published online 
March 15. DOI:10.1016/S0140-6736(10)62226-X.  
 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
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 > 3x 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 – ALT, AST, TBL  
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
No change 
to study 
treatment 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours. 
• 
Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 


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ALT 
TBL 
Liver Symptoms 
Action 
  
If normal at 
baseline: 
ALT > 5 x ULN 
for more than two 
weeks 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt 
study 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 participants 
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) 


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Table 16-5 
Follow up requirements for liver events and laboratory triggers – 
Isolated Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
 
 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
• 
 Interrupt treatment 
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
 Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF 
ALT, AST, TBL, 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 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage – 
related conditions; non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-6 
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 (Kidney Disease Improving Global Outcomes) criteria for Acute Kidney Injury 
* For point of care tests (POCT), the clinical sites in China will be allowed to analyze these tests as per clinical 
site practice (refer to China laboratory manual for further details) 
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event: 
• Blood pressure assessment (after 5-minute rest, with an appropriate cuff size) 
• Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema 
• Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis 
Table 16-7 
Renal event follow-up 
Follow-up of renal events 
1. Assess, document and record in CRF 
• 
Urine dipstick* and sediment microscopy evidence of drug induced nephrotoxicity: crystals, red blood 
cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells 
• 
Blood pressure and body weight 


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Follow-up of renal events 
• 
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric 
acid 
• 
Urine output 
2. Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (Magnetic Resonance Imaging etc.) in the CRF 
3. 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 
4. Analysis of urine markers in samples collected over the course of the drug induced nephrotoxicity event 
*For point of care tests (POCT), the clinical sites in China will be allowed to analyze these tests as per clinical 
site practice (refer to China laboratory manual for further details) 
16.4 
Appendix 4 Sampson Criteria for anaphylaxis 
 














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16.7 
Appendix 7: World allergy organization grading system 
Figure 16-1 
World allergy organization subcutaneous immunotherapy systemic 
reaction grading system 
 

SAP_001.pdf: 


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SAP 
 
Study No. CQGE031E12301 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
07-
Nov-
2021 
Prior 
to 
FPFV 
Creation of 
final 
version 
N/A - First version 
NA 
5-
May-
2022 
Prior 
to 
LPLV 
Study early 
Termination 
Changes to statistical analyses and 
summarization due to sample size 
limitations 
2. 
Statistical 
Methods 
4. Change to 
protocol 
specified 
analyses 
 


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List of abbreviations 
AC 
Adjudication Committee 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
ATE 
Arterial Thromboembolic Event 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
 
CINDU 
Chronic Inducible Urticaria 
ClinRO 
Clinician Reported Outcomes 
CMO&PS 
Chief Medical Office and Patient Safety  
COA 
Clinical Outcome Assessment 
COVID-19 
Corona Virus Disease of 2019 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CS 
Corticosteroids 
CSR 
Clinical Study Report 
CSU 
Chronic Spontaneous Urticaria 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Critical Temperature Threshold 
DIN 
Drug Inducted Nephrotoxicity 
 
DMC 
Data Monitoring Committee 
DMS 
Document Management System 
EC 
European Community 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medical Association 
EOS 
End of Study 
EOT 
End of Treatment 
 
 
 
 
 


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EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trial Database 
FAS 
Full Analysis Set 
FcεRI 
High Affinity Immunoglobulin E Receptor 
FcεRII 
Low Affinity Immunoglobulin E Receptor 
FDA 
Food and Drug Administration 
Fric 
Friction 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
H1-AH 
H1 antihistamines 
HA 
Health Authorities 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin  
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
HLT 
High Level Term 
 
IA 
Interim Analysis 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection Site Reaction 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LLOQ 
lower limit of quantification 
LT 
Life Threatening 
MAR 
Missing at Random 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MRCT 
Multi Regional Clinical Trial 
MRI 
Magnetic Resonance Imaging 


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NRS 
Numeric Rating Scale 
PCE 
Pulse Controlled Ergometry 
PGA 
Physician Global Assessment 
 
 
PRO 
Patient Reported Outcomes 
PSD 
Premature Subject Discontinuation 
PSDS 
Post Study Drug Supply 
PT 
Prothrombin Time 
QMS 
Quality Management System  
QoL 
Quality of Life 
QTcF 
QT interval corrected by Fridericia’s formula 
RBC 
red blood cell(s) 
RDO 
Retrieved Drop-out 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SC 
Subcutaneous 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Query  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Events 
TFS 
Total Fric Score 
TNF 
Tumor Necrosis Factor 
 
ULN 
upper limit of normal 
UPV 
Unplanned Visit 
US 
United States 
 
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
 


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Table of contents 
List of abbreviations ............................................................................................................ 3 
Table of contents ................................................................................................................. 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................ 8 
1.1.1 
Screening ................................................................................................. 9 
1.1.2 
Double-blinded treatment period ............................................................ 9 
1.2 
Study objectives, endpoints and estimands ........................................................... 11 
1.2.1 
Primary estimand(s) .............................................................................. 14 
1.2.2 
Secondary estimand(s) .......................................................................... 15 
2 
Statistical methods ............................................................................................................. 18 
2.1 
Data analysis general information ......................................................................... 18 
2.1.1 
General definitions ................................................................................ 18 
2.2 
Analysis sets .......................................................................................................... 21 
2.2.1 
Subgroup of interest .............................................................................. 22 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 22 
2.3.1 
Patient disposition ................................................................................. 22 
2.3.2 
Demographics and other baseline characteristics ................................. 23 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 24 
2.4.1 
Study treatment / compliance ................................................................ 24 
2.4.2 
Prior and concomitant therapies ............................................................ 24 
2.5 
Analysis supporting primary objective(s) .............................................................. 25 
2.5.1 
Primary endpoint(s) ............................................................................... 25 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 25 
2.5.3 
Handling of intercurrent events ............................................................. 26 
2.5.4 
Sensitivity analyses ............................................................................... 27 
2.5.5 
Supplementary analyses ........................................................................ 27 
2.6 
Analysis supporting secondary objectives ............................................................. 28 
2.6.1 
Secondary endpoint(s) ........................................................................... 28 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 28 
2.6.3 
Handling of intercurrent events ............................................................. 31 
2.6.4 
Handling of missing values not related to intercurrent event ............... 33 
2.6.5 
Sensitivity analyses ............................................................................... 33 
2.6.6 
Supplementary analyses ........................................................................ 33 
2.7 
Safety analyses....................................................................................................... 34 


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2.7.1 
Adverse events (AEs) ............................................................................ 35 
2.7.2 
Deaths .................................................................................................... 37 
2.7.3 
Laboratory data ..................................................................................... 37 
2.7.4 
Other safety data ................................................................................... 38 
 
 39 
 
 40 
 
 40 
 
 40 
 40 
 40 
 41 
 43 
 44 
 45 
 45 
 45 
 46 
 46 
 46 
 47 
2.13 
Interim analysis ...................................................................................................... 48 
3 
Sample Size ....................................................................................................................... 48 
4 
Change to protocol specified analyses .............................................................................. 52 
5 
Appendix ........................................................................................................................... 53 
5.1 
Classification of study regions by country ............................................................ 53 
5.2 
Derivation rules for Week 12 treatment period ..................................................... 53 
5.3 
Imputation rules ..................................................................................................... 54 
5.3.1 
Study drug ............................................................................................. 54 
5.3.2 
AE date imputation ............................................................................... 54 
5.3.3 
Concomitant medication date imputation ............................................. 55 
5.4 
AEs coding/grading ............................................................................................... 58 
5.5 
Laboratory parameters derivations ........................................................................ 58 
5.6 
Statistical models ................................................................................................... 60 
5.7 
Rule of exclusion criteria of analysis sets.............................................................. 60 
6 
Reference ........................................................................................................................... 60 


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1 
Introduction 
The purpose of Statistical Analysis Plan (SAP) is to describe the statistical analysis planned in 
the protocol for the clinical study report.  The clinical study report will describe the results from 
this SAP. 
This SAP is based on the original protocol version 0.0, dated 07-Jul-2021 
: 
 
Due to the early termination of the trial, screening was stopped and all subjects in treatment 
where discontinued, therefore the trial has a  limited sample size. No statistical analyses will be 
performed on any dataset. Summarization of the data will be limited to data listings and 
summary tables where necessary Sections of the SAP are written as per protocol, language was 
added at the end of each section to address the termination of the study. Below are specific, 
high level changes to the SAP and subsequent output: 
• Screening was stopped and all subjects in treatment where discontinued 
• No statistical analyses will be performed on the  primary endpoints 
• No statistical analyses will be performed on the  secondary endpoints 
 
 
• No interim analysis will be preformed  
• No summary tables will be produced for efficacy 
 
 
1.1 
Study design 
This is a Phase III multicenter, randomized, double-blind, placebo-controlled study to 
demonstrate superiority of ligelizumab 72 mg and/or 120 mg sc q4w over placebo as an add-on 
therapy to H1-antihistamines at local-approved doses in adults  and adolescents for the 
treatment of Chronic Inducible Urticaria (CINDU). The study will be approximately 40 weeks 
in duration with the primary endpoint assessed at Week 12. There are 3 subtypes of CINDU 
populations being assessed in three parallel cohorts: symptomatic dermographism, cold 
urticaria and cholinergic urticaria. The study consists of 3 distinct periods: 
Screening period (Day - 28 to Day 0): Duration of up to 4 weeks in which participants who 
have given informed consent are assessed for eligibility. 
Treatment period (24 weeks): There are 7 visits during this period. Participants will receive 
treatment at 6 visits (Week 0, Week 4, Week 8, Week 12, Week 16 and Week 20). Week 24 is 
the End of Treatment visit; no treatment will be given at this visit. Provocation testing will be 
done at Week 0, Week 4, Week 8, Week 12 and Week 24. 


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Follow-up period (12 weeks): The participants should be seen in the clinic every 4 weeks until 
Week 36. There will be no study treatment administered at these visits; provocation testing will 
be done at Week 36 only. 
On 06 April 2022, following extensive assessment of data from the Phase III studies of 
ligelizumab in CSU, Novartis communicated a strategic decision to discontinue further clinical 
development of ligelizumab in chronic urticaria (CSU and chronic inducible urticaria (CINDU)). 
The decision to not proceed was not based on any safety concerns with ligelizumab. As a result 
of this decision, this study CQGE031E12301 was terminated. At the time of study termination 
39 participants were enrolled in the study.   
1.1.1 
Screening 
Screening was stopped as of 6th April 2022.  
As per protocol, the screening period was up to 4 weeks. The screening period can be shortened 
depending on the availability of the laboratory results and adherence to wash-outs related to 
non-allowed medication. Only in exceptional circumstances, when information concerning 
eligibility is outstanding (e.g., pending laboratory data), will an extended period be permitted. 
Along with the participant's background medication, participants will also be allowed to take 
rescue medication (non-sedating H1-AH) on an as needed basis for unbearable symptoms from 
screening up to the end of the study.  
Rescreening may be allowed for participants who failed initial screening. Only 1 rescreening 
will be allowed. If a participant is rescreened for the study, the participant must sign a new 
informed consent and will be issued a new participant number. Informed consent for a 
rescreened participant must be obtained prior to performing any study-related assessments or 
collecting any data for the Screening visit. 
1.1.2 
Double-blinded treatment period 
As a result of study termination, all subjects in the treatment phase were discontinued from 
treatment and moved into the follow-up phase. Only 3 subjects had completed Week 12 visit.  
Below is a description of the  treatment period as per protocol: 
Symptomatic dermographism and cold urticaria cohorts: On Day 1, participants werel  
randomized equally into ligelizumab 120mg vs ligelizumab 72 mg vs placebo, with participants 
in the placebo arm being randomly re-allocated to ligelizumab 120 mg and ligelizumab 72 mg 
at week 12. Randomization will only be performed once at Day 1, in a 2:2:1:1 fashion into 4 
arms: ligelizumab 120 mg, ligelizumab 72 mg, placebo to ligelizumab 120 mg and placebo to 
ligelizumab 72 mg. 
During the treatment period, doses are administered at 6 visits: Week 0, Week 4, Week, 8, Week 
12, Week 16 and Week 20. Participants randomized to the placebo arm will receive placebo for 
the first three treatment visits; Week 0, Week 4 and Week 8 and will then switch to ligelizumab 
120 mg q4w or ligelizumab 72 mg q4w (1:1 ratio) for the remaining 3 treatment visits; Week 
12, Week 16 and Week 20. Participants will continue to use their stable background therapy 
(H1-AH) at stable doses during the study. 


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Cholinergic urticaria cohort: On Day 1, participants will be randomized into a 1:1 fashion to 
ligelizumab 120 mg q4w vs. placebo. Participants of the placebo arm will be allocated to 
ligelizumab 120 mg at Week 12. Participants of the cholinergic urticaria cohort will not receive 
the ligelizumab 72 mg dose. During the treatment period, doses are administered at 6 visits: 
Week 0, Week 4, Week, 8, Week 12, Week 16 and Week 20. Participants randomized to the 
placebo arm will receive placebo for the first three treatment visits; Week 0, Week 4 and Week 
8 and will then switch to ligelizumab 120 mg q4w for the remaining 3 treatment visits; Week 
12, Week 16 and Week 20. Participants will continue to use their stable background therapy 
(H1-AH) at stable doses during the study. 
At weeks 0, 4, 8, 12, 24 and 36 participants from all cohorts will be subjected to provocation 
tests in order to elicit symptoms. A positive response at Week 0 (Day 1) to the FricTest®4.0, 
TempTest®4.0 or Pulse Controlled Ergometry is required to be randomized to the symptomatic 
dermographism, cold urticaria or cholinergic urticaria cohorts, respectively. Based on medical 
history, if a participant has more than one form of inducible urticaria (example: symptomatic 
dermographism and cold urticaria) then the participant must be considered for randomization 
into the group that is most bothersome to the participant. Since thresholds are not defined in 
CINDU, it is left to the investigator's judgement to enroll only those participants with moderate 
or severe disease burden. 
For the symptomatic dermographism cohort, it is planned to allocate approximately 168 
participants so that each treatment arm has 56 participants. For the cold urticaria cohort, it is 
planned to allocate approximately 102 participants so that each treatment arm has 34 patients. 
For the cholinergic urticaria, it is planned to allocate approximately 158 participants so that 
each treatment arm has 79 participants. For details on the calculation of the sample size for each 
of the three cohorts, see Section 3. 
Due to the low prevalence of this indication among the three cohorts, it is plausible that not all 
cohorts will be able reach their planned sample size, requiring modification of the sample size 
and modification to the statistical analysis with different data cut-offs for the different cohorts. 
Follow-up period 
The follow-up period is 12 weeks with the last follow-up visit (Week 36) corresponding to 16 
weeks after the last treatment dose. No study treatment will be given during the post-treatment 
follow-up period. Participants will continue with the background medication and will be 
allowed to take their rescue medication on an as needed basis, 
 
Participants will be required to visit the study center every 4 weeks during post-
treatment / follow-up period. 
Remote procedures 
As per section 4.6 of the study protocol, 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  ensure participant safety and trial integrity, the option of conducting the entire visit 
170 and visit 180 remotely may be offered to participants. For any other visit it may also be 
possible to conduct certain assessments for safety and efficacy remotely as described within 
Section 8. Any assessment performed remotely will be performed under the oversight of the 


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Investigator, who retains accountability for the oversight and all efficacy and safety decisions 
with delegation of tasks to an off-site healthcare professional. The remote procedures will be 
offered in certain countries and sites as determined by Novartis based on national and local 
regulations. The off-site healthcare professionals whether provided by Novartis or by the site 
must be agreed with Novartis before use.  
Figure 1-1 
Study design 
 
1.2 
Study objectives, endpoints and estimands  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
To demonstrate superiority of ligelizumab versus 
placebo with regards to the change from 
baseline in response to a standardized 
provocation test for each CINDU subtype 
Symptomatic Dermographism 
Change from baseline in Total Fric Score (TFS) 
at Week 12 in response to FricTest® 4.0 
Cold Urticaria 
Change from baseline in critical temperature 
threshold (CTT) at Week 12 in response to the 
TempTest® 4.0 
Cholinergic Urticaria 
Change from baseline in itch numerical rating 
scale (NRS) at Week 12 in response to the 
pulse-controlled ergometry test. 


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Objective(s) 
Endpoint(s) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
To demonstrate superiority of ligelizumab versus 
placebo with regard to proportion of participants 
with a complete response after standardized 
provocation test 
 
To demonstrate superiority of ligelizumab versus 
placebo in itch NRS following the provocation 
test. 
Symptomatic Dermographism 
Proportion of participants with complete 
response in FricTest® at Week 12 
Change from baseline in itch NRS following 
provocation test at Week 12, in participants with 
itch NRS > 0 at baseline 
Cold Urticaria 
Proportion of participants with complete 
response in TempTest® at Week 12 
Change from baseline in itch NRS following 
provocation test at Week 12, in participants with 
itch NRS > 0 at baseline 
Cholinergic Urticaria 
Proportion of participants with itch NRS=0 
following the pulse-controlled ergometry test at 
Week 12 
Proportion of participants with physician global 
assessment of severity of hives=0 following the 
pulse-controlled ergometry test at Week 12 
 
To assess the safety of ligelizumab  
Safety endpoints will include but not be limited 
to: 
• 
Occurrence of treatment emergent 
adverse events (serious and non-serious) 
during the study 
• 
Occurrence of treatment emergent 
adverse events during the study leading to 
discontinuation of study treatment 
• 
Occurrence of treatment emergent 
adverse events of interest listed as either 
identified or potential risks, during the study 
• 
Changes in safety parameters  


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1.2.1 
Primary estimand(s) 
 
The estimand is the precise description of the treatment effect and reflects strategies to 
address events occurring during trial conduct which could impact the interpretation of the trial 
results (e.g premature discontinuation of treatment). 
For each subtype of CINDU, the primary clinical question of interest is: what is the treatment 
effect of the ligelizumab treatment versus placebo on the primary endpoint in participants with 
H1-AH as background medication, regardless of use of rescue medications and/or prohibited 
medications and treatment discontinuations due to either AE, or use of prohibited medications, 
or lack of efficacy, assuming that participants had never discontinued treatment due to other 
reasons or missed any treatment prior to Week 12 due to other non-human controlled emergency 
situations (e.g. COVID-19). 
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of additional background and rescue medications, mirroring the conditions in 
clinical practice. This will also enable an estimation of the effect of study drug for the full 
duration of the study. Further details can be found in study protocol section 5. 
The primary estimand for each of the CINDU cohort is described by the following attributes: 
• Population: participants receiving H1-antihistamines therapy at local-approved dose level 
as background medication suffering from symptomatic dermographism, cold urticaria, or 
cholinergic urticaria and meeting study inclusion/exclusion criteria (as listed in study 
protocol Section 5.1 and 5.2). Further details about the population are provided in study 
protocol section 5. 
• Endpoint: 
1. Symptomatic Dermographism: change from baseline to Week 12 in Total Fric Score 
(TFS, i.e., score derived based on results from the Fric Test 4.0, see study protocol 
Section 8.3.1.1 for details) 


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2. Cold urticaria: change from baseline to Week 12 in critical temperature thresholds 
(CTT, i.e. the highest temperature hives are triggered, see study protocol Section 
8.3.1.2 for details) in response to the TempTest® 
3. Cholinergic urticaria: change from baseline to Week 12 in itch numerical rating scale 
(itch NRS) in response to the pulse-controlled ergometry (see study protocol Section 
8.3.1.3 for details). 
• Treatment of interest: ligelizumab or the placebo treatment (no further treatment for 
patients who discontinue treatment due to AE, lack of efficacy or intake of prohibited 
medications) with stable H1-antihistamines at local-approved doses as background 
medication + allowed rescue medication. The dose of the allowed background medication 
for CINDU must remain stable during the trial. Further details about the investigational 
treatment and control treatment are provided in study protocol Section 6. 
• Handling of remaining intercurrent events: 
• Discontinuation of initial assigned study treatment prior to Week 12 due to either 
adverse events (AE), or use of prohibited medications, or lack of efficacy (LoE): 
Participants who discontinue from study treatment early will be encouraged to stay in 
the study as detailed in study protocol Section 9.1.1. Retrieved drop out (RDO) data 
collected after study treatment discontinuation will be used for analysis. (treatment 
policy). 
• Discontinuation of initial assigned study treatment prior to Week 12 due to reasons 
other than adverse events (AE), use of prohibited medications, or lack of efficacy 
(LoE): had participants taken the assigned treatment up to Week 12 (hypothetical 
strategy) 
• Use of prohibited medications prior to Week 12 and not result in treatment 
discontinuation: ignore (treatment policy) 
• Missed treatment prior to Week 12 due to other non-human controlled emergency 
situations (e.g. COVID-19): had participants not missed treatment prior to Week 12 
other non-human controlled emergency situations (hypothetical strategy) 
• The summary measure: 
1. Symptomatic Dermographism: difference in mean change from baseline in Total Fric 
Score at Week 12 between treatments (ligelizumab 72 mg q4w vs placebo and 
ligelizumab 120 mg q4w vs placebo) 
2. Cold urticaria: difference in mean change from baseline of CTT at Week 12 between 
treatments (ligelizumab 72 mg q4w vs placebo and ligelizumab 120 mg q4w vs 
placebo) 
3. Cholinergic urticaria: difference in mean change from baseline in itch NRS in response to 
the pulse-controlled ergometry test at Week 12 between treatments (ligelizumab 120 mg 
q4w vs placebo) 
1.2.2 
Secondary estimand(s)  
For each subtype of CINDU, the secondary clinical questions of interest are similar as the 
primary clinical questions of interest and are based on the secondary endpoints. The only 


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difference is that, for the endpoint of complete responder status, participants with 
discontinuation of initially assigned study treatment prior to Week 12 due to either AEs, or use 
of prohibited medications, or lack of efficacy (LoE) will be considered as non-responders (i.e. 
composite strategy). 
The secondary estimand for each of the CINDU cohort is described by the following attributes: 
• Population: participants receiving H1-antihistamines therapy at local-approved dose level 
as background medication suffering from symptomatic dermographism, cold urticaria, or 
cholinergic urticaria and meeting study inclusion/exclusion criteria (as listed in study 
protocol Section 5.1 and 5.2). 
• Endpoints: 
Symptomatic dermographism: 
1. proportion of participants achieving complete response (i.e. TFS = 0) in the FricTest®4.0 
at week 12. 
2. change from baseline to Week 12 in itch numeric rating scale (NRS) following the 
FricTest ®4.0. 
Cold urticaria: 
1. proportion of participants achieving complete response (a negative provocation test 
result for the lowest temperature (4°C) in TempTest®4.0 at week 12.  
2. change from baseline to Week 12 in itch numeric rating scale (NRS) following the 
TempTest®4.0. 
Cholinergic urticaria: 
1. proportion of participants achieving complete response in itch NRS (itch NRS =0) 
following the pulse-controlled ergometry test at Week 12.  
2. proportion of participants achieving complete response in physician global assessment 
of severity of hives (i.e. PGA hive score=0) following the pulse-controlled ergometry 
test at week 12. 
• Treatment of interest: ligelizumab or the placebo treatment (no further treatment for 
patients who discontinue treatment due to AE, lack of efficacy or intake of prohibited 
medications) with stable H1-antihistamines at local-approved doses as background 
medication + allowed rescue medication. The dose of the allowed background medication 
for CINDU must remain stable during the trial.  
• Handling of remaining intercurrent events: 
1. Discontinuation of initial assigned study treatment prior to Week 12 due to either 
adverse events (AE), or use of prohibited medications, or lack of efficacy (LoE): 
a. For continous endpoints “change from baseline to Week 12 in itch NRS following 
provocation tests” (applicable to symptomatic dermographism and cold uriticaria 
cohorts): participants who discontinue from study treatment early will be 
encouraged to stay in the study as detailed in study protocol Section 9.1.1. 


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Retrieved drop out (RDO) data collected after study treatment discontinuation will 
be used for analysis (treatment policy). 
b. For binary endpoints (see table below): participants with discontinuation of 
initially assigned study treatment prior to Week 12 due to AEs, use of prohibited 
medications or lack of efficacy (LoE) will be considered as non-responders. 
(composite strategy). 
 
Cohort 
Endpoints 
• symptomatic 
dermographism  
• cold urticaria 
proportion of participants achieving complete response 
at Week 12 in response to provocation tests 
• cholinergic urticaria 
proportion of participants achieving complete response 
in itch NRS (itch NRS =0) following the pulse-
controlled ergometry test at Week 12 
proportion of participants achieving complete response 
in physician global assessment of severity of hives (i.e. 
PGA hive score=0) following the pulse-controlled 
ergometry test at week 12 
 
2. Discontinuation of initial assigned study treatment prior to Week 12 due to reasons 
other than adverse events (AE), use of prohibited medications, or lack of efficacy 
(LoE): had participants taken the assigned treatment up to Week 12 (hypothetical 
strategy) 
3. Use of prohibited medications prior to Week 12 and not result in treatment 
discontinuation: ignore (treatment policy) 
4. Missed treatment prior to Week 12 due to other non-human controlled emergency 
situations (e.g. COVID-19): had participants not missed treatment prior to Week 12 
other non-human controlled emergency situations (hypothetical strategy) 
• The summary measure: 
Symptomatic dermographism and cold urticaria: 
1. difference in complete response rates at Week 12 between treatments (ligelizumab 72 mg 
q4w vs placebo and ligelizumab 120 mg q4w vs placebo) 
2. difference in mean change from baseline of itch NRS following provocation tests at Week 
12 between treatments (ligelizumab 72 mg q4w vs placebo and ligelizumab 120 mg q4w 
vs placebo) 
Cholinergic urticaria: 
1. difference in proportion of participants achieving itch NRS=0 at week 12 between 
treatments (ligelizumab 120 mg q4w vs placebo) 
2. difference in proportion of participants achieving PGA hive score=0 at week 12 between 
treatments (ligelizumab 120 mg q4w vs placebo) 




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• Ligelizumab 72 mg q4w 
• Ligelizumab 120 mg q4w 
• Placebo – Ligelizumab 72 mg q4w 
• Placebo – Ligelizumab 120 mg q4w 
For cholinergic urticaria cohort, study treatment groups used for analysis are defined as below: 
• Ligelizumab 120 mg q4w 
• Placebo – Ligelizumab 120 mg q4w 
2.1.1.2 
Study Day 1 and other study days 
The first day of administration of randomized study treatment (first dose) is defined as study 
Day1 or Day 1.  
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for a particular event date will be calculated as [Date of event] - [Date of first dose] + 1. 
For the dates before Day 1, study day for an event date will be calculated as [Date of event] - 
[Date of first dose]. 
Duration of an event will be calculated as (Event end date – Event start date + 1). 
The descriptor “Day 0” will not be used. 
2.1.1.3 
Study Week based on RaveX collected visit information 
For efficacy and safety data collected by eCRF at scheduled visit (provocation test outcomes, 
lab results, ECGs, vital signs, PROs, 
 etc..), study week will be defined based on the visit 
name. For by visit summary tables, all the information collected at the scheduled visit will be 
included for the analyses. Unscheduled visit information will not be included in the by visit 
summary descriptive statistics. The unscheduled visit information will be only included in the 
maximum or minimum post treatment assessment summaries. 






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Domains 
Analyses 
sets 
Analysis Period 
Treatment group labels for each 
analysis period 
• Protocol deviations 
• Demographics 
• Other baseline characteristics 
RAS 
Entire study  
Ligelizumab 72 mg q4w
† 
Ligelizumab 120 mg q4w 
Placebo- Ligelizumab 72 mg q4w
† 
Placebo- Ligelizumab 120 mg q4w 
Total 
Efficacy data 
FAS 
Up to Week 12*  
 
Ligelizumab 72 mg q4w
 † 
Ligelizumab 120 mg q4w 
Placebo 
Entire study 
Ligelizumab 72 mg q4w
 † 
Ligelizumab 120 mg q4w 
Placebo- Ligelizumab 72 mg q4w
 † 
Placebo- Ligelizumab 120 mg q4w 
• Study treatment exposure and  
• Safety data  
 
SAF  
Up to Week 12*  
 
 
 
Ligelizumab 72 mg q4w
 † 
Ligelizumab 120 mg q4w 
Placebo 
 
SAF  
Entire Study  
 
Ligelizumab 72 mg q4w
 † 
Ligelizumab 120 mg q4w 
Placebo- Ligelizumab 72 mg q4w
 † 
Placebo- Ligelizumab 120 mg q4w 
*Week 12 is defined as described in Appendix. 
†Not applicable to the cholinergic urticaria cohort. 
2.2.1 
Subgroup of interest 
There will be no subgroup analyses. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Patient disposition will be summarized and listed for each cohort separately 
The number of screened subjects who complete the screening period will be given and the 
reasons for not entering into the double-blind treatment period will be summarized based on the 
ENR set.  
The number and percentage of subjects in the RAS who got mis-randomized, completed or 
discontinued the treatment period will be presented by treatment group and overall. Reasons for 
discontinuation will be listed.  
The number and percentage of subjects in the RAS who completed or discontinued the follow-
up period, and the reasons for discontinuation will also be presented by treatment group and 
overall. The number and percentage of subjects who completed the entire study (defined as 
completed both the treatment period and the follow-up period) will be presented by treatment 
group and overall as well.  


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2.3.2 
Demographics and other baseline characteristics 
For each CINDU cohort, demographics and other baseline data including disease characteristics 
will be listed and summarized descriptively by treatment group in the RAS. Relevant medical 
history will be listed.  
Summary statistics will be presented for continuous demographics and baseline characteristic 
variables for each treatment group and for all subjects in the RAS. The number and percentage 
of subjects in each category will be presented for categorical variables for each treatment group 
and all subjects. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
2.3.2.1 
Demographics (collected at Visit 1) 
• Age  
• Age group (adolescents (12-17 years), adults (18 - <65 years, ≥ 65 years)) 
• Sex  
• Race  
• Ethnicity  
• Region 
• Weight  
• Height  
• Body Mass Index (BMI) – calculated as weight (kg) / (height (m))2 
• BMI group (< 25, 25 - < 30, >= 30 kg/m2) 
2.3.2.2 
Disease characteristics at baseline  
 
 
 
 
• Baseline score in response to the provocation test (TFS for symptomatic 
dermographism, CTT for cold urticaria, itch NRS for all three cohort) 
• Baseline itch NRS=0 status 
 
 
 
 
 
 
• Duration of CINDU – calculated as (first study treatment date – first diagnosis date 
+1)/365.25 years) 
• Duration of a typical angioedema episode 
• Type of prior urticaria medication 
• Experienced angioedema within the past 4 weeks 
• Duration of a typical episode of angioedema 


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2.3.2.3 
Medical History 
Any conditions entered as medical history or current medical condition at baseline will be coded 
using the MedDRA dictionary. They will be listed and include  system organ class and preferred 
term of the MedDRA dictionary for RAS. Listings for CINDU-specific medical history will be 
provided as well. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The analysis of treatment will be performed by each treatment group based on the SAF in each 
cohort separately. 
The number of participants and the duration of exposure to each study drug and dose will be 
summarized by treatment. Duration of exposure is defined as the date of the last treatment minus 
the date of first study drug administration plus 4 weeks (28 days).    
In addition, the number of doses will be presented. A partial dose will be considered as if 100% 
of the dose of the assigned treatment has been administered. 
For all protocol deviations (PDs) listings will be generated by PD category and treatment groups 
in each cohort separately. 
2.4.2 
Prior and concomitant therapies 
For each CINDU cohort, the Safety set will be used for the analyses below. Due to the limited 
sample size of the safety dataset only listing will be presented for prior, concomitant, and post 
therapies.  
Prior medications are defined as medications taken by trial subject and the use was stopped 
prior to first dose of study treatment. Prior medications for CINDU and non-related to CINDU 
will be listed. 
Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the date of the last study visit. The medications started taking 
prior to the first dosing and still be used on or after the first dosing date will be also counted as 
concomitant medications. CINDU-related background medications, CINDU related 
concomitant medication and non-CINDU related medications listings will be provided. 
Listings for rescue medication (H1-antihistamin) will be generated 
Concomitant medication and rescue listings will be provided for: 
• Up to Week 12 visit (Visit 130) in the treatment period: in all the treatment groups and 
will include data from the placebo arm prior to (and on) transition to active treatment 
(transitioned to ligelizumab 72mg or ligelizumab 120mg group). If the start date is 
before the 12 week treatment period cut off definition, it will be counted in the listing 
for the 12 weeks treatment period. 


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Entire study period: in all the treatment groups and will include data from the placebo arm after 
transition to active treatment (transitioned to ligelizumab 72mg or ligelizumab 120mg group).  
2.5 
Analysis supporting primary objective(s) 
2.5.1 
Primary endpoint(s) 
For the three CINDU cohorts, the primary endpoint(s) is defined in the “endpoint” attribute of 
the primary estimand (Section 1.2). 
2.5.2 
Statistical hypothesis, model, and method of analysis  
Symptomatic Dermographism: 
The aim is to estimate the treatment effect of ligelizumab compared to placebo, for the target 
population on the primary endpoint (i.e. change from baseline to week 12 in Total Fric Score). 
The justification of the corresponding primary estimand is detailed in Section 1.2.1. 
The primary analysis method is based on a two-sample t-test. 
The null hypothesis test (H0) for the primary endpoint is that the change from baseline at Week 
12 in TFS in any of the ligelizumab groups (low or high dose) is not superior to the placebo 
group: 
H01.SDerm: μligelizumab ≥ μPlacebo versus HA1.SDerm: μligelizumab < μPlacebo 
where μ is the mean change from baseline of TFS at week 12, negative value indicates 
improvement. 
No formal statistical analysis will be performed due to limited sample size (see Section 4.). 
Listings will be presented for change from baseline at week 12 of Symptomatic Dermographsim. 
Cold Urticaria: 
The aim is to estimate the treatment effect of ligelizumab compared to placebo, for the target 
population on the primary endpoint (i.e. change from baseline to week 12 in CTT). The 
justification of the corresponding primary estimand is detailed in Section 1.2.1. 
The primary analysis method is based on a two-sample t-test. 
The null hypothesis (H0 ) for the primary endpoint is that the change from baseline at Week 12 
in CTT in any of the ligelizumab groups (low or high dose) is not superior to the placebo group: 
H01.Cold: μligelizumab ≥ μPlacebo versus HA1.Cold: μligelizumab < μPlacebo 
where μ is the mean change from baseline of CTT at week 12, negative value indicates 
improvement. 
No formal statistical analysis will be performed due to limited sample size (see Section 4.). 
Listings will be presented for change from baseline at week 12 of Cold Urticaria.  
 
 


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Cholinergic Urticaria: 
.The aim is to estimate the treatment effect of ligelizumab compared to placebo, for the target 
population on the primary endpoint (i.e. change from baseline to week 12 in itch NRS following 
the pulse-controlled ergometry test). The justification of the corresponding primary estimand is 
detailed in Section 1.2.1. 
The primary analysis method is based on a two-sampe t-test. 
The null hypothesis (H0) for the primary endpoint is that the change from baseline at Week 12 
in itch NRS in the ligelizumab 120 mg q4w group is not superior to the placebo group: 
H01.Chol: μligelizumab ≥ μPlacebo versus HA1.Chol: μligelizumab < μPlacebo 
where μ is the mean change from baseline in itch NRS following the pulse controlled ergometry 
test at week 12, negative value indicates improvement. 
All primary and secondary endpoints will be tested against the respective alternative hypotheses 
in a closed testing procedure (Bretz et al 2009), so that the family-wise type I error will be 
controlled at 0.025 (one-sided) for each sub-type. The detailed testing strategy is provided in 
Section 2.6.2. 
No formal statistical analysis will be performed due to limited sample size (see Section 4.). 
Listings will be presented for change from baseline at week 12 of Cholinergic Urticaria 
2.5.3 
Handling of intercurrent events  
For all three CINDU subtypes (i.e., symptomatic dermographism, cold urticaria, and 
cholinergic urticaria), the primary analysis for the primary estimand will account for 
different intercurrent events as explained in the following: 
• Discontinuation of assigned study treatment prior to Week 12 either for the 
reasons of AE, or lack of efficacy, or use of prohibited medications: Retrieved drop 
out (RDO) data collected after study treatment discontinuation will be used for 
analysis. If provocation tests are performed at the EOT and/or the EOS visit, and the 
provocation test date(s) is within the +/- 4 weeks window of the date of the planned 
Week 12 visit, then the outcomes yield from the EOT or EOS provocation test, 
whichever is closer to the planned Week 12 date, will be considered as the RDO data 
for the primary endpoint.  If no RDO data was collected after study treatment 
permanent discontinuation, missing data for ligelizumab groups will be multiply 
imputed based on information borrowed from the placebo, and under the MAR 
assumption for the placebo group (Treatment policy). 
• Discontinuation of study treatment prior to Week 12 for the reasons other than 
AE or lack of efficacy or use of prohibited medications: primary variable will be 
replaced by the multiply imputed values under the MAR assumption for all the groups 
(hypothetical strategy). 
• Use of prohibited medications prior to Week 12 and not result in treatment 
discontinuation: handled by treatment policy, data collected after the intercurrent 
event will be used as it is (Treatment policy). 


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• Missed treatment prior to Week 12 due to other non-human controlled 
emergency situations (e.g. COVID-19): primary variable will be replaced by the 
multiply imputed values under the MAR assumption for all the groups (hypothetical 
strategy). 
2.5.3.1 
Multiple intercurrent events occurring prior to Week 12 
Multiple intercurrent events occurring prior to Week 12 will be handled by the hypothetical 
strategy only if all of them are classified as to be handled by the hypothetical strategy 
individually, in which case, data after the first intercurrent event will be replaced by 
multiply imputed values under the MAR assumption.   
2.5.3.2 
Handling of missing values not related to intercurrent event 
For each of the CINDU cohort, the following will be considered as intermittent missing 
data, which are not related to intercurrent event: 
The provocation test is stopped due to any reason e.g. participant discomfort, technical 
issues the data will be considered as missing. 
The provocation test is not performed due to any reasons other than specified intercurrent 
events 
Symptomatic dermographism 
Handling of missing or incomplete results in the FricTest 4.0: 
The missing TFS will be multiply imputed under the MAR assumption for all the groups. 
Cold urticaria 
Handling of missing or incomplete results in response to the TempTest®: 
The missing CTT will be multiply imputed under the MAR assumption for all the groups. 
Cholinergic urticaria 
Handling of missing or incomplete itch NRS results following the pulse-controlled 
ergometry test: 
The missing itch NRS will be multiply imputed under the MAR assumption for both 
treatment groups. 
2.5.4 
Sensitivity analyses  
No sensitivity analyses will be performed. 
2.5.5 
Supplementary analyses 
No supplementary analyses will be performed. 


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2.6 
Analysis supporting secondary objectives  
2.6.1 
Secondary endpoint(s) 
For the three CINDU cohorts, the secondary endpoint(s) is defined in the “endpoint” attribute 
of the secondary estimand (Section 1.2.2). 
2.6.2 
Statistical hypothesis, model, and method of analysis 
The following secondary endpoints will be assessed and included into the testing strategy for 
the three CINDU cohorts : 
• Symptomatic dermographism 
1. proportion of participants achieving complete response in response to the FricTest 4.0 
(Total Fric Score=0) at Week 12 
2. absolute change from baseline to Week 12 on itch NRS following the FricTest 4.0. 
• Cold urticaria 
1. proportion of participants achieving complete response in response to the TempTest at 
Week 12 
2. change from baseline to Week 12 on itch NRS following the TempTest. 
• Cholinergic urticaria 
1. proportion of participants achieving complete response in itch NRS following the 
pulse-controlled ergometry test, assessed as itch NRS=0 at Week 12. 
2. proportion of participants achieving complete response in physician global assessment 
(PGA) of severity of hives following the pulse-controlled ergometry test, assessed as 
PGA hive score=0 at Week 12. 
The proportion of participants with complete response at Week 12 will be compared by the 
Fisher's Exact test between each of the ligelizumab dose group and the placebo group. In case 
of missing data caused by discontinuation due to reasons other than AE, lack of efficacy, or 
intake of prohibited medication, or missing data not related to intercurrent events, missing 
responder status in corresponding provocation test (i.e. TFS, CTT, and itch NRS) will be 
multiply imputed in similar manner as described in Section 2.5.3 and Section 2.5.4, respectively.  
Change from baseline to Week 12 on itch NRS in response to provocation tests will be analyzed 
by two-sample t-test. In case of missing data caused by discontinuation due to reasons other 
than AE, lack of efficacy, or intake of prohibited medication, or missing data not related to 
intercurrent events, itch NRS will be imputed in a same manner as described in Section 2.5.3 
and Section 2.5.4, respectively. 
Testing strategy for symptomatic dermographism and cold urticaria 
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) for each CINDU cohort. 
 


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Primary endpoints 
Total Fric Score/CTT change from baseline at Week 12 
H01: μligelizumab ≥ μPlacebo versus HA1: μligelizumab < μPlacebo 
where μ is the mean change from baseline in Total Fric Score/CTT at Week 12, as described in 
Section 1.2.1. 
Secondary endpoints 
• proportion of participants achieving complete response in response to FricTest 4.0 and 
TempTest at Week 12 
H02:πligelizumab ≤ πPlacebo versus HA2: πligelizumab > πPlacebo 
where π is the proportion of participants achieving complete response status at Week 12, as 
described in Section 1.2.2. 
• itch NRS following provocation tests change from baseline at Week 12 
H03: μligelizumab ≥ μPlacebo versus HA3: μligelizumab < μPlacebo 
where μ is the mean change from baseline in itch NRS following the FricTest 4.0 and TempTest 
at Week 12, as described in Section 2.2. 
Figure 2-1 
Testing strategy for symptomatic dermographism and cold urticaria 
 
For symptomatic dermographism and cold urticaria CINDU cohort, the hypotheses are mapped 
into two families. 
The first family consists of four hypotheses: H11, H12, H21, and H22. These four hypotheses form 
two branches such that hypotheses within a same branch correspond to the same ligelizumab 


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dose regimen (72 mg q4w or 120 mg q4w). In essence, the type-I-error probability will be 
equally split for both branches of hypotheses and within each branch the hypotheses are tested 
sequentially as follows: 
The initial alpha level for each branch is set to α/2=0.0125 (one-sided). The first hypothesis 
(H11 and H12) is tested with 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 hypotheses (H21 and/or H22) of high/low dose ligelizumab versus placebo 
regarding the secondary endpoint on complete response is tested with α/2. 
In the first family, the testing within each dose is strictly hierarchical: the secondary endpoint 
on complete response will only be assessed if efficacy was shown previously for the primary 
endpoint. If efficacy is shown for both the primary and the secondary endpoint for one of the 
doses, the associated weight is passed on to the other dose. 
The second family consists of H31 and H32, will only be tested if all four hypotheses in the first 
family are rejected. The initial alpha level will be equally split (i.e. is set to α/2=0.0125, one-
sided) for each hypothesis. If either of the hypotheses is rejected, the associated weight is passed 
on to the other dose, so that other hypothesis is tested with α. 
Testing strategy for cholinergic urticaria 
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) for cholinergic urticaria. 
Primary endpoint 
Itch NRS change from baseline at Week 12 
H01: μligelizumab ≥ μPlacebo versus HA1: μligelizumab < μPlacebo 
where μ is the mean change from baseline in itch NRS following the pulse-controlled ergometry 
test at Week 12, as described in Section 1.2.1. 
Secondary endpoints 
• proportion of participants achieving complete response in itch NRS (itch NRS=0 ) 
following the pulse-controlled ergometry test at Week 12 
H02:πitchligelizumab ≤ πitchPlacebo versus HA2: πitchligelizumab >πitchPlacebo 
where πitch is the proportion of participants achieving complete response in itch NRS at Week 
12, as described in Section 1.2.2. 
• proportion of participants achieving complete response in physician global assessment of 
severity of hives (PGA hive score =0) following the pulse-controlled ergometry test at 
Week 12 
H03:πhiveligelizumab ≤ πhivePlacebo versus HA3: πhiveligelizumab > πhivePlacebo 
where πhive is the proportion of participants achieving complete response in PGA hive score=0 
at Week 12, as described in Section 1.2.2. 


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Figure 2-2 
Testing strategy for cholinergic urticaria 
 
For cholinergic urticaria, the hypotheses are tested sequentially in a fix order as follows: 
The initial alpha level is set to α=0.025 (one-sided) for the first hypothesis (H1) of ligelizumab 
120 mg q4w versus placebo regarding the primary endpoint. If H1 is rejected, the second 
hypothesis (H2) of ligelizumab versus placebo regarding the secondary endpoint on complete 
response in itch NRS is tested with α. If H2 is rejected, the third hypothesis (H3) of ligelizumab 
versus placebo regarding the secondary endpoint on complete response in physician global 
assessment of severity of hives is tested with α. 
There will be no statistical modeling, hypothesis testing, or methodology used for symptomics 
dermographism, cold urticaria, cholinergic urticaria due to limited sample size. 
 
2.6.3 
Handling of intercurrent events  
Participants who discontinue from study treatment early will be encouraged to stay in the study 
following the procedure described in study protocol Section 9.1.1. These are considered as 
retrieved drop-out (RDO) participants. 
For all three CINDU subtypes, symptomatic dermographism, cold urticaria, and cholinergic 
urticaria, the primary analysis for the secondary estimands will account for different intercurrent 
events as explained in the following: 
• Discontinuation of assigned study treatment prior to Week 12 either for the 
reasons of AE, or lack of efficacy, or use of prohibited medications:  
a. For endpoints of “change from baseline to Week 12 in itch NRS following 
provocation tests” (applicable to symptomatic dermographism and cold uriticaria 
cohorts): participants who discontinue from study treatment early will be 
encouraged to stay in the study as detailed in study protocol Section 9.1.1. 


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Retrieved drop out (RDO) data collected after study treatment discontinuation will 
be used for analysis (treatment policy). If provocation tests are performed at the 
EOT and/or the EOS visit, and the provocation test date(s) is within the +/- 4 
weeks window of the date of the planned Week 12 visit, then the outcomes yield 
from the EOT or EOS provocation test, whichever is closer to the planned Week 
12 date, will be considered as the RDO data for the secondary endpoint.  If no 
RDO data was collected after study treatment permanent discontinuation, missing 
data for ligelizumab groups will be multiply imputed based on information from 
the placebo, and under the MAR assumption for the placebo group. 
b. For binary endpoints (see table below): participants with discontinuation of 
initially assigned study treatment prior to Week 12 due to AEs, use of prohibited 
medications or lack of efficacy (LoE) will be considered as non-responders. 
(composite strategy). 
 
Cohort 
Endpoints 
• symptomatic dermographism  
• cold uriticaria 
proportion of participants achieving complete response at 
Week 12 in response to provocation tests 
• cholinergic urticaria 
proportion of participants achieving complete response in itch 
NRS (itch NRS =0) following the provocation test at Week 12 
proportion of participants achieving complete response in 
physician global assessment of severity of hives (i.e. PGA hive 
score=0) following the provocation test at week 12 
• Discontinuation of study treatment prior to Week 12  for the reasons other than 
AE or lack of efficacy or use of prohibited medications: complete response status 
(Section 1.2.2) and itch NRS following the provocation tests will be treated as missing 
and multiply imputed under the MAR assumption for all the groups (hypothetical 
strategy). 
• Use of prohibited medications prior to Week 12 and not result in treatment 
discontinuation: handled by treatment policy, data collected after the intercurrent 
event will be used as it is (treatment policy). 
• Missed treatment prior to Week 12 due to other non-human controlled 
emergency situations (e.g. COVID-19): complete response status (Section 1.2.2) and 
itch NRS following the provocation tests will be treated as missing and multiply 
imputed under the MAR assumption for all the groups (hypothetical strategy). 
2.6.3.1 
Multiple intercurrent events occurring prior to Week 12 
For secondary estimands, multiple intercurrent events occurring prior to Week 12 will be 
handled by the following rules: 
• If all of them are classified as to be handled by the hypothetical strategy individually: 
the hypothetical strategy will be used. Data after the first intercurrent event will be 
replaced by multiply imputed values under the MAR assumption. 


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• If one of them is classified as to be handled by the composite strategy: other 
intercurrent events will be ignored, complete response status after the composite-
strategy intercurrent event will be regarded as non-responder. 
2.6.4 
Handling of missing values not related to intercurrent event 
For each of the CINDU cohort, the following will be considered as intermittent missing data, 
which are not related to intercurrent event: 
• The provocation test is stopped due to any reason e.g. participant discomfort, 
technical issues the data will be considered as missing. 
• The provocation test is not performed due to any reasons other than specified 
intercurrent events 
Symptomatic dermographism 
Handling of missing or incomplete results in the FricTest 4.0: 
• The missing TFS=0 complete response status will be multiply imputed under the 
MAR assumption for all the groups. 
• The missing itch NRS following the provocation test will be multiply imputed under 
the MAR assumption for all the groups. 
Cold urticaria 
Handling of missing or incomplete results in response to the TempTest®: 
• The missing complete response status (a negative provocation test result for the 
lowest temperature (4°C) in TempTest®4.0 ) will be multiply imputed under the 
MAR assumption for all the groups. 
• The missing itch NRS following the provocation test will be multiply imputed under 
the MAR assumption for all the groups. 
Cholinergic urticaria 
Handling of missing or incomplete results the following the pulse-controlled ergometry test: 
• The missing itch NRS=0 complete response status will be multiply imputed under the 
MAR assumption for both treatment groups. 
The missing PGA hive score=0 complete response status will be multiply imputed under the 
MAR assumption for both treatment groups. 
2.6.5 
Sensitivity analyses 
No sensitivity analyses will be performed. 
2.6.6 
Supplementary analyses 
No Supplementary analyses will be performed. 


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2.7 
Safety analyses 
The following applies to each of the three cohorts (i.e., symptomatic dermographism, cold 
urticaria, and cholinergic urticaria) separately, and in the overall CINDU population. 
For all safety analyses (i.e. AEs, laboratory data, vital signs, and ECG), the SAF will be used. 
All data will be included in the analysis regardless of rescue medication use.  
All listings and tables will be presented by treatment group.  
Treatment groups for evaluation of treatment period 
The summaries for evaluation of the treatment periods will allow for comparisons of treatment 
groups with placebo, before treatment switch is initiated. Therefore, the safety data for the 
Placebo-Ligelizumab 72mg/120mg q4w group will be provided in two separate periods.  
As adverse event tables will be provided for the treatment period up to Week 12 separately, the 
Week 12 treatment period definition is the treatment period up to Week 12 dosing date 
(excluding the Week 12 dosing date). For the Placebo-Ligelizumab 72mg/120mg q4w group, 
if the first dosing date transitioning to ligelizumab happened earlier or later than the Week 12 
dosing date (e.g. Week 4 or Week 8) due to a dosing error, the placebo treatment period will be 
cut-off by all the information prior to the first ligelizumab dosing date. The detailed description 
of the Week 12 cutoff date definition is provided in the statistical analysis plan appendix. 
Treatment groups for evaluation of entire study 
The summaries for evaluation of entire study will include all the information following the 
study design treatment groups. In addition, the following combined groups may be used for 
safety analysis. 
Table 2-3 
Treatment groups for safety analysis 
 
Ligelizumab 72mg 
q4w 
Ligelizumab 120mg 
q4w 
Placebo  
Transitioned to 
Ligelizumab 
72mg/120mg q4w 
Treatment 
Period up to 
Week 12 visit 
Yesa 
Yesa 
Yes1 
No 
Entire Study 
Yes 
Yes 
No 
Yes2 
1 The information before the treatment switching is initiated will be included. It means only the 
safety information from the period when participants receive placebo will be included in the 
analysis. 
2 The information after the treatment transitioned is initiated will be included. It means only the 
safety information from the period when participants receive ligelizumab 72mg/120mg q4w 
will be included in the analysis.  
a The treatment groups will be included in the summary tables include information up to Week 
12 visit.  


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2.7.1 
Adverse events (AEs) 
Treatment emergent adverse events (TEAEs) are events which started on or after the first dose 
of study treatment and within 16 weeks after the last study treatment, or events present prior to 
the first dose of study treatment but increased in severity based on preferred term within 16 
weeks after the last study treatment. 
TEAEs will be summarized in each cohort separately by the actually received treatment group: 
• The number and exposure-adjusted incidence of subjects having any TEAE by system 
organ class (SOC) and preferred term (PT): For the participants in the placebo arm, 
adverse events after switching to ligelizumab (on or after Week 12) will be summarized 
separately for the treatment phase. The summary of the TEAEs up to Week 12 will 
include all the TEAEs up to Week 12 for all the treatment groups, including the placebo 
only group. The summary of the TEAEs for the entire study will be provided for all the 
treatment groups listed in Table 2-3.    
• The number and exposure-adjusted incidence of subjects having any TEAE by severity: 
if a subject reported more than one adverse event with the same preferred term, the 
adverse event with the greatest severity will be presented. If a subject reported more 
than one adverse event 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.  
• The number and exposure-adjusted incidence of subjects having any related TEAEs.: if 
a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one 
adverse event 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. 
• The number exposure-adjusted incidence of subjects having any serious treatment 
emergent adverse events (TESAEs), related TESAEs. The following significant adverse 
event will be listed -  TEAEs leading to discontinuation and dose interruption, and 
TEAE adverse events of special interest (AESIs). For AESIs with adjudication 
(anaphylaxis, malignancy, CCV), separate listings will be provided based on the 
adjudicated results.  
• A listing will be provided for safety topics of immunogenicity, COVID-19 infection, 
Liver Toxicity.  
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables with 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and with treatment emergent serious adverse events and SAEs suspected to be 
related to study treatment, will be provided by system organ class and preferred term on the 
safety set population. These tables will not be included in the CSR. 
If for the same participant, several consecutive TEAEs (irrespective of study treatment 
causality, seriousness and severity) occurred with the same SOC and PT: 


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• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding TEAE and the start date of the consecutive TEAE. 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding TEAE and the start date of the consecutive TEAE. 
For occurrence, the presence of at least one TESAE / TESAE suspected to be related to study 
treatment / non TESAE has to be checked in a block e.g., among TEAE's in a ≤ 1 day gap 
block. If at least one SAE is occurring, then one occurrence is calculated for that TESAE. 
The number of deaths resulting from TESAEs suspected to be related to study treatment and 
TESAEs irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.1.1 
Exposure-Adjusted Incidence Rate 
Due to expected differences in exposure and follow-up due to varied duration of study 
participation between participants, adverse event incidence rates will be provided as “exposure 
adjusted AE incidence rates”.  
The EAIR is defined as the number of subjects with a specific event divided by the total 
exposure-time among the subjects in the study group. That is, the EAIR is calculated as: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸= n / 𝛴𝛴 ti , where n is the number of subjects having the ith type event, and ti is a subject's 
exposure time and defined as the shortest of the following: 
1) time to the first episode of the ith type event (if the event occurs), 
2) duration of study treatment plus the 16-week washout period (approximately 
corresponding to five half-lives) after last treatment dose, or 
3) end of the analysis period (Week 12 for the placebo period, week 36 for all safety 
follow-up). 
The total exposure time of all subjects in a treatment group is 𝛴𝛴 ti. The EAIR is interpreted as 
the number of events occurring in a population per unit time. The exact Poisson 95% confidence 
interval for the EAIR will be provided as well, where an exact 100*(1-α)% confidence interval 
will be derived as follows (Garwood 1936, Sahai and Khurshid 1993): 
• Lower confidence limit 𝐿𝐿=
0.5𝐶𝐶𝛼𝛼/2,2𝑛𝑛
∑𝑡𝑡𝑖𝑖
  for n>0, 0 otherwise,  
• Upper confidence limit 𝑈𝑈=
0.5𝐶𝐶1−𝛼𝛼/2,2𝑛𝑛+2
∑𝑡𝑡𝑖𝑖
, 
where 𝐶𝐶𝛼𝛼,𝑘𝑘 is the αth quantile of the Chi-square distribution with k degrees of freedom. 
Whenever applicable, exposure adjusted incidence rates will be provided for the type as below: 
1. TEAE and TESAE: Primary SOC level, PT level 
2. Most frequent (at least 5% in any treatment group) TEAE: Primary SOC level, PT level 
Treatment emergent AE of special interest. 


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2.7.1.2 
Adverse events of special interest / grouping of AEs 
Treatment emergent adverse events of special interest (TEAESIs) for ligelizumab treatment will 
be summarized in each cohort separately.  
AEs of special interest for QGE031 treatment include the following, specified as compound-
level risk factors defined in the Case Retrieval Strategy (eCRS). The search criteria in the latest 
eCRS corresponding the MedDRA version at the database lock will be used and reported in the 
CSR:  
• Hypersensitivity reactions (including anaphylaxis) 
• Cardiovascular and Cerebrovascular (CCV) events 
• Neoplastic conditions  
• Injection site reactions 
• Serum Sickness  
• Churg-Strauss syndrome-Hypereosinophilic syndrome (HES) 
• Parasitic (Helminthic) infections  
• Thrombocytopenia 
 
 
 
Adjudicated AEs 
From the AESIs listed above, the following AEs will be adjudicated by the independent 
committee. The adjudicated events will be listed and a summary table will be provided 
following the adjudication.    
• Anaphylaxis 
• Cardiovascular and Cerebrovascular (CCV) events 
• Neoplastic conditions 
COVID-19 infection related analyses 
Listings of all TEAE COVID infections will be presented. All suspected and confirmed 
infection will be provided. The COVID-19 infection will be filtered based on eCRS. 
2.7.2 
Deaths 
Death will be reported as part of TESAE with a fatal outcome and will be listed in separate 
listings. 
2.7.3 
Laboratory data 
The listings for  laboratory evaluations will be presented for 3 groups of laboratory tests 
(hematology, serum chemistry, urinalysis) in each cohort separately.  


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Listings for the change from baseline to each study visit and maximum/minimum value will be 
generated. These listings 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 for quantitative parameters, and the maximum/minimum value could come from post-
baseline scheduled, unscheduled or premature discontinuation visits. Data from local 
laboratories will be presented  in the listings together. For point of care tests (POCT), the clinical 
sites in China will be allowed to analyze several parameters such as urine/serum for pregnancy 
test and urinalysis as per clinical site practice, these results will be flagged in the listings. 
The numerical part of the reported result will be treated as the actual LLOQ or ULOQ. These 
laboratory values will be displayed in listings using the standard unit with the reported sign (“<” 
or “>”). 
The number of participants with newly occurring or worsening abnormalities during the study 
will be listed by treatment based on the range of the observed data . A case is considered as a 
newly occurring abnormality if the value is not notable or missing at baseline but is notable 
thereafter during the study. A case is considered as a worsening abnormality if the value is 
notable at baseline and at least one post-baseline value during the study is worse than baseline.  
If an adolescent subject turned to be an adult subject during the study, the normal range, notable 
criteria for analysis will be based on the age by the visit assessment. 
 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
All listings will be provided for each CINDU cohort separately. A listing of all newly occurring 
or worsening abnormalities will be provided, as well as a by-subject listing of all quantitative 
ECG parameters.   
The following will be considered as notable values for adults: QT > 500 msec; QTcF > 450 
msec (males), QTcF > 460 msec (females); QTcF change from baseline > 30 msec, >60 msec; 
PR > 250 msec. The following were considered as notable ECG values for adolesents: QTcF 
>450 msec (males), QTcF >460 msec (females); QTcF change from baseline >30 msec, >60 
msec; PR >250 msec. 
2.7.4.2 
Vital signs 
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: same normal range for adult will be used for adolescents. 


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2.13 
Interim analysis 
The early termination of the trial was due to limited enrollment and hence  a limited sample 
size. Therefore, a futility analysis will not be conducted. 
A final analysis will be performed after all participants have completed Week 36 (or 
discontinued prior to Week 36). Formal testing of the primary endpoint with full level alpha 
will be performed at the primary analysis time point. 
Due to the low prevalence of cholinergic urticaria, an interim futility analysis may be conducted 
in case there is an obvious difference in recruitment speed in the three cohorts. In other words, 
this interim futility analysis would be triggered when approximately 50% of randomized 
participants in the cholinergic urticaria cohort have completed the Week 12 visit while 100% 
of randomized participants in the symptomatic dermographism and cold urticaria cohorts have 
completed the Week 12 visit. During this analysis, there will be no decision rules applied for 
the symptomatic dermographism and cold urticaria cohort. This analysis will be conducted to 
assess whether efficacy met a pre-specified level only for the cholinergic urticaria cohort. 
Futility analysis results will be evaluated by the DMC based on calculated predictive 
probabilities of the primary estimand (see Section 2) for cholinergic urticaria. Details of the 
calculations and the associated thresholds will be described in the DMC Charter and its 
associated analysis plan. Additional analyses on the secondary estimand (see section 2) and 
safety will also be performed to assist in the futility evaluation, as planned in the DMC charter. 
Additional analyses may be performed to support health authority interactions as necessary. 
 
3 
Sample Size 
Symptomatic dermographism 
The sample size justification is based on change from baseline in Total Fric Score and 
achievement of complete response in FricTest®4.0 at Week 12. 
Cold urticaria 


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The sample size justification is based on change from baseline in CTT (in response to 
TempTest®4.0) and achievement of complete response in TempTest®4.0 at Week 12. 
Cholinergic Urticaria 
The sample size justification is based on change from baseline in itch NRS in response to the 
pulse-controlled ergometry test and achievement of complete response in itch NRS (itch NRS=0) 
at Week 12. 
For symptomatic dermographism and cold urticaria, participants will be randomized in a 2:2:1:1 
ratio to ligelizumab 72 mg q4w, ligelizumab 120 mg q4w, placebo - ligelizumab 120 mg q4w, 
and placebo - ligelizumab 72 mg q4w, respectively. In other words, participants are randomly 
assigned to ligelizumab 72 mg q4w, ligelizumab 120 mg q4w, and placebo group with a 1:1:1 
ratio in the placebo-controlled period (i.e. up to Week 12). For cholinergic urticaria, participants 
will be randomized in a 1:1 ratio to ligelizumab 120 mg q4w and placebo- ligelizumab 120 mg 
q4w. 
All sample size calculations were performed with SAS 9.4 PROC POWER. 
Based on simulation studies, the sample sizes calculated below for each of the three CINDU 
cohorts are sufficient to maintain the power of overall multiple testing strategy (at least 90%) 
for the primary endpoint (see Section 2.1) and the first secondary endpoint (i.e. complete 
response rate following the FricTest®4.0 for symptomatic dermographism, complete response 
rate following the TempTest®4.0 for cold urticaria, and complete response rate in itch NRS 
following the pulse-controlled ergometry test for cholinergic urticaria) through the recycled 
alpha. 
Data from each subtype is analyzed separately. Hence if sample size is not achieved for one of 
the subtypes, this will not impact the analysis for the other subtypes. 
3.1.1 
Primary endpoint(s) 
3.1.1.1 
Symptomatic Dermographism 
Since two ligelizumab dose regimens will be tested versus placebo with respect to the primary 
endpoints (change from baseline in Total Fric Score at Week 12), the type-I-error will be split 
to 1.25% one-sided for each comparison. 
Assuming the treatment difference in change from baseline to Week 12 in Total Fric Score is 
at least 1.3 in favor of the ligelizumab group, and a standard deviation of approximately 1.7, a 
sample size of approximate 56 participants per group and a drop-out rate of 10% provides 93.7% 
power to show that the primary analysis based on a two-sample t-test will be statistically 
significant at the one-sided 1.25% significance level (SAS 9.4, PROC POWER, difference in 
two sample means). 
Mean changes from baseline in Total Fric Score of -0.6 (standard deviation: 1.4) in placebo 
group, -1.78 (standard deviation: 1.66) in omalizumab 150 mg group, and - 2.0 (standard 
deviation: 1.67) in omalizumab 300 mg group have been reported in Maurer et al 2017. 


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Table 3-1 
Sensitivity of power to changes in assumptions (Symptomatic 
Dermographism) 
True treatment 
difference 
ligelizumab vs 
placebo 
(Total Fric Score) 
SD (Total 
Fric Score) 
Power for primary endpoint (one-sided α =1.25%, for N= 56 per arm) 
With 5% drop-out rate 
With 10% drop-out 
rate 
With 15% drop-out 
rate 
1.5 
1.3 
1.3 
1 
2 
2 
1.7 
1.3 
94.2% 
85.6% 
95.0% 
95.3% 
92.8% 
83.3% 
93.7% 
94.0% 
91.1% 
80.7% 
92.1% 
92.5% 
SD=Standard Deviations 
3.1.1.2 
Cold urticaria 
Since two ligelizumab dose regimens will be tested versus placebo with respect to the primary 
endpoints (change from baseline in critical temperature thresholds (CTT) at Week 12), the type-
I-error will be split to 1.25% one-sided for each comparison. 
Assuming the treatment difference in change from baseline to Week 12 in CTTs is at least 10°C 
in favor of the ligelizumab group, and a standard deviation of approximately 8°C, a sample size 
of approximate 34 participants per group a drop-out rate of 10% provides >99% power to show 
that the primary analysis based on a t-test will be statistically significant at the one-sided 1.25% 
significance level (SAS 9.4, PROC POWER, difference in two sample means). 
Mean changes from baseline in CTT of -0.3°C (standard deviation: 3.9°C) in placebo group, 
CTT of -10.6°C (standard deviation: 7.6°C) in omalizumab 150 mg group, and CTT of -10.4°C 
(standard deviation: 9.4°C) in omalizumab 300 mg group have been reported in Metz et al 2017. 
Table 3-2 
Sensitivity of power to changes in assumptions (cold urticaria) 
True treatment 
difference 
ligelizumab vs 
placebo 
(°C) 
SD (°C) 
Power for primary endpoint (one-sided α =1.25%, for N=34 per arm) 
With 5% drop-out rate 
With 10% drop-out 
rate 
With 15% drop-out 
rate 
11 
10 
10 
8 
10 
10 
9 
8 
98.1% 
95.3% 
98.3% 
95.3% 
97.3% 
93.9% 
97.5% 
93.9% 
96.2% 
92.1% 
96.5% 
92.1% 
SD=Standard Deviation 
3.1.1.3 
Cholinergic Urticaria 
Assuming the treatment difference in change from baseline to Week 12 in itch NRS following 
the pulse-controlled ergometry test is at least 1.65 in favor of the ligelizumab 120 mg q4w group, 
and a standard deviation of approximately 3.0, a sample size of approximate 79 participants per 
group and a drop-out rate of 10% provides 90.2% power to show that the primary analysis based 
on a two-sample t-test will be statistically significant at the one-sided 2.5% significance level 
(SAS 9.4, PROC POWER, difference in two sample means). 


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Median pre-treatment itch VAS of 60 (25th percentile=40, 75th percentile=80) and median 
post-treatment itch VAS of 30 (25th percentile=20, 75th percentile=70) in the overall 
population after 4 doses of omalizumab 300 mg have been reported in Gastaminza et al. 
Table 3-3 
Sensitivity of power to changes in assumptions (cholinergic urticaria) 
True treatment 
difference 
ligelizumab vs 
placebo 
(itch NRS) 
SD (itch NRS) 
Power for primary endpoint (one-sided α =2.5%, N=79 per arm) 
With 5% drop-out rate 
With 10% drop-out 
rate 
With 15% drop-out 
rate 
1.5 
1.5 
1.65 
1.8 
2.5 
3.0 
3 
2.5 
95.5% 
86.0% 
91.7% 
99.2% 
94.4% 
84.1% 
90.2% 
98.9% 
93.2% 
81.9% 
88.5% 
98.5% 
SD= Standard Deviation 
Table 3-4 
Required sample size for different targeted statistical power 
(cholinergic urticaria) 
True treatment 
difference 
ligelizumab vs 
placebo (itch 
NRS) 
SD (itch NRS) 
Targeted 
statistical 
power for 
primary 
endpoint (one-
sided α=2.5%) 
  
Sample size required (%), from N=79 per arm 
  
with 5% drop-
out rate 
with 10% drop-
out rate 
with 15% drop-
out rate 
1.65 
3.0 
90% 
75% 
79% 
84% 
1.65 
3.0 
80% 
56% 
59% 
63% 
SD=Standard Deviation 
3.1.2 
Secondary endpoint(s) 
3.1.2.1 
Symptomatic dermographism 
• Complete response rate 
Assuming a type-I-error of 2.5% two-sided and a complete response (negative outcome in the 
FricTest®4.0) rate of 11% in the placebo group. With approximate 56 participants per group 
and a drop-out rate of 10%, the power to show a complete response rate of 44% in the 
ligelizumab groups based on Fisher’s exact test (SAS 9.4, two group Fisher’s-exact test of equal 
proportions) is 91.5%. 
Placebo-response rates of 11% (2 out of 18) have been reported in Maurer et al 2017. 
The power of the all the endpoints included in the testing strategy is confirmed based on the 
simulation through the recycled alpha as planned. The detail simulation results will be provided 
in the statistical analysis plan. 
3.1.2.2 
Cold urticaria 
• Complete response rate 


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Assuming a type-I-error of 2.5% two-sided and a complete response (negative outcome in the 
TempTest®4.0) rate of 5% in the placebo group. With approximate 34 participants per group 
and a drop-out rate of 8%, the power to show a complete response rate of 40% in the ligelizumab 
groups based on Fisher’s exact test (SAS 9.4, two group Fisher’s-exact test of equal proportions) 
is 81.8%. 
Placebo-response rates of 0% (0 out of 12) and 5% (1 out of 20) have been reported in 
Metz et al 2017 and Krause et al 2013, respectively. 
The power of the all the endpoints included in the testing strategy is confirmed based on the 
simulation through the recycled alpha as planned. The detail simulation results will be provided 
in the statistical analysis plan. 
Cholinergic urticaria 
• Complete response rate in itch NRS 
For complete response in itch NRS, assuming a type-I-error of 5% two-sided and a complete 
response (see Section 2.2) rate of 13% in the placebo group. With approximate 79 participants 
per group and a drop-out rate of 10%, the power to show a complete response rate of 38% in 
the ligelizumab groups based on Fisher’s exact test (SAS 9.4, two group Fisher’s-exact test of 
equal proportions) is 91.1%. 
In Gastaminza et al, complete response rates of 22% (2 out of 9) and 8% (1 out of 13) have been 
reported for placebo and omalizumab 300 mg group during the blinded treatment period, and 
37.5% (6 out of 16) in the overall population in the open label treatment period 
4 
Change to protocol specified analyses 
Due to the early termination of the trial and limited sample size no statistical analyses will be 
performed on any dataset. Summarization of the data will be limited to data listings and 
summary tables where necessary Below are specific changes to the SAP and subsequent output: 
- 
No statistical analyses will be performed on the  primary endpoints 
- 
No statistical analyses will be performed on the  secondary endpoints 
 
- 
No interim analysis will be preformed  
- 
No summary tables will be produced for efficacy 
-
 


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5 
Appendix 
5.1 
Classification of study regions by country 
Table 5-1 Region stratification defined by  country enrollment: 
Name 
Study Countries 
Asia 
China; Korea; Malaysia; Thailand; Singapore;Vietnam; Philippines;Taiwan 
Non-Asia 
Other   
 
5.2 
Derivation rules for Week 12 treatment period 
Week 12 treatment period cut-off date 
The cutoff date for Week 12 treatment period is defined as below. 
For the Placebo-Ligelizumab 72mg/120mg q4w group, 
1. The first ligelizumab dosing date will be used if available; 
2. Otherwise, if no ligelizumab dosing happened, then the cutoff date = min(end of study 
date, withdrawal of ICF date, date of death, IA cutoff date(if applicable)). 
For other groups, 
1. If participants complete treatment period or are still ongoing, the cutoff date is the first 
non-missing date of the following dates: Week 12 dosing date, Week 12 visit date, PD 
date of missing visit at Week 12, first dosing date + 12 weeks. 
2. If participants early discontinue treatment, 
a. If last dosing visit is less than Week 12, then the cutoff date = min(end of study 
date, withdrawal of ICF date, date of death, IA cutoff date(if applicable)). 
b. If last dosing visit is great than or equal to Week 12, then the cutoff date is the  
first non-missing date of the following dates:  Week 12 dosing date, Week 12 
visit date, PD date of missing visit at Week 12, first dosing date + 12 weeks. 
 
Adverse events summary tables:  
The summary table is will be generated based on the cut-off date following the definition of  
“treatment period up to Week 12” in Table 2-5: 
Adverse events happened at the same day with this cut-off date NOT included in “treatment 
period up to Week 12” tables. 




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Impute AE start date:  
1. If the AE start date year value is missing, then the date uncertainty is too high to impute a 
rational date.  Therefore, if the AE year value is missing, then the imputed AE start date is 
set to NULL. 
2. If the AE start date year value is less than the treatment start date year value, then the AE 
started before treatment.  Therefore: 
a. If AE month is missing, then the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Otherwise, if AE month is not missing, then the imputed AE start date is set to the 
mid-month point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, then the 
AE started after treatment.  Therefore: 
a. If the AE month is missing, then the imputed AE start date is set to the year start 
point (01JanYYYY). 
b. Otherwise, if the AE month is not missing, then the imputed AE start date is set to 
the later of month start point (01MONYYYY) or AE start reference date + 1 day. 
4. If the AE start date year value is equal to the treatment start date year value: 
a. If the AE month is missing, then the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. If the AE month is less than the treatment start month, then the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Otherwise, if the AE month is equal to the treatment start date month or greater than 
the treatment start date month, then the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.3.3 
Concomitant medication date imputation 
Rules for imputing the CM end date (including on-going records): 
• When the medication is ongoing at the end of the study, no numeric end date is 
derived. 
• If the end date is completely missing no numeric end date is derived.  
a) If CM end day is missing and CM month/year are non-missing, then impute CM date 
as the minimum of study end date and the last day of the month. 
b) If CM end day/month are missing and CM year is non-missing, then impute CM date 
as the minimum of study end date and the end of the year (31DECYYYY). 




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a) And the CM month is missing or the CM month is equal to the Treatment start 
date (TR01SDT) month, then the imputed CM start date is set to one day prior  
Treatment start date (TR01SDT). 
b) Else if the CM month is less than the Treatment start date (TR01SDT) month, 
then the imputed CM start date is set to the mid-month point (15MONYYYY). 
c) Else if the CM month is greater than the Treatment start date (TR01SDT) month, 
then the imputed CM start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the complete (imputed) CM end date, then imputed CM start date should be set to the complete 
(imputed) CM end date. 
If there is no end date and ongoing check is not ticked, the CM will be considered as ongoing 
and included in the summary table. 
5.3.3.1 
Prior therapies date imputation 
All therapies on the Prior urticaria therapy CRF page will be considered as prior. No additional 
imputation will be performed.  
5.3.3.2 
Post therapies date imputation 
Not applicable. 
5.3.3.3 
Other imputations 
Surgical and medical procedures date imputation 
Missing data for surgical and medical procedures will be imputed following the same rule for 
CM date. 
Medication history date imputation 
Only missing medication history date for CSU diagnosis will be imputed to calculate the 
duration of CSU. No additional imputation will be performed for other medical history 
information.  
Rules for imputing the MH start date: 
1. If the MH start date year value is missing, the imputed MH start date is set to one day 
prior to Treatment start date (TR01SDT); 
2. If the MH start date year value is less than the Treatment start date (TR01SDT) year 
value, the MH started before treatment; Therefore: 
a) If the MH month is missing, the imputed MH start date is set to the mid-year 
point (01JulYYYY). 
b) Else if the MH month is not missing, the imputed MH start date is set to the mid-
month point (15MONYYYY). 
3. If the MH start date year value is equal to the Treatment start date (TR01SDT) year 
value; 


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a) And the MH month is missing or the MH month is equal to the Treatment start 
date (TR01SDT) month, then the imputed MH start date is set to one day prior  
Treatment start date (TR01SDT). 
b) Else if the MH month is less than the Treatment start date (TR01SDT) month, 
the imputed MH start date is set to the mid-month point (15MONYYYY). 
c) Else if the MH month is greater than the Treatment start date (TR01SDT) month, 
the imputed MH start date is set to the month start point (01MONYYYY). 
5.4 
AEs coding/grading 
Not applicable. 
5.5 
Laboratory parameters derivations 
Type Clinically notable criteria 
The following notable criteria will be used in the study:  
Table 5-2 
Clinically notable criteria  
Variable 
Notable criterion 
Creatinine (umol/L), Plasma/Serum 
Platelets (10E9/L), Blood 
>= 50% increase compared to baseline 
< 75 x10E9/L 
Creatinine (umol/L), Plasma/Serum 
>ULN – 1.5 x ULN 
>1.5 - 3.0 x ULN; >1.5 - 3.0 x baseline 
>3.0 - 6.0 x ULN; >3.0 x baseline 
Blood urea nitrogen* (mmol/L) 
 
1.25 – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10.0 x ULN 
>10.0 x ULN 
Albumin (g/L) 
<LLN - 30 g/L 
<30 - 20 g/L 
<20 g/L 
Alanine aminotransferase, ALT (U/L)  
 
Normal baseline 
>ULN - 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Baseline abnormal 
1.5 – 3.0 x baseline 
>3.0 – 5.0 x baseline 
>5.0 – 20.0 x baseline 
>20.0 x baseline 
Aspartate aminotransferase, AST 
(U/L)  
 
Normal baseline 
>ULN - 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Baseline abnormal 
1.5 – 3.0 x baseline 
>3.0 – 5.0 x baseline 
>5.0 – 20.0 x baseline 
>20.0 x baseline 


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Variable 
Notable criterion 
Alkaline phosphatase, ALP (U/L)  
 
Normal baseline 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Baseline abnormal 
2.0 – 2.5 x baseline 
>2.5 – 5.0 x baseline 
>5.0 – 20.0 x baseline 
>20.0 x baseline 
Gamma glutamyl transferase, GGT 
(U/L) 
Normal baseline 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Baseline abnormal 
2.0 – 2.5 x baseline 
>2.5 – 5.0 x baseline 
>5.0 – 20.0 x baseline 
>20.0 x baseline 
Bilirubin (umol/L) 
Normal baseline 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
Baseline abnormal 
>1.0 – 1.5 x baseline 
>1.5 – 3.0 x baseline 
>3.0 – 10.0 x baseline 
>10.0 x baseline 
Platelets (10E9/L), Blood 
<LLN # to 75 x10E9/L 
<75 - 50 x10E9/L   
< 50- 25 x10E9/L 
< 25 x10E9/L 
Leukocytes, WBC  
(10E9/L) 
<LLN - 3.0 x 10E9/L 
<3.0 - 2.0 x 10E9/L 
<2.0 - 1.0 x 10E9/L 
<1.0 x 10E3 /mL 
>100 x 10E9/L (leukocytosis, grade 3) 
Hemoglobin (g/L) 
<LLN - 100 g/L 
<100 - 80g/L 
<80 g/L 
Lymphocytes (10E9/L) 
<LLN - 0.8 x 10E9/L 
<0.8 - 0.5 x 10E9/L 
<0.5 - 0.2 x 10E9/L 
<0.2 x 10E9/L 
>4.0 - 20 x 10E9/L (grade 2 lymphocytosis) 
>20 x 10E9/L (grade 3 lymphocytosis) 
Neutrophils (10E9/L) 
<LLN - 1.5 x 10E9/L 
<1.5 - 1.0 x 10E9/L 
<1.0 - 0.5 x 10E9/L 
<0.5 x 10E9/L 
# LLN = 140 x10E9/L 
* No CTCAE grades provided for BUN. Values derived from Division of Microbiology and Infectious Diseases 
(DMID) grading system 
When the parameters have different criteria for different baseline status (e.g., ATL, AST), the patients with normal 
baseline will follow the criteria on the left side, and the patients with abnormal baseline will follow the criteria on the 
right side. 
Liver-enzyme abnormalities 
Table 5-3 
Liver- enzyme abnormalities  
Parameter 
Notable criterion 
ALT 
>3xULN; >5xULN; >10xULN; >20xULN 


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Study No. CQGE031E12301 
 
 
 
Parameter 
Notable criterion 
ALT or AST 
>3xULN; >5xULN; >8 xULN;>10xULN; >20xULN 
(ALT or AST) & TBL 
>3xULN & (TBL >1.5xULN; >2xULN) 
(ALT or AST) & INR 
>3xULN & INR>1.5 
TBL  
1 xULN; 1.5xULN ; >2xULN 
ALP 
1.5xULN ; >2xULN; >5xULN 
ALP & TBL  
> 3xULN; > 5xULN; & (TBL 2xULN;) 
(ALT or AST) & TBL & ALP 
ALT or AST>3xULN & (TBL)>2xULN & 
ALP<2xULN (potential Hy’s Law case) 
AST = Aspartate aminotransferase; also known as SGOT, ALT = Alanine aminotransferase; also known as SGPT, 
ALP = Alkaline phosphatase, TBL = Total bilirubin  
5.6 
Statistical models 
Not applicable 
5.7 
Rule of exclusion criteria of analysis sets  
No PD will be used for excluding from any analysis set.  
Table 5-4 
Subject Classification 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
RAS 
NA 
Not randomized 
FAS 
NA 
Not in RAS; 
Mistakenly randomized and no double-blind 
study drug taken 
SAF 
NA 
No double-blind study drug taken 
 
 
 
 
 
 
6 
Reference 
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Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat; 23(6):1352-71. 
Garwood F (1936). Fiducial limits for the Poisson distribution. Biometrica 28:437-442.