A Multi-center, Double-blinded and Open-label Extension Study to Evaluate the Efficacy and Safety of Ligelizumab as Retreatment, Self-administered Therapy and Monotherapy in Chronic Spontaneous Urticaria Patients Who Completed Studies CQGE031C2302, CQGE031C2303, CQGE031C2202 or CQGE031C1301
Phase: PHASE3
Conditions: Chronic Spontaneous Urticaria
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 1 (09-Apr-2021)............................................................................................13
Protocol summary..............................................................................................................18
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose ..................................................................................................................22
2
Objectives and endpoints...................................................................................................23
3
Study design ......................................................................................................................26
3.1
Screening period....................................................................................................29
3.2
First observation period.........................................................................................29
3.3
First half of the treatment period ...........................................................................30
3.4
Second observation period.....................................................................................31
3.5
Second half of treatment period.............................................................................32
3.6
Follow-up period ...................................................................................................33
4
Rationale............................................................................................................................34
4.1
Rationale for study design .....................................................................................34
4.1.1
Rationale for choice of background therapy.........................................35
4.2
Rationale for dose/regimen and duration of treatment ..........................................36
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................41
4.4
Purpose and timing of interim analyses/design adaptations..................................41
4.5
Risks and benefits..................................................................................................42
4.6
Rationale for Public Health Emergency mitigation procedures ............................44
5
Population..........................................................................................................................44
5.1
Inclusion criteria ....................................................................................................45
5.2
Exclusion criteria...................................................................................................45
6
Treatment...........................................................................................................................48
6.1
Study treatment......................................................................................................48
6.1.1
Investigational and control drugs..........................................................48
6.1.2
Additional study treatments ..................................................................48
6.1.3
Treatment arms/group ...........................................................................48
6.1.4
Treatment duration................................................................................49

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6.2
Other treatment(s)..................................................................................................49
6.2.1
Concomitant therapy.............................................................................49
6.2.2
Prohibited medication ...........................................................................50
6.2.3
Rescue medication ................................................................................51
6.3
Subject numbering, treatment assignment, randomization....................................52
6.3.1
Subject numbering ................................................................................52
6.3.2
Treatment assignment, randomization ..................................................53
6.4
Treatment blinding.................................................................................................53
6.5
Dose escalation and dose modification..................................................................56
6.5.1
Dose modifications................................................................................56
6.5.2
Follow-up for toxicities.........................................................................56
6.6
Additional treatment guidance...............................................................................56
6.6.1
Treatment compliance...........................................................................56
6.6.2
Emergency breaking of assigned treatment code..................................56
6.7
Preparation and dispensation.................................................................................57
6.7.1
Handling of study treatment and additional treatment..........................57
6.7.2
Instruction for prescribing and taking study treatment .........................59
7
Informed consent procedures ............................................................................................62
8
Visit schedule and assessments .........................................................................................63
8.1
Screening ...............................................................................................................74
8.1.1
Information to be collected on screening failures.................................75
8.2
Subject demographics/other baseline characteristics.............................................75
8.3
Efficacy..................................................................................................................75
8.3.1
eDiary assessments................................................................................76
8.3.2
Other Patient Reported Outcome (PRO) assessments ..........................79
8.3.3
Appropriateness of efficacy assessments..............................................80
8.4
Safety.....................................................................................................................80
8.4.1
Laboratory evaluations..........................................................................81
8.4.2
Electrocardiogram (ECG) .....................................................................82
8.4.3
Pregnancy and assessments of fertility .................................................83
8.4.4
Assessment of parasitic infections ........................................................83
8.4.5
Anaphylaxis assessment........................................................................84
8.4.6
Assessment of cardio-cerebrovascular events.......................................84
8.4.7
Assessment of neoplastic events...........................................................85
8.4.8
Appropriateness of safety measurements..............................................85
8.5
Additional assessments..........................................................................................85
8.5.1
Resource utilization...............................................................................85

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Table 2-1
Objectives and related endpoints ..........................................................23
Table 6-1
Investigational drug...............................................................................48
Table 6-2
Prohibited Medication...........................................................................50
Table 6-3
Blinding and unblinding plan (applies to all subjects in this study 
transitioning from the core studies till completion of Week 12 in 
the first half of the treatment period and the primary analysis has 
been completed) ....................................................................................54
Table 8-1
Assessment Schedule (Screening, First and Second half of the 
treatment period and Follow-up period) ...............................................64
Table 8-2
Assessment Schedule (First and Second Observation period)..............72
Table 8-3
Urticaria Patient Daily Diary (UPDD)..................................................76
Table 8-4
Hives Severity Score (HSS)..................................................................76
Table 8-5
Itch Severity Score (ISS).......................................................................77
Table 8-6
Sleep interference score ........................................................................77
Table 8-7
Activity interference score....................................................................77
Table 8-8
Actions/treatments for Angioedema .....................................................78
Table 8-9
DLQI/CDLQI score bands and impact on patient’s life .......................79
Table 8-10
Assessments & Specifications...............................................................81
Table 8-11
Laboratory assessments.........................................................................82
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................96
Table 10-2
Base Renal Monitoring .........................................................................98
Table 12-1
95% confidence interval based on number of subjects enrolled 
from the core studies (CQGE031C2302/2303)...................................109
Table 12-2
Number of subjects required at the baseline of re-treatment for 
each treatment arm enrolled from the core studies 
(CQGE031C2302/2303) .....................................................................109
Table 16-1
Best Blood Pressure (BP) Measurement Practices - Pediatrics ..........115
Table 16-2
Upper and lower limits for adolescents’ vital signs that may be 
considered of concern if newly identified may be identified using 
the following table for guidance1 ........................................................115
Table 16-3
Liver event and laboratory trigger definitions ....................................116
Table 16-4
Follow-up requirements for liver laboratory triggers – ALT, TBL 
with and without liver symptoms........................................................116
Table 16-5
Follow-up requirements for liver laboratory triggers – isolated 
hyperbilirubinemia..............................................................................117
Table 16-6
Specific renal alert criteria and actions...............................................118
Table 16-7
Renal event follow-up.........................................................................119

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List of figures
Figure 3-1
Study design..........................................................................................28
Figure 4-1
Change from baseline in HSS7, ISS7, and UAS7 by visit....................37

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List of abbreviations
AAS
Angioedema Activity Score
AAS7
Weekly Angioedema Activity Score
AC
Adjudication Committee
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CDLQI
Children’s Dermatology Life Quality Index
CFR
Code of Federal Regulation
CIU
Chronic Idiopathic Urticaria
CK
Creatine Kinase
COVID-19
Corona Virus Disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSU
Chronic Spontaneous Urticaria
CT
Computed Tomography
CTC
Common Toxicity Criteria
CU Index
Chronic Urticaria Index
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-Linked Immunosorbent Assay
EMA
European Medicines Agency
EOOBS1
End of Observation Period 1
EOOBS2
End of Observation Period 2
EOS
End of Study
EOT
End of Treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FcεRI
High Affinity Immunoglobulin E Receptor
FcεRII
Low Affinity Immunoglobulin E Receptor
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GLDH
Glutamate Dehydrogenase
H1-AH
H1-Antihistamine
hCG
Human Chorionic Gonadotropin
HRQoL
Health Related Quality of Life

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HSS
Hives Severity Score
HSS7
Weekly Hives Severity Score
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFU
Instructions For Use
IgE
Immunoglobulin E
IgG
Immunoglobulin G
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISS
Itch Severity Score
ISS7
Weekly Itch Severity Score
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLOQ
Lower Limit of Quantification
LTRA
Leukotriene Receptor Antagonist
MCP-Mod
Multiple Comparison Procedure Modeling
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NSD
Needle Safety Device
PD
Pharmacodynamic(s)
PFS
Pre-Filled Syringe
PK
Pharmacokinetic(s)
PRO
Patient Reported Outcome
PT
Prothrombin Time
q4w
once every 4 weeks
QoL
Quality of Life
QTcF
Fridericia QT Correction Formula
RBC
Red Blood Cell(s)
RDO
Retrieved Dropout
s.c.
Subcutaneous
SAE
Serious Adverse Event
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total Bilirubin
UAS
Urticaria Activity Score
UAS7
Weekly Urticaria Activity Score
ULN
Upper Limit of Normal
UPDD
Urticaria Patient Daily Diary
UPV
Unplanned Visit

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WBC
White Blood Cell(s)
WHO
World Health Organization

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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Biologic sample
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject.
Control drug
A study drug 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.
Core studies
CQGE031C2302 and CQGE031C2303 studies
Dosage
Dose of the study treatment given to the subject in a time unit.
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 subject 
or at a later point in time as defined by the protocol.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained. The action of enrolling one or more subjects.
Investigational 
drug/treatment
The study drug whose properties are being tested in the study.
Medication number
A unique identifier on the label of medication kit.
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.).
Patient
An individual with the condition of interest for the study
Patient-Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the patient 
about the status of a subject’s health condition without amendment or 
interpretation of the patient's report by a clinician or anyone else.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis.
Preceding studies
CQGE031C2302, CQGE031C2303, CQGE031C2202 and 
CQGE031C1301 studies
Personal data
Subject information collected by the Investigator that is transferred to
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned.
Re-screening
If a subject fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol.
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study.
Self-administration
The process by which the drug is administered outside the clinic.

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Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
Study drug 
discontinuation
Point/time when subject permanently stops taking investigational drug 
for any reason.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s).
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date.
Subject
A trial participant
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study.
Withdrawal of study 
consent (WoC) / 
Opposition to use of 
data/biological samples
Withdrawal of consent from the study occurs when the subject 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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Amendment 1 (09-Apr-2021)
Amendment rationale
CQGE031C2302E1 study is currently recruiting. This amendment primarily aims to introduce 
measures to allow more flexibility to the subjects successfully completing one of the preceding 
studies to be able to continue receiving investigational treatment. These measures include 
allowance of a limited amount of missing e-diary entries prior to the first treatment visit and 
ensuring exclusion criteria and prohibited medications are not more stringent than the original 
preceding study criteria.
Further, the original compliance criteria for eDairy HSS and ISS entries in the week prior to 
Week 52 visit has been removed. In case subjects would not meet full compliance with eDiary 
entries the subjects would have moved to the second observation period, however it is more 
appropriate for the subjects to be allowed to continue treatment even in the case of some missing 
eDiary entries as long as the UAS7 score is calculable as per the definition: A minimum of 4 
out of 7 daily scores are needed to reliably calculate a weekly HSS7, ISS7 or UAS7 score. This 
is also the definition that would be used to calculate UAS7 scores for the analysis.
Additional changes in this amendment include:

Instructions on Public Health Emergency mitigation procedures

Protocol template updates v4.0

Clarifications on roles and responsibilities for blinded and unblinded study personnel for 
handling and administering liquid in vial and prefilled syringes
Changes to protocol and rationale:
Section
Changes made
List of abbreviations
Updated
Glossary of terms
Updated
Section 3
Clarification added subjects will not be allowed a gap between 
preceding and extension study except under specified conditions
Section 3, Section 5.2 and 
Table 6-2
Correction made to specify omalizumab allowed up to 16 weeks 
prior to Visit 101/201
Section 3.2
Clarified wording for Visit 2 assessments and eligibility
Section 3.2
Changed criterion of 100% e-diary compliance to allow for at least 
12 out of 14 records for HSS and ISS respectively in one 
assessment week before treatment
Section 3.3
Removed the compliance criteria for score calculation prior to 
Week 52 to align score calculation for patient management with 
score calculation for statistical purposes
Section 3.5
Moved sentence concerning the discussion with the subject to the 
correct scenario for UAS7 score.

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Section 4.1, Section 6.4, 
Table 6-3
Specified the duration of the blinding by adding “and the primary 
analysis has been completed”.
Blinding and unblinding plan updated to specify the blinding levels 
of the individual team members in case of any additional analysis 
required to support Health Authority interactions.
Section 4.5 and Section 5
Updated numbers of subjects according to latest information
Updated edition of Investigator Brochure
Section 4.5
Sentence added to confirm that based on currently available data 
from the ligelizumab clinical program, there is no evidence of an 
increased risk of infections/viral infections and that at this time 
there is no specific data to inform on incidence or severity of 
Corona Virus Disease 2019 (COVID-19) (due to severe acute 
respiratory syndrome coronavirus 2) in patients receiving 
ligelizumab.
Deleted ‘sexually active males’ from requirement of contraception 
while receiving ligelizumab as this was incorrect.
Section 4.6
New section added to provide rationale for Public Health 
Emergency mitigation procedures
Section 5.1
Inclusion criterion 6 has been updated to require a minimum of 12 
out of 14 records for HSS and ISS respectively must be present in 
the week the UAS7 score is assessed. 
Section 5.2
Exclusion criteria 20: removed GGT and ALP to ensure exclusion 
criterion is not more stringent than the original preceding studies’ 
criteria
Section 5.2
Exclusion criteria 24:

Replaced “basic” with “effective” methods of contraception.

Added the word “bilateral” to tubal ligation.

Specified the wording of the exclusion criteria for post-
menopausal women.

Added standard sentence: If local regulations deviate from the 
contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed 
consent form (ICF).

Added footnote (applicable for exclusion criteria #20, #21 and 
#22): Subjects who did not meet applicable eligibility criteria at 
Visit 2, will be discontinued from the study and will not enter 
treatment. Clarified that these subjects will not be considered 
screen failure subjects.
Table 6-1
Replaced “supply type” with “presentation according to Novartis 
protocol template v4.0.
Section 6.2.1
Concomitant H1-AH background medication: added possible 
exceptions for subjects to use a different H1-AH than used in the 
preceding study.
Table 6-2
Prohibited medication: Removed “Drugs of well-known or ill-
defined mechanism of action, that are used for urticaria or allergic 
conditions in general (e.g. suplatast tosilate) 30 days prior to Visit 
1. Since this prohibition is too vague and broad it is difficult to 
assess.

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Section 6.2.3
Anti-histamine rescue medication: Added “if the medication is no 
longer available in the country” to allow more flexibility in case a 
switch of H1-AH rescue medication is required.
Section 6.4, Table 6-3

Added sentence to specify the involvement in any other trial 
activities of personnel aware of treatment assignment data.

Reworded the method of blinding the liquid volume.

Removed the following redundant sentence “The study will 
run open-label after Week 12 (Visit 204) and once all subjects 
from core studies have completed Week 12 (Visit 204) in this 
study”.
Section 6.7
Removed redundant sentence on recording and returning of 
syringes and unused medication (details are available in Section 
6.7.1.)
Section 6.7.1.1
Corrected sentence to remove handling and storage of liquid in 
vial by the unblinded pharmacist.
Section 6.7.2
Clarifications added on roles and responsibilities for blinded and 
unblinded study personnel for handling and administering liquid in 
vial and prefilled syringes.
Section 7
Added mitigation procedure of remote informed consent 
discussion (e.g., telephone, video conference) during a Public 
Health emergency.
Section 8, Section 8.4
Added mitigation procedure of phone calls, virtual contacts (e.g., 
tele consult) to replace on-site visits in case of a Public Health 
emergency
Table 8-1

Row “height and weight” re-worded and updated to specify 
that for adults height measurement only required at screening.

Reminder added that for any ECG with clinically significant 
findings, 2 additional ECGs must be performed to confirm the 
finding to align with Section 

Footnote 5: corrected to align with Section 3
Table 8-2

Update made to allow the remote PROs collection in case the 
patient cannot attend the visit at site due to a Public Health 
emergency.

Update made to allow samples collection & analysis in a 
certified local laboratory in case of a Public Health 
emergency.
Section 8.1

Added clarification for assessments not taken at V1999 of 
preceding studies.

Clarification that a retest is allowed for transient and non-
clinically significant laboratory values at Visit 2.

Added clarification regarding data collection for subjects 
entered first observation period and discontinue study without 
entering treatment period.

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Section 16.2
Revised Tables 16-3 and 16-5 and added Table 16-4 for more 
detailed guidance on Follow-up and management of liver safety 
events as per updated Novartis protocol template.
Changes to the protocol summary have been aligned with the changes as above where applicable.
Changes are shown in the track changes version of the protocol using strike through red font 
for deletions and red underlined for insertions.
Editorial changes have been made in the document for more clarity and to maintain consistency 
within the document.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amendment protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Protocol summary
Protocol 
number
CQGE031C2302E1
Full Title
A multi-center, double-blinded and open-label extension study to evaluate the 
efficacy and safety of ligelizumab as retreatment, self-administered therapy and 
monotherapy in Chronic Spontaneous Urticaria patients who completed studies 
CQGE031C2302, CQGE031C2303, CQGE031C2202 or CQGE031C1301
Brief title
Study of efficacy and safety of ligelizumab in chronic spontaneous urticaria 
patients who completed a previous study with ligelizumab
Sponsor and 
Clinical Phase
Novartis
Phase IIIb
Investigation 
type
Biological
Study type
Interventional
Purpose and 
rationale
The purpose of this extension study is to establish efficacy and safety of 
ligelizumab. This will be assessed in adult and adolescent chronic spontaneous 
urticaria (CSU) patients who have completed a preceding ligelizumab study and 
have relapsed, following treatment in these preceding studies, despite standard of 
care H1-antihistamine (H1-AH) treatment. In a subset of subjects, the safety and 
efficacy of ligelizumab monotherapy will be assessed.
This study will also fulfill the Novartis commitment to provide post-trial access to 
patients who have completed studies CQGE031C2302, CQGE031C2303, 
CQGE031C2202 or CQGE031C1301.
Primary 
Objective(s) 
To evaluate the efficacy of ligelizumab assessed as the proportion of subjects 
achieving weekly urticaria activity score (UAS7) ≤6 after 12 weeks of retreatment, 
in subjects previously treated in CQGE031C2302/CQGE031C2303 (the core 
studies) as well as in the subset of subjects who previously achieved UAS7 ≤6 in 
the core studies.
Secondary 
Objectives

To describe the efficacy of ligelizumab assessed as the proportion of subjects 
achieving UAS7 = 0 after 12 weeks of retreatment, in subjects previously 
treated in the core studies

To describe the efficacy of ligelizumab assessed as the reduction from 
extension study baseline in the UAS7 and its components (weekly itch 
severity score (ISS7) and weekly hives severity score (HSS7) subjects 
previously treated in the core studies

To describe the efficacy of ligelizumab in achieving an angioedema-free 
period at Week 12 previously treated in the core studies

To describe the efficacy of ligelizumab in achieving Dermatology Life Quality 
Index (DLQI) = 0-1 at Week 12 previously treated in the core studies

To describe the efficacy of ligelizumab in the treatment of CSU (UAS7≤6), 12 
weeks after starting self-administration

To assess the safety and tolerability of ligelizumab in all subjects

To assess the safety and tolerability of ligelizumab pre-filled syringe (PFS)

To assess the safety and tolerability of ligelizumab in all subjects who self-
administer
Study design
This is a Phase IIIb multi-center, double-blinded and open-label extension study 
to evaluate efficacy and safety of ligelizumab retreatment with H1-AHs background
therapy with conditional options for monotherapy and self-administration

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Subjects rolling over from study CQGE031C1301 and CQGE031C2202 will not be 
included in this primary analysis. The efficacy data for these subjects will be 
analyzed separately.
Key words
Anti-IgE, chronic spontaneous urticaria, CSU, hives severity score, itch severity 
score, urticaria activity score, retreatment, ligelizumab

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1
Introduction
1.1
Background
Chronic Spontaneous Urticaria (CSU), also known as Chronic Idiopathic Urticaria (CIU) is 
defined as the spontaneous occurrence of itchy wheals (hives), angioedema or both lasting for 
at least 6 weeks (Zuberbier et al 2014, Kaplan et al 2016, Zuberbier et al 2018). The classic 
description of urticaria is a wheal and flare with a pale elevated lesion and surrounding erythema, 
ranging in size from a few millimeters to a few centimeters across, usually occurring in groups 
and often coalescing to form large confluent lesions. CSU can be debilitating, is associated with 
intense itching and has a major impact on patient’s wellbeing, suggested to be comparable to 
that of severe coronary artery disease (Greaves 2003, Powell et al 2007). The overall burden of 
CSU is substantial. The symptoms of urticaria and urticaria associated angioedema adversely 
affect daily activities and sleep resulting in a negative impact on patients’ lives, health related 
quality of life (HRQoL) and work productivity (O'Donnell et al 1997, Maurer et al 2017).
Current treatment guidelines recommend H1-antihistamine at licensed dose as first-line therapy 
for CSU. If no adequate response is achieved, second line therapy should be H1-antihistamines 
at doses up to 4-fold the approved dose (Zuberbier et al 2018). Generally up to 50% of patients 
may respond (Zuberbier et al 2018). The use of H2-antihistamines and Leukotriene Receptor 
Antagonists (LTRAs) has in the past been recommended in treatment guidelines for patients 
who remained symptomatic despite treatment with H1-antihistamines (Zuberbier et al 
2009, Bernstein et al 2014), although their use has not been as well supported by clinical studies. 
In the latest version of the treatment guidelines (Zuberbier et al 2018), neither H2-
antihistamines nor LTRAs are now perceived to have evidence to maintain them as 
recommendable in the algorithm. In addition, the current treatment guidelines suggest that while 
systemic corticosteroids are sometimes added to the treatment regimens for up to ten days, 
however, they are not recommended in treatment guidelines for long-term treatment as patients 
are then at risk of adverse effects associated with chronic systemic corticosteroid exposure.
Omalizumab, a monoclonal antibody that targets immunoglobulin E (IgE), has been approved 
globally, including the European Union, the United States, Japan and Switzerland, as add-on 
therapy in patients with CSU with symptoms despite treatment with antihistamines. 
Omalizumab improved the signs and symptoms of urticaria (i.e. hives and itch) in patients who 
failed treatment with H1-antihistamines as well as in those who failed treatment with a 
combination of H1- and H2-antihistamines and a LTRA (Gober et al 2008, Kaplan et al 2008, 
Maurer et al 2013, Kaplan et al 2013).
Ligelizumab (QGE031) is a newer humanized immunoglobulin G (IgG)-type monoclonal 
antibody that binds to human IgE with higher affinity than omalizumab. Upon binding to 
specific epitopes in the C3 region of IgE, ligelizumab is able to block the interaction of IgE with 
both the high and low affinity IgE receptors (FcεRI and FcεRII). Ligelizumab does not mediate 
IgE receptor cross-linking and consequent histamine release (i.e. is non-activating). This overall 
mechanism of action is shared with omalizumab (Chang et al 2015).
When subjects are treated with ligelizumab, circulating IgE is rapidly bound by the anti-IgE 
antibody and becomes inaccessible to IgE receptors on mast cells and basophils. Ligelizumab 
has demonstrated dose- and time-dependent suppression of free IgE and reduction in basophil 
FcεRI expression and thus basophil surface IgE, and inhibition of skin prick test responses to 

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allergens which is superior in extent and duration to those observed with omalizumab (Arm et 
al 2014, Gauvreau et al 2016). These studies support the scientific rationale for the development 
of ligelizumab in IgE driven diseases. Data from the CQGE031C2201, the first clinical study 
in CSU, demonstrated that ligelizumab (24, 72 and 240 mg q4w s.c.) was efficacious when 
added to standard of care treatment in patients with moderate to severe CSU. At Week 12, a 
statistically significant higher proportion of ligelizumab treated patients (72 and 240 mg q4w) 
achieved weekly hives severity score (HSS7) = 0 compared to omalizumab 300 mg q4w
(Maurer et al 2019). Data from CQGE031C2201E1 study, an open-label extension for subjects 
who completed the CQGE031C2201 study and presented with active disease, demonstrate that 
1 year treatment with ligelizumab 240 mg q4w results in a high rate of early onset, sustained 
and complete control of hives and itch (weekly urticaria activity score (UAS7) = 0), and 
angioedema. There were no newly identified or unexpected safety issues.
Definition of CSU Disease States
The disease activity states of CSU are commonly defined as complete control, well controlled, 
mild, moderate and severe (Stull et al 2017). When described by their associated UAS7 scores, 
the disease activity states are defined as in Table 1-1:
Table 1-1
Urticaria disease states based on UAS7 scoring
Disease State
UAS7 Score
Severe activity
28-42
Moderate activity
16-27
Mild activity
7-15
Well controlled
1-6
Urticaria free (completely controlled)
0
In this clinical trial, in addition to the inclusion and exclusion criteria, Week 52 of the treatment 
period is a key decision point, and is based on the CSU disease state i.e. the respective UAS7 
scores (see Section 3). When scores are whole numbers the ranges and the thresholds are 
straightforward. However weekly scores can be fractional (e.g. 6.5) and hence to maintain 
accuracy, the values will not be rounded up or down. Therefore, the above noted thresholds are 
slightly revised to account for this (Section 3). For example in this study “Mild CSU” is defined 
as UAS7 > 6 and < 16.
1.2
Purpose
The purpose of this extension study (up to 104 weeks of treatment and up to 52 weeks of post-
treatment follow-up) is to establish efficacy and safety of ligelizumab (QGE031) 120 mg s.c. 
q4w. This will be assessed in adult and adolescent CSU patients who have completed one of 
the studies CQGE031C2302, CQGE031C2303, CQGE031C2202 or CQGE031C1301 (the 
"preceding studies") and who have relapsed, following treatment in these preceding studies,
despite standard of care treatment with H1-antihistamines (H1-AH) (at local label approved 
doses), in the following scenarios:

re-treatment with ligelizumab 72 or 120 mg s.c. q4w following treatment in the preceding 
studies;

self-administration of ligelizumab 120 mg s.c. q4w outside of the clinic setting;

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
ligelizumab 120 mg s.c. q4w used as monotherapy, i.e. when background H1-AH 
medication is discontinued
In addition, this study will evaluate whether ongoing long-term treatment drives drug-mediated 
remission of disease. This study will also fulfill the Novartis commitment to provide post-trial 
access to patients who have completed studies CQGE031C2302, CQGE031C2303, 
CQGE031C2202 or CQGE031C1301.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
To evaluate the efficacy of retreatment with 
ligelizumab 72 mg or 120 mg q4w in subjects 
previously treated in the core studies
(CQGE031C2302/CQGE031C2303)
To evaluate the efficacy of retreatment 
with ligelizumab in the subgroup of these 
subjects who achieved a weekly urticaria 
activity score (UAS7) ≤ 6 after 12 weeks 
of treatment in these core studies
The proportion of subjects with 
well-controlled disease (UAS7 ≤ 6) 
at Week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)
For retreatment efficacy evaluation:
To describe the efficacy of ligelizumab 72 mg 
or 120 mg q4w in achieving complete control 
of chronic spontaneous urticaria (CSU) at 
Week 12 when used as retreatment for 
subjects previously treated in the core studies 
(CQGE031C2302/CQGE031C2303)
The proportion of subjects with 
completely controlled disease 
(UAS7 = 0) at Week 12
To describe the efficacy of ligelizumab with 
respect to a reduction from extension study 
baseline in the UAS7 and its components 
(weekly itch severity score (ISS7) and weekly 
hives severity score (HSS7) at Week 12 in all 
subjects receiving the same dose regimen as in 
the core studies, i.e. 72 mg or 120 mg q4w
Absolute change from extension 
study baseline in the UAS7 and its 
components (ISS7 and HSS7) at 
Week 12
To describe the efficacy of ligelizumab in 
achieving an angioedema-free period at Week 
12 in all subjects receiving the same dose 
regimen as in the core studies, i.e. 72 mg or 
120 mg q4w
Cumulative number of weeks that 
subjects achieve weekly 
angioedema activity score (AAS7) = 
0 between extension study baseline 
and Week 12
To describe the efficacy of ligelizumab in 
achieving Dermatology Life Quality Index 
Percentage of subjects achieving 
DLQI = 0-1 at Week 12

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Objective(s)
Endpoint(s)
(DLQI) = 0-1 at Week 12 when used as re-
treatment for all subjects receiving the same 
dose regimen as in the core studies, i.e. 72 mg 
or 120 mg q4w
For self-administration efficacy evaluation:
To describe the efficacy of ligelizumab in the 
treatment of CSU, 12 weeks after starting self-
administration
The proportion of subjects with 
well-controlled disease (UAS7 ≤ 6),
12 weeks after starting self-
administration
For safety & tolerability evaluation:
To assess the safety and tolerability of 
ligelizumab in all subjects
In each dose group, and for each 
duration of treatment:
Occurrence of treatment emergent 
adverse events during the study
Occurrence of treatment emergent 
serious adverse events during the 
study
Vital signs
Lab assessments
To assess the safety and tolerability of 
ligelizumab 120 mg q4w 1mL pre-filled 
syringe (PFS)
For the duration of treatment:
Occurrence of treatment emergent 
serious adverse events during study 
Week 12 onwards
Vital signs Week 12 onwards
Lab assessments Week 12 onwards
To assess the safety and tolerability of 
ligelizumab 120 mg q4w in all subjects who 
self-administer
Occurrence of treatment emergent 
adverse events
Occurrence of treatment emergent 
serious adverse events
Vital signs
Lab assessments

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3
Study design
This is a Phase IIIb multi-center, double-blinded and open-label, extension study to evaluate 
efficacy and safety of ligelizumab 72 mg and 120 mg s.c. q4w as add-on therapy to H1-AHs
with an option for monotherapy i.e. with discontinuation of background H1-AH in adult and 
adolescent CSU subjects who have completed one of the CQGE031C2302, CQGE031C2303, 
CQGE031C2202 or CQGE031C1301 studies (“preceding studies”), in the setting of retreatment
and self-administration.
As per Table 1-1, the definition of the disease states for CSU, for purposes of this study protocol 
and used for decisions described in this section is:

Urticaria-free (Completely controlled disease): UAS7 = 0;

Well controlled disease: UAS7 ≤ 6;

Mild Disease: UAS7 > 6 and < 16 and

Moderate to severe disease: UAS7 ≥ 16.
As depicted in Figure 3-1, the study consists of 5 distinct periods

Screening period (Day -28 to Day -7), duration 1 to 4 weeks;

First observation period, duration up to 36 weeks;

Treatment period, duration of 2 years (104 weeks);

Second observation period, duration up to 52 weeks;

Post-treatment follow-up period, duration of 12 weeks or 52 weeks.
The minimum duration of a subject’s stay in the study without early discontinuation is
approximately 37 weeks: 1 week screening plus 36 weeks in first observation period until the 
subject exists the study without a relapse.
The maximum duration of a subject’s stay in the study without early discontinuation is 
approximately 208 weeks: 4 weeks screening, 36 weeks in first observation period, 52 weeks 
in first half of the treatment period, 52 weeks in the second half of the observation period, 52 

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weeks in second half of the treatment period and 12 weeks in the follow-up period until the 
subject exits the study.
If the study site is ready to enroll subjects in the extension study, and the subject completed the 
preceding study’s End of Study Visit (EOS, Visit 1999), the subject can “roll-over” into this 
extension study. When the site is ready to enroll subjects, the subject should be enrolled into 
the extension study in as short time-frame as possible. Subsequently, all subjects who refuse 
participation in the extension study at the time of V1999 will not be allowed to enter at a later 
time unless there are circumstances beyond their control. All assessments done as a part of Visit 
1999 for preceding studies will be considered for screening for the extension study. These 
subjects will have their Screening Visit 1 for the extension study on the same day as Visit 1999 
of the preceding study.
Subjects who complete Visit 1999 of the preceding studies prior to the study site being ready 
to enroll subjects in the extension study, will have a gap between their Visit 1999 and Screening 
Visit 1 i.e. Visit 1999 and screening Visit 1 will not occur on the same day. Informed consent 
for the extension study will be signed off prior to or at Screening Visit 1. If this gap between 
the two visits is less than or equal to 30 days, all Visit 1999 assessments can still be used to 
determine eligibility into the extension study. If this gap between the two visits exceeds 30 days, 
subjects will be re-assessed for eligibility into the trial at Screening Visit 1. During this gap 
between completion of preceding studies and enrolment into extension study:

Subjects can use second generation H1-AH as per CSU treatment guidelines.

Subjects can use omalizumab, if needed, provided there is at least 16 weeks between last 
dose of omalizumab and Visit 101 or V201.

Subjects can use oral corticosteroids, if needed, provided there is at least 30 days between 
last dose of oral corticosteroid and Screening Visit 1 of this study.

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Figure 3-1
Study design

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3.1
Screening period
For all study participants, the first visit of the extension phase at Visit 1 should occur on the 
same day as the preceding studies’ EOS visit (Visit 1999), or in as short time-frame as possible 
after the Visit 1999 of the preceding studies, as described below.

At or prior to Visit 1, (Visit 1999 of the preceding studies, if the subject is transitioning 
immediately), eligible subjects will sign an informed consent form (ICF).

All lab assessments performed at Visit 1999 (if not more than 30 days prior to the extension 
screening Visit 1) and all other required assessments as per extension study protocol will be 
used to determine eligibility to enroll into this extension study. If the gap between the Visit 
1999 of preceding studies and extension screening Visit 1 is greater than 30 days, then all 
lab and other required assessments will need to be re-done at extension screening Visit 1.

Subjects must remain on the same H1-AH background medication they were taking in the 
preceding studies.

Subjects should use the same H1-AH rescue medication that was agreed with the 
investigator at Visit 1 of this study.

Use of oral corticosteroid rescue medication is not permitted during the screening period.

Subjects’ relevant medical conditions and concomitant medications will be reviewed at 
Visit 1 (Visit 1999 of the preceding studies, if the subject is transitioning immediately to 
the extension study).

The subjects will continue to complete all eDiary assessments, including assessment of UAS. 
The 7 days prior to Week 0 will be used to calculate the UAS7 score:

If the subject has moderate to severe disease, defined as UAS7 ≥ 16, the subject will 
enter the treatment period immediately at Visit 201 (Week 0) to start treatment, as 
described in Section 3.3.

If the subject has a UAS7 of < 16, the subject will transition to the first observation 
period at Visit 101 (Week 0), as described in Section 3.2.
Rescreening may be allowed for subjects who fail initial screening (see Section 5.1 and 
Section 5.2 on when rescreening is allowed). Only one rescreening will be allowed. If a subject 
is rescreened for the study, the subject must sign a new informed consent and will be issued a 
new subject number. Informed consent for a rescreened subject must be obtained prior to 
performing any study-related assessments or collecting any data for the Screening Visit.
3.2
First observation period

Visit 101 (Week 0) to 199 (Week 36 also referred to as End of Observation Period 
1/EOOBS1).

If the subject’s UAS7 is < 16 at Week 0, the subject will enter the first (investigational 
treatment-free) observation period, performing assessments for Visit 101 after which they 
will be assessed remotely (i.e. outside the clinic) by a safety phone call from the site every 
4 weeks, unless there is an in-clinic visit scheduled.

Subjects will have in-clinic safety and efficacy assessments done at 12-week intervals.

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
Subjects must remain on the same H1-AH background medication they were taking in the 
preceding studies.

Subjects should use the same H1-AH rescue medication that was agreed with the 
investigator at Visit 1 of this study.

Use of oral corticosteroid rescue medication is not permitted during this first observation 
period.

Subjects will continue to complete the eDiary twice daily as per protocol, in order to monitor 
the activity of their disease.

Subjects who present with moderate to severe active disease (UAS7 ≥ 16; having at least 12 
out of 14 records for HSS and ISS respectively completed in one assessment week during 
observation) will be brought back to clinic as soon as possible:
a. Subjects will perform the Visit 201 if they had Visit 1 in the last 30 days.
b. Subjects for whom Visit 1 occurred more than 30 days ago will perform assessments 
from screening Visit 2. Assessments from Visit 2 will be used to determine eligibility 
as applicable (see Section 5.2).

Subjects with UAS7 < 16 by the end of this first observation period will perform Visit 199 
(EOOBS1) of this extension study to exit the study.

Subjects who wish to discontinue from the first observation period and study, will be 
expected to complete Visit 199 (EOOBS1).
3.3
First half of the treatment period

Week 0 (Visit 201) to Week 52

Subjects receive their first dose of ligelizumab at Visit 201 (Week 0) and last dose of 
ligelizumab of this first half of the treatment period at Visit 213 (Week 48).

Subjects must remain on the same H1-AH background medication they were taking in the 
preceding studies.

Subjects should use the same H1-AH rescue medication that was agreed with the 
investigator at Visit 1 of this study.

Oral corticosteroid rescue medication is permitted only at and after Visit 204 (Week 12)
(after all assessments are completed), with the limitations as per protocol (see Section 6.2.3).

Subjects entering the first half of the treatment period from the preceding studies will be 
assigned to treatment as follows:

Core studies CQGE031C2302 and CQGE031C2303:

For the first 12 weeks, the blinded treatment assignment will be determined 
according to the treatment group assignment during the core studies following 
these rules:

Subjects treated with ligelizumab 72 mg liquid in vial s.c. q4w in the core studies 
will be treated with ligelizumab 72 mg liquid in vial s.c. q4w in a double-blind 
manner such that their prior treatment regimen will not be unblinded.

All other subjects from the core studies will be treated with ligelizumab 120 mg 
liquid in vial s.c. q4w in a double-blind manner such that their prior treatment 
regimen will not be unblinded.

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
Studies CQGE031C1301 and CQGE031C2202:

All subjects from these studies will be treated with ligelizumab 120 mg liquid in 
vial s.c. q4w in an open-label manner for the first 12 weeks.

If the subject in the screening period or first observation period presents with moderate to 
severe disease, defined as UAS7 ≥ 16, the subject will enter the treatment period at Visit 
201 (Week 0), and start the treatment assigned as above.

At Visit 204 (Week 12), all subjects will be switched to ligelizumab 120 mg s.c. pre-filled 
syringe (PFS) q4w in an open-label manner.

At Visit 204 (Week 12) subjects will be offered an opportunity to administer ligelizumab 
outside the clinic. For details regarding self-administration outside of the clinic and 
monitoring post ligelizumab administration, see Section 6.7.2.

All subjects, whether in the clinic-administered or outside the clinic self-administered group 
will continue to complete the eDiary twice daily as per protocol.

All subjects should complete their eDiary for the 7 days prior to Visit 214 (Week 52) to 
ensure the UAS7 thresholds are available for evaluation at Visit 214 (Week 52).

At Week 52 UAS7 needs to be assessed:

Subjects who have achieved a UAS7 ≤ 6 will transition to the second observation 
period Visit 301 (see Section 3.4).

Subjects who have achieved a UAS7 > 6 and < 16 will continue treatment without 
interruption into the second half of the treatment period (Visit 214), unless a decision 
to stop treatment is made based on a risk-benefit discussion between the investigator 
and subject, in which case the subject would move to the second observation period
Visit 301).

For subjects with a UAS7 ≥ 16, the investigator must reassess the risk-benefit with 
the subject and decide whether the subject will continue with the investigational 
treatment (Visit 214) or move to the follow-up period and perform Visit 9998 (see 
Section 4.2 – Rationale for duration of treatment).
3.4
Second observation period

Visit 301 (Week 0) to 399 (Week 52 also referred to as End of Observation Period 2, 
EOOBS2).

If the subject’s UAS7 is ≤ 6 at Week 52, the subject will enter the second (investigational 
treatment-free) observation period Visit 301 (Week 0) and will be assessed remotely (i.e. 
outside the clinic) by a safety phone call from the site every 4 weeks, unless there is an in-
clinic visit scheduled.

Subjects will have in-clinic safety and efficacy assessments done at 12 or 16 week intervals.

Subjects must remain on the same H1-AH background medication they were taking in the 
preceding studies.

Subjects should use the same H1-AH rescue medication that was agreed with the 
investigator at Visit 1 of this study.

Use of oral corticosteroid rescue medication is not permitted during this second 
observation period.

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
Subjects will continue to complete the eDiary twice daily as per protocol, in order to monitor 
the activity of their disease. All subjects should complete their eDiary for the 7 days prior 
to Visit 214 (i.e. one assessment-week) to ensure the UAS7 thresholds are available.

Subjects who present with moderate to severe active disease (UAS7 ≥ 16) will be brought 
back to clinic to be treated as soon as possible to perform Visit 214 (Week 52) in the second 
half of the treatment period) and restart treatment with ligelizumab 120 mg PFS q4w.

Subjects with a UAS7 < 16 by the end of this second observation period will perform 
Visit 399 (EOOBS2) of this extension study to exit the study.

Subjects who wish to discontinue from this observation period will be expected to complete 
at least Visits 301, 302 and 303 (Week 0, 4 and 8), and perform Visit 399 
(Week 52/EOOBS2) and exit the study.
3.5
Second half of treatment period

Visit 214 to 9998 (Week 52 to Week 104)

At Week 52:
Subjects who have achieved UAS7 of > 6 and < 16 will be assessed based on a risk-
benefit discussion between the subject and the investigator on whether to continue 
treatment without interruption into the second half of the treatment period, or, move to the 
second observation period.

These subjects, with an uninterrupted treatment period of 104 weeks will complete 
the second half of the treatment period at Visit 9998 (Week 104/EOT (End of 
Treatment)), and transition to the 52-week follow-up period Visit 501 (Week 116).

These subjects will not be allowed to discontinue H1-AH background medication.
For subjects who have achieved a UAS7 ≥16, the investigator must reassess the risk-
benefit with the subject. This discussion with the individual subject will include whether 
or not the subject has had enough improvement from their initial disease state at the start 
of the treatment period, even though they still have moderate to severe disease, to justify 
continuing in the treatment period.
Based on this benefit risk assessment and discussion with the subject, the subject and 
investigator will decide whether to

continue with the investigational treatment (ligelizumab 120 mg s.c. q4w PFS) in the 
second half of the treatment period or 

discontinue the treatment, and complete Visit 9998 (Week 104/EOT) and transition to 
the 12-week follow-up period Visit 9999 (Week 156/EOS).

These subjects will not be allowed to discontinue H1-AH background medication.
For the sub-group of subjects who achieved a UAS7 ≤ 6 at Week 52, and re-entering 
treatment (second half of the treatment period) from the second observation period due to 
a relapse (UAS7 ≥ 16):

These subjects must enter the second half of the treatment period at Visit 214 
(Week 52).

At Visit 403 (Week 64), only this sub-group of subjects will be offered the 
opportunity, after discussion with the investigator, to discontinue their H1-AH 
background medication (i.e. ligelizumab 120 mg s.c. q4w PFS monotherapy).

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
To support the investigator in making the decision for monotherapy, subjects 
should complete their eDiary for the 7 days prior to Visit 403 (i.e. one 
assessment-week) to ensure the UAS7 thresholds are available.

The investigator will decide whether monotherapy is appropriate considering the 
UAS7 score. It is recommended that only subjects with UAS7 ≤ 6 at Visit 403 
(Week 64) discontinue H1-AH.

These subjects must be advised that, if needed to use their H1-AH background 
medication, they must then remain on their H1-AH background medication for 
the rest of the study. Any worsening of CSU symptoms can be managed with the 
use of H1-AH rescue medication without the need to resume H1-AH background 
medication.

All subjects completing the second half of the treatment period will complete the 
Visit 9998 (Week 104/EOT), and transition to the 12-week follow-up period 
Visit 9999 (Week 156/EOS).

All subjects, whether in the clinic-administered or outside the clinic self-administered 
group will continue to complete the eDiary twice daily as per protocol.

Subjects should use the same H1-AH rescue medication that was agreed with the 
investigator at Visit 1 of this study.

Use of oral corticosteroid rescue medication is permitted during the second half of the 
treatment period, with the limitations as per Section 6.2.3.

For details regarding monitoring post ligelizumab administration and self-administration 
outside of the clinic, see Section 6.7.2.
3.6
Follow-up period

Visit 501 to 9999 (Week 116 to Week 156)

Subjects who do not complete a continuous 104-week treatment will enter the follow-up 
period for 12 weeks duration and will only perform Visit 9999 (Week 156).

Subjects who have completed the full 104-week treatment period without interruption will 
enter the follow-up period of 52 weeks duration and will perform Visit 501 to Visit 9999 
(Week 116 to Week 156).

After completion of the follow-up period, subjects will perform the EOS visit (Visit 9999) 
and exit the study.

Subjects will continue to complete the eDiary twice daily as per protocol (see Table 8-1), in 
order to monitor the activity of their disease.

Subjects who decided to remain on H1-AH background medication will continue to use H1-
AH background medication. Subjects who decided to go off H1-AH background medication 
should continue to remain off.

Subjects should use the same H1-AH rescue medication that was agreed with the 
investigator at Visit 1 of this study.

Use of oral corticosteroid rescue medication is permitted during the follow-up period, with 
the limitations as per protocol (see Section 6.2.3).

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background medication. All subjects will initially receive standard of care therapy (H1-
antihistamines at approved doses, per local label) as background medication.
Subjects being kept on background H1-AH medication must remain on a stable treatment 
regimen (type and dose of H1-AH) throughout the study, including the observation periods.
Subjects who achieved UAS7 ≤ 6 at Week 52 in the treatment period and re-entering the second 
half of the treatment period from the second observation period, will be considered for 
discontinuation of their background H1-AH use after three doses of ligelizumab in the second 
half of the treatment period. The rationale for selecting this subgroup of subjects to evaluate 
ligelizumab monotherapy is that this population is considered to be more responsive to 
treatment and thus eligible for evaluation of ligelizumab monotherapy. Ligelizumab 
monotherapy will be offered to this sub-group at Visit 403 (Week 64). The rationale for 
selecting this timepoint is based on data from the Phase IIb study CQGE031C2201 study where
it was noted that, following administration of the third dose of ligelizumab 72 mg slightly higher 
numbers of subjects achieved UAS7 = 0 compared to following the first and second dose 
administrations (44.0% compared to 29.8 and 40.5%, respectively). A similar trend was noted 
with regards to numbers of subjects achieving UAS7 ≤ 6 following administration of 
ligelizumab 72 mg (60.5 % compared to 48.8 and 54.2%). In choosing this time point of 12 
weeks after re-entering second half of the treatment period and receiving 3 doses of ligelizumab 
on standard background therapy, it was considered that the effect of ligelizumab would be well-
established, and the likelihood of experiencing a flare-up of CSU would be notably diminished
by this time.
4.2
Rationale for dose/regimen and duration of treatment
Rationale for dose/regimen
The doses of 72 and 120 mg s.c. q4w 
 are selected 
based on the totality of observed clinical data in the Phase IIb CQGE031C2201 study and the 
lack of any safety concerns across the doses tested and modeling and simulation data (overview 
of Phase 2 clinical data provided below). The 72 mg s.c. q4w dose was tested in the 
CQGE031C2201 study and demonstrated efficacy while the 120 mg s.c. q4w dose was only 
administered as a single dose and modeled to be an efficacious q4w dose based on dose-
response and exposure-response modeling.
In this extension study, until Week 12 (Visit 204) both 72 mg and 120 mg s.c. q4w will be 
evaluated. Subjects who received 72 mg liquid in vial s.c. q4w in the core studies will continue 
to receive 72 mg until Week 12 (Visit 204) in this extension study. All other subjects from the 
other treatment arms in the Phase 3 studies, subjects from CQGE031C2202 and 
CQGE031C1301 studies will receive ligelizumab 120 mg s.c. q4w in this extension study. This 
dose i.e. 120 mg is the higher of the two doses being evaluated in the Phase 3 core studies and 
is the only dose being evaluated in the CQGE031C1301 study. The rationale for including the 
72 mg dose until Week 12 (Visit 204) is to allow ligelizumab retreatment efficacy comparison 
between the Phase 3 core studies and the extension study until primary endpoint at Week 12
(Visit 204).
Overview of Phase 2 clinical data

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extended treatment of ligelizumab. Hence, this will allow observation of subjects from the 
preceding studies for relapse of disease over an extended period of time. Those presenting with 
a relapse of moderate to severe disease will be enrolled directly to a 104 week (2 year) treatment 
period with a decision branch point at Week 52. Subjects who have not relapsed by the end of 
the first observation period will exit from the study.
Rationale for treatment period duration
In order to parallel clinical practice, where patients with long-term CSU are likely to be treated 
for up to 6 or 12 months then reassessed for ongoing disease and the need for ongoing treatment, 
the treatment period has been designed with a three-way branch point at the half-way mark, i.e. 
Week 52. Here the subject will be assessed by the investigator. Depending on the results of the 
UAS7 scores and a discussion between the investigator and the subject, the subject will either 
continue treatment or stop and transition to the second observation period, move to the follow-
up period or exit the study. The three options are:

Subjects with a UAS7 ≤ 6:
These subjects, having reached the state of their CSU being well-controlled, will transition 
to the second observation period, to permit a drug "holiday" and following the subject for 
evidence of persistent remission / control of disease or relapse.

Subjects with a UAS7 > 6 and < 16:
These subjects have improved from their original enrollment status of moderate-to-severe 
disease to the level of mild disease. Nonetheless, the persistence of active disease 
demonstrates the need for ongoing treatment to keep their disease suppressed. These 
subjects will continue uninterrupted treatment unless a decision is made, based on a risk-
benefit discussion with the investigator, to move the subject to the second observation 
period.

Subjects with a UAS7 ≥16:
As these subjects still have moderate-to-severe disease, yet also may have had significant 
improvement from their enrollment status, it is important that they are given the 
opportunity to be evaluated on an individual basis by the investigator. Evidence from the 
literature supports the opinion that these subjects will have had more severe and 
longstanding disease prior to initiating anti-IgE therapy and require long-term treatment 
(Vadasz et al 2017). Therefore, the investigator must reassess the risk-benefit with the 
subject and decide whether to continue or discontinue treatment (see Section 9.1.1). This 
discussion with the individual subject will include whether or not the subject has had 
enough improvement from their initial disease state at the start of the treatment period, 
even though they still have moderate to severe disease, to justify continuing in the 
treatment period. 

One example of this scenario: a subject enters the screening period with a UAS7 of 36 
(severe urticaria) and at Week 52, has a UAS7 of 18 (moderate urticaria). In this 
scenario, the subject may feel that this has been a significant enough improvement to 
warrant continuation of treatment to Visit 9998 (Week 104/EOT). Here the 
investigator must review the risk-benefit with the subject to ensure that all efficacy 
and safety factors are reviewed and the investigator is in agreement with the subject to 
continue without any undue risk. This may include a review of any adverse events 

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(AEs)/serious adverse events (SAEs) that the subject may have reported up to this 
point, and any other relevant information from the investigator’s perspective.
As always, subject may discontinue treatment or from the study at any time, including at this 
Week 52 branch point.
This two-year overall treatment period, with flexibility for two observation periods closely 
reflects the practicing physician's treatment plan for the long-term management of patients with 
this chronic relapsing disease.
In addition, the duration of this study with its long-term treatment period and observation 
periods will support Novartis' commitment to post trial access for patients completing pivotal 
Phase 3 studies.
Rationale for route of administration
In the completed CQGE031C2201, CQGE031C2201E1 studies, the ongoing CQGE031C2302, 
CQGE031C2303,
CQGE031C2202
and CQGE031C1301 studies, ligelizumab was/is 
administered subcutaneously. The subcutaneous (s.c.) route of administration will continue to 
be used, due to the favorable bioavailability demonstrated with ligelizumab in previous studies 
and because of its ease of administration and tolerability.
Rationale for using pre-filled syringes (PFS)
In this extension study, after Visit 204 (Week 12), all subjects will be administered ligelizumab 
in X100L pre-filled syringes (ligelizumab 120 mg PFS preassembled with an off-the shelf 
needle safety device). The rationale for using pre-filled syringes is to allow easy administration 
of a single fixed dose of ligelizumab 120 mg for any drug administrator in clinic or outside the 
clinic. To allow any efficacy comparison at Week 12 (Visit 204) (the primary endpoint) between 
the 
preceding 
studies 
(CQGE031C2302, 
CQGE031C2303, 
CQGE031C2202, 
CQGE031C1301), all of which use ligelizumab liquid in vial, and this extension study, 
ligelizumab administration in PFS will begin only at Week 12 (Visit 204).
Rationale for self-administration option
In this study protocol, the term "self-administration" refers to the process by which the
investigational drug is actually administered to the subject in any setting outside of the clinic, 
and may take any of the following forms:

An adult subject who is appropriately trained (see Section 6.7.2) and takes complete 
responsibility for the injection;

an adult subject whose adult lay caregiver is appropriately trained (see Section 6.7.2), takes 
complete responsibility of preparing the subject for the injection and carries out the actual 
injection of the adult subject with ligelizumab; or

an adolescent subject whose adult lay parent / caregiver is appropriately trained, takes 
complete responsibility of preparing the subject for the injection and carries out the actual 
injection of the adolescent subject with ligelizumab.
A. The benefits of self-administration of medication (Richardson et al 2014)

Significantly reduces the burden on patients, caregivers, healthcare professional and the 
overall health care systems, as well as direct and indirect costs for the patient and the 
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Additional information on risks associated with omalizumab is found in the local health 
authority approved product information. Severe thrombocytopenia has been reported in 
preclinical studies in cynomolgus monkeys with high doses of omalizumab. Although 
thrombocytopenia has not been observed with ligelizumab in the toxicology studies in non-
human primates or in the clinical program conducted so far, the current protocols include 
monitoring of platelets as part of the hematology assessment. Ligelizumab is in the same class 
as omalizumab and therefore, in theory, carries the similar risks as omalizumab.
IgE is an antibody that may have an adaptive role in immunity to parasitosis, particularly 
helminthic infections. Thus, blocking the interaction of IgE and its receptors with ligelizumab 
may alter immunologic responsiveness to parasites. Bearing this in mind, screening will be 
carried out for the presence of parasitosis, particularly helminthic infections and these subjects 
will be excluded prior to enrollment. In addition, monitoring for the occurrence of infection and 
response to therapy is recommended for subjects at high risk of geohelminth infection who 
receive ligelizumab. Insufficient data are available to determine the length of monitoring 
required for geohelminth infections after stopping ligelizumab. However, it is expected that 
ligelizumab will not interfere with a polyclonal reaction triggered by exposure to parasites. The 
resulting increase of IgE production would decrease the half-life of ligelizumab, through target 
mediated disposition, hence restoring normal IgE levels more rapidly.
Based on currently available data from the ligelizumab clinical program, there is no evidence 
of an increased risk of infections/viral infections. At this time there are no specific data to 
inform on incidence or severity of Corona Virus Disease 2019 (COVID-19) (due to severe acute 
respiratory syndrome coronavirus 2) in patients receiving ligelizumab.
Therefore, based on the cumulative data available across all clinical studies in different patient 
populations for ligelizumab, the current evidence indicates that ligelizumab is safe and well 
tolerated and thus appropriate for further development.
The non-clinical safety evaluation for ligelizumab supports a clinical treatment of children 
down to the age of 2 years. There is no evidence to suggest that ligelizumab will have a different 
mode of action or will be cleared differently in pediatric versus adult subjects. No new or 
unexpected safety signals were identified in the CQGE031C2201 or CQGE031C2201E1 
studies in adults.
The data from CQGE031C2201 and CQGE031C2201E1 demonstrates that ligelizumab 
administration results in significant improvement of CSU symptoms including itch, hives, 
angioedema and quality of life (QoL) irrespective of chronic urticaria (CU) index status. Hence,
the potential benefit to the subject from participation in the current study is that treatment with 
ligelizumab could improve their CSU symptoms, leading to a better QoL.
The inclusion and exclusion criteria are selected to enroll subjects with CSU likely to benefit 
from participating in the study. The overall risk will be minimized by compliance with the 
inclusion/exclusion criteria, close clinical monitoring including periodic review of data by an 
independent Data Monitoring Committee (DMC), the use of an electronic diary at home to 
monitor symptoms and the use of rescue medication. Furthermore, a dedicated clinical safety 
team at Novartis will actively monitor the safety of subjects and take proper actions to address 
any safety concerns that may emerge during the study.

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The majority of subjects will be adults, as only about 5% of subjects completing the Phase 3 
pivotal studies are expected to be adolescents, only the 49 subjects in the CQGE031C2202 study 
are adolescents and there are no adolescents in the CQGE031C1301 Japan safety study.
All the enrolled subjects will be assigned to the treatment groups according to the preceding 
study treatment group.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Subject’s, parent’s or legal guardian’s signed written informed consent and child’s assent, 
if appropriate, must be obtained before any assessment is performed. Of note, if the subject 
reaches age of consent (age as per local law) during the study, they will also need to sign 
the corresponding study Informed Consent Form (ICF) at the next study visit.
3. Subjects who successfully completed all of the treatment period and the follow-up period 
of any of the following studies: CQGE031C2302, CQGE031C2303, CQGE031C2202 or
CQGE031C1301.
a. Subjects who had completed the preceding studies prior to start of this extension study 
are also allowed to participate, provided they perform the full Screening Period as soon 
as the extension study had been initiated at their study site.
4. Male and female, adult and adolescent subjects ≥12 years of age (NOTE: Recruitment of 
adolescent subjects, ≥ 12 to < 18 years of age, will be in accordance with local 
regulatory/ethics committee requirements).
5. Willing and able to complete a daily symptom eDiary for the duration of the study and 
adhere to the study visit schedule.
6. Subjects must not have had missing eDiary entries in the 7 days prior to the first visit of the 
first half of the treatment period* or first visit of the first observation period (at least 12 out 
of 14 records for HSS and ISS respectively must be present in the week the UAS7 score is 
assessed).
*Subjects must reach UAS7 score ≥16 prior to treatment.
For subjects entering treatment directly from the screening period the score will be assessed 
in the 7 days prior to first treatment visit.
Rescreening may be considered only once.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Use of investigational drugs, other than those in use in the preceding studies, at the time of 
enrollment, or within 30 days or 5 half-lives prior to Visit 1 (Screening visit), whichever is 
longer.
2. Use of omalizumab within 16 weeks of Visit 101 or 201 (whichever occurs first).
3. History of hypersensitivity to the study drug ligelizumab or its components, or to drugs of 
similar chemical classes (i.e. to murine, chimeric, or human antibodies).
4. New onset or signs and symptoms of any form of chronic urticarias other than CSU during 
the preceding studies CQGE031C2302, CQGE031C2303 or CQGE031C2202.

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
This includes, but is not limited, to the following:

Inducible urticaria: symptomatic dermographism (urticaria factitia), cold-, heat-, 
solar-, pressure-, delayed pressure-, aquagenic-, cholinergic-, or contact-urticaria.
5. Diseases with possible symptoms of urticaria or angioedema such as urticarial vasculitis, 
erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa), and hereditary or 
acquired angioedema (e.g., due to C1 inhibitor deficiency).
6. Subjects with evidence of helminthic parasitic infection as evidenced by stools being 
positive for a pathogenic helminth according to local guidelines. All subjects should have 
been assessed for evidence of parasitic infection at Visit 1999 of the preceding studies (see
Section 8.4.3 of respective preceding study’s protocol). If stool testing is positive for 
pathogenic helminthic organisms, the subject will not be enrolled in to this extension study 
and will not be allowed to rescreen.

In the event that stool samples from Visit 1999 of the preceding studies were not 
collected or the results from these are not available, subjects will be assessed for 
evidence of parasitic infection at Visit 1 (see Section 8.4.4). If stool testing is positive 
for pathogenic helminthic organisms, the subject will not be enrolled to this extension 
study and will not be allowed to rescreen.
7. Any other skin disease associated with chronic itching that might in the opinion of the 
investigator, confound the study evaluations and results (e.g. atopic dermatitis, contact 
dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus etc.).
8. Any H2-antihistamine use after Visit 1 in this study.
9. Any LTRA (e.g. montelukast or zafirlukast) use after Visit 1 in this study.
10. Any H1-antihistamine background medication used at greater than the local label approved 
doses after Visit 1.

H1-antihistamine rescue medication may be used at up to 4 times the local label 
approved doses after Visit 1, at the discretion of the investigator (see Section 6.2.3).
11. Prior exposure to any anti-IgE antibody therapy other than omalizumab and ligelizumab.
12. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to 
enrollment.
13. Inability to comply with study and follow-up procedures.
14. Subjects taking medications prohibited by the protocol (see Section 6.2.2, Table 6-2).
15. Contraindications to or hypersensitivity to study drugs including but not limited to 
fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine, rupatadine or epinephrine 
or any of their ingredients.
16. Documented history of anaphylaxis.
17. Onset of malignancy of any organ system within the past 5 year (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).
18. Presence of clinically significant cardiovascular (such as but not limited to myocardial 
infarction, unstable ischemic heart disease, New York Heart Association Class III/IV left 
ventricular failure, arrhythmia, uncontrolled hypertension within 12 months prior to Visit 
1), neurological, psychiatric, metabolic or other pathological conditions (such as but not 

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limited to cerebrovascular disease, neurodegenerative diseases or other neurological disease, 
uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, 
hyperadrenergic state, or ophthalmologic disorder) that could interfere with or compromise 
the safety of the subject, interfere with evaluation or interpretation of the study results or 
preclude completion of the study.
19. 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.
20. History of, or current treatment for, hepatic disease including but not limited to acute or 
chronic hepatitis, 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 Visit 1 or Visit 2*.
21. History of renal disease or creatinine level above 1.5 x ULN at Visit 1 or Visit 2*.
22. Platelets < 100,000/μL at Visit 1 or Visit 2*.
23. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test.
24. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during dosing 
of investigational drug (and approx. 4 months, i.e. 5 half-lives, after last dose of 
ligelizumab). Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable 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 
taking investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

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 or intrauterine system 
In case of use of oral contraception, women should have been stable on the same contraceptive 
pill for a minimum of 3 months before taking investigational drug.
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms). Women are considered not of child bearing potential if they are post-menopausal
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or bilateral 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 childbearing potential.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed consent form (ICF).
*Subjects who did not meet applicable eligibility criteria at Visit 2, as listed above, will be 
discontinued from the study and will not enter treatment. Since these subjects have been initially 
eligible at Visit 1 and participated in the first observation period, they will not be considered 
screen failure subjects if they do not enter treatment.
6
Treatment
6.1
Study treatment
Novartis Global Clinical Supply will supply Ligelizumab (QGE031) 120 mg per 1 mL liquid 
in vial and 120 mg per 1 mL as PFS with a needle safety device (NSD).
6.1.1
Investigational and control drugs
Table 6-1
Investigational drug
Investigational 
(Name and 
strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor (global 
or local)
Ligelizumab 120 
mg per 1 mL
Liquid in vial 
s.c.
Open-label 
subject kits; vials
Sponsor global
Ligelizumab 
(QGE031) 120 
mg per 1 mL
Solution for 
injection in a pre-
filled syringe
s.c
Open-label 
subject kits; pre-
filled syringe
Sponsor global
No placebo or active comparator will be used.
6.1.2
Additional study treatments
No additional treatment beyond investigational treatment (ligelizumab) is requested for this trial. 
Subjects will continue to use their background medication (H1-AH at local label-approved 
doses) with a stable regimen during the study except for those on monotherapy. For rescue 
medication, see Section 6.2.3.
6.1.3
Treatment arms/group
First half of the treatment period
For subjects rolling over from the core studies CQGE031C2302 and CQGE031C2303:
a. Blinded treatment period (Week 0, 4 and 8; Visits 201, 202, 203 respectively):

Ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab (120 mg/mL) liquid in vial 
s.c. q4w

Ligelizumab 72 mg arm: 1 injection of 0.6 mL ligelizumab (120 mg/mL) liquid in vial 
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b. Open-label treatment period (Week 12 through Week 52; Visits 204 to 214):

Ligelizumab 120 mg arm: 1 PFS injection of 1.0 mL ligelizumab s.c. q4w 
For subjects rolling over from CQGE031C2202 and CQGE031C1301:
a. Open-label treatment period ( Week 0, 4 and 8; Visits 201, 202, 203 respectively):

Ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab (120 mg/mL) liquid in vial
s.c. q4w
b. Open-label treatment period (Week 12 through Week 52; Visits 204 to 214):

Ligelizumab 120 mg arm: 1 PFS injection of 1.0 mL ligelizumab s.c. q4w
Second half of the treatment period
For all subjects:
a. Open-label treatment period (Week 52 to Week 104; Visits 214 to 9998/EOT)

Ligelizumab 120 mg arm: 1 PFS injection of 1.0 mL ligelizumab s.c. q4w
Further details are provided in Section 6.3.2, Section 6.7 and Table 8-1.
6.1.4
Treatment duration
As described above in Section 3 and Section 4.2, the longest possible treatment is 104 weeks
however this treatment might not be continuous and might span over a period of 156 weeks due 
to possibly entering the observation period.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Concomitant H1-AH background medication
This study requires concurrent use of one second generation H1-AH at local label approved 
doses as background medication except for the subgroup of subjects who will be offered a 
choice to go off background medication in the second half of the treatment period.
Subjects must remain on the same H1-AH background medication they were taking in the 
preceding studies (exceptions may apply, e.g., subjects experienced an AE related to the specific 
antihistamine or due to unavailability). Subjects must remain on the same H1-AH while taking 
background H1-AH and will only be allowed to switch to another background H1-AH (at 
approved dose) due to an AE.
If a subject must switch to another background H1-AH as a result of an AE, the subject will be 
considered to have remained on stable treatment.
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study must be recorded on the appropriate electronic Case 
Report Forms (eCRFs).

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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis monitor before enrolling a 
subject or allowing an enrolled subject to start a new medication.
6.2.2
Prohibited medication
Use of the class of treatments displayed in Table 6-2 is NOT allowed after start of screening. 
The minimum required period without prohibited treatment is also listed in Table 6-2. Each 
concomitant drug must be individually assessed against all exclusion criteria and Table 6-2 to 
see if it is allowed. If in doubt, the investigator should contact Novartis or delegate before 
enrolling a subject or allowing an enrolled subject to start a new medication.
Table 6-2
Prohibited Medication
Medication or Treatment
Minimum 
required 
period 
without 
medication or treatment
Omalizumab*
At least 16 weeks prior to V101 or V201
(whichever occurs first)
Any anti-IgE antibody therapy other than omalizumab 
and ligelizumab
No prior use allowed
Routine oral corticosteroids (more than 3 doses over 
a 5 day period)**
30 days prior to Visit 1
Intramuscular /intra-articular /intravenous - injections 
of corticosteroids
30 days prior to Visit 1
Beta-blocker therapy
7 days prior to Visit 1
Leukotriene antagonists
Stop at Visit 1
H2-antihistamines
Stop at Visit 1
First generation H1-antihistamines
Stop at Visit 1
Any 
second 
generation 
(non-sedating) 
H1-
antihistamine at greater than local label approved 
dose(s)***
Stop at Visit 1
Hydroxychloroquine or chloroquine
Dapsone
30 days prior to Visit 1
30 days prior to Visit 1
Other immunosuppressive medication with or without
known effect on CSU including but not limited to 
Methotrexate, cyclosporine A, cyclophosphamide, 
tacrolimus and mycophenolate mofetil
30 days prior to Visit 1
Intravenous immunoglobulin G
30 days prior to Visit 1
Plasmapheresis
30 days prior to Visit 1
Regular (daily or every other day) doxepin (oral)
14 days prior to Visit 1
Vaccination with inactivated viruses
48 hours prior to each dosing visit
Live attenuated vaccine
30 days prior to Visit 1
*If a subject takes concomitant omalizumab during the study the subject must discontinue from the 
study, in which case,

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** Allowed only as rescue therapy, in the form of oral corticosteroids, on an as-needed basis for 
unbearable symptoms as per Section 6.2.3. Other preparations of corticosteroids (e.g. intra-nasal or 
topical corticosteroids) with limited systemic exposure for non-CSU indications can be used on an as
needed basis.
*** Applies to H1-antihistamines used as background medication, or as a concomitant medication for 
non-CSU indication. The six H1-AH permitted as rescue medications may be used at up to 4 times 
local label approved dose at the discretion of the investigator (see Section 6.2.3).
If the prohibited treatment was used during the study for any indication, the subject must 
discontinue use of the prohibited treatment if the subject wishes to continue in the study. If the 
subject must continue a prohibited medication during the study, the subject must discontinue 
study treatment. If the subject receives a live virus vaccination during the study, the subject 
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 subjects on the 
acceptable treatment for managing their disease with the use of rescue medication, thereby 
allowing subjects to continue in the study as long as possible. At the same time, the provision 
for use of rescue medications has been designed to minimize interference with efficacy 
assessment of the investigational drug. Therefore, investigators must instruct subjects on rescue 
medication use with this purpose in mind, i.e. to assess the need for rescue medication on a day-
by-day basis, and following the limitations below for both H1-AH and oral corticosteroid rescue 
medications.
Anti-histamine rescue medication
Fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine and rupatadine H1-AHs, in 
addition to being allowed as background medication, will be allowed as rescue medication and 
used on an as-needed basis during screening, observation, treatment and follow-up periods for 
treatment of unbearable symptoms. The six H1-AH permitted as rescue medications may be 
used at up to 4 times local label approved dose at the discretion of the investigator. The selection 
of the H1-AH rescue medication should be made once for an individual subject at Visit 1. A 
switch of the H1-AH rescue medication for an individual subject will only be permitted in the 
event of an associated AE that prevents the subject from taking the original H1-AH rescue 
medication or if the medication is no longer available in the country. The reason for the change 
of H1-AH rescue medication must be clearly documented in detail in the appropriate eCRF.
Corticosteroid rescue medication
In addition, after the Week 12 (Visit 204) primary endpoint, subjects will be permitted to use 
oral corticosteroids such as prednisone and its equivalents as rescue medication if needed, for 
treatment of unbearable symptoms.
The CSU treatment guidelines suggest that systemic corticosteroids may be used for up to 10 
consecutive days to manage flare-ups in clinical practice. However in this clinical study, in 

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order to minimize any confounding suppression of signs and symptoms of CSU, oral 
corticosteroid use will be restricted to after the Week 12 (Visit 204) assessments for all subjects.
In addition, for all subjects, the number of doses of oral corticosteroids will be limited to:

a maximum of 3 days per 30 days;

a maximum of 9 doses total (i.e. a maximum of 9 days of corticosteroids in total) in the 
first half of the treatment period after Week 12

a maximum of 9 doses total in the second half of the treatment period;

a maximum of 9 doses total in the 52-week follow-up period;

a maximum of 3 doses total in the 12-week follow-up period.
Use of oral corticosteroid rescue medication is not permitted during the first and second 
observation periods, in order to avoid masking the signs and symptoms of CSU that would make 
the subject eligible to start / re-start treatment with ligelizumab. If a subject uses more than 
allowable doses of corticosteroids in each half of the treatment period, then the subject will be 
discontinued from study treatment.
While the dose of oral corticosteroid should be individualized for subject comfort, it is 
suggested that the investigator consider a maximum daily dose, in order to minimize the risk of 
significant interference with the quality of data. Using oral prednisone as an example, this might 
be in the range of 0.5 mg/kg. If a subject requires prednisone in excess of 0.5 mg/kg as a daily 
dose of rescue medication on an ongoing basis, it is suggested that that they might not be 
considered suitable subjects for the study as they would likely exceed the allowed corticosteroid 
doses.
The selection of the oral corticosteroid rescue medication should be made once for an individual 
subject. A switch of the oral corticosteroid rescue medication for an individual subject will only 
be permitted in the event of an associated AE that prevents the subject from taking the original 
oral corticosteroid rescue medication. The change of oral corticosteroid rescue medication must 
be clearly documented in detail in the appropriate eCRF.
Rescue medication will be sourced locally. Use of H1-AH and oral corticosteroids rescue 
medication (number of tablets taken and name of rescue medication) only for CSU will be 
recorded on the eDiary by the subject. The rescue medication information will be captured on 
the appropriate eCRF.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number that will be assigned in the electronic 
data capture system (EDC) when the subject is first enrolled for screening Visit 1. The Subject 
Number is retained as the primary identifier for the subject throughout his/her participation in 
the entire trial. The Subject Number consists of the Center Number (as assigned by Novartis to 
the investigative site) with a sequential Subject Number suffixed to it, so that each subject is 
numbered uniquely across the entire database. Upon signing the ICF, the subject is assigned to 
the next sequential Subject Number available.

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6.3.2
Treatment assignment, randomization
No randomization will be performed in this study. The assignment of treatment will depend on 
the previous study treatment assignment.
At Visit 201 (Week 0), all eligible subjects will be assigned to investigational treatment via 
Interactive Response Technology (IRT). All subjects will receive 120 mg s.c. q4w except 
subjects treated with 72 mg s.c. q4w in the core studies CQGE031C2302 or CQGE031C2303, 
who will continue to receive 72 mg s.c. q4w in this extension study for the first 12 weeks (see 
Section 3.3 and Section 6.1.3). The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign the 
subject, to a treatment arm and will specify a unique medication number for the package of 
investigational treatment to be dispensed to the subject. All kits of study treatment assigned by 
the IRT will be recorded in the IRT system.
The treatment assignment list for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Subjects, investigator staff and personnel performing the study assessments for studies 
CQGE031C2302 and CQGE031C2303 will remain blinded to the identity of the treatment from 
the time of enrollment (Visit 201, Week 0) until all subjects in this study have completed 
Week 12 in the first half of the treatment period and the primary analysis has been completed. 
An unblinded study monitor will visit the study site to monitor study drug related administration 
(see Section 11.3).
Should additional analysis be required to support Health Authority interactions (prior to the 
primary analysis), sponsor team members may be unblinded for such analysis. These unblinded 
team members will not be further involved in the study conduct until the primary analysis has 
been completed.
No blinding is required for subjects transitioning from study CQGE031C2202 and 
CQGE031C1301, as all subjects will receive 120 mg s.c. q4w ligelizumab.
Treatment blinding will be maintained at Visits 201, 202 and 203 (Weeks 0, 4 and 8) when 
subjects are being administered with liquid in vial (see Section 3.3) using the following 
methods:
1. Treatment assignment data are kept strictly confidential until the time of unblinding, and 
will not be accessible by anyone else involved in the study with the following exceptions:

Bioanalyst (
): to enable identification of samples from the ligelizumab treatment 
arms of the study to facilitate bioanalysis;

Independent personnel (external to Novartis) involved in monitoring anaphylaxis, 
neoplastic and cerebro-cardiovascular events (Adjudication Committee members), if 
needed; and

An independent DMC (see Section 10.2.3) and the independent statistician supporting 
the DMC activities (Table 6-3).

These personnel will not be involved in any other trial activities.

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2. The following measures will be applied to keep the subject and study personnel blinded 
despite differences of the investigational treatments in volume:

The investigational drug must be prepared by an independent unblinded pharmacist (or 
authorized delegate) and administered by an independent unblinded administrator who 
are both not involved in any of the study assessments. If an unblinded pharmacist is not 
available, preparation and administration of the investigational drug may also be 
performed by a single independent unblinded site person if he/she is authorized to do 
both.

Preparation of the investigational drug must be done in a separate space/room where 
subjects and blinded study personnel have no access during time of preparation.

To blind the liquid volume in the syringe, one method is to cover the syringe by a strip 
of opaque tape. The differences in length of the syringe plunger, related to the 
differences in the volume, should also be covered by the way of administration (see 
Pharmacist Manual).

The prepared syringes must be placed on a tray which is covered by an opaque towel 
to ensure the syringes are not visible to the subject at any time.

The independent unblinded authorized site persons (pharmacist/administrator) should 
not communicate the volume and any perceived sensation associated with the 
administration of the investigational drug.

The subject will be instructed to look away, from the tray of prepared syringes 
(whenever the tray is uncovered) and from the injection site.
The procedural details relating to treatment blinding and unblinded drug administration will be 
described in the Pharmacist Manual, which is provided separately.
Unblinding will occur in the case of subject emergencies.
Health authorities will be granted access to unblinded data if needed.
Table 6-3
Blinding and unblinding plan (applies to all subjects in this study 
transitioning from the core studies till completion of Week 12 in the first 
half of the treatment period and the primary analysis has been 
completed)
Role
Time or Event
DMC 
Analysis
Any 
additional 
analyses to 
support 
health 
authority 
interactions 
prior to 
primary 
analysis
Treatment 
assignment 
list 
generated
Treatment 
allocation 
& dosing
Safety event 
(single 
subject 
unblinded)
Subjects
B
B
B
B
B
Investigator and Site 
staff
B
B
UI
B
B

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Role
Time or Event
DMC 
Analysis
Any 
additional 
analyses to 
support 
health 
authority 
interactions 
prior to 
primary 
analysis
Treatment 
assignment 
list 
generated
Treatment 
allocation 
& dosing
Safety event 
(single 
subject 
unblinded)
Unblinded site staff e.g., 
pharmacy staff and 
investigational drug 
administrator 
B
UI
NA
B
B
Global Clinical Supply 
and Randomization 
Office
UI
UI
UI
UI
UI
Unblinded sponsor staff 
e.g., for study treatment 
re-supply, unblinded 
monitor(s)
B
UI
NA
B
B
Unblinded 
Pharmacovigilance 
sponsor staff
B
B
UI
B
B
Trial 
Statistician/statistical 
programmer
B
B
B
B
B
Independent 
Statistician/statistical 
programmer
B
B
B
UI
UI
Independent 
committees used for 
assessing interim 
results, if required (e.g., 
DMC)
B
UI
UI
UI
UI
Adjudication committee
B
B
B*
B
B
Bioanalyst (
)
B
UI
B
B
B
All other sponsor staff 
not identified above 
(trial team, project team, 
management & decision 
boards, support 
functions)
B
B
B
B
B
Unblinded sponsor team 
for additional analyses 
(if needed)
B
B
B
B
UI
UI: Allowed to be unblinded on individual subject level
B: Remains blinded
NA: Not applicable to role
*Unblinded if needed

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6.5
Dose escalation and dose modification
6.5.1
Dose modifications
Investigational drug dose adjustments are not permitted.
Any interruption of investigational drug administration should be discussed with Novartis or 
delegate regarding the subject’s eligibility to continue investigational treatment.
Any missed or altered investigational drug administration must be recorded on the appropriate 
eCRF in order to reconstruct an accurate dosing history for each subject.
6.5.2
Follow-up for toxicities
Not applicable.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Subjects will have one s.c. injection every 4 weeks at 13 visits during the first half of the 
treatment period and for 48 weeks at 13 visits during the second half of the treatment period.
For the first 3 treatment visits, the subjects will receive the injection as liquid in vial and 
thereafter as PFS.
The investigator must promote compliance by instructing the subject to take the study 
treatments (investigational, background and rescue medications) exactly as prescribed, by 
stating that compliance is necessary for the subject’s safety and the validity of the study data. 
The subject must also be instructed to contact the investigator if he/she is unable, for any reason,
to take the study treatment as prescribed.
For subjects receiving investigational treatment at the site, compliance is assured, as study drug 
must be administered by study personnel via s.c. injection.
For subjects self-administering investigational treatment, compliance will be assessed by the 
investigator and/or study personnel at each in-clinic visit (see Table 8-1) using medication 
package counts and information provided by the subject. This information should be captured 
in the source document and corresponding eCRF at each in-clinic visit. All study treatment 
dispensed and returned must be recorded as per Section 6.7.1.
6.6.2
Emergency breaking of assigned treatment code
Emergency breaking of treatment code is only applicable for all subjects from the two core 
studies CQGE031C2302 and CQGE031C2303 until they complete Visit 204 (Week 12).
Emergency code breaks must only be undertaken when it is required in the interest of subject 
safety. Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a subject, he/she must provide the requested subject 
identifying information and confirm the necessity to break the treatment code for the subject. 
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subject and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

investigational drug name

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason.
Investigational treatment must be discontinued after emergency unblinding.
6.7
Preparation and dispensation
Each study site will be supplied with investigational study drug in kits as described under
Section 6.7.1.1.
Please refer to the Pharmacist Manual and Instructions For Use (IFU) for drug preparation and 
administration.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
IRT and obtaining the medication number(s). The study medication has a 2-part label (base plus 
tear-off label). Immediately before dispensing the study medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
From Visit 207 (Week 24), selected subjects will perform outside of clinic administrations at 
the protocol specified time points. For these cases, the investigator (or authorized delegate) will 
dispense, via IRT, an appropriate number of investigational treatment kits for outside of clinic
administrations and detach the outer part of the label from the packaging in order to adhere it 
on the drug accountability log. Please refer to Section 6.7.1 for returning and recording study 
treatment.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Subjects transitioning from CQGE031C2302 and CQGE031C2303
Ligelizumab liquid in vial and ligelizumab PFS must be received by a designated person at the 
study site, handled and stored safely and properly and kept in a secured location to which only 
the investigator and designated site personnel have access. Upon receipt, all study treatment 

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must be stored according to the instructions specified on the labels and in the Investigator’s 
Brochure. Clinical supplies are to be dispensed only in accordance with the protocol. Technical 
complaints are to be reported to the respective Novartis Country Organization Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
For ligelizumab liquid in vial, an accurate record of the shipment, dispensing and 
collection/destruction of study treatment must be maintained in a drug accountability log by the 
independent unblinded site personnel. 
For PFS, an accurate record of the shipment, dispensing and collection/destruction of study 
treatment must be maintained in a drug accountability log by the study site personnel.
Monitoring of drug accountability will be performed by unblinded monitors (for liquid in vial) 
and monitors (for PFS) during site visits or remotely and at the completion of the trial.
Subjects who do outside of clinic investigational drug administration will record the date(s) of 
administration on a diary/form and will be asked to return all used and unused investigational 
treatment, syringes and packaging as well as unused rescue medication at each in-clinic visit 
and the end of the study or at the time of discontinuation of study treatment. Site staff will 
record in the appropriate documents the dates of the administration. Detailed instructions will 
be provided separately.
At the conclusion of the study, and as appropriate during the course of the study, the study site 
personnel will return all used and unused investigational treatment, syringes, unused rescue 
medication, packaging, drug labels, and a copy of all the completed drug accountability logs to 
the Novartis monitor or to the Novartis address provided in the investigator folder at each site.
Subjects transitioning from CQGE031C2202 and CQGE031C1301
Investigational treatment (liquid in vial or PFS) must be received by a designated person at the 
study site, handled and stored safely and properly and kept in a secured location to which only 
the investigator and designated site personnel have access. Upon receipt, all study treatment 
must be stored according to the instructions specified on the labels and in the Investigator’s 
Brochure. Clinical supplies are to be dispensed only in accordance with the protocol. Technical 
complaints are to be reported to the respective Novartis Country Organization Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The study site personnel must maintain an accurate record of the shipment, dispensing and 
collection/destruction of study treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by monitors during site visits or remotely and at the 
completion of the trial.
Subjects who do outside of clinic investigational drug administration will record the date(s) of 
administration on a diary/form and will be asked to return all used and unused investigational 

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treatment syringes and packaging as well as unused rescue medication at each in-clinic visit and 
the end of the study or at the time of discontinuation of study treatment. Site staff will record in 
the appropriate documents the dates of the administration. Detailed instructions will be provided 
separately.
At the conclusion of the study, and as appropriate during the course of the study, the study site 
personnel will return all used and unused investigational treatment syringes, unused rescue 
medication, packaging, drug labels, and a copy of the completed drug accountability log to the 
Novartis monitor or to the Novartis address provided in the investigator folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
For all subjects transitioning from the core studies receiving treatment administration in the 
clinic setting, study treatment will be administered as follows to ensure blinding in the core 
studies:

Blinded personnel involved in the core studies cannot at the same time act as unblinded 
personnel in the extension study.

Unblinded pharmacist or designee of the core studies can prepare and administer both 
blinded (i.e. liquid in vial injection) and open label (i.e. PFS) investigational treatment in 
the extension study.

Blinded personnel involved in the core studies can prepare and administer open label 
ligelizumab prefilled syringes from Week 12 onwards.
Since all subjects transitioning from CQGE031C1301 or CQGE031C2202 receive open label 
ligelizumab 120 mg (liquid in vial injection and PFS) there is no blinding restrictions and any 
site staff including blinded site staff can prepare and administer investigational treatment for 
these subjects throughout this study.
The liquid in vial injection at Visits 201, 202, 203 (Weeks 0, 4 and 8) and the PFS injection 
from Visit 204 (Week 12) onwards will be administered in the deltoid region on the right or left 
arm, or in the right or left thigh, or the abdomen as preferred by subject and/or site. The 
injections are administered subcutaneously after aspiration of the plunger of the syringe. If 
blood appears at the needle hub or blood is drawn into the syringe upon aspiration, the needle 
must be withdrawn without administration of the dose and the injection site changed.
Please refer to the Pharmacist Manual and IFU for drug preparation and administration.
Please refer to Section 6.4 for treatment blinding.
All subjects will be monitored in accordance with the recommendations for omalizumab, the 
currently available anti-IgE therapy, from 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 Omalizumab Joint Task Force (Cox 
et al 2011).

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All subjects receiving treatment at the sites, in all treatment arms, must remain at the site and 
monitored for 2 hours for the first three treatment administration visits, when starting or re-
starting treatment and for 30 minutes for the remaining treatment visits.
Therefore, whether they are in the clinic-administered or self-administered group:

subjects starting treatment at Visit 201 (Week 0) and subsequent visits 202 and 203 
(Weeks 4 and 8) will be monitored at the site for 2 hours after administration, and for 30 
minutes for all remaining visits as long as their treatment is not interrupted during the full 
104 week treatment period; and

subjects who are entering the second half of the treatment period (Visit 214, Week 52) 
from the second observation period will be monitored at the site for 2 hours after 
administration for the first three Visits 214, 401 and 402 (Weeks 52, 56 and 60).

All subjects receiving treatment in clinic will remain in clinic for a 30 min 
observation period for all remaining treatment visits.

All subjects self-administering ligelizumab in their out-of-clinic setting should remain 
in a quiet environment for 30 minutes after administration for self-observation for all 
remaining treatments.
Self-administration outside of clinic
PFS injections should only be administered by adults or adult caregivers.
Subject will be given the option to start self-administration at Visit 204 (Week 12) or Visit 403 
(Week 64). During these visits subjects who are willing to self-administer, should be evaluated 
according to the below criteria. If the criteria are satisfied, then the IFU will be provided and 
the subjects or caregiver who will perform the administration will undergo training.
The clinical criteria for self-administering ligelizumab is below:

The subject should not have experienced any severe/serious hypersensitivity reactions
(including during the preceding studies)

The subject should know how to recognize symptoms/signs of severe hypersensitivity 
reactions

The subject should be capable and willing to self-administer ligelizumab
For the first and second use of PFS at Visit 204 (Week 12) / Visit 403 (Week 64) and Visit 205 
(Week 16) / Visit 404 (Week 68) respectively, the self-injection will take place as a site staff 
assisted injection i.e. with the help of the site staff performing the injection steps. At the third 
use of PFS at Visit 206 (Week 20) / Visit 405 (Week 72), the self-injection will take place under 
supervision however without the help of the site staff, i.e. the site staff only observes and does 
not help in performing the injection steps. The training for each injection, be it assisted or under 
supervision, will be provided individually by the site staff to the subject.
Subjects who self-administered in the first half of treatment period and continuing straight into 
the second half of treatment (i.e. without transitioning into the second observation period) will 
continue to self-administer in the second half of treatment. These subjects do not have to be re-
evaluated or re-trained at Week 64.
Visit 204 (Week 12) or Visit 403 (Week 64) – assisted

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
The site staff will show the subject how to use the PFS based on the instructions provided 
in the IFU, with emphasis on specific checks for device use evaluation.

The subject will be given the opportunity to raise questions if any

The subject will perform the injection into an appropriate injection site of the body with 
the site staff actively assisting them during the injection. If the site staff observes that the 
subject is performing an action that may jeopardize the subject’s safety, site staff will 
intervene to prevent any potential harm and guide/correct the subject.
Visit 205 (Week 16) or Visit 404 (Week 68) - assisted

Study staff should ask the subject whether they wish to be retrained prior to injection. If 
needed, site staff will retrain the subject.

The subject will perform the injection into the appropriate injection site of the body with 
the site staff actively assisting them during the injection.
Visit 206 (Week 20) or Visit 405 (Week 72) - supervised

The subject will perform the injection into the appropriate injection site of the body 
mimicking an outside of clinic administration i.e. without the active assistance of the site 
staff but under their supervision.

If the site staff observes that the subject is performing an action that may jeopardize the 
subject’s safety, site staff will intervene to prevent any potential harm and guide/correct 
the subject.

The site staff will observe that the dose is administered in accordance to the steps 
indicated in the self-injection assessment list and the potential hazard assessment list as 
described in the pharmacist manual. The site staff will observe the subject actions as per 
the lists to evaluate if the subject is capable of self-administration outside of clinic.
Thereafter, outside of clinic administrations should be done at pre-defined time points as per 
assessment schedule (Table 8-1). If self-administration is not chosen, these administrations can 
be performed by a trained caregiver who will then be trained as outlined above.
Subjects carrying out self-administration outside the clinic setting will:

have in-clinic safety and efficacy assessments done at 12 to 16 week intervals and will be 
provided with three/four kits for self-administration outside of the clinic; and

be assessed remotely (i.e. outside of clinic) by safety phone call from the site every 4 
weeks, unless there is an in-clinic visit scheduled (at 12 to 16 week intervals per protocol).
During outside of clinic administrations, subjects are expected to contact the investigator/site 
staff in case they are experiencing any AE/SAEs or have any concerns.
At any time during the study, should a self-administering subject, caregiver or investigator 
decide not to continue with self-administration, the subject must contact the site, or the site staff 
must contact the subject, to arrange for all subsequent visits and treatments to be administered 
at the site.
All study drug dosages prescribed and dispensed to the subject and all dosing errors or missed 
administrations during the study must be recorded on the appropriate eCRF.
All kits of study treatment assigned by the IRT will be recorded in the IRT system. The 
investigator must promote compliance by instructing the subject to take the study treatment 

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Table 8-1
Assessment Schedule (Screening, First and Second half of the treatment period and Follow-up period)
Epoch Screening <----------------------------First half of the Treatment---------------------------->
<----------------------------Second half of the Treatment--------------------------->
Visit Numbers1
12
23
201 202 203 204 205 206 207 208 209 210 211 212 213 2144,5 401 402 403 404 405 406 407 408 409 410 411 412 9998
Days -28 to 
-7
-14 
to 
-1
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421 449 477 505 533 561 589 617 645 673 701 729/ 
EOT
Weeks
-4 to 
-1
-2 
to 
-1
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
104
Informed Consent
X6
Inclusion / Exclusion criteria
X
X
X
Demography
X
Relevant medical history 
(including CSU history)8
X
Prior urticaria treatment
X
Prior urticaria non-drug therapy
X
Family malignancy history9
X
Prior and Concomitant 
medication usage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Surgery and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescreening (rescreening eCRF 
should be recorded if the subject 
is rescreened)
X
Rescue medication usage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense H1-AH rescue 
medication10
S
S
S
S
S
S
S
S
S
S11
S11
S
S11
S11
S
S
S11
S11
S
S11
S11
S
S11
S11
S
S11
S11
S11
S
Dispense oral corticosteroid 
rescue medication12
S
S
S
S
S11
S11
S
S11
S11
S
S
S11
S11
S
S11
S11
S
S11
S11
S
S11
S11
S11
S
Dispense Subjects' eDiary
S
Collect Subjects' eDiary
Visit at the site
X
X
X14
X14
X14
X
X
X
X15
X13
X13
X
X13
X13
X
X14
X14
X14
X
X13
X13
X
X13
X13
X
X13
X13
X13
X

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Epoch Screening <----------------------------First half of the Treatment---------------------------->
<----------------------------Second half of the Treatment--------------------------->
Visit Numbers1
12
23
201 202 203 204 205 206 207 208 209 210 211 212 213 2144,5 401 402 403 404 405 406 407 408 409 410 411 412 9998
Days -28 to 
-7
-14 
to 
-1
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421 449 477 505 533 561 589 617 645 673 701 729/ 
EOT
Weeks
-4 to 
-1
-2 
to 
-1
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
104
Safety phone call15
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X16
X
X
X16
X
X
X
X16
X
X
X16
X
X
X16
X
X
X16
X
X
X
X
Liquid in vial investigational 
study drug administration
X
X
X
PFS investigational study drug 
administration
X
X
X
X
X
X
X
X
X
X
X17
X
X
X
X
X
X
X
X
X
X
X
X
Self-administration training
X
X
X
X27
X27
X27
PFS outside of clinic
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subjects' eDiary (review
compliance) includes the 
urticaria subject daily diary 
(UPDD) and AAS (Angioedema 
activity score)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DLQI (Dermatology Life Quality 
Index/CDLQI (Children's DLQI)
X
X28
X28
X28
X28
X28
X28
X
X28
X28
X28
X28
Stool ova and parasite 
evaluation: if diarrhea, or any 
other symptoms suggestive of 
parasitic infection, develops at 
any time between visits before 
end of study, additional stool 
sampling for assessment of 
parasitic conditions should be 
done asap
X18,19
X3
Hematology (INR only at Visit 
201 and unscheduled Visit)
X20
X
X
X29
X29
X29
X29
X29
X29
X29
X29
X29
X29
X29

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Epoch Screening <----------------------------First half of the Treatment---------------------------->
<----------------------------Second half of the Treatment--------------------------->
Visit Numbers1
12
23
201 202 203 204 205 206 207 208 209 210 211 212 213 2144,5 401 402 403 404 405 406 407 408 409 410 411 412 9998
Days -28 to 
-7
-14 
to 
-1
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421 449 477 505 533 561 589 617 645 673 701 729/ 
EOT
Weeks
-4 to 
-1
-2 
to 
-1
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
104
Clinical chemistry (FSH to be 
done only if indicated in Section 
8.4.3)
X20
X
X
X29
X29
X29
X29
X29
X29
X29
X29
X29
X29
X29
Serum β-hCG
X22
IgE-autoantibodies (Marker of 
hypersensitivity)
X
Chronic urticaria (CU) index 
panel (CU index, thyroid 
peroxidase IgG, thyroglobulin 
IgG)
X
Total tryptase
X
Urine dipstick (local) (When a 
dipstick evaluation is abnormal, 
e.g. positive for WBC and/or 
blood, a urine sample must be 
sent for microscopic examination 
to the central lab)
X20
X
X
X
X
X
X
X

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Epoch Screening <----------------------------First half of the Treatment---------------------------->
<----------------------------Second half of the Treatment--------------------------->
Visit Numbers1
12
23
201 202 203 204 205 206 207 208 209 210 211 212 213 2144,5 401 402 403 404 405 406 407 408 409 410 411 412 9998
Days -28 to 
-7
-14 
to 
-1
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421 449 477 505 533 561 589 617 645 673 701 729/ 
EOT
Weeks
-4 to 
-1
-2 
to 
-1
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
92
96
100
104
Urine Pregnancy Test (local) (If 
positive, confirmation by serum 
β-hCG test should be done by 
central lab)
S18
S
S
S
S
S
S
S
S
S24
S24
S
S24
S24
S
S
S24
S24
S
S24
S24
S
S24
S24
S
S24
S24
S24
S
Physical Examination (Physical 
exam on Screening Visit 1 and 2
is comprehensive but 
subsequent physical exams 
maybe limited)
S18
S
S
S
S
S
S
S
S
S
S
S
S
S
Vital signs
X18
X
X
X
X
X
X
X
X
X
X
X
X
Height and Weight (for adult 
subjects after screening, only 
body weight will be measured )
X25
X
X
X
Electrocardiogram (ECG)
X30
X30
X30
Adverse Events
As required
Liver safety monitoring
S18
S
S
S
S
S
S
S
S
S
S
S
S
S
Renal safety monitoring
S18
S
S
S
S
S
S
S
S
S
S
S
S
S
Treatment 
completion/discontinuation form
X
Study 
completion/discontinuation form
X

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Epoch
Follow-Up26
Visit Numbers1
501
502
503
9999
Days
813
897
981
1093/ EOS
UPV
Weeks
116
128
140
156
-
Informed Consent
Inclusion / Exclusion criteria
Demography
Relevant medical history (including CSU history)8
Prior urticaria treatment
Prior urticaria non-drug therapy
Family malignancy history9
Prior and Concomitant medication usage
X
X
X
X
X
Surgery and procedures
X
X
X
X
X
Rescreening (rescreening eCRF should be recorded if the subject is rescreened)
Rescue medication usage
X
X
X
X
Dispense H1-AH rescue medication10
S
S
S
Dispense oral corticosteroid rescue medication12
S
S
S
Dispense Subjects' eDiary
Collect Subjects' eDiary
S
Visit at the site
X
X
X
X
X
Safety phone call
PFS outside of clinic administration
Contact IRT
Liquid in vial investigational study drug administration
PFS investigational study drug administration
Subjects' eDiary (review compliance) includes the urticaria subject daily diary (UPDD) 
and AAS (Angioedema activity score)
X
X
X
X
DLQI (Dermatology Life Quality Index/CDLQI (Children's DLQI)
X28
X28
X28
X28

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Epoch
Follow-Up26
Visit Numbers1
501
502
503
9999
Days
813
897
981
1093/ EOS
UPV
Weeks
116
128
140
156
-
Stool ova and parasite evaluation: if diarrhea, or any other symptoms suggestive of 
parasitic infection, develops at any time between visits before end of study, additional 
stool sampling for assessment of parasitic conditions should be done asap
X
X
Hematology 
X29
X29
X29
X29
X21,29
Clinical chemistry 
X29
X29
X29
X29
X29
IgE-autoant bodies (Marker of hypersensitivity)
X
Chronic urticaria (CU) index panel (CU index, thyroid peroxidase IgG, thyroglobulin IgG)
X
Total tryptase
X
Urine dipstick (local) (When a dipstick evaluation is abnormal, e.g. positive for WBC 
and/or blood, a urine sample must be sent for microscopic examination to the central 
lab)
X
X
Urine Pregnancy Test (local) (If positive, confirmation by serum β-hCG test should be 
done by central lab)
S
S
S
S
S
Physical Examination (Physical exam on Screening Visit 1 and 2 is comprehensive but 
subsequent physical exams maybe limited)
S
S
S
S
S
Vital signs
X
X
X
X
X
Height and Weight (for adult subjects, only body weight will be measured)
X
Electrocardiogram (ECG)
X30
Adverse Events
As required
X
Liver safety monitoring
S
S
S
S
S
Renal safety monitoring
S
S
S
S
S
Treatment completion/discontinuation form
Study completion/ discontinuation form
X

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Subjects who become eligible to enroll into the extension study at Visit 1999 of the preceding studies must complete all lab assessments done as a part 
of end of preceding study visit (Visit 1999) and all lab and other required assessments as per this extension study protocol. Refer to the latest version of 
the preceding protocols regarding assessments related to Visit 1999.
3 Only for subjects in the observation period who have not had these assessment completed in the past 30 days. Stool samples should be collected at 
Visit 2 unless the subject has not had any symptoms indicative of parasitic infection including diarrhea since Visit 1 and the subject has not travelled to 
an area of higher risk of parasitic infection since Visit 1.
4 (1) Continuation of treatment for (i) subjects who have UAS7 >6 and <16, or (ii) subjects who have UAS7 ≥16 when the investigator has reassessed 
the risk-benefit with the subject and decided to continue the subject's treatment. (2) Restarting of treatment for subjects relapsing in the second 
observation period.
5 The first task at Week 52 in the treatment period must be to check the UAS7 score: If the subject enters the second observation period, then the 
assessment must be done for Visit 301 (Week 0) and recorded on eCRF for Visit 301. If the subject continues in the second half of the treatment period,
then the assessment must be done for Visit 214 (Week 52) and recorded for eCRF Visit 214 (Week 52).
6 Informed consent can also be obtained prior to or at Visit 1999 of the preceding studies.
8 Relevant ongoing medical conditions that were already present at the time of informed consent should be recorded in medical history eCRF. Medical 
history that are ongoing from the preceding studies will be transcribed.
9 Completed Family malignancy history CRFs from the preceding studies should be transcribed to the extension Family malignancy history CRF. Family 
malignancy history CRF in this extension study should be completed if the subject develops malignancy during this study.
10 For subjects self-administering investigational drug, the dispensing of H1-AH rescue medication will take place as needed at each scheduled in-clinic 
visit.
11 For subjects who do not perform self-administration of investigational drug, H1-AH and oral corticosteroid rescue medication may be dispensed as 
needed at each visit.
12 For subjects self-administering investigational drug, the dispensing of oral corticosteroids will take place as needed at each scheduled in-clinic visit.
13 For subjects who do NOT perform self-administration of investigational drug, these visits will be used for drug administration and local urine pregnancy 
test only.
14 All subjects will remain in-clinic for 2 hours observation after ligelizumab administration at Visits 201, 202, 203 (Weeks 0, 4 and 8). Subjects 
transitioning from the second observation period to re-start treatment at Visits 214, 401 and 402 (Weeks 52, 56 and 60) will remain in-clinic for 2 hours 
observation after ligelizumab administration.
15 Detailed arrangements for safety phone calls on a regular basis per protocol must be planned at Visit 207 (Week 24) for all subjects self-administering 
investigational drug and safety phone call will replace visits at site for these subjects.
16 IRT to dispense kits to take with them for subjects who do self-administration.
17 (a) Continuation of treatment and (b) Restarting of treatment for subjects relapsing in the second observation period

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
18 Transcribe results from Visit 1999 of the preceding studies to screening eCRF if Visit 1999 date and Screening Visit 1 date are less than or equal to 30 
days apart. If Visit 1999 date and Screening Visit 1 date are more than 30 days apart assessment has to be repeated.
19 In the event that the 3 stool samples from Visit 1999 of the preceding studies were not collected, or the results from these are not available, or Visit 
1999 date and Screening Visit 1 date are more than 30 days apart, subjects must be assessed at Visit 1 (see Section 8.4.4).
20 Hematology and chemistry results will be transcribed automatically by central lab from Visit 1999 to Visit 1. Urine dipstick results need to be 
transcribed to the respective eCRF.
21 INR (International Normalized Ratio) at Visit 201 and unscheduled Visit only
22 hCG for all female subjects of child-bearing potential at Visit 1 only
24 Urine pregnancy tests will be provided to all self-administration subjects who are women of child-bearing age, for home use. In the event that the home 
test is positive, the subject must call site and arrange for an immediate visit to perform a serum pregnancy test.
25 Transcribe weight for adults and adolescents from Visit 1999 of the preceding studies to screening eCRF; If Visit 1999 date and Screening Visit 1 date 
are more than 30 days apart assessment has to be repeated. Transcribe height for adolescents from Visit 1999 of the core phase 3 studies and 
CQGE031C2202 to screening eCRF; If Visit 1999 date and Screening Visit 1 date are more than 30 days apart assessment has to be repeated.  
Measure height for adult subjects and record on screening eCRF.
26 (a) Subjects who complete all visits on investigational drug during the 104 weeks treatment period without interruption will complete a 52 weeks post-
treatment follow-up period. (b) all other subjects will complete a 12 week post-treatment follow-up period. For all subjects last visit is EOS/9999.
27 Subjects who do self-administration in the first half of the treatment period and continue uninterrupted in the second half of the treatment period with 
self-administration are not required to re-do the training.
28 Remote PROs collection is possible in case the patient cannot attend the visit at site due to a Public Health emergency
29 Samples can be collected & analyzed in a certified local laboratory (if feasible) due to a Public Health emergency
30 For any ECG with subject safety concern, 2 additional ECGs must be performed to confirm the finding.
31 For subjects who only performed self-administration in the second half of the treatment period

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Table 8-2
Assessment Schedule (First and Second Observation period)
Epoch
First Observation
Second Observation
Visit Numbers1 101 102 103 104 105 106
107 108 109
199
301 302 303 304 305 306 307 308 309 310 311 312 313
399
Days
1
29
57
85
113 141
169 197 225
253/
EOOBS1
1
29
57
85
113 141 169 197 225 253 281 309 337
365/ 
EOOBS2 UPV
Weeks
0
4
8
12
16
20
24
28
32
36
0
4
8
12
16
20
24
28
32
36
40
44
48
52
-
Visit at the site
X3
X
X
X
X
X
X
X
X
Safety phone call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and Concomitant medication usage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Surgery and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication usage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense H1-AH rescue medication
S
S
S
S
S
S
S
Collect Subjects' eDiary
X2
X2
Subjects' eDiary (review compliance) includes 
the urticaria subject daily diary (UPDD) and AAS 
(Angioedema activity score)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DLQI (Dermatology Life Quality Index/CDLQI 
(Children's DLQI)
X
X4
X4
X4
X4
X4
X4
X4
X4
Stool ova and parasite evaluation: if diarrhea, or 
any other symptoms suggestive of parasitic 
infection, develops at any time between visits 
before end of study, additional stool sampling for 
assessment of parasitic conditions should be 
done asap
X
X
Hematology
X5
X5
X5
X5
X5
X5
X5
X5
X5
Clinical chemistry
X5
X5
X5
X5
X5
X5
X5
X5
X5

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
Epoch
First Observation
Second Observation
Visit Numbers1 101 102 103 104 105 106
107 108 109
199
301 302 303 304 305 306 307 308 309 310 311 312 313
399
Days
1
29
57
85
113 141
169 197 225
253/
EOOBS1
1
29
57
85
113 141 169 197 225 253 281 309 337
365/ 
EOOBS2 UPV
Weeks
0
4
8
12
16
20
24
28
32
36
0
4
8
12
16
20
24
28
32
36
40
44
48
52
-
Urine Pregnancy Test (local) (If positive, 
confirmation by serum β-hCG test should be 
done by central lab)
S
S
S
S
S
S
S
S
S
S
Urine dipstick (local) (When a dipstick evaluation 
is abnormal, e.g. positive for WBC and/or blood, 
a urine sample must be sent for microscopic 
examination to the central lab)
X
X
X
X
X
X
X
X
X
Physical Examination (Physical exam on 
Screening Visit 1 and 2 is comprehensive but 
subsequent physical exams maybe limited)
S
S
S
S
S
S
S
S
S
Liver safety monitoring
S
S
S
S
S
S
S
S
S
S
Renal safety monitoring
S
S
S
S
S
S
S
S
S
S
Electrocardiogram (ECG)
X
Vital signs
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study completion/discontinuation form
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Applies to subjects who are not eligible to start treatment
3 Detailed arrangements for safety phone calls on a regular basis per protocol must be planned at Visit 101 (Week 0) of the first observation 
period.
4 Remote PROs collection is possible in case the patient cannot attend the visit at site due to a Public Health emergency
5 Samples can be collected & analyzed in a certified local laboratory (if feasible) due to a Public Health emergency

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
8.1
Screening
Subjects will have up to 4 week screening period to establish eligibility for the study. Subjects 
will be required to attend one visit during screening period, Visit 1 (Day -28 to Day -7) which 
is equivalent to Visit 1999 of the preceding studies or in as short time-frame as possible after 
the Visit 1999 of the preceding studies. An extended screening period will be permitted only in 
exceptional circumstances when information concerning eligibility is outstanding (e.g., pending 
laboratory data).

All lab assessments performed at Visit 1999 (if not more than 30 days prior to the extension 
screening Visit 1) and all additional other required assessments as per extension study 
protocol (e.g. serum pregnancy tests) will be used to determine eligibility to enroll into this 
extension study. If the gap between the Visit 1999 of preceding studies and extension 
screening Visit 1 is greater than 30 days, then all lab and other required assessments will 
need to be re-done at extension screening Visit 1.

Subjects' relevant medical conditions and concomitant medications will be reviewed at 
Visit 1 (Visit 1999 of the preceding studies, if the subject is transitioning immediately to
the extension study).

The subjects will continue to complete all eDiary assessments (for the UAS7 score 
calculation), between Visit 1 (Visit 1999 of the preceding studies, if the subject is 
transitioning immediately) and start of treatment.

Start of treatment should occur approximately 7 to 28 days after Visit 1 assessments
(Visit 1999 of the preceding studies if subject is transitioning immediately).
Once all screening assessments are done:

If the subject has moderate to severe disease (defined as UAS7 ≥ 16), the subject will 
enter the treatment period immediately at Visit 201 (Week 0).

If the subject has a UAS7 of < 16, the subject will transition to the first observation period. 
Once UAS7 ≥ 16 has been met in the first observation period the subject will have to 
complete screening Visit 2 (Day -14 to -1) if the required assessments at that visit had not 
been completed in the past 30 days (e.g. during a regular visit as per assessment schedule 
Table 8-2).
Rescreening may be allowed for subjects who fail initial screening (see Section 5.1 and 
Section 5.2 on when rescreening is allowed). Only 1 rescreening will be allowed. If a subject is 
rescreened for the study, the subject must sign a new informed consent and will be issued a new 
subject number. Informed consent for a rescreened subject must be obtained prior to performing 
any study-related assessments or collecting any data for the screening visit.
Subjects who did not meet applicable eligibility criteria at Visit 2, will be discontinued from 
the study and will not enter treatment. These subjects are not considered screen failure subjects.
For subjects who did not meet applicable eligibility criteria at Visit 2 due to a transient and non-
clinically significant lab abnormality one re-test (AST, ALT, albumin, TBL, creatinine, 
platelets) can be performed.

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Amended Protocol Version 01 (clean)
Protocol No. CQGE031C2302E1
8.1.1
Information to be collected on screening failures
Subjects who sign an ICF and subsequently found to be ineligible prior to start of treatment will 
be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate eCRF. The demographic information, informed consent and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a SAE
during the screening phase (see Section 10.1.3 for reporting details). AEs that are not SAEs will 
be followed by the investigator and collected only in the source data. If the subject fails to enter 
the treatment period, the IRT must be notified within 2 days of the screen failure i.e. that the 
subject did not enter treatment.
Subjects who enter the treatment period and fail to start treatment, e.g., subject entered treatment 
period in error, subject was transitioned from observation period to treatment period in error,
the local Country Organization is to be contacted whether subject should continue to remain in 
the study. In case of early termination, the reason should be recorded on the appropriate eCRF.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects include age, 
sex, race and ethnicity. Participant race and ethnicity, as required by some Health Authorities, 
are collected to assess the diversity of the study population and to evaluate their impact on the 
safety and efficacy parameters in the study. Relevant medical history (including CSU 
history)/current medical condition present before signing the informed consent will be captured. 
Where possible, diagnoses, and not symptoms, will be recorded. Data on subjects’ family 
history of malignancies will be collected on the respective eCRF page, only when a subject has 
a malignancy event, to assess possible risk factors related to any malignancies.
8.3
Efficacy
All subjects will be provided with an electronic device (eDiary) that contains the following 
assessments: Urticaria Patient Daily Diary (UPDD), Angioedema Activity Score (AAS), 
Dermatology Life Quality Index (DLQI) for adults and Children Dermatology Life Quality 
Index (CDLQI) for adolescents
Site and subjects will receive appropriate training and guidance on the use of the eDiary and 
will receive clear instructions on the completion of the assessments.
Assessments will be completed once or twice daily or monthly depending on the questions.
Site must allow subjects to complete the eDiary questionnaires on their own without any 
assistance from the site staff.
The eDiary assessment must be completed prior to any other assessment and prior to 
administration of any investigational medication.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, patient reported outcome assessments (DLQI/CDLQI,
 may be collected remotely 
as per Assessment Schedule Table 8-1 and Table 8-2.

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8.3.1
eDiary assessments
8.3.1.1
Urticaria Patient Daily Diary (UPDD)
Urticaria Patient Daily Diary (UPDD) includes UAS which assesses twice daily the severity of 
itch and number of hives, and once-daily the use of rescue medication, sleep and activity 
interference, angioedema occurrence and its management and records the calls to a health care 
practitioner (Appendix 4, Patient Diary - Urticaria Patient Daily Diary (UPDD)) Urticaria 
Patient Daily Diary (UPDD)). The components are presented in the Table 8-3 and the relevant 
weekly scores are described below.
Table 8-3
Urticaria Patient Daily Diary (UPDD)
Diary component
When assessed
Urticaria Activity Score (UAS)

Itch severity

Number of hives
Morning & evening
Sleep interference
Morning
Daily activity interference
Evening
Rescue medication use
Evening
Angioedema

Whether patient had an episode

If patient had an episode, how did they 
manage it
Evening
Contact health care provider
Evening
8.3.1.1.1 Weekly Hives Severity Score (HSS7)
The HSS, defined by number of hives (wheals), will be recorded by the subject twice daily in 
their eDiary, on a scale of 0 (none) to 3 (see Table 8-4). A weekly score (HSS7) is derived by 
adding up the average daily scores of the 7 preceding days. The possible range of the weekly 
score is therefore 0 – 21.
Complete hives response is defined as HSS7 = 0.
Table 8-4
Hives Severity Score (HSS)
Score
Hives (Wheals) (every 12 hours)
0
None
1
1-6 hives/12 hours
2
7-12/12 hours
3
> 12 hives/12 hours
When either the morning or evening score is missing, the non-missing score for that day 
(morning or evening) will be used as the daily score. When 1 or more of the daily scores are 
missing, the following principles will be applied to handle the missing data:
The HSS7 score will be derived based on the sum of the available eDiary score during that week. 
It will be considered calculable with at least 4 daily scores provided in that week, otherwise, 
the weekly score will be left missing.

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8.3.1.1.2 Weekly Itch Severity Score (ISS7)
The severity of the itch will be recorded by the subject twice daily in their eDiary, on a scale of 
0 (none) to 3 (intense/severe) (see Table 8-5). A weekly score (ISS7) is derived by adding up 
the average daily scores of the 7 preceding days. The possible range of the weekly score is 
therefore 0-21 (maximum itch). Partially missing diary entries will be handled in the same way 
as described for the HSS7.
Complete itch response is defined as ISS7 = 0.
Table 8-5
Itch Severity Score (ISS)
Score
Pruritus (Itch) (every 12 hours)
0
None
1
Mild (minimal awareness, easily tolerated)
2
Moderate (definite awareness, bothersome but 
tolerable)
3
Severe (difficult to tolerate)
8.3.1.1.3 Weekly Urticaria Activity Score (UAS7)
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly 
UAS7 score is 0 – 42 (highest activity).
8.3.1.1.4 Weekly Sleep interference score
Sleep interference will be assessed by the subject, once daily in the morning in the eDiary. It is 
scored on a scale from 0 to 3 (see Table 8-6). The weekly sleep interference score ranges from 
0 to 21 (Table 8-6).
Table 8-6
Sleep interference score
Score
Sleep interference
0
No interference
1
Mild, little interference with sleep
2
Moderate, awoke occasionally, some 
interference with sleep
3
Substantial, woke up often, severe interference 
with sleep
8.3.1.1.5 Weekly Activity interference score
Activity interference will be assessed by the subjects on a scale of 0 to 3 (Table 8-7), once daily 
in the evening in the eDiary. Daily activities could include, school, sports, hobbies and activities 
with friends and family. The weekly activity interference score ranges from 0-21 (Table 8-7).
Table 8-7
Activity interference score
Score
Activity interference
0
No interference
1
Mild, little interference with daily activities
2
Moderate, some interference with daily activities

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Score
Activity interference
3
Substantial, severe interference with daily 
activities
8.3.1.1.6 H1-AH rescue medication use
The number of tablets of rescue medication used over the past 24 hours to control conditions 
such as itch or hives is recorded once daily in the eDiary by the subject. The dose per day of 
rescue medication will be calculated as the daily number of tablets times the dose of each tablet 
and then the dose per week of rescue medication will be calculated as the sum of the dose per 
day, over 7 days.
8.3.1.1.7 Angioedema occurrence
Angioedema occurrence is recorded once daily in the evening in the eDiary by the subject. 
Angioedema will be reported as number of days with angioedema. Actions and/or treatments 
related to those angioedema occurrences will be also recorded in the eDiary (Table 8-8).
Table 8-8
Actions/treatments for Angioedema
Actions/treatments
Did nothing
Took some prescription or non-prescription medication
Called my doctor, nurse or nurse practitioner
Went to see my doctor, nurse or nurse practitioner
Went to the emergency room at the hospital
Was hospitalized
8.3.1.1.8 Number of calls to doctor or nurse
The number of calls to doctor, nurse or nurse practitioner because of the subject’s skin condition 
will be recorded once daily in the eDiary by the subject.
8.3.1.2
Angioedema Activity Score (AAS)
Angioedema activity score is recorded once daily in the evening in the eDiary by the subject. 
This validated tool assesses occurrence of episodes of angioedema by an opening question. If 
“yes” is the answer to the opening question the subject will continue to answer questions about 
the duration, severity and impact on daily functioning and appearance of the angioedema 
(Appendix 4, Patient Diary - Angioedema Activity Score (AAS)) Angioedema Activity Score 
(AAS)). A score between 0 and 3 is assigned to every answer field. The AAS score in this study 
will be reported as weekly AAS (AAS7). The possible range of the AAS7 score is 0−105. 
Higher score means higher severity. The opening question will be used to count the number of 
angioedema affected days during the AAS documentation period but has no score.

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8.3.2
Other Patient Reported Outcome (PRO) assessments
8.3.2.1
Dermatology Life Quality Index (DLQI)
The DLQI is a 10-item (grouped in 6 domains) dermatology-specific QoL measure (Finlay AY 
and Khan GK 1994). The DLQI was validated for patients aged 16 and above.
In this study, DLQI will be administered only in adult subjects (18 years and older, Appendix 4, 
Dermatology Life Quality Index (DLQI)). These subjects rate their dermatology symptoms as 
well as the impact of their skin condition on various aspects of their lives thinking about the 
previous 7 days.
In this study, subjects of age 17 at the time of consenting are considered in the adolescent group 
and therefore they, along with the subjects aged 12 through 16, will be administered the CDLQI, 
which was designed initially for use in children from age 4 to age 16 (Lewis-Jones and Finlay 
AY 1995, Appendix 4, Children’s Dermatology Life Quality Index (CDLQI)). At Visits 201 
and 214 (Weeks 0 and 52), if an adolescent has turned 18, they will be considered in the adult 
group and administered DLQI.
An overall score is calculated and ranges from 0 to 30 for both instruments (higher score 
meaning worse dermatology QoL). For DLQI, the domain scores are calculated for: Symptoms 
and Feelings (0-6), Daily Activities (0-6), Leisure (0-6), Work and School (0-3), Personal 
Relationships (0-6) and Treatment (0-3). For CDLQI, the domain scores are calculated for: 
Symptoms and Feelings (0-6), Leisure (0-9), School and holidays (0-3), Personal Relationships 
(0-6), Sleep (0-3) and Treatment (0-3).
The scores were split into score bands (Hongbo et al 2005, Waters et al 2010) and validated in 
terms of their meaning/relevance to patients as follows:
Table 8-9
DLQI/CDLQI score bands and impact on patient’s life
DLQI band
CDLQI band
Significance of score
0-1
0-1
No effect on patients life
2-5
2-6
Small effect on patients life
6-10
7-12
Moderate effect on patients life
11-20
13-18
Very large effect on patients life
21-30
19-30
Extremely large effect on patients life
A DLQI/CDLQI score of > 10 is relevant for a very large impact on patients’ life and 
justification for a biologic prescription for example in psoriasis (Finlay AY 2005). The DLQI 
and CDLQI questionnaires are administered according to Table 8-1 and Table 8-2.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the DLQI and CDLQI questionnaires may be collected remotely as per Assessment 
Schedule Table 8-1 and Table 8-2.

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8.3.3
Appropriateness of efficacy assessments
At the time the omalizumab studies were carried out, the treatment paradigm focused primarily
on itch (ISS7) as a key symptom of CSU. Over the past several years the goal of therapy has 
evolved and the current target of therapy as described in the current CSU treatment guidelines 
(Zuberbier et al 2018) is to treat the disease until it is gone, i.e. complete control of the disease 
(UAS7 = 0). Given the current emphasis on UAS7 in the medical community and as reflected 
in the CSU treatment guidelines, data from the Phase 2 study CQGE031C2201 supported the 
change from baseline in UAS7 (which is a composite of ISS7 and HSS7) at Week 12 being 
assessed as the primary endpoint in the ongoing Phase 3 core studies. In this Phase 3 extension 
study, which is reflective of long-term real world management of CSU, the primary endpoint is 
well-controlled urticaria at Week 12 in the first half of the treatment period, assessed as 
percentage of subjects achieving UAS7 ≤ 6. This is consistent with the longer-term realistic 
clinical goal of achieving well-controlled disease (UAS7 ≤ 6), which also includes completely 
controlled disease (UAS7 = 0).
Disease recurrence after investigational drug is withdrawn will be measured during the post-
treatment follow-up periods. Disease worsening, after well-controlled disease (UAS7 ≤ 6) will 
be measured during the second observation period.
For all subjects, symptom scores will be measured during the observation, treatment and post-
treatment follow-up periods.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.1.
Main safety and tolerability assessments include:

AEs and SAEs, including AEs leading to treatment discontinuation and events of interest 
such as injection site reactions, anaphylaxis, pre-malignancy/malignancy, cardio-
cerebrovascular events

Physical examination

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
Vital signs

Laboratory evaluations

ECG (Electrocardiogram)
Table 8-10
Assessments & Specifications
Assessment
Specification
Physical examination
A comprehensive physical examination will include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, and extremities and 
vascular and neurological systems. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams will 
be performed.
A short physical exam will include the examination of general 
appearance and vital signs. A short physical exam will be conducted at 
all visits starting from Visit 1 except where a comprehensive physical 
examination is required (see Table 8-1 / Table 8-2).
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate eCRF that captures medical history. Significant findings 
made after signing the informed consent which meet the definition of an 
AE must be recorded as an AE.
Vital signs
Vital signs include blood pressure and pulse measurements. After the 
subject has been sitting for 5 minutes, with back supported and both feet 
placed on the floor, systolic and diastolic blood pressure will be 
measured 3 times using an automated validated device with an 
appropriately sized cuff. The repeat sitting measurements will be made 
at 1 – 2 minute intervals and the mean of the 3 measurements will be 
used. In case the cuff sizes available are not large enough for the 
subject’s arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used.
Clinically notable vital signs are defined in Appendix 1.
Height and Weight
Height in cm and Body weight (to the nearest 0.1 kg in indoor clothing, 
but without shoes) will be measured.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents required on-site 
study visits, regular phone or virtual calls can occur (every 4 weeks or more frequently if 
needed) for safety monitoring and discussion of the participant´s health status until it is safe for 
the participant to visit the site again.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section unless 
noted otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual.
Clinically notable laboratory findings are defined in Appendix 1.
Clinically significant abnormalities must be recorded on the relevant section of the eCRFs 
capturing medical history/Current medical conditions/AEs.

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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, an alternative lab (local) collection site may be used for protocol specified safety lab 
assessments. It is recommended to use certified local laboratories, if feasible. If a local 
laboratory is used during a Public Health emergency, local laboratory reports need to be 
collected, reviewed, filed in the patient medical record or chart at the site, and entered into the 
CRF.
Table 8-11
Laboratory assessments
Test Category
Test Name
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential and platelet count will be measured.
Chemistry
Albumin, total bilirubin, ALP, AST, ALT, LDH (lactate 
dehydrogenase), GGT, chloride, sodium, potassium, magnesium, 
calcium, inorganic phosphorus, creatinine, urea/BUN (blood urea 
nitrogen) and uric acid will be measured. If the TBL concentration 
is increased above 1.5 times ULN, direct and indirect reacting 
bilirubin should be differentiated.
Urinalysis
A midstream urine sample (approximately 30 mL) will be 
obtained, in order to avoid contamination with epithelial cells and 
sediments, and allow proper assessments. Semi-quantitative 
“dipstick” evaluation for specific gravity, pH, glucose, protein, 
bilirubin, ketones, leukocytes and blood will be performed at site. 
When a dipstick evaluation is abnormal, e.g., positive for WBC 
(white blood cells) and/or blood, a urine sample must be sent to 
the Central Lab for microscopic examination including RBC (red 
blood cells) and WBC. (Details on collection of urine for analysis 
by central laboratory are provided to investigators in the 
laboratory manual.)
Coagulation
At Visit 201 coagulation will be assessed by INR (international 
normalized ratio).
Parasite screening
Local laboratory assessment of stool samples for parasitic 
infections (see Section 8.4.4)
Pregnancy Test
Serum / Urine pregnancy test (see Section 8.4.3)
8.4.2
Electrocardiogram (ECG)
Standard 12 lead ECGs must be recorded after 10 minutes rest in the supine position to ensure 
a stable baseline. The preferred sequence of cardiovascular data collection during study visits 
is ECG collection first, followed by vital signs, and blood sampling. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions.
Single ECGs will be collected at Screening (Visit 1), Visit 214 (Week 52), Visit 9998/EOT 
(Week 104) and unscheduled as required.
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 

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“identical” duplicates must be labeled with study number, subject initials, subject number, date 
and time, and signed and archived in the study site source documents.
For any ECGs with clinically significant findings, two additional ECGs must be performed to 
confirm the abnormal findings.
Clinically significant ECG findings prior to dosing with investigational treatment must be 
discussed with the sponsor. Clinically significant abnormalities must be recorded on the CRF 
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
A serum β-hCG will be collected at Screening Visit 1 for all female subjects of child-bearing 
potential before entering the treatment period.
All pre-menopausal women who are of child-bearing potential will have urine pregnancy testing
during the treatment and observation period. A positive urine test needs to be confirmed with a 
central lab serum test during all study periods. If positive, the subject must be discontinued from 
study treatment.
Additional pregnancy testing might be performed if requested by local regulatory/ ethics 
committee requirements.
Pregnancy tests must be performed prior to investigational drug administration.
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 testing is 
required at screening. If the Follicle Stimulating Hormone level is available from the preceding 
studies, and subject is of confirmed post-menopausal status, a repeat FSH is not needed.
Post-menopausal status should be recorded in the CRF.
8.4.4
Assessment of parasitic infections
Reduction in IgE levels may confer increased susceptibility to parasitic 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.
Subjects should have had three stool samples analyzed from Visit 1999 of the preceding studies, 
except subjects from CQGE031C2202, and these results must be transcribed to the appropriate 

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screening eCRF for this extension study. In the event that three stool samples from Visit 1999 
were not collected, (i.e. all subjects from CQGE031C2202 and subjects from the other 
preceding studies who missed collection of three stool samples), or the results from these are 
not available, these subjects will be given stool sample collection kits at screening Visit 1. Stool 
sample kits will be provided by the site or site’s local laboratory. Subjects will take the stool 
sample kits home. Three stool samples will be collected, as per instructions from the local 
laboratory. Subjects will return the three stool samples to the site or the local lab, according to 
arrangements made by the site, as soon as possible after Visit 1 in order to allow processing 
within the screening period.
Stool samples should be collected at Visit 2 unless, since the time of Visit 1:

the subject has not had any symptoms indicative of a parasitic infection, including 
diarrhea and 

the subject has not travelled to an area of higher risk for parasitic infection
Stool samples for parasitic disease will be examined for ova and parasites by the local laboratory. 
The identification of organisms in positive stools will be made by local laboratory. If stool 
testing is positive for pathogenic organisms (pathogenic as defined by local laboratory), the 
result must be recorded in the source document and the subject will not be enrolled and will not 
be allowed to rescreen. Stool samples negative for pathogenic helminthic infections must be 
recorded in the source document before enrollment.
Subjects must be advised that if diarrhea, or any other symptoms suggestive of parasitic 
infection, develops at any time between visits before end of study, three additional stool 
sampling for assessment of parasitic conditions should be done at the next visit or sooner if 
possible, following the above process. In addition, subjects will also be asked to provide three
stool samples for analysis at the last study visit (Visit 9999/Week 156/EOS) (no later than 7 
days after Visit 9999/EOS in unavoidable circumstances).
Subjects who develop stools positive for pathogenic helminthic infections during the study 
should be discontinued from treatment, have their infection treated according to current local 
practice and transition to the follow-up period for all scheduled assessments.
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 
MedDRA (Medical dictionary for regulatory activities) Queries may represent true cases of 
anaphylaxis. Further details regarding the AC will be documented in the AC charter.
8.4.6
Assessment of cardio-cerebrovascular events
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of cardio-cerebrovascular events. The clinical presentation 
and association of these events with pre-existing risk factors will be part of the assessment.

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8.4.7
Assessment of neoplastic events
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of neoplastic events. The clinical presentation and 
association of these events with pre-existing risk factors will be part of the assessment.
8.4.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population. Events of 
special interest such as anaphylaxis, malignancies, and cardio-cerebrovascular events will be 
monitored and will be adjudicated by independent expert ACs.
8.5
Additional assessments
8.5.1
Resource utilization
Healthcare utilization (contacting a doctor, nurse, or nurse practitioner) will be reported by the 
subject in the daily diary. The action(s) taken by the subject in response to their angioedema 
will be also reported in the daily diary.

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8.5.4
Biomarkers
8.5.4.1
Chronic Urticaria (CU) index panel
The CU index panel consists of the CU Index®, thyroid peroxidase IgG and thyroglobulin IgG 
assays.
The CU Index® is an in vitro basophil histamine release assay in which a subject’s serum is 
mixed with donor basophils and the released histamine levels are measured through a 
quantitative enzyme immunoassay. Biagtan et al found that a positive or elevated CU Index 
value suggested an increased severity of chronic urticaria. In addition, a CU Index value of 
greater than or equal to 10 indicated that the subject had either an autoimmune basis for their 
disease or an alternate histamine-releasing factor (Biagtan et al 2011).
In a number of common autoimmune disorders, the presence of other autoantibodies would be 
considered not usual. Several independent studies have reported that a significant number of 
subjects with CSU (up to 33% in some studies) exhibit high levels of autoantibodies to thyroid 
antigens like thyroid peroxidase IgG and thyroglobulin IgG. Interestingly, subjects with 
significant amounts of thyroid antigens have also significantly higher IgE levels (Chang et al 
2015). Although the pathophysiology behind this association remains unclear, there is some 
consensus among allergists that it likely represents an epiphenomenon (Viswanathan et al 2012).

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8.5.4.2
Total Tryptase
Tryptase is a neutral serine protease and is the most abundant mediator stored in mast cell 
granules. Measuring a subject’s tryptase levels at baseline, and again in the event of a suspected 
anaphylactic reaction is reported to be helpful in assessing whether the event was indeed an 
anaphylactic reaction. It is a specific biomarker of mast-cell activation and plays a part in the 
allergic inflammation and is reported to be elevated in anaphylactic events. Although individual 
baseline levels and levels during / following acute hypersensitivity events may vary greatly, 
serum tryptase levels in blood samples taken 15–180 min after symptom onset can support the 
clinical diagnosis of anaphylaxis in some but not all subjects. However, reliance on elevation 
of only one mediator of inflammation to confirm the clinical diagnosis of anaphylaxis is likely 
to be insufficient (Simons et al 2015). Serial measurement of tryptase levels during an 
anaphylactic episode, and measurement of a baseline level after recovery are reported to be 
more useful than measurement at only one point in time (Simons et al 2011). In this study, total 
tryptase will be measured at Visit 201 (Week 0) and again, whenever possible, at the time of a 
suspect hypersensitivity event.

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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of investigational treatment for a subject occurs when investigational treatment 
is stopped earlier than the protocol planned duration, and can be initiated by either the subject 
or the investigator.
The investigator must discontinue investigational treatment for a given subject if he/she 
believes that continuation would negatively impact the subject's well-being.
Investigational treatment must be discontinued under the following circumstances:

Subject/guardian decision

AEs for which continued exposure to the study drug would be detrimental

Abnormal renal laboratory results requiring discontinuation (see Appendix 3)

Abnormal liver laboratory results requiring discontinuation (see Appendix 2)

Platelets < 75000/μL

Pregnancy (see Section 8.4.3 and Section 10.1.4)

Subject develops stools positive for pathogenic helminthic infections

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
Subject develops a medical condition that requires use of prohibited treatment as per 
Section 6.2.2, or if subject exhibits a behavior of non-compliance regarding prohibited 
medications

Subject receives a live virus vaccination during the study

Subject experiences an unexpected hypersensitivity reaction of grade 5, as defined by the 
World Allergy Organization Grading System (Cox et al 2017), see Appendix 7

Lower or upper respiratory: Respiratory failure with or without loss of consciousness; 
or

Cardiovascular: Hypotension with or without loss of consciousness

Emergency use of epinephrine due to anaphylactic or anaphylactoid reaction

Use of prohibited treatment as per protocol in Section 6.2.2, when subject safety is 
compromised and / or there is potential for significant impact on data integrity. Instances of 
this nature should be discussed as soon as possible with a member of the Global Study 
Team.

If a subject uses rescue corticosteroids for CSU more than 3 doses in a 30 day period or
more than 9 doses after week 12 in first half of the treatment period or more than 9 doses in 
the second half of the treatment period.

Any other protocol deviation that results in a significant risk to the subject’s safety

Any situation in which continued study participation might result in a safety risk to the 
subject
If discontinuation of investigational treatment occurs, the investigator should make a reasonable 
effort to understand the primary reason for the subject’s premature discontinuation of 
investigational treatment and record this information. Always consider reasons which are 
related to safety and efficacy first.
Subjects who discontinue investigational treatment or who decide they do not wish to 
participate in the study further should NOT be considered withdrawn from the study UNLESS 
they withdraw their consent (see Section 9.1.3). They will be expected to perform the Visit 
9998/EOT (Week 104) assessments 4 weeks after their last dose and will be expected to perform 
assessments at follow-up Visit 9999, 12 weeks after Visit 9998/EOT. If they fail to return for 
these assessments for unknown reasons, every effort (e.g., telephone, e-mail, letter) should be 
made to contact the subject/pre-designated contact as specified in Section 9.1.4. This contact 
should preferably be done according to the study visit schedule.
For subjects who wish to prematurely discontinue treatment prior to the primary endpoint for 
any reason, every effort should be made to have them continue study visits as per the assessment 
schedule, at least until Visit 204 (Week 12). At the final visit, all dispensed investigational 
product should be reconciled and the AE and concomitant medications reconciled on the 
appropriate eCRF.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule until a 
decision is made to return to the site for discussion about ongoing treatment, or to discontinue 
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The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
9.1.2
Discontinuation from observation periods
Subjects who wish to discontinue from the first observation period will be expected to complete 
Visit 199 (EOOBS1).
Subjects who wish to discontinue from the second observation period will be expected to 
complete at least Visits 301, 302 and 303 (Week 0, 4 and 8), and perform Visit 399 
(Week 52/EOOBS2) 16 weeks after the last investigational drug administration and exit the 
study.
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples
Withdrawal of consent/opposition to use data/biological samples occurs when a subject:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
subject’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 subject’s decision to withdraw his/her 
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 subject therefore cannot withdraw consent. However, they still retain the right 
to object to the further collection or use of their Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
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.

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9.1.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw 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 subject, e.g. dates of telephone calls, registered letters, etc. A subject 
should not be considered as lost to follow-up until due diligence has been completed. 
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time. Reasons for early termination may include.

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a subject who discontinued from study treatment. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion Visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision.
Should the subject complete this extension study prior to the investigational treatment becoming 
available in the country of the participant and is in the opinion of the investigator still deriving 
clinical benefit from ligelizumab, every effort will be made to continue provision of study 
treatment.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events (AEs)
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying AEs.

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Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
or, for self-administering subjects at each scheduled safety phone call, during the study. 
AEs also may be detected when they are volunteered by the subject during or between visits or 
telephone calls 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 subject;
3. its duration (start and end dates), or if the event is ongoing, an outcome of not recovered/not 
resolved, must be reported;
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met;
5. action taken regarding with study treatment
All AEs must be treated appropriately. Treatment may include 1 or more of the following:

Dose not changed

Dose Reduced/increased

Drug interrupted/permanently discontinued; and
6. its outcome i.e., its recovery status or whether it was fatal.
Relevant conditions that were already present at the time of informed consent should be 
recorded in medical history of the subject.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued for at least 30 days following the last dose of study 
treatment or end of study visit, whichever is longer.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (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 Brochure.

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Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. See Appendix 1 for alert ranges for laboratory and other test 
abnormalities.
For lab values provided without related clinical information, the CTCAE scale must be used to 
determine the seriousness. Any value of Grade 4 and above on this CTCAE scale must be 
considered serious.
10.1.2
Serious adverse events (SAEs)
An SAE is defined as any AE, i.e. appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria:

fatal

life-threatening 

Life-threatening in the context of a SAE refers to a reaction in which the subject was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D 
Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 

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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 SAE irrespective 
of whether a clinical event has occurred or not.
10.1.3
Serious adverse event (SAE) reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the subject’s 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. Any SAEs 
reported up to the subject’s last visit will be reported in the eCRF. SAEs beyond that date will 
only be recorded in the Novartis Safety database.
To comply with regulations, all suspected, unexpected, serious adverse reactions (SUSARs) 
occurring in a clinical trial must be reported in an expedited timeframe (7 or 15 days) to 
competent authorities.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification to inform all investigators involved in any study with the same study treatment that 
this SAE has been reported.
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
Any SAEs experienced after the 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations.

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10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the investigational treatment 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, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not they are associated with an AE/SAE and 
reported to Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE within 24 
hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.

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10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events must be followed.
The following two categories of abnormalities / AEs have to be considered during the course 
of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 16-3 in Appendix 2 for complete definitions of liver laboratory triggers.
Once a subject 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 (ALT, AST, TBL, prothrombin time (PT)/INR, ALP 
and GGT) to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of

Treatment interruption if deemed appropriate

Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

A thorough follow-up of the liver event: Assessments should be based on 
investigator’s discretion and can include serology tests, imaging and pathology 
assessments, gastroenterologist or hepatologist’s consultancy, obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug 
use, exclusion of underlying liver disease, imaging such as abdominal ultrasound, 
computed tomography (CT) or magnetic resonance imaging (MRI) scans and 
obtaining a history of exposure to environmental chemical agents
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.

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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:
Table 10-2
Base Renal Monitoring
Assessments 
Assessment Frequency 
Serum creatinine, Electrolytes (Na, Ca, K)
1. Single baseline
2. Steady State assessment
3. 6-monthly during study
4. Final visit ≥ 48h after last dose
Urine Dipstick (Spot urine sample)
Every renal laboratory trigger or renal event as defined in Table 16-6 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-7.
10.2.3
Data Monitoring Committee (DMC)
This study will include a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The DMC will assess at defined intervals the progress of a clinical trial, safety data, 
and critical efficacy variables and recommend to the sponsor whether to continue, modify, or 
terminate a trial.
The DMC will review clinical trial data from this extension study at least until all subjects 
completed the Week 12 time-point after which all subjects will be receiving open label 
treatment.
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.
10.2.4
Adjudication committee (AC)
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 eCRFs. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR (Code of Federal Regulation) Part 11 requirements, Investigator site staff will not be given 
access to EDC system until they have been trained. Automatic validation programs check for 

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The occurrence of relevant protocol deviations will be determined.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Additionally, a central analytics organization may analyze data 
and  identify risks and trends for site operational parameters, and provide reports to Novartis 
clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the subject’s file. The 
investigator must also keep the original ICF signed by the subject (a signed copy is given to the 
subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Full Analysis Set comprises all enrolled subjects who received at least one dose of study 
treatment. Subjects will be analyzed according to the treatment group they have been assigned 
to.
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received (i.e. actual treatment). 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.

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12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the subjects included in the Full Analysis Set. Information 
from all enrolled subjects; which includes subjects who complete only first observation period 
and do not transition into the first half of the treatment period, will be included in the listing. 
Information on screen-failed subjects will not be included.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions collected from preceding study 
baseline before patients receiving any study drug will be summarized by system organ class and 
preferred term, by treatment group.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The number of subjects and the duration of exposure to investigational 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 investigational drug administration plus 4 weeks (28 days).
In addition, the number of doses, total cumulative dose, and number of missed doses will be 
presented. A partial dose will be considered as if 100% of the dose of the assigned treatment 
has been administered.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. Concomitant medications will be summarized for the 
safety set separated for urticaria related background medications and non-urticaria related 
medications. Similarly, use of rescue medication will also be summarized.
12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The primary endpoint is the proportion of subjects with well-controlled urticaria at Week 12 
(Visit 204) in the first half of the treatment period based on the UAS7 score. Well-controlled 
urticaria at Week 12 is assessed as achieving UAS7 ≤ 6 at Week 12.
The UAS7 is the sum of the HSS7 score and the ISS7 score, and ranges from 0-42. Weekly 
scores (HSS7 and ISS7 scores) will be derived by adding up the average daily scores of the 
7 days preceding the visit.
Regardless of the use of rescue medication or discontinuation of the study assigned-treatment 
due to any reason up to the assessment time point, all available data collected for UAS7 scores 
will be used for primary endpoint calculation.

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12.4.2
Statistical model, hypothesis, and method of analysis
To show retreatment efficacy of ligelizumab 120 mg q4w or 72 mg q4w in achieving well-
controlled CSU at Week 12 in the first half of the treatment period in subjects transitioning from 
the core studies, the summary statistics for the proportion of subjects achieving UAS7 ≤ 6 at 
Week 12 of the first half of the treatment period in this extension study will be provided. The 
primary analysis will be performed for subjects receiving the same dose of ligelizumab they 
received in the core studies, i.e. 72 mg or 120 mg for one year. The corresponding 95% 
confidence interval also will be derived based on the score method including continuity 
correction.
For the subgroup of subjects who achieved UAS7 ≤ 6 at Week 12 in the core studies, and who 
received either 72 mg or 120 mg ligelizumab, the proportion of subjects with the response of 
UAS7 ≤ 6 at Week 12 of the first half of the treatment period in this extension study will be 
provided together with a 95% confidence interval.
Subjects rolling over from study CQGE031C1301, who received ligelizumab 120 mg, will not 
be included in this primary analysis. As this is an open-label Japan safety study, the efficacy 
data for these subjects will be analyzed separately to avoid potential confounding issues.
Subjects rolling over from the adolescent PK/PD study CQGE031C2202 will also not be 
included in this primary analysis, as they received treatment doses of ligelizumab of 24 mg or 
120 mg for different treatment times. The efficacy data for these subjects will be analyzed 
separately.
12.4.3
Handling of missing values/censoring/discontinuations
The UAS7 score is derived from the sum of the HSS7 score and the ISS7 score, as noted above. 
The HSS7 and ISS7 score will be derived by adding up the daily HSS and ISS scores of the 
7 days preceding the visit, respectively. The daily score (HSS and ISS) will be calculated by 
averaging the morning and evening HSS and ISS score, respectively. If one of the morning or 
evening scores is missing, the non-missing score for that day (morning or evening) will then be 
used as the daily score.
A minimum of 4 out of 7 daily scores are needed to reliably calculate a weekly HSS7, ISS7 or 
UAS7 score. For each weekly score from UPDD (i.e. HSS7, ISS7 and UAS7 score), if one or 
more of the daily scores are missing, the following principles will be applied to handle the 
missing data:

If a subject has at least 4 “non-missing” daily scores within the 7 days prior to the study 
visit, the weekly score will be calculated as the sum of the available eDiary scores of that 
week, divided by the number of non-missing days, multiplied by 7.

If there are less than 4 “non-missing” daily scores within the prior 7 days, then the weekly 
score will be considered as missing for that week.
Subjects who discontinue from study treatment early will be encouraged to stay in the study 
following the procedures described in Section 9.1.1. These are considered as retrieved dropout 
(RDO) subjects.
The primary analysis will account for different post-dosing events for missing data handling as 
follows:

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
Discontinuation of initially assigned study treatment prior to Week 12 (Visit 204) due to 
AEs or lack of efficacy  or any other reasons:
Retrieved dropout (RDO) data collected after study treatment discontinuation will be used for 
analysis. If no RDO data was collected after study treatment permanent discontinuation, non-
responder imputation will be applied for missing data imputation.

Use of rescue medication prior to Week 12 of the first half of the treatment period (V204):
Efficacy data collected during intake of rescue medication will not be excluded from the 
analysis.
H1-AH is being used as rescue medication in addition to background medication. Considering 
that, the patient population are refractory to H1-AHs and that ligelizumab efficacy is being 
evaluated on top of H1-AH therapy, all data collected will be used for analysis.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
Not applicable.
Supportive analyses
To provide relevant insight into efficacy of subject with different features, additional supportive 
analyses will be provided for the following subgroups, if applicable:

Adolescent subjects (12 - 17 years) versus adult subjects (≥18 years)
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)

Complete control of urticaria at Week 12 after retreatment of ligelizumab for subjects 
receiving the same dose regimen as in the core studies, assessed as percentage of subjects 
achieving UAS7 = 0.
The proportion of subjects with UAS7 = 0 at Week 12 will be summarized in a 
descriptive manner, it will be provided together with 95% confidence interval. Missing 
data will be considered as non-responder in the analysis.

Absolute change from extension study baseline in UAS7 at Week 12 after retreatment of 
ligelizumab for subjects receiving the same dose regimen as in the core studies.
The absolute change from extension study baseline in UAS7 score at Week 12 will be 
summarized descriptively, it will be provided together with 95% confidence interval.
The change from extension study in UAS7 components (ISS7 and HSS7) will also be 
provided in descriptive manner at Week 12.

No impact on subjects QoL at Week 12 after retreatment of ligelizumab for subjects 
receiving the same dose regimen as in the core studies, assessed as percentage of subjects 
achieving DLQI = 0-1.
An overall score will be calculated according to the scoring manual. The proportion of 
subjects with overall DLQI scores ≤ 1 at Week 12 will be summarized in a descriptive 

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manner, it will be provided together with a 95% confidence interval. Missing data will 
be considered as non-responder in the analysis.

Cumulative number of weeks that subjects achieve AAS7 = 0 between extension study 
baseline and Week 12
The cumulative number of weeks achieving AAS7 = 0 response between baseline and 
Week 12 will be derived based on the AAS eDiary. A weekly AAS7 score will be 
derived by adding up the daily scores of the 7 days preceding the visit, and ranges from 
0 to 105. For a weekly AAS7 score, if one or more of the daily scores are missing, the 
same principles as handling the weekly score from UPDD will be applied to handle 
the missing data. If the AAS7 score is missing, it will be considered as a non-response 
for the cumulative number of weeks that subjects achieve AAS7 = 0 response 
calculation. The cumulative frequency plot will be provided together with the 
summary statistics.

Well-controlled urticaria at 12 weeks after starting self-administration in the first half of the 
treatment period, assessed as percentage of subjects achieving UAS7 ≤ 6 at 12 weeks after 
starting self-administration.
The proportion of subjects with UAS7 ≤ 6, 12 weeks after starting self-administration 
will be summarized in a descriptive manner, and it will be provided together with 95% 
confidence interval. Missing data will be considered as non-responder in the analysis.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All subjects enrolled into the extension study, 
regardless of which preceding studies they came from will be included in the safety analysis. 
All listings and tables will be presented by treatment group. All data will be included in the 
analysis regardless of rescue medication use.
Adverse events (AEs)
Treatment emergent AEs will be summarized by treatment group. Treatment emergent AEs are 
defined as the events started after the first dose of study treatment within 16 weeks of last dose 
of 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 dose of the study treatment.
The number (and percentage) of subjects 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.
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation. The number (and proportion) of subjects with AEs
of special interest/related to identified and potential risks will be summarized by treatment. A 
subject with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class.
AEs which will be counted for a specific treatment period are those which are treatment-
emergent. These events are those with an onset after the start of the treatment period, or which 

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were present prior to the start of the treatment period but increased in severity, and developed 
into SAEs after the start of the treatment period.
For safety and tolerability of ligelizumab for all subjects during the study, a summary table will 
be provided for the two subgroups of subjects below:

Subjects who receive two years continuous ligelizumab treatment.

Subjects who receive one year ligelizumab treatment and move to the second observation 
period before move to the second half of the treatment.
To investigate the safety and tolerability of ligelizumab 120 mg PFS, a summary table will be 
provided to include the AEs after the first dose of PFS use. Only the subjects who receive at 
least one dose of ligelizumab 120 mg PFS use will be included in this analysis.
To investigate the safety and tolerability of ligelizumab 120 mg in all subjects who will be self-
administered, a summary table will be provided to include the information after the first dose 
using self-administration. Subjects who move from self-administration back to in- clinic 
administration during the study, they will be included in this analysis if majority (>50%) of 
drug use is based on self-administration.
SAE summaries will be provided in a similar manner.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Subjects with notable vital signs as defined in 
Appendix 1 will be listed.
12-lead electrocardiogram (ECG)
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
The summary of laboratory evaluations will be presented for 2 groups of laboratory tests 
(hematology and serum chemistry). Descriptive summary statistics for the change from baseline 
to each study visit will be presented. These descriptive summaries will be presented by 
laboratory test and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post baseline values. Shift tables using the low/normal/high/ (low and 
high) classification will be used to compare baseline to the worst on-treatment value.
Other safety evaluations

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Resource utilization
Data relating to resource utilization will be used for the purpose of economic evaluation and 
will be carried out and reported as a separate activity.
12.5.5
Biomarkers
Available biomarker data will be listed by treatment group, subject and visit. Summary statistics 
will be provided by treatment and visit. The number of values outside of the limits of 
quantification will be reported in each table.

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12.7
Interim analyses
The first interim analysis is planned once all subjects of the CQGE031C2302 and 
CQGE031C2303 have completed Week 12 (Visit 204) in the first half of the treatment period
to evaluate the primary endpoint of retreatment efficacy (or discontinued the trial or completed
the first observation period without relapse).
The second interim analysis will be performed at the end of the first half of the treatment period 
at Week 52 to evaluate endpoints up to the end of 1 year treatment.
Additional analyses may be performed to support health authority interactions as necessary.
At the End of Study, a final analysis of all data collected up to last study visit will be performed 
when all subjects have completed the last study visit.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The total number of subjects enrolled will be determined by the drop-out rate prior to the 
Phase 3 extension study from studies CQGE031C2302, CQGE031C2303, CQGE031C2202
and CQGE031C1301.
Based on interim results from CQGE031C2201, it is assumed that the proportion of subjects 
achieving UAS7 ≤ 6 at Week 12 is around 55% for ligelizumab 72 mg q4w. It is assumed that 
the well-controlled response for ligelizumab 120 mg q4w will be similar. The corresponding 

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95% confidence interval is listed based on different assumptions of number of subjects who 
will be enrolled for each treatment arm.
Table 12-1
95% confidence interval based on number of subjects enrolled from 
the core studies (CQGE031C2302/2303)
Number of 
subjects 
enrolled
Number of 
subjects for 
each treatment 
group
Drop out rate at 
Week 12
Assumed 
proportion of 
subjects 
achieving UAS7 
≤ 6 at Week 12
Corresponding 
95% confidence 
interval
500
250
10%
55%
(48.6% - 61.6%)
900
450
10%
55%
(50.2% - 59.9%)
1200
600
10%
55%
(50.8% - 59.2%)
To evaluate the retreatment efficacy in the subgroup of subjects who achieved UAS7 ≤ 6 at 
Week 12 after the retreatment on the same ligelizumab dose, the 95% confidence interval of the 
response rate will be provided for each treatment group. It is assumed that 50% of subjects 
enrolled into this extension study were well-controlled responders during the core studies for 
each ligelizumab treatment group. A 15% drop out rate is assumed for each treatment group 
before Week 12. The number of subjects required at the baseline of re-treatment for each 
treatment arm is listed in Table 12-2 below, based on different assumptions of the retreatment 
response rates and the corresponding precision levels (width of the 95% confidence interval).
Table 12-2
Number of subjects required at the baseline of re-treatment for each 
treatment arm enrolled from the core studies (CQGE031C2302/2303)
Precision
Response rate after 
retreatment
10%
12%
15%
70%
191
135
85
80%
146
102
66
90%
83
59
38
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 International Council for Harmonisation (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 

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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 European Union Drug Regulating Authorities Clinical Trials Database (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 at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System that includes all activities involved in 
quality assurance and quality control, to ensure compliance with written Standard Operating 
Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13.5
Patient Engagement
The following patient engagement initiatives are included in this study and will be provided as 
available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis.

Thank You letter – end of trial

Plain language trial summary – after Clinical Study Report publication
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 

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other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request
Arcara K, Tschudy M (eds) (2011) The Harriet Lane Handbook. The Johns Hopkins Hospital. 
Philadelphia:Mosby. 
Arm JP, Bottoli I, Skerjanec A, et al (2014) Pharmacokinetics, pharmacodynamics and safety 
of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp 
Allergy; 44(11):1371-85.
Bernstein JA, Lang DM, Khan DA, et al (2014) The diagnosis and management of acute and 
chronic urticaria: 2014 update. J Allergy Clin Immunol; 133(5):1270-7.
Biagtan MJ, Viswanathan RK, Evans MD, et al (2011) Clinical utility of the Chronic Urticaria 
Index. J Allergy Clin Immunol; 127(6):1626-7.
Bretz F, Pinheiro JC, Branson M, et al (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics; 61(3):738-48.
Chang TW, Chen C, Lin CJ, et al (2015) The potential pharmacologic mechanisms of 
omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol; 
135(2):337-42.
Church M, Weller K, Stock P, et al (2011) Chronic spontaneous urticaria in children: Itching 
for insight. Pediatric Allergy Immunology; 22 (1 Pt 1):1-8.
Collier DH, Bitman B, Coles A, et al. (2017) A novel electromechanical autoinjector, 
AutoTouch™, for self-injection of etanercept: real-world use and benefits. Postgrad Med; 
129(1):118-25.
Cox L, Lieberman P, Wallace D, et al (2011) American Academy of Allergy, Asthma & 
Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated 
Anaphylaxis Joint Task Force follow-up report. J Allergy Clin Immunol; 128(1):210-2.
Cox LS, Sanchez-Borges M, Lockey RF (2017) World Allergy Organization Systemic 
Allergic Reaction Grading System: Is a Modification Needed? J Allergy Clin Immunol Pract; 
5(1):58-62.
EMA (2014) Qualification Opinion on MCP-Mod as an efficient statistical methodology for 
model-based design and analysis of Phase II dose finding studies under model uncertainty.
FDA (2016) guidance document: <https www fda.gov/drugs/development-approval-process-
drugs/drug-development-tools-fit-purpose-initiative>.
Finlay AY, Khan GK (1994) Dermatology Life Quality Index (DLQI)--a simple practical 
measure for routine clinical use. Clin Exp Dermatol; 19(3):210-6.
Finlay AY (2005) Current severe psoriasis and the Rule of Tens. Br J Dermatol; 152(5):861-7.
Gauvreau GM, Arm JP, Boulet LP, et al (2016) Efficacy and safety of multiple doses of 
QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early 
asthmatic responses. J Allergy Clin Immunol; 138(4):1051-9.

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Richardson SJ, Brooks HL, Bramley G, et al (2014) Evaluating the effectiveness of self-
administration of medication (SAM) schemes in the hospital setting: a systematic review of 
the literature. PLos One; 9(12): e113912.
Simons FE, Ardusso L, Bilo B, et al (2011) World Allergy Organization Guidelines for the 
Assessment and Management of Anaphylaxis. World Allergy Organ J; 4(2):13-37.
Simons FE, Ebisawa M, Sanchez-Borges M, et al (2015) 2015 update of the evidence base: 
World Allergy Organization anaphylaxis guidelines. World Allergy Organ J; 8(1):32.
Stull D, McBride D, Tian H, et al (2017) Analysis of disease activity categories in chronic 
spontaneous/idiopathic urticaria. Br J Dermatol; 177(4):1093-101.
Vadasz Z, Tal Y, Rotem M, et al (2017) Omalizumab for severe chronic spontaneous 
urticaria: Real-life experiences of 280 patients. J Allergy Clin Immunol Pract; 5(6):1743-5.
Viswanathan RK, Biagtan MJ, Mathur SK (2012) The role of autoimmune testing in chronic 
idiopathic urticaria. Ann Allergy Asthma Immunol; 108(5):337-41.
Waters A, Sandhu D, Beattie P, et al (2010) Severity stratification of Children’s Dermatology 
Life Quality Index (CDLQI) scores. Br J Dermatol; 163(1):121.
Zuberbier T, Aberer W, Asero R, et al (2014) The EAACI/GA2LEN/EDF/WAO Guideline 
for the definition, classification, diagnosis, and management of urticaria: the 2013 revision 
and update. Allergy; 69(7):868-87.
Zuberbier T, Asero R, Bernstein JA, et al (2018) The EAACI/GA²LEN/EDF/WAO Guideline 
for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision 
and Update. Allergy; 73(7):1393-414.
Zuberbier T, Asero R, Bindslev-Jensen C, et al (2009) EAACI/GA2LEN/EDF/WAO 
guideline: management of urticaria. Allergy 64:1427-43.
16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Refer to Appendix 1.1 for clinically notable vital sign values for adolescents.
Refer to Appendix 2 for clinically notable laboratory values for hepatotoxicity.
Refer to Appendix 3 for clinically notable laboratory values for nephrotoxicity.
The following other specific criteria have been identified for this study:
Platelets < 75 000/μL

Any patient who have platelets < 75 000/μL after being randomized should discontinue 
study treatment.

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For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outside of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the CRF as an AE.
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 
subjects, the Central CRO will use age-and gender-specific reference values.
16.1.1
Appendix 1.1: Clinically notable vital signs – adolescent subjects
16.1.1.1 Guideline for pediatric blood pressure measurements:
Table 16-1
Best 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
Table 16-2
Upper and lower limits for adolescents’ vital signs that may be 
considered of concern if newly identified may be identified using the 
following table for guidance1
Age
Systolic BP2,3
Diastolic BP2,3
HR3
12 yrs
101-135
59-91
60-110
13 yrs
104-137
60-91
60-110

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Age
Systolic BP2,3
Diastolic BP2,3
HR3
14 yrs
106-140
60-92
60-110
15 yrs
107-142
61-93
60-110
16 yrs
108-145
63-94
60-110
17 yrs
108-147
64-97
60-100
18 yrs
-
-
60-100
1 The table above was developed from multiple resources listed below. The normal values for vital 
signs in children vary greatly with age, growth and development. The purpose of these values is to 
guide investigators to identify or screen for values of concern in pediatric patients by age. These are 
not normal values, which can be found in sources such as the Harriet Lane Pediatric Handbook but 
rather are upper and lower limits for children’s vital signs that may be considered of concern if newly 
identified. The significance of these findings must be considered in view of the patient’s disease, 
time course and overall clinical condition.
2 Based on percentiles by height (50th - 99th)
3 (Arcara K and Tschudy M 2011). The Harriet Lane Handbook 
who.int/childgrowth/standards/w_f_a_tables_p_girls/en/index.html 
who.int/childgrowth/standards/second_set/hcfa_girls_p_exp.txt 
who.int/childgrowth/standards/second_set/hcfa_boys_p_exp.txt
16.2
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements
Table 16-3
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS if ALT, AST and 
TBL normal at baseline

ALT or AST >5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 3 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and (TBL > 2 x ULN or INR > 1.5)

Potential Hy’s Law cases defined as ALT or AST > 3 x 
ULN, combined with elevation of serum TBL to > 2 x ULN
(mainly conjugated fraction), without notable increase of 
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 > 3 x baseline or > 300 U/L (whichever occurs 
first)
Table 16-4
Follow-up requirements for liver laboratory triggers – ALT, TBL with
and without liver symptoms
ALT
TBL
Liver Symptoms
Actions
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 3 × ULN
Normal
For patients with
Gilbert’s
syndrome: No
change in
None

No change to 
study 
treatment

Measure ALT, 
AST, ALP, GGT, 
If elevated at baseline:
ALT > 2 × baseline or > 300 
U/L (whichever

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ALT
TBL
Liver Symptoms
Actions
occurs first)
baseline TBL
TBL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.

Follow-up for 
symptoms.
If normal at baseline:
ALT > 5 × ULN for more 
than two weeks
Normal
For patients with
Gilbert’s
syndrome: No
change in
baseline TBL
None

Interrupt study 
drug

Measure ALT, 
AST, ALP, GGT,
TBL, 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 × baseline or > 300 
U/L (whichever occurs first) 
for more than two weeks
If normal at baseline:
ALT > 8 × ULN
Normal
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 × ULN
TBL > 2 x ULN
(or INR > 1.5)
For patients with
Gilbert’s
syndrome:
Doubling of direct
bilirubin
None
If elevated at baseline:
ALT > 2 × baseline
or > 300 U/L (whichever
occurs first)
Normal or
elevated
Severe fatigue,
nausea, vomiting,
right upper
quadrant pain
If normal at baseline:
ALT > 3 x ULN
If elevated at baseline:
ALT > 2 x baseline
or > 300 U/L (whichever
occurs first)
Table 16-5
Follow-up requirements for liver laboratory triggers – isolated 
hyperbilirubinemia
Criteria
Actions required
Follow-up monitoring
TBL (isolated)
>1.5 – 3 × ULN
Maintain treatment
Repeat LFTs within 48-72 hours
Monitor LFTs weekly until 
resolution to ≤Grade 1 or 
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 (eg, conmeds, med hx, lab) 
in the appropriate CRF
Monitor ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT weekly 
until resolution to ≤ Grade 1 or 
baseline
Test for hemolysis (eg, 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 10 × ULN
Discontinue the study treatment 
immediately
Hospitalize the patient
Establish causality
Record the AE and contributing 
factors (eg, conmeds, med hx, lab) 
in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution 
(frequency at investigator 
discretion)

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Any AE potentially 
indicative of a liver 
toxicity
Consider study treatment 
interruption or discontinuation
Hospitalization if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (eg, conmeds, med hx, lab) 
in the appropriate CRF
Investigator discretion
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.
16.3
Appendix 3: Specific renal alert criteria and actions and event 
follow-up
Refer to Section 10.2.2.
Table 16-6
Specific renal alert criteria and actions
Renal Event
Actions
Confirmed serum creatinine increase 25% –
49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase ≥ 50% + OR 
if <18 years old,
eGFR < 35mL/min/1.73 m2

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation
unless other causes are diagnosed and
corrected

Consider patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥3+
OR
Protein-creatinine ratio (PCR) ≥1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation
unless other causes are diagnosed and 
corrected
New onset hematuria ≥3+ on urine dipstick

Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess SCR

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO (Kidney Disease Improving Global Outcomes) criteria for Acute Kidney Injury
Whenever a renal event is identified, a detailed patient history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event:

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
Blood pressure assessment (after 5-min 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

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 (MRI 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
16.4
Appendix 4: PRO tools
Samples of questionnaire provided here are for illustrative purpose only. The text format and 
wording might slightly vary.

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Patient Diary: Urticaria Patient Daily Diary (UPDD)

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Patient Diary: Angioedema Activity Score (AAS)

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Children Dermatology Life Quality Index (CDLQI)

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16.7
Appendix 7: World allergy organization grading system
World allergy organization subcutaneous immunotherapy systemic reaction 
grading system