A Multi-center, Open-label Study to Investigate the Safety/Tolerability and Efficacy of Ligelizumab (QGE031) in the Treatment of Adult Japanese Patients With Chronic Spontaneous Urticaria (CSU) Inadequately Controlled With H1 Antihistamines
Phase: PHASE3
Conditions: Chronic Spontaneous Urticaria
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
QGE031 / Ligelizumab
Clinical Trial Protocol CQGE031C13011&7
A multi-center, open-label study to investigate the 
safety/tolerability and efficacy of ligelizumab (QGE031) in 
the treatment of adult Japanese patients with Chronic 
Spontaneous Urticaria (CSU) inadequately controlled with 
H1 antihistamines
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
NA
Version number:
v01
Clinical Trial Phase:
III
Release date:
14-Feb-2020
Property of Novartis/sponsor
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 01(14-Feb-2020)...........................................................................................12
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Objectives and endpoints...................................................................................................20
3
Study design ......................................................................................................................21
4
Rationale............................................................................................................................22
4.1
Rationale for study design .....................................................................................22
4.1.1
Rationale for choice of background therapy.........................................23
4.2
Rationale for dose/regimen and duration of treatment ..........................................23
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................24
4.4
Purpose and timing of interim analyses/design adaptations..................................24
4.5
Risks and benefits..................................................................................................24
5
Population..........................................................................................................................26
5.1
Inclusion criteria ....................................................................................................26
5.2
Exclusion criteria...................................................................................................26
6
Treatment...........................................................................................................................29
6.1
Study treatment......................................................................................................29
6.1.1
Investigational drugs.............................................................................29
6.1.2
Additional study treatments ..................................................................29
6.1.3
Treatment arms/group ...........................................................................29
6.1.4
Treatment duration................................................................................29
6.2
Other treatment(s)..................................................................................................30
6.2.1
Concomitant therapy.............................................................................30
6.2.2
Prohibited medication ...........................................................................30
6.2.3
Rescue medication ................................................................................31
6.3
Subject numbering, treatment assignment, randomization....................................32
6.3.1
Subject numbering ................................................................................32
6.3.2
Treatment assignment, randomization ..................................................32
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6.4
Treatment blinding.................................................................................................32
6.5
Dose escalation and dose modification..................................................................32
6.6
Additional treatment guidance...............................................................................32
6.6.1
Treatment compliance...........................................................................32
6.6.2
Emergency breaking of assigned treatment code..................................32
6.7
Preparation and dispensation.................................................................................32
6.7.1
Handling of study treatment and additional treatment..........................33
6.7.2
Instruction for prescribing and taking study treatment .........................33
7
Informed consent procedures ............................................................................................34
8
Visit schedule and assessments .........................................................................................35
8.1
Screening ...............................................................................................................40
8.1.1
Information to be collected on screening failures.................................40
8.2
Subject demographics/other baseline characteristics.............................................40
8.3
Efficacy..................................................................................................................40
8.3.1
Electronic Diary (eDiary) assessments .................................................41
8.3.2
Other PRO assessments.........................................................................44
8.3.3
Other assessments: Evidence of urticaria..............................................45
8.3.4
Appropriateness of efficacy assessments..............................................45
8.4
Safety.....................................................................................................................46
8.4.1
Laboratory evaluations..........................................................................46
8.4.2
Electrocardiogram (ECG) .....................................................................47
8.4.3
Assessment of parasitic infections ........................................................48
8.4.4
Pregnancy and assessments of fertility .................................................48
8.4.5
Anaphylaxis assessment........................................................................49
8.4.6
Assessment of cardio-cerebrovascular events.......................................49
8.4.7
Assessment of neoplastic events...........................................................49
8.4.8
Appropriateness of safety measurements..............................................49
8.5
Additional assessments..........................................................................................49
8.5.1
Resource utilization...............................................................................49
50
8.5.3
Anti-ligelizumab antibody in serum......................................................51
51
52
9
Study discontinuation and completion ..............................................................................52
9.1
Discontinuation......................................................................................................52
9.1.1
Discontinuation of study treatment .......................................................52
9.1.2
Withdrawal of informed consent...........................................................53
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9.1.3
Lost to follow-up...................................................................................54
9.1.4
Early study termination by the sponsor.................................................54
9.2
Study completion and post-study treatment ..........................................................54
10 Safety monitoring and reporting........................................................................................55
10.1
Definition of adverse events and reporting requirements......................................55
10.1.1
Adverse events ......................................................................................55
10.1.2
Serious adverse events ..........................................................................56
10.1.3
SAE reporting........................................................................................57
10.1.4
Pregnancy reporting ..............................................................................58
10.1.5
Reporting of study treatment errors including misuse/abuse................59
10.2
Additional Safety Monitoring................................................................................59
10.2.1
Liver safety monitoring.........................................................................59
10.2.2
Renal safety monitoring........................................................................60
10.2.3
Adjudication committee........................................................................61
11 Data Collection and Database management......................................................................61
11.1
Data collection.......................................................................................................61
11.2
Database management and quality control............................................................61
11.3
Site monitoring ......................................................................................................62
12 Data analysis and statistical methods ................................................................................62
12.1
Analysis sets ..........................................................................................................62
12.2
Subject demographics and other baseline characteristics......................................63
12.3
Treatments .............................................................................................................63
12.4
Analysis of the primary endpoint(s) ......................................................................63
12.4.1
Definition of primary endpoint(s).........................................................63
12.4.2
Statistical model, hypothesis, and method of analysis..........................64
12.4.3
Handling of missing values/censoring/discontinuations.......................64
12.4.4
Sensitivity and Supportive analyses......................................................64
12.5
Analysis of secondary endpoints ...........................................................................64
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................64
12.5.2
Safety endpoints....................................................................................64
.65
66
66
12.7
Interim analyses.....................................................................................................66
12.8
Sample size calculation..........................................................................................66
12.8.1
Primary endpoint(s)...............................................................................66
12.8.2
Secondary endpoint(s)...........................................................................67
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13 Ethical considerations and administrative procedures ......................................................67
13.1
Regulatory and ethical compliance........................................................................67
13.2
Responsibilities of the investigator and IRB/IEC..................................................67
13.3
Publication of study protocol and results...............................................................67
13.4
Quality Control and Quality Assurance.................................................................67
14 Protocol adherence ............................................................................................................68
14.1
Protocol amendments.............................................................................................68
15 References .........................................................................................................................69
16 Appendices ........................................................................................................................72
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................72
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................73
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......77
16.4
Appendix 4: PRO tools..........................................................................................78
16.5
Appendix 5 
ADA Log...............................................................................89
16.6
Appendix 6: World allergy organization grading system......................................90
91
91
91
91
91
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 6-1
Investigational drug...............................................................................29
Table 6-2
Prohibited medication ...........................................................................30
Table 8-1
Assessment Schedule ............................................................................36
Table 8-2
Urticaria Patient Daily Diary (UPDD)..................................................41
Table 8-3
Hives Severity Score.............................................................................41
Table 8-4
Itch Severity Score ................................................................................42
42
43
43
Table 8-8
DLQI score bands and impact on patient’s life.....................................44
Table 8-9
Assessments & Specifications...............................................................46
Table 8-10
Laboratory Assessments........................................................................47
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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................59
Table 10-2
Base Renal Monitoring .........................................................................60
Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................73
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers...73
Table 16-3
Specific Renal Alert Criteria and Actions.............................................77
Table 16-4
Renal event follow-up...........................................................................78
List of figures
Figure 3-1
Study design..........................................................................................21
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List of abbreviations
AC
Adjudication Committee
ACR
Albumin-Creatinine Ratio 
ADA
Anti-Drug Antibodies
AE
Adverse Event
AH
Anti-Histamine
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BP
Bullous pemphigoid
bpm
Beats per minute
CINDU
Chronic inducible urticaria
CIU
Chronic Idiopathic Urticaria
CMO & PS
Chief Medical Office and Patient Safety
CO
Country Organization
CRF
Case Report/Record Form (paper or electronic)
CRO
clinical research organization
CS
Corticosteroids
CSU
Chronic Spontaneous Urticaria
CT
Computerized Tomography
CTC
Common Toxicity Criteria
CTCAE
common terminology criteria for adverse events
CU
Chronic Urticaria
CV
coefficient of variation
DDE
Direct Data Entry
DLQI
Dermatology Life Quality Index
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
eDiary
Electronic Diary
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EoS
End of study
EoT
End of treatment
EU
european union
FcεRI
IgE receptor
FcεRII
IgE receptor
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FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
β-hCG
Beta-Human Chorionic Gonadotropin
HRQoL
Health-Related Quality of Life
HSS
Hives Severity Score
HSS7
Weekly Hives Severity Score
IB
Investigator’s Brochure
IC
Informed consent
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISS
Itch Severity Score
ISS7
Weekly Itch Severity Score
IUD
Intrauterine device
IUS
Intrauterine system
JDA
japanese dermatological association
LLOQ
lower limit of quantification
LTRA
Leukotriene Receptor Antagonist
MedDRA
Medical dictionary for regulatory activities
MMRM
Mixed effect Model Repeat Measurement
MoA
Mechanism of Action
MRI
Magnetic Resonance Imaging
NYHA
New York Heart Association
PMDA
Pharmaceuticals and Medical Devices Agency
PRO
Patient Reported Outcomes
PSD
Premature subject discontinuation
PT
prothrombin time
q4w
Every 4 weeks
QALYs
Quality-adjusted life-years
QMS
Quality Management System
QoL
Quality of life
QTcF
QT interval corrected by Fridericia’s formula
SAE
Serious Adverse Event
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sc
Subcutaneous
sCr
Serum creatinine
SD
standard deviation
SOC
System organ class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TD
Study Treatment Discontinuation
UAS
Urticaria Activity Score
UAS7
Weekly Urticaria Activity Score
ULN
upper limit of normal
UPDD
Urticaria patient daily diary
VAS
Visual Analog Scale
WHO
World Health Organization
WoC
Withdrawal of consent
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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria and generally treated at the 
same time
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
eCRF
Electronic case report form
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the 
use of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in subjects with established disease and in 
those with newly-diagnosed disease
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
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
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
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Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first subject
Study treatment
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data
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Protocol No. CQGE031C1301
Amendment 01(14-Feb-2020)
Amendment rationale:
CQGE031C1301 is currently recruiting. This amendment primarily aims to provide 
clarification on:
a. Clarifies that an urinalysis sample is to be collected Week 24
b. Clarifies that if a subject takes concomitant omalizumab (outside of study assigned 
treatment), the subject must discontinue from the study, in which case, 
/ADA 
samples should not be collected at the End of Study (EoS) visit.
c. Clarifies that all subjects will be given three stool samples collection kits at 
screening Visit1 and Visit320.
It also includes other minor clarifications and editorial changes. 
Changes to protocol and rationale:
!
Glossary of terms: updated with the ‘Personal data’ definitions.
!
Protocol summary includes the following changes: 
!
“CSU diagnosis for ≥ 6 months” changed to “CSU diagnosis for ≥ 6 months (defined 
as onset of CSU with supporting documentation)”. Section 5.1 updated accordingly
!
“Subjects must be on H1-AH at only approved doses for treatment of CSU starting at 
Visit 1 (Day -28 to Day -14)” changed to “Subjects must be on H1-AH at only local 
label approved doses for treatment of CSU starting at Visit 1 (Day -28 to Day -14)” 
similar change is reflected in Section 4.1.1 and Section 5.1
!
“Any H2 antihistamine, Leukotriene Receptor Antagonist (LTRA) (montelukast or 
zafirlukast) or H1 antihistamines use at greater than approved dose after Visit 1” 
changed to “Any H2 antihistamine use or LTRA (montelukast or zafirlukast) after 
Visit 1 and any H1 antihistamine used as background medication at greater than local 
label approved doses after Visit 1” similar changes is reflected in Section 5.2
!
Section 4.1.1: Added, “If a subject must switch to another background H1-AH (at 
approved dose) as a result of an AE, the subject will be considered to have remained on 
stable treatment.”
!
Section 5.1: Included the word “local label” in Inclusion Criterion 4.
!
Section 5.2: Added the term “background medication” and “local label” to Exclusion
Criterion #10 in order to clarify that higher than approved doses of H1-AH as background 
medication are not allowed after Visit 1. This criterion does not apply to H1-AH taken as 
rescue medication which can be taken up to 4 times the approved dose.  
!
Section 5.2: Exclusion criterion 14 is amended to exclude hypersensitivity to all study 
drugs
!
Section 5.2: Exclusion criterion 19, changed “History of” to “History of” and clarifies, 
that an INR > 1.5 (not INR > 1.5 ULN) is an exclusion criterion for this study.
!
Section 5.2: Exclusion criterion 24, changed “basic contraception methods” to 
“Acceptable contraception methods” to be consistent with the CTFG guidelines for 
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contraception requirements in order to participate in the study. Section 4.5 and Section 7
updated accordingly.
!
Section 6.2.2: Table 6-2 
!
Clarifies the term Routine as “more than 3 doses over a 5 day period” use of oral 
corticosteroids. Included IV/IM/IA corticosteroids as prohibited systemic routes of 
corticosteroid administration, with minimum required period without medication 
mentioned as 30 days prior to Visit 1.
!
Included the phrase “Other immunosuppressive medication with or without known 
effect on CSU including but not limited to” to clarify that immunosuppressive 
medication is not limited to the medications mentioned in the table.
!
Revised the footnote to clarify the use of oral corticosteroids as rescue therapy is 
allowed only after Week 12.
!
Footnote clarifies that other preparations of corticosteroids (CS) with limited systemic 
exposure for non-CSU indications can be used (e.g. Intra nasal or any topical CS) as-
needed basis
!
Section 6.2.2: Section is updated to clarify that if subjects are administered omalizumab 
(outside of study assigned treatment) in the follow-up phase they should be discontinued 
from the study and collection of any efficacy or safety assessments should not be done at 
EoS visit. Table 8-1 footnotes updated accordingly. Section 9.1.1 updated accordingly
!
Section 6.2.3: Provided clearer guidance and discontinuation criteria on the use of oral 
corticosteroids as rescue therapy and deleted the sentence indicating that instructions on 
use of corticosteroids will be provided to the investigators. 
!
Section 8: Following changes made to Table 8-1 
!
Clarification added to “Family history of malignancy” indicating that CRF is to be 
completed retrospectively for any subject who develops malignancy during the study.  
!
There is no need to dispense H1-AH or oral corticosteroids as rescue medications at 
Visit 1999 or Week 64, hence “s” deleted at that Visit
!
Clarifies that “At Visit 1 and Visit 320, dispense 3 stool collection kits. Patients 
should collect samples, within seven days of Visit1 and in the week prior to Visit 
1999/EOS/PSD”
!
Added “INR at Visit 1, V110 and UPV” for determining exclusion criteria 19 and 
liver safety follow up. Table 8-10 updated accordingly.
!
Added Urine Dipstick to Visit 170/Week 24 for renal safety monitoring
!
Added a separate line for “serum β-hCG” to clarify that a serum β-hCG sample 
should be taken for all pre-menopausal women who are not surgically sterile at Visit 
1, followed by urine pregnancy test starting at V110 to Visit 1999/EOS/PSD. 
!
Section 8.4.1: is updated with text ‘In case of lab abnormalities, an additional re-draw for 
central laboratory assessment is allowed during the screening period to confirm eligibility 
criteria’ and ‘A serum β-hCG will be collected for all pre-menopausal women who are not 
surgically sterile at Visit 1’.
!
Section 8.4.3: Clarification is provided on stool sample dispensation and collection of 
stool samples at not only Screening period Visit 1 and Visit 320 but also advised that if 
diarrhea, or any other symptoms suggestive of parasitic infection, develops at any time 
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before the end of study. The section also clarifies that pathogenicity of parasitic organisms 
will be defined as per the local laboratory.
!
Section 8.4.4: Section update to provide clear guidance on pregnancy and assessments of 
fertility 
!
Section 10.1.3: Section updated to provide clarification on SAE reporting
!
Section 10.1.4: Clarifies that pregnancy follow-up should be for up to 12 months 
following the birth of the baby.
!
Section 11.2: the updated details pertaining to ‘Stool samples will be processed by local 
labs and the results will be collected by Novartis via eCRFs’ AND Patients will fill in 
their daily diary data on a smart phone device at home. PROs will be completed by 
patients on site on the day of applicable visits.
!
Section 16.2: Table 16-1 and 16-2 clarifies the definition of liver events to be identified 
based on Guidance for detection, assessment, and management of drug-induced liver 
injury (DILI) in clinical development, Version 2 (15-Apr-2019)
!
Section 16.3: Updated Table 16-3 and 16-4 based on the Clinical Development Safety 
Guideline for Drug Induced Nephrotoxicity Version 2.0 (DIN ClinDevSafetyGuide 2017)
!
Section 16.6: Updated Appendix 6: World allergy organization grading system based on 
Cox L, 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. Reference in section 9.1.1 updated accordingly.
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Protocol summary
Protocol 
number
CQGE031C1301
Full Title
A multi-center, open-label study to investigate the safety/tolerability and efficacy 
of ligelizumab (QGE031) in the treatment of adult Japanese patients with 
Chronic Spontaneous Urticaria (CSU) inadequately controlled with H1 
antihistamines
Brief title
A Phase III study of safety and efficacy of ligelizumab in the treatment of CSU in 
Japanese patients inadequately controlled with H1- antihistamines
Sponsor and 
Clinical Phase
Novartis Phase III
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the safety and efficacy of ligelizumab in 
adult Japanese subjects with CSU, who remain symptomatic despite treatment 
with H1-antihistamines (AHs) at locally approved doses.
Primary 
Objective(s) 
The primary objective of this study is to investigate the safety and tolerability of 
ligelizumab 120 mg subcutaneous (sc) every 4 weeks (q4w) for 12 months.
Secondary 
Objectives
The secondary objective is to evaluate the efficacy of ligelizumab 120 mg sc q4w 
by evaluation of:
!
Weekly Urticaria Activity Score (UAS7), Weekly Hives Severity Score 
(HSS7) and Weekly Itch Severity Score (ISS7) change from Baseline over 
time
!
Achievement of the complete UAS7 = 0, HSS7 = 0 and ISS7 = 0 response 
over time
!
Profile of change from baseline in the Dermatology Life Quality Index (DLQI)
!
Achievement of DLQI = 0/1 by visit up to end of study (EoS)
Study design
This is a Phase III multi-center, open-label, single arm study. There is screening 
period of up to 28 days, a 52 week treatment period, and a 12 week post-
treatment follow-up period.
Population
The study population will consist of approximately 65 male and female subjects 
aged ≥ 18 years who have been diagnosed with CSU and who remain 
symptomatic despite the use of H1-AH.
Key Inclusion 
criteria
!
Signed informed consent must be obtained prior to participation in the study
!
Male and female subjects ≥ 18 years of age at the time of screening
!
CSU diagnosis for ≥ 6 months (defined as onset of CSU with supporting 
documentation)
!
Diagnosis of CSU refractory to H1-AH at locally-approved doses at the time 
of Baseline (Visit 110, Day 1), as defined by all of the following: 
!
The presence of itch and hives for ≥6 consecutive weeks at any time 
prior to Visit 1 (Day -28 to Day -14) despite current use of non-sedating 
H1-AH (at locally approved doses) during this time period
!
UAS7 score (range 0-42) ≥16 and HSS7 (range 0-21) ≥8 during the 
7 days prior to baseline (Visit 110, Day 1)
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!
Subjects must be on H1-AH at only local label approved doses for 
treatment of CSU for starting at Visit 1 (Day -28 to Day -14)
!
Willing and able to complete a daily symptom electronic Diary (eDiary) for 
the duration of the study and adhere to the study visit schedules
!
Subjects must not have had any missing eDiary entries in the 7 days prior to 
baseline (Day 1, Visit 110). i.e., 14 eDiary entries required. Rescreening may 
be considered only once
Key Exclusion 
criteria
!
History of hypersensitivity to any of the study treatments or excipients or to 
drugs of similar chemical classes (i.e. to murine, chimeric, or human 
antibodies)
!
Subjects having a clearly defined, predominant trigger of their chronic 
urticaria (CU) (chronic inducible urticaria (CINDU)) including 
!
urticaria factitia (symptomatic dermographism), cold-, heat-, solar-, 
pressure-, delayed pressure-, aquagenic-, cholinergic-, or contact-
urticaria
!
Diseases, other than chronic urticaria, with urticarial or angioedema 
symptoms such as urticarial vasculitis, erythema multiforme, cutaneous 
mastocytosis (urticaria pigmentosa), and hereditary or acquired angioedema 
(e.g., due to C1 inhibitor deficiency)
!
Subjects with evidence of helminthic parasitic infection as evidenced by 
stools being positive for a pathogenic organism according to local guidelines. 
All subjects will be screened at Visit 1. If stool testing is positive for 
pathogenic organism, the subject will not enter treatment period and will not 
be allowed to rescreen
!
Any other skin disease associated with chronic itching that might influence in 
the investigator's opinion the study evaluations and results (e.g. atopic 
dermatitis, bullous pemphigoid (BP), dermatitis herpetiformis, senile pruritus, 
etc)
!
Prior exposure to ligelizumab
!
Any H2 antihistamine use or LTRA (montelukast or zafirlukast) after Visit 1 
and any H1 antihistamine used as background medication at greater than 
local label approved doses after Visit 1
Study 
treatment
Ligelizumab 120 mg sc q4w
Efficacy 
assessments
!
Weekly urticaria activity score (UAS7)
!
Weekly hives severity score (HSS7)
!
Weekly itch severity score (ISS7)
!
Dermatology Life Quality Index (DLQI)
Key safety 
assessments
Safety evaluations include adverse events (AEs), laboratory values, vital signs 
and electrocardiogram (ECG).
Other 
assessments 
 
!
Anti-drug antibodies 
(ADA), 
Data analysis
As the study objective is to assess the safety with no specific safety hypothesis, 
treatment emergent adverse events during the study will be considered as a 
primary variable. All adverse events which start after the first dose of the study 
medication will be summarized as treatment emergent adverse event by system 
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organ class (SOC) and preferred term. No formal statistical analysis will be 
provided. 
Key words
Anti-Immunogloblin E (IgE), chronic spontaneous urticaria (CSU), safety, 
Japanese, hives severity score (HSS), itch severity score (ISS), urticaria activity 
score (UAS), long term, ligelizumab, QGE031, UAS7
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1
Introduction
1.1
Background
Urticaria is classified into inducible and spontaneous. Spontaneous urticaria presents with hives 
spontaneously without a direct cause, and the Japanese Dermatological Association Guideline 
for the Treatment of Urticaria 2011 (hereafter referred to as the JDA Guideline 2011) defines 
chronic urticaria as “urticaria persistent for ≥1 month from onset” (Hide et al 2011). The 
Western EAACI/GA2LEN/EDF/WAO Guideline 2017 (hereafter referred to as the EAACI 
Guideline 2017) defines chronic Spontaneous Urticaria (CSU), also known as Chronic 
Idiopathic Urticaria (CIU) 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). These Japanese and foreign guidelines use the different terms and define 
the different duration of symptoms, but these differences do not interfere with diagnosis and 
thus, these are considered the same disorder (Hide et al 2012).
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 symptoms of urticaria and urticaria associated angioedema adversely 
affect daily activities and sleep (O'Donnell et al 1997). The overall burden of CSU is 
substantial; CSU has a negative impact on patients’ lives and health-related quality of life 
(HRQoL) and work productivity (Maurer et al 2017).
Urticaria treatment aims at fully suppressing both symptoms of itch and hives and ultimately 
preventing the occurrence of symptoms altogether without need for medication, and all in all 
Japan and other countries share this treatment strategy (Hide et al 2012).
A majority of CSU patients can be treated with H1-antihistamine (H1-AH) monotherapy 
(Kozel and Sabroe 2004), which is frequently used at doses up to 4 fold the approved dose 
(Zuberbier et al 2014, Zuberbier et al 2018). The use of H2 antihistamines and Leukotriene 
Receptor Antagonists (LTRAs) has in the past been recommended in treatment guidelines for 
patients 
who 
remained 
symptomatic 
despite 
treatment 
with 
H1-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. These drugs are not approved for treatment of CSU in Japan 
and other countries (Hide et al 2012). Systemic corticosteroids are sometimes added to the 
treatment regimens, however they are not recommended in treatment guidelines for long term 
treatment as patients are then at risk of adverse effects associated with chronic systemic 
corticosteroid exposure.
In patients not responding adequately or intolerant to these treatment options, use of 
cyclosporine or other immunosuppressants is considered an option as alternative treatment 
(Hide et al 2012). However, cyclosporine has not been approved in Japan and is associated with 
renal dysfunction, hypertension and other adverse reactions even at low doses. Thus, its use is 
limited to severe patients (Hide et al 2011).
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More recently omalizumab, a less potent monoclonal antibody than ligelizumab that also targets 
immunoglobulin E (IgE), has been approved in several countries including those in the 
European Union, the United States, Japan and Switzerland as add-on therapy in patients with 
CSU with symptoms despite treatment with antihistamines. Omalizumab improved the signs 
and symptoms of urticaria (i.e. hives and itch) in patients who failed treatment with 
H1-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, Hide et al 2017).
Ligelizumab (QGE031) is a humanized IgG-type monoclonal antibody that binds to human IgE 
with higher affinity than omalizumab. Upon binding to specific epitopes in the C3 region of 
IgE, ligelizumab is able to block the interaction of IgE with both the high and low affinity IgE 
receptors (FcεRI and FcεRII). Ligelizumab does not mediate IgE receptor cross-linking and 
consequent histamine release (i.e. is non-activating). This overall mechanism of action (MoA) 
is shared with omalizumab (Chang et al 2015).
When subjects are treated with ligelizumab, circulating IgE is rapidly bound by the anti-IgE 
antibody and becomes inaccessible to IgE receptors on mast cells and basophils (Arm et al 2014, 
Gauvreau et al 2016). Ligelizumab has demonstrated dose- and time-dependent suppression of 
free IgE, reduction in basophil FcεRI expression and thus basophil surface IgE, and inhibition 
of skin prick test responses to allergens, superior in extent and duration to those observed with 
omalizumab (Arm et al 2014, Gauvreau et al 2016). IgE is necessary for the enhanced 
expression 
of 
the 
FcεRI 
seen 
in 
atopic 
subjects 
(MacGlashan et al 1997, 
MacGlashan et al 1998), and thus a decrease in FcεRI expression on circulating basophils 
accompanies ligelizumab treatment. Other potentially beneficial effects from anti-IgE therapy 
include decreased IgE production (Lowe and Renard 2011), reduced IgE+ B cell numbers 
(Ota et al 2009) and reduced cytokine production by T cells (Coyle et al 1996).
1.2
Purpose
The effect of ligelizumab in patients with CSU inadequately controlled with H1-antihistamines 
was investigated in the Phase II dose-range finding study [CQGE031C2201] and demonstrated 
a dose-dependent response to ligelizumab and superior efficacy in multiple ligelizumab dose 
groups compared to the omalizumab treatment group. No safety concerns were identified in the 
ligelizumab groups. Two ongoing Phase III studies, [CQGE031C2302] and [CQGE031C2303], 
are intended to support the registration of ligelizumab for the treatment of patients with CSU in 
adolescents and adults inadequately controlled with H1-antihistamines.
There is relatively low number of Japanese subjects treated with the intended dose for 
registration or higher for 1 year in those Phase III studies above. Therefore, the purpose of this 
CQGE031C1301 study is to evaluate the safety and efficacy of ligelizumab in adult Japanese 
subjects with CSU, who remain symptomatic despite treatment with H1-antihistamines at 
locally-approved doses, over 12 months of treatment with ligelizumab and a post-treatment 
follow-up period of up to 12 weeks. It is a trial intended to support the registration of 
ligelizumab for the treatment of CSU in Japan.
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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
!
The primary objective of this study is to 
investigate the safety and tolerability of 
ligelizumab 120 mg q4w for 12 months
!
Overall safety data, assessed as treatment 
emergent adverse events during the study
Secondary objective(s)
Endpoint(s) for secondary objective(s)
!
To evaluate the efficacy of ligelizumab 120 
mg q4w by evaluation of:
!
UAS7, HSS7 and ISS7 change from 
baseline over time
!
Achievement of the complete UAS7 = 
0, HSS7 = 0 and ISS7 = 0 response 
over time
!
Profile of change from baseline in the 
Dermatology Life Quality Index (DLQI)
!
Achievement of DLQI = 0/1 by visit up 
to end of study
!
Absolute change from baseline of UAS7, 
HSS7 and ISS7 by visit up to end of 
study
!
Proportion of subjects with UAS7 = 0, 
HSS7 = 0, and ISS7 = 0 response by visit 
up to the end of study
!
Absolute change from baseline of DLQI 
by visit up to end of study
!
Proportion of subjects with DLQI = 0/1 by 
visit up to end of study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objective(s)
Endpoint(s)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3
Study design
This is a Phase III multi-center, open-label, single arm study. The study consists of 3 distinct 
periods:
!
Screening period (Day -28 to Day -14): Duration of up to 4 weeks in which subjects who 
have given informed consent are assessed for eligibility.
!
Treatment period (52 weeks): The subjects will be seen in the clinic every 4 weeks.
!
Post-treatment follow-up period (12 weeks): This period consists of a subject visit in the 
clinic every 4 weeks with the final visit (Visit 1999) occurring 16 weeks after the last 
treatment dose.
Figure 3-1
Study design
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Screening period
Subjects will have a screening period to establish eligibility for the study. Subjects will be 
required to attend 1 visit during screening period: Visit 1 (Day -28 to Day -14). An extended 
screening period will be permitted only in exceptional circumstances when information 
concerning eligibility is outstanding (eg, pending laboratory data).
Rescreening may be allowed for subjects who failed initial screening. Only 1 rescreening will 
be allowed (see Section 5.1 and Section 5.2 ). If a subject is rescreened for the study, the subject 
must sign a new informed consent and will be issued a new subject number. Informed consent 
for a rescreened subject must be obtained prior to performing any study-related assessments or 
collecting any data for the Screening visit.
Treatment period
On Day 1, eligible subjects will enter an open-label treatment period to receive ligelizumab 120 
mg sc q4w. The first dose of study drug will be administered on Day 1 (Visit 110). The last 
dose of ligelizumab 120 mg will be administered on Day 337 (Week 48, Visit 230) study visit.
Approximately 65 subjects will be allocated to the ligelizumab 120 mg q4w arm. Subjects are 
expected to attend all site visits based on the assessment schedule ( Table 8-1 ).
Post-treatment follow-up period
The post-treatment follow-up period is 12 weeks with the last follow-up visit (Visit 1999) 
corresponding to 16 weeks after the last treatment dose. No investigational treatment will be 
given during the post-treatment follow-up period. Subjects will be allowed to take their rescue 
medication on an as needed basis, assessed on a daily basis by the subjects. Subjects will be 
required to visit the study center every 4 weeks during the post-treatment follow-up period.
Patients will be eligible for post-trial access after completion of the study.
4
Rationale
4.1
Rationale for study design
Data from the dose-range finding Study [CQGE031C2201] suggest that ligelizumab treatment 
improves itch and hives in adult subjects with CSU who have failed treatment with H1-
antihistamines and those who failed treatment with a combination of H1 and H2 antihistamines 
and LTRA. The Phase III studies [CQGE031C2302] / [CQGE031C2303] are ongoing to further 
evaluate the efficacy and safety of ligelizumab in adults and adolescent CSU subject's refractory 
to antihistamines at ligelizumab doses 72 mg or 120 mg for 1 year, respectively. As the number 
of Japanese CSU patients exposed to ligelizumab of the intended dose or higher for registration 
is expected to be limited, the study, CQGE031C1301, is designed to obtain additional safety 
data of ligelizumab of 120 mg for one year in Japanese CSU patients to support the registration 
of ligelizumab in Japan.
An open-label design without comparator arm is considered adequate to evaluate long term 
safety for CSU in Japanese and accepted by Japanese Health Authority.
The target population for this study consists of CSU subjects who remain symptomatic despite 
treatment with H1-AHs at locally approved doses.
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Subjects treated with omalizumab previously as well as subjects with chronic spontaneous 
urticaria as their predominant disease who also suffer from chronic inducible urticaria will be 
allowed to enroll into this study to collect the safety data in Japanese CSU patients.
After the completion of the treatment period, subjects will enter a post-treatment follow-up 
period to allow for further characterization of 
 
, collection of additional efficacy and safety data (eg, 
relapse), and evaluation of the presence of anti-drug antibodies (ADAs).
4.1.1
Rationale for choice of background therapy
All subjects will receive standard of care therapy (H1-antihistamines at (local) approved 
doses) as background medication. Subjects must remain on a stable treatment regimen (type 
and dose of H1-AH) throughout the study. If a subject must switch to another background H1-
antihistamines (at approved dose) as a result of an AE, the subject will be considered to have 
remained on stable treatment.
4.2
Rationale for dose/regimen and duration of treatment
Rationale for dose/regimen
One ligelizumab dose of 120 mg will be tested in this Phase III study. On-going global Phase 
III studies [CQGE031C2302] / [CQGE031C2303] are evaluating two doses of ligelizumab, 72 
mg and 120 mg in CSU patients including Japanese.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for route of administration
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Ligelizumab was administered subcutaneously in the CQGE031C2201 study and is also 
administered subcutaneously in the on-going Phase III studies CQGE031C2302 and 
CQGE031C2303. The subcutaneous 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.
 
 
 
 
 
 
 
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
No formal interim analysis is planned for this study.
4.5
Risks and benefits
In the overall ligelizumab clinical program, approximately 900 subjects have been exposed 
across 12 studies, covering the indications of CSU, asthma, atopic dermatitis, and bullous 
pemphigoid (BP). The longest individual continuous exposure to ligelizumab is 12 months 
([CQGE031C2201E1] and [CQGE031B2201E1]). Cumulative (continuous and interrupted) 
human duration of exposure to ligelizumab is approximately 16 and 17 months (across the 
[CQGE031B2201]/CQGE031B2201E1 
asthma 
studies 
and 
the 
[CQGE031C2201]/CQGE031C2201E1 CSU studies, respectively). The following doses have 
been tested in the clinical programs: 12 mg, 24 mg, 36 mg, 72 mg, 180 mg and 240 mg sc q4w, 
280 mg q2w and 120 mg sc single dose. To date in the CSU program alone, 254 subjects have 
been exposed to ligelizumab at doses up to 240 mg sc q4w.
Overall, no apparent dose-dependent safety signals (except for a trend in injection site reactions, 
which can be easily managed clinically) have been observed to date, although the number of 
subjects studied is relatively small, in line with the development phase of the CSU program. In 
the clinical study CQGE031B2201 in the patients with asthma, there appeared to be a dose 
dependency of injection site reactions between ligelizumab high dose group (28.6% of 199 
subjects) and ligelizumab low dose group (12.5% of 40 subjects), which was comparable to 
omalizumab (14.5% of 131 subjects). The incidence of injection site reactions was higher 
among all the active treatment groups compared to that of placebo (5.2% of 96 subjects). 
Similarly, in the CSU dose-finding study (CQGE031C2201), the overall safety profile was 
comparable between different doses of ligelizumab (24 mg, 72 mg and 240 mg q4w or 120 mg 
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single dose), omalizumab and placebo. In both studies (CQGE031B2201 and CQGE031C2201), 
the patients on the higher doses of 180 mg and 240 mg had 2 injections with active in contrast 
to the patients on lower doses of 12 mg, 36 mg, 72 mg and 120 mg who received one active and 
one placebo injection. The exceptions were AEs related to injection site reactions, where a 
possible trend of dose dependency for ligelizumab was observed. All cases of injection site 
reactions (except 1 case of medical significance) regardless of treatment group or doses were 
non-serious, mild to moderate in severity, reversible, and did not lead to discontinuation of 
study treatment.
With regards to Serious Adverse Events (SAEs), the incidence of SAEs was comparable 
between subjects treated with ligelizumab and those receiving placebo in both asthma and CSU 
indications. There has been no dose dependency in SAEs observed among subjects treated with 
different doses of ligelizumab ([CQGE031B2201] in asthma and [CQGE031C2201] in CSU).
IgE is an antibody that may have an adaptive role in immunity to parasitosis, particularly 
helminthic infections. Thus, blocking the interaction of IgE and its receptors with ligelizumab 
may alter immunologic responsiveness to parasites. Bearing this in mind, monitoring for the 
occurrence of infection and response to therapy is recommended for subjects at high risk of 
geohelminth infection who receive ligelizumab. Insufficient data are available to determine the 
length of monitoring required for geohelminth infections after stopping ligelizumab. However, 
it is expected that ligelizumab will not interfere with a polyclonal reaction triggered by exposure 
to parasites. .
Therefore, based on the cumulative data available across all clinical studies in different patient 
populations for ligelizumab, the current evidence demonstrates that ligelizumab demonstrates 
a favourable benefit-risk profile and is well-tolerated and thus appropriate for further 
development.
The data from CQGE031C2201 demonstrates that ligelizumab administration results in 
significant improvement of CSU symptoms including itch, hives, angioedema and quality of 
life (QoL) irrespective of 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, the use of an electronic diary at home to 
monitor symptoms 
.
Investigators will be instructed on acceptable treatments for managing worsening of disease 
with rescue medication during the course of this study (see Section 6.2.3 ), thereby allowing 
subjects to continue in the study as long as possible. The investigator will provide the subject 
with written instructions to contact them if symptoms of CSU worsen.
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to acceptable  
contraception measures as outlined in the exclusion criteria (Section 5.2). If there is any 
question that the subject will not reliably comply, they should not be entered or continue in the 
study.
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5
Population
The study population will consist of approximately 65 male and female subjects aged ≥ 18 years 
who have been diagnosed with CSU and who remain symptomatic despite the use of H1-AH.
It is anticipated that approximately 81 subjects will need to be screened (an estimated screening 
failure rate of 20%) in order to enroll approximately 65 subjects into the 52 week treatment 
period (see Figure 3-1 ).
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
Main study
1. Signed informed consent must be obtained prior to participation in the study.
2. Male and female subjects ≥18 years of age at the time of screening
3. CSU diagnosis for ≥ 6 months (defined as onset of CSU with supporting documentation).
4. Diagnosis of CSU refractory to H1-AH at locally approved doses at the time of baseline 
(Visit 110, Day1), as defined by all of the following:
a. The presence of itch and hives for ≥6 consecutive weeks at any time prior to Visit 1 
(Day -28 to Day -14) despite current use of non-sedating H1-AH (at locally approved 
doses) during this time period
b. UAS7 score (range 0-42) ≥16 and HSS7 (range 0-21) ≥8 during the 7 days prior to 
baseline (Visit 110, Day 1)
c. Subjects must be on H1-AH at only local label approved doses for treatment of CSU for 
starting at Visit 1 (Day -28 to Day -14)
5. Willing and able to complete a daily symptom eDiary for the duration of the study and 
adhere to the study visit schedules.
6. Subjects must not have had any missing eDiary entries in the 7 days prior to baseline (Day 
1, Visit 110). i.e., 14 eDiary entries required. Re-screening may be considered only once.
 
5.2
Exclusion criteria
Main study
1. Use of other investigational biological drugs within 5 half-lives, or within 30 days (for 
small molecules) prior to Visit 1, or until the expected PD effect has returned to baseline 
(for biologics), whichever is longer.
2. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes (i.e. to murine, chimeric, or human antibodies).
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3. Subjects having a clearly defined, predominant trigger of their chronic urticaria (chronic 
inducible urticaria) including:
- urticaria factitia (symptomatic dermographism), cold-, heat-, solar-, pressure-, delayed 
pressure-, aquagenic-, cholinergic-, or contact-urticaria.
4. Diseases, other than chronic urticaria, with urticarial or angioedema symptoms such as 
urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa), 
and hereditary or acquired angioedema (e.g., due to C1 inhibitor deficiency).
5. Subjects with evidence of helminthic parasitic infection as evidenced by stools being 
positive for a pathogenic organism according to local guidelines. All subjects will be 
screened at Visit 1(see Section 8.4.3). If stool testing is positive for pathogenic organism, 
the subject will not enter treatment period and will not be allowed to rescreen.
6. Any other skin disease associated with chronic itching that might influence in the 
investigator's opinion the study evaluations and results (e.g. atopic dermatitis, bullous 
pemphigoid, dermatitis herpetiformis, senile pruritus, etc.).
7. Prior exposure to ligelizumab.
8. Any H2 antihistamine use after Visit 1.
9. Any LTRA (montelukast or zafirlukast) after Visit 1.
10. Any H1 antihistamine used as background medication at greater than local label approved 
doses after Visit 1.
11. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to 
baseline (Visit 110, Day 1).
12. Inability to comply with study and follow-up procedures.
13. Use of prohibited treatment detailed in protocol (Table 6-2).
14. Contraindications to or hypersensitivity to suggested rescue medications including but not 
limited to fexofenadine, loratadine cetirizine, rupatadine, epinephrine, levocetirizine, 
desloratadine or any of their ingredients.
15. Documented history of anaphylaxis.
16. History of malignancy of any organ system within the past 5 years (except for basal cell 
carcinoma, actinic keratoses or Bowen disease (carcinoma in situ) that have been treated 
with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or 
non-invasive malignant colon polyps that have been removed).
17. Presence of clinically significant cardiovascular (such as but not limited to myocardial 
infarction, unstable ischemic heart disease, New York Heart Association (NYHA) Class 
III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 12 months 
prior to Visit 1), neurological, psychiatric, metabolic, or other pathological conditions 
such as but not limited to cerebrovascular disease, neurodegenerative 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 subjects, interfere with evaluation or 
interpretation of the study results, or preclude completion of the study.
18. Medical examination or laboratory findings that suggest the possibility of decompensation 
of co-existing conditions for the duration of the study. Any items that are cause for 
uncertainty will be reviewed with the investigator.
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19. History of, or current treatment for, hepatic disease including but not limited to acute or 
chronic hepatitis, cirrhosis or hepatic failure or Aspartate aminotransferase (AST)/Alanine 
aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) and
International Normalized Ratio (INR) of more than 1.5 at Visit 1.(see Section 8.4.1)
20. History of renal disease or creatinine level above 1.5x ULN at Visit 1.
21. Platelets < 100,000/μL at Visit 1.
22. History of long QT syndrome or whose QT interval corrected by Fridericia's formula 
(QTcF) (Fridericia) measured at Visit 1 is prolonged (> 450 ms for males or > 460 ms for 
females) and confirmed by a central assessor (these subjects should not be re-screened).
23. Pregnant or nursing (lactating) women.
24. Women of child bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic (acceptable effective) methods of 
contraception for the duration of study (approx. 4 months, i.e. 5 half-lives, after last dose 
of ligelizumab). Acceptable contraception methods include:
a. 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
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject
d. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps)
e. Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should be stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
 
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6
Treatment
6.1
Study treatment
6.1.1
Investigational drugs
Table 6-1
Investigational drug
Investigational Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administrati
on
Supply Type
Sponsor (global 
or local)
Ligelizumab 120 mg 
per 1 mL
Liquid in vial
sc
Open label 
subject packs; 
vials
Sponsor local
6.1.2
Additional study treatments
No other additional treatment beyond investigational treatment is requested for this trial. 
Subjects will continue to use their background medication H1-antihistamines at (locally 
approved doses) with a stable regimen during the study. For rescue medication, see 
Section 6.2.3.
6.1.3
Treatment arms/group
All eligible subjects will be assigned at Visit 110 to ligelizumab group. Each subject will receive 
1 injection of 1.0 mL ligelizumab every 4 weeks.
During the treatment period, study drug will be administered for 13 visits as per Table 8-1.
6.1.4
Treatment duration
The planned duration of treatment is 52 weeks. Subjects may be discontinued from treatment 
earlier due to safety concerns or disease progression and/or at the discretion of the investigator 
or the subject. For subjects who in the opinion of the investigator are still deriving clinical 
benefit from QGE031, every effort will be made to continue provision of study treatment.
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6.2
Other treatment(s)
6.2.1
Concomitant therapy
This study requires concurrent use of one second generation H1-AH at locally approved doses 
as background medication. Subjects must remain on a stable treatment regimen (type and dose 
of H1-AH) throughout the study.
If a subject must switch to another background H1-AH (at approved dose) as a result of an AE, 
the subject will be considered to have remained on stable treatment.
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study must be recorded on the appropriate electronic Case 
Report Forms (eCRF).
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
entering a subject into treatment period or allowing a new medication to be started.
6.2.2
Prohibited medication
Use of the class of treatments displayed in Table 6-2 is NOT allowed after start of screening. 
The minimum required period without prohibited treatment before Visit 1 is also listed in 
Table 6-2. Each concomitant medication must be individually assessed against all exclusion 
criteria and the table below to see if it is allowed. If in doubt, the investigator should contact 
Novartis medical monitor or delegate before entering a subject to treatment period or allowing 
a new medication to be started.
Table 6-2
Prohibited medication
Medication
Minimum required period without 
medications
Omalizumab
4 months prior to Visit 1
Ligelizumab
No prior use allowed
Routine (more than 3 doses over a 5 day period) 
oral corticosteroids*
30 days prior to Visit 1
IV/IM/IA corticosteroids
30 days prior to Visit 1
Beta-blocker therapy
7 days prior to Visit 1
Leukotriene antagonists
Stop at Visit 1
H2-antihistamines
Stop at Visit 1
First generation H1-antihistamines
Stop at Visit 1
Hydroxychloroquine or chloroquine
30 days prior to Visit 1
Other immunosuppressive medication with or 
without known effect on CSU including but not 
limited to Methotrexate, cyclosporine A, 
cyclophosphamide, tacrolimus and 
mycophenolate mofetil
30 days prior to Visit 1
Intravenous immunoglobulin G
30 days prior to Visit 1
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Medication
Minimum required period without 
medications
Plasmapheresis
30 days prior to Visit 1
Regular (daily or every other day) doxepin (oral)
14 days prior to Visit 1
Vaccination with inactivated viruses
48 hours prior to each dosing visit (i.e. Visit 110 
to Visit 230)
Live attenuated vaccine
30 days prior to Visit 1
 
* Allowed only as rescue therapy only after Week12, on an as-needed basis for unbearable symptoms 
as per Section 6.2.3. Other preparations of CS with limited systemic exposure for non-CSU indications 
can be used (e.g. Intra nasal or topical CS) as needed basis.
If the prohibited treatment was used during the study for any indication, the subject must 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. If the 
subject received a live virus vaccination during the study, the subject must discontinue study 
treatment.
If a subject takes concomitant omalizumab (outside of study assigned tr
 in the follow-
up phase, the subject must discontinue from the study, in which case
ADA samples 
should not be collected at the End of Study (EoS) visit.
The table is not considered all inclusive. Medication should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.
6.2.3
Rescue medication
In addition to being used as background medication (see Section 6.2.1 ), the non-sedating 
H1-AH fexofenadine, loratadine, cetirizine, rupatadine levocetirizine and desloratadine will 
also be allowed as rescue medication used on an as needed basis for subjects with flare-ups of 
unbearable symptoms of their disease during screening, treatment and post-treatment follow-
up periods. The selection of a H1-AH rescue medication should be made only once for an 
individual subject. For each individual subject, the AH rescue medication used must differ from 
the AH used for background medication (see Section 6.2.1 ), in order to avoid AHs at non-
approved doses. A switch of the H1-AH rescue medication for an individual subject is not 
permitted except due to an adverse event.
Prior to Week 12, any corticosteroid use for CSU is prohibited. After the Week 12, subjects will 
be permitted to use oral corticosteroids such as prednisone, or its equivalent, as rescue 
medication if needed. The selection of oral corticosteroid to be used as rescue medication after 
Week12, should be made only once for an individual subject. A switch of oral corticosteroids 
as rescue medication for an individual is not permitted except due to an adverse event. The CSU 
treatment guidelines suggest that systemic corticosteroids may be used for up to 10 consecutive 
days to manage flare-ups in clinical practice. However in this clinical study, corticosteroid use 
will be limited to 3 days in a 30 day period and a maximum of 9 doses in total (i.e. a maximum 
of 9 days of corticosteroids in total) after Week 12 to avoid any confounding suppression of 
signs and symptoms of CSU.  If a subject uses more than 3 doses of corticosteroid in a 30 day 
period or more than 9 doses of corticosteroid in total during the study period (including the 
follow-up period), the subject will be discontinued from study treatment.
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Rescue medication will be sourced locally.
 
 
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.; as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available.
6.3.2
Treatment assignment, randomization
This is a single arm, non-randomized study.
Upon completion of all the required screening assessments, eligible subjects will start 
ligelizumab treatment at Visit 110.
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff, persons performing the assessments.
6.5
Dose escalation and dose modification
Study drug dose adjustments are not permitted. Any interruption of study drug administration 
should be discussed with Novartis or delegate regarding the subject’s eligibility to continue 
investigational treatment.
Any missed or altered study drug administration must be recorded on the appropriate eCRF in 
order to reconstruct an accurate dosing history for each subject.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Subjects will receive 1 subcutaneous injection every 4 weeks at 13 visits during the treatment 
period. Compliance is assured as study drug must/ will be administered by investigator and/or 
study personnel via subcutaneous injection at the site. Administration of study drug must be 
recorded in the source documents and the corresponding eCRF for each administration.
6.6.2
Emergency breaking of assigned treatment code
Not applicable for this open-label study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under Section 6.7.1.1.
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6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels 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 (CO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
The injections can be administered in the deltoid region on the right and/or left arm, and/or in 
the right and/or left thigh, or the abdomen as preferred by subject and/or site. The injections are 
administered subcutaneously after aspiration of the plunger of the syringe. If blood appears at 
the needle hub or blood is drawn into the syringe upon aspiration, the needle must be withdrawn 
without administration of the dose and the injection site changed. Each injection must be 
administered at a different site (eg, right arm and left thigh).
The guidelines for the preparation and administration of study medication are described in the 
pharmacist manual.
Subjects will remain on-site for observation for a period of 2 h post-dose for the first 3 study 
drug administrations at Visits 110, 120 and 130, and 30 min post-dose for all other drug 
administrations. These observation periods follow the recommendation suggested by the 
National Heart, Lung, and Blood Institute and by the American Academy of Allergy, Asthma 
& Immunology and the American College of Allergy, Asthma and Immunology Executive 
Committees Joint Task Force (Cox et al 2007) for the anti-IgE therapy currently available 
(omalizumab). As described in the Investigator Brochure (IB), the site needs to ensure readiness 
to react to anaphylactic events (eg, have available injectable epinephrine, antihistamine, 
corticosteroids, intravenous supplies, oxygen, an oral airway, Ambu bag and the ability to 
transport a subject rapidly to an emergency department/hospital).
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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.
The investigator must promote compliance by instructing the subject to ensure scheduled visits 
are made to the site in order to take the study treatment as prescribed and by stating that 
compliance is necessary for the subject’s safety and the validity of the study.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonisation of Technical Requirements for 
Registration for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the acceptable contraception requirements.
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
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8
Visit schedule and assessments
Table 8-1 lists all of the assessments. All data obtained from the assessments listed in Table 8-1
must be supported in the subject’s source documentation. The table indicates which data are 
entered into the eCRF from the source data (X), remain in the source documents only (S) or are 
loaded into the database from separate source documents, i.e. outside vendors (XS).
Subjects must be seen for all visits on the designated day, or as close to it as possible. The 
subject should be instructed to contact the investigator if he/she is unable for any reason to 
attend the visit as planned and the visit should be rescheduled as close as possible to the original 
date. Missed or rescheduled visits should not lead to automatic treatment or study 
discontinuation.
All subjects who complete the treatment period will be expected to attend all follow-up visits 
(Visit 310 to 1999).
Subjects who discontinue treatment early will be expected to perform the Week 52 assessment 
(last visit in the treatment period) 4 weeks after they receive their last dose. At the final visit, 
all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the eCRF.
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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Follow-up
Unplanned
Visit Name
1
110 120 130 140 150 160 170 180 190 200 210 220 230 240/EoT/TD1 310 320 1999/EoS/PSD2
UPV3
Days
-28 to -14
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421
449
-
Weeks
-4 to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
-
Informed consent
X4
Inclusion / Exclusion criteria
X
X
Demography
X
Relevant medical history (including 
CSU history)
X
Evidence of urticaria
X
Prior urticaria treatment
X
Family malignancy history (CRF to 
be completed if subject develops 
malignancy during the study)
X
Prior and Concomitant medication 
usage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Surgery and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Re-screening (re-screening eCRF 
should be recorded if the subject is 
re-screened)
X
Dispense H1-AH rescue 
medication
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Dispense oral corticosteroid rescue 
medication14
S
S
S
S
S
S
S
S
S
S
S
S
S
Study drug administration
X
X
X
X
X
X
X
X
X
X
X
X
X
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Period
Screening
Treatment
Follow-up
Unplanned
Visit Name
1
110 120 130 140 150 160 170 180 190 200 210 220 230 240/EoT/TD1 310 320 1999/EoS/PSD2
UPV3
Days
-28 to -14
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421
449
-
Weeks
-4 to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
-
ePROs should be completed prior 
to any other assessment and prior 
to administration of any 
medication7
Dispense Subjects’ eDiary
S
Collect Subjects’ eDiary
S
Subjects’ eDiary (review 
compliance) Includes the urticaria 
patient daily diary (UPDD) 
 
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
DLQI (Dermatology Life Quality 
Index)
XS
XS
XS
XS
XS
XS
XS
XS
XS
Laboratory evaluations
Stool ova and parasite evaluation8
X
X
X
Hematology (*INR at Visit1, Visit 
110 and UPV)
XS*
XS* XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS*
Clinical chemistry (**hCG at Visit 1 
only)9
XS**
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Anti-Drug(ligelizumab) antibodies 
(ADA)
X
X
X
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Period
Screening
Treatment
Follow-up
Unplanned
Visit Name
1
110 120 130 140 150 160 170 180 190 200 210 220 230 240/EoT/TD1 310 320 1999/EoS/PSD2
UPV3
Days
-28 to -14
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421
449
-
Weeks
-4 to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
-
Urine dipstick (local) (When a 
dipstick evaluation is abnormal, eg 
positive for WBC and/or blood, a 
urine sample must be sent for 
microscopic examination to the 
central lab)
X
X 
X
X
X
Serum β-hCG (for all
pre-menopausal
women who are not
surgically sterile)
Section 8.4.4
XS
Urine Pregnancy Test (local) (If 
positive, confirmation by serum β-
hCG test should be done by 
central lab)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Safety
Physical Examination11
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
X
Electrocardiogram (ECG)12
XS
XS
XS
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver safety monitoring
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Renal safety monitoring
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Others
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Period
Screening
Treatment
Follow-up
Unplanned
Visit Name
1
110 120 130 140 150 160 170 180 190 200 210 220 230 240/EoT/TD1 310 320 1999/EoS/PSD2
UPV3
Days
-28 to -14
1
29
57
85
113 141 169 197 225 253 281 309 337
365
393 421
449
-
Weeks
-4 to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
-
Treatment completion/ 
discontinuation form
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 EoT = End of Treatment, TD = Study Treatment Discontinuation
2 EoS = End of study, PSD = Premature Subject Discontinuation
3 UPV = Unplanned visit (NOTE – assessments as listed should be done only at the discretion of the investigator, according to the reason for the 
unplanned visit)
4 IC obtained prior to all study-specific screening procedures during or as close to the start of the screening period as possible
 
6 XS=assessment data to be received in loaded format from separate source documents i.e. external vendors
7 ePRO = Electronic Patient Reported Outcomes
8 If diarrhea, or any other symptoms suggestive of parasitic infection, develops at any time between visits before end of study, additional stool sampling 
for assessment of parasitic conditions should be done as soon as possible. At Visit 1 and Visit 320, dispense 3 stool collection kits. Patients should 
collect samples, within seven days of Visit1 and in the week prior to Visit 1999/EOS/PSD.
9 hCG = human Chorionic Gonadotropin
10 Samples to be taken pre-dose. 
ADA samples should not be collected at the End of Study (EoS) visit, if the subject takes omalizumab (outside of the study 
assigned treatment).
11 Physical exam on Screening Visit 1 is comprehensive but subsequent physical exams maybe limited
12 Single ECG to be taken at Visits 1 and 240/EoT/TD
 
14 A subject must not have access to more than 3 doses of corticosteroids in a 30 day period or more than 9 doses of corticosteroid in total during the 
study period( including the follow-up period)..
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8.1
Screening
Subjects will have up to 4 week screening period to establish eligibility for the study. Subjects 
will be required to attend 1 visit during screening period: Visit 1 (Day -28 to Day -14). An 
extended screening period will be permitted only in exceptional circumstances when 
information concerning eligibility is outstanding (eg, pending laboratory data).
Rescreening may be allowed for subjects who failed initial screening as described in Section 3. 
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. 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 serious adverse event during the screening phase (see Section 10.1.3 for reporting 
details). Adverse events that are not SAEs will be followed by the investigator and collected 
only in the source data.
Subjects who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered a prematurely withdrawn subject. The reason for 
prematurely withdrawn should be captured on the appropriate disposition 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. 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), 
 
Dermatology Life Quality Index (DLQI), 
 
 will be assessed at sites at the visits described in Table 8-1.
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 should be completed prior to any other assessment (except at Visit 1) 
and prior to administration of any investigational medication.
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8.3.1
Electronic Diary (eDiary) assessments
8.3.1.1
Urticaria Patient Daily Diary (UPDD)
UPDD includes Urticaria Activity Score (UAS) which assesses twice daily the severity of itch 
and number of hives, 
 
 
ection 16.4 Appendix 4, Patient Diary: Urticaria Patient Daily Diary (UPDD)). The 
components are presented in the Table 8-2 and the relevant weekly scores are described below.
Table 8-2
Urticaria Patient Daily Diary (UPDD)
Diary component
When assessed
Urticaria Activity Score (UAS)
● Itch severity
● Number of hives
Morning and evening
Sleep interference
Morning
Daily activity interference
Evening
 
8.3.1.1.1 Weekly Hives Severity Score (HSS7)
The hives severity score, defined by number of hives (wheals), will be recorded by the subject 
twice daily in their eDiary, on a scale of 0 (none) to 3 (see Table 8-3). A weekly score (HSS7) 
is derived by adding up the average daily scores of the seven preceding days. The possible range 
of the weekly score is therefore 0 – 21.
Complete hives response is defined as HSS7 = 0.
Table 8-3
Hives Severity Score
Score
Hives (Wheals) (every 12 hours)
0
None
1
1-6 hives/12 hours
2
7-12/12 hours
3
> 12 hives/12 hours
When either the morning or evening score is missing, the non-missing score for that day 
(morning or evening) will be used as the daily score. When 1 or more of the daily scores are 
missing, the following principles will be applied to handle the missing data:
The weekly Hives Severity Score (HSS) score will be derived based on the sum of the available 
eDiary score during that week. It will be considered calculable with at least 4 daily scores 
provided in that week, otherwise, the weekly score will be left missing.
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Note that for the screening assessments, 14 of 14 consecutive eDiary entries are required in the 
7 days prior to baseline as per inclusion criteria.
8.3.1.1.2 Weekly Itch Severity Score (ISS7)
The severity of the itch will be recorded by the subject twice daily in their eDiary, on a scale of 
0 (none) to 3 (intense/severe) (see Table 8-4). A weekly score (ISS7) is derived by adding up 
the average daily scores of the seven 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 weekly HSS.
Complete itch response is defined as ISS7 = 0.
Table 8-4
Itch Severity Score
Score
Pruritus (Itch) (every 12 hours)
0
None
1
Mild (minimal awareness, easily tolerated)
2
Moderate (definite awareness, bothersome but tolerable)
3
Severe (difficult to tolerate)
8.3.1.1.3 Weekly Urticaria Activity Score (UAS7)
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly 
UAS7 score is 0 – 42 (highest activity).
Complete UAS7 response is defined as UAS7 = 0.
 
 
 
 
 
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8.3.2
Other PRO assessments
8.3.2.1
Dermatology Life Quality Index (DLQI)
The Dermatology Life Quality Index (DLQI) is a 10-item (grouped in 6 domains) dermatology-
specific quality of life (QoL) measure (Finlay and Khan 1994). The DLQI was validated for 
patients aged 16 and above.
In this study, subjects rate their dermatology symptoms as well as the impact of their skin 
condition on various aspects of their lives thinking about the previous 7 days.
An overall score is calculated and ranges from 0 to 30 (higher score meaning worse 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).
The scores were split into score bands (Hongbo et al 2005) and validated in terms of their 
meaning/relevance to patients as follows:
Table 8-8
DLQI score bands and impact on patient’s life
DLQI band
Significance of score
0-1
No effect on patients life
2-5
Small effect on patients life
6-10
Moderate effect on patients life
11-20
Very large effect on patients life
21-30
Extremely large effect on patients life
A DLQI score of > 10 is relevant for a very large impact on patients’ life and usually considered 
as a justification for a biologic prescription for example in psoriasis (Finlay 2005). The 
DLQI questionnaires are administered at baseline (Visit 110, Day 1) and at Weeks 4, 8, 12, 24, 
52 and every visit in the follow-up period.
 
 
 
 
 
 
 
 
 
 
 
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8.3.3
Other assessments: Evidence of urticaria
The investigator must confirm the presence of urticaria in each subject at Screening visit (Visit 
1) by direct physical examination. In the absence of active disease being visible at Visit 1, the 
following will be acceptable: (a) a clearly identifiable photograph of the subject showing the 
presence of urticaria, or (b) the investigator must have seen the subject with active CSU in the 
past 6 months.
8.3.4
Appropriateness of efficacy assessments
At the time the omalizumab studies were carried out, the treatment paradigm focused primarily 
on itch (ISS7) as a key symptom of CSU. Over the past several years the goal of therapy has 
evolved and the current target of therapy as described in the current CSU treatment guidelines 
(Zuberbier et al 2018) is to treat the disease until it is gone, i.e. complete control of the disease 
(UAS7 = 0). Given the current emphasis on UAS7 in the medical community and as reflected 
in the CSU treatment guidelines, data from the Phase II study CQGE031C2201 support the 
change from baseline in UAS7 (which is a composite of ISS7 and HSS7) as well as the 
achievement of UAS7 = 0 over time which will be assessed as secondary endpoints included in 
the testing strategy.
Disease recurrence after study drug is withdrawn will be measured during the post-treatment 
follow-up period. For all subjects, symptom scores will be measured during both the treatment 
and post-treatment follow-up periods.
Data collected during this study will be used to provide information that will support selection 
of doses for further evaluation and patient reported outcome (PRO) tools and potential 
biomarkers which may be included in future studies.
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8.4
Safety
Main safety and tolerability assessments include:
!
AEs and SAEs, including AEs leading to treatment discontinuation and events of interest 
such as injection site reactions, anaphylaxis, pre-malignancy/malignancy, cardio-
cerebrovascular events
!
Physical examination
!
Vital signs
!
Laboratory evaluations
!
ECG (Electrocardiogram)
Table 8-9
Assessments & Specifications
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, and extremities and vascular and 
neurological systems. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
A short physical exam will include the examination of general appearance 
and vital signs. A short physical exam will be conducted at all visits 
starting from Visit 1 except where a complete physical examination is 
required (see Table 8-1). Information for all physical examinations must be 
included in the source documentation at the study site. Clinically relevant 
findings that are present prior to signing informed consent must be 
recorded on the appropriate eCRF that captures medical history. 
Significant findings made after signing the informed consent which meet 
the definition of an Adverse Event must be recorded as an Adverse Event.
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 Section 16.1 Appendix 1.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured as specified in 
Table 8-1.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section unless 
noted otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual.
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Clinically notable laboratory findings are defined in Section 16.1 Appendix 1. In case of lab 
abnormalities, an additional re-draw for central laboratory assessment is allowed during the 
screening period to confirm eligibility criteria.
Clinically significant abnormalities must be recorded on the relevant section of the Case 
report/Record Forms (CRFs) capturing medical history/Current medical conditions/AEs.
A sample for serum β-hCG assessment will be collected at screening Visit 1 for all pre-
menopausal women who are not surgically sterile.
Table 8-10
Laboratory Assessments
Test Category
Test Name
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential and platelet count will be measured.
Coagulation
At Visits 1 and 110 coagulation will be assessed by International 
Normalized Ratio (INR).
Chemistry
Albumin, total bilirubin, alkaline phosphatase, AST, ALT, LDH, GGT, 
chloride, sodium, potassium, magnesium, calcium, inorganic phosphorus, 
creatinine, urea/BUN and uric acid will be measured. If the total bilirubin 
concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated. Serum hCG is 
assessed at Visit 1 only.
Urinalysis
A midstream urine sample (approximately 30 mL) will be obtained, in order 
to avoid contamination with epithelial cells and sediments, and allow 
proper assessments. Semi-quantitative “dipstick” evaluation for specific 
gravity, glucose, protein, bilirubin, ketones, leukocytes, blood and pH will 
be performed at site. When a dipstick evaluation is abnormal, eg, positive 
for WBC and/or blood, a urine sample must be sent to the Central Lab for 
microscopic examination including RBC and WBC. (Details on collection 
of urine for analysis by central laboratory are provided to investigators in 
the laboratory manual.)
Parasite screening
Assessment of stool samples for parasitic infections (refer to Assessment 
of parasitic infections Section 8.4.3)
Pregnancy Test
Serum / Urine pregnancy test (refer to Pregnancy and assessments of 
fertility Section 8.4.4). If urine preganancy test is positive, confirmation by 
serum β-hCG test should be done by central lab. 
WBC: white blood cell(s); RBC: red blood cell(s); LDH: lactate dehydrogenase; GGT: gamma-glutamyl 
transferase
8.4.2
Electrocardiogram (ECG)
Standard 12 lead ECGs must be recorded after 10 minutes rest in the supine position to ensure 
a stable baseline. The preferred sequence of cardiovascular data collection during study visits 
is ECG collection first, followed by vital signs, and blood sampling. The Fridericia QT 
correction formula (QTcF) should be used for clinical decisions.
Single ECGs will be collected at Visits 1 and Visit 240/End of treatment (EoT)/Sudy Treatment 
Discontinuation (TD).
The original ECG will be sent electronically to the Clinical Research Organization (CRO) 
directly from the provided ECG machine. Two “identical” duplicate print-outs will be generated 
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on non-heat sensitive paper and kept at the investigator site as source documentation and as 
back-up for submission to the vendor in case of problems with the electronic transmission. The 
“identical” duplicates must be labeled with study number, subject initials, subject number, date 
and time, and signed and archived in the study site source documents.
Clinically significant ECG findings prior to dosing with investigational treatment must be 
discussed with the sponsor. Clinically significant abnormalities must be recorded on the 
relevant section of the CRFs capturing Medical history/Current medical conditions/AE as
appropriate.
Full details of all procedures relating to the ECG collection and reporting will be contained in 
a technical manual to be provided by the CRO to each investigator site.
For any ECGs with subject safety concerns, 2 additional ECGs must be performed to confirm 
the safety finding.
8.4.3
Assessment of parasitic infections
 
 
 
.
All subjects will be given three stool sample collection kits at screening Visit 1 and Visit320 by 
the site or site’s local laboratory. Subjects will take the stool sample kits home and collect stool 
samples, from three different bowel movements, ideally on three different days, within seven 
days of Visit 1 and in the week prior to Visit 1999. Subjects will return the three stool samples 
to the site as soon as possible after Visit 1 (in order to allow processing within the screening 
period) and at Visit 1999.
Stool samples for parasitic disease will be examined for ova and parasites by the local laboratory. 
The identification of organisms in positive stools will be made by local laboratory. If stool 
testing is positive for pathogenic organisms (pathogenic as defined by the local laboratory), the 
result must be recorded in the eCRF and the subject will not enter treatment period and will not 
be allowed to rescreen. Stool samples negative for pathogenic organisms must be recorded in 
the eCRF before Visit 110.
Subjects must be advised that if diarrhea, or any other symptoms suggestive of parasitic 
infection, develops at any time before the end of study, three additional stool samples must be 
collected at next visit or sooner and sent to local laboratory for analysis.
8.4.4
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have sample for serum β-hCG 
test collected at screening Visit 1. Post-menopausal status should be recorded in the CRF.
At Visit 110 and subsequent study visits until Visit 1999/EOS/PSD, all pre-menopausal women 
who are not surgically sterile will have urine pregnancy testing performed BEFORE 
administration of the study medication. A positive urine test needs to be confirmed with a 
central lab serum test prior to study drug administration. If positive, the subject must be 
discontinued from study treatment. 
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Additional pregnancy testing might be performed if requested by local regulatory/ethics 
committee requirements.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required at screening/baseline.
8.4.5
Anaphylaxis assessment
An adjudication committee (AC) will be put in place to determine whether cases of 
hypersensitivity identified through a search algorithm based on the Standardized Medical 
dictionary for regulatory activities (MedDRA) Queries may represent cases of anaphylaxis. 
Further details regarding the AC will be documented in the AC charter. See Section 10.2.3 for 
details.
8.4.6
Assessment of cardio-cerebrovascular events
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of cardio-cerebrovascular events. The clinical presentation 
and association of these events with pre-existing risk factors will be part of the assessment. See 
Section 10.2.3 for details.
8.4.7
Assessment of neoplastic events
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of neoplastic events. The clinical presentation and 
association of these events with pre-existing risk factors will be part of the assessment. See 
Section 10.2.3 for details.
8.4.8
Appropriateness of safety measurements
In addition to safety assessments that are standard in this population, the potential of selected 
biomarkers will be evaluated for monitoring subjects’ safety. Events of special interest such as 
anaphylaxis, malignancies, and cardio-cerebrovascular events will be monitored and will be 
adjudicated by expert ACs.
8.5
Additional assessments
 
 
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8.5.3
Anti-ligelizumab antibody in serum
The presence of anti-ligelizumab antibodies will be assayed using a 3-tiered testing strategy 
consisting of a screening assay, a confirmatory assay and a titration of anti-ligelizumab 
responses by a titration assay for samples confirmed positive. A specific assay will be used to 
determine if ADAs are neutralizing in nature.
The detailed method to assess immunogenicity will be described in the bioanalytical raw data 
of the study and in the bioanalytical data report.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 decision
!
Adverse events for which continued exposure to the study drug would be detrimental
!
Abnormal renal laboratory results requiring discontinuation (see Section 16.3 Appendix 3)
!
Abnormal liver laboratory results requiring discontinuation (see Section 16.2 Appendix 2)
!
Platelets < 75,000/μL
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!
Pregnancy (See Section 8.4.4 and Section 10.1.4)
!
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 received a live virus vaccination during the study
!
Subject experiences an unexpected hypersensitivity reaction of grade 5, as defined by the 
World Allergy Organization Grading System (Cox et al 2017), see Section 16.6 Appendix 
6: 
!
Lower or upper respiratory: Respiratory failure with or without loss of consciousness; 
or
!
Cardiovascular: Hypotension with or without loss of consciousness
!
Emergency use of epinephrine due to anaphylactic or anaphylactoid reaction
!
Any other protocol deviation that results in a significant risk to the subject’s safety
!
Any situation in which study participation might result in a safety risk to the subject
!
If a subject uses rescue oral corticosteroids for CSU more than 3 doses in a 30 day period 
or more than 9 doses of in total after week 12 during the study period (including the 
follow-up period).
If discontinuation of investigational treatment occurs, the investigator should make a reasonable 
effort to understand the primary reason for the subject’s premature discontinuation of study 
treatment and record this information. Always consider reasons which are related to safety and 
efficacy first.
Subjects who discontinue investigational treatment or who decide they do not wish to 
participate in the study further should NOT be considered withdrawn from the study UNLESS 
they withdraw their consent (see Section 9.1.2, withdrawal of informed consent). They will be 
expected to perform the Wk 52/Visit 240/EoT/TD assessments 4 weeks after their last dose and 
will be expected to perform all follow-up assessments (Visits 310-1999). If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should 
be made to contact the subject/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule.
At the final visit, all dispensed investigational product should be reconciled and the adverse 
event and concomitant medications reconciled on the appropriate eCRF. 
If subjects discontinue from investigational treatment and are administered Xolair®
(omalizumab) in the follow-up period, the subject should be discontinued from the study and 
no efficacy or safety assessments should be collected from the subject at the EOS visit.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent (WoC) occurs only when a subject:
!
Does not want to participate in the study anymore
and
!
Does not allow further collection of personal data
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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject's sample until the time of withdrawal) according to applicable 
law.
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. Follow-up is recommended until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:
!
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 the subject's welfare and 
safety. Should early termination be necessary, subjects must be seen as soon as possible and 
treated as a prematurely withdrawn subject. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the subject’s interests. The investigator or sponsor, depending on the local 
regulation, will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
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appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
Patients will be eligible for post-trial access after completion of the study.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the appropriate CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (version 5 or higher);
2. its relationship to the study treatment and other investigational treatment. If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject;
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported;
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met;
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:
!
Dose not changed
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!
Dose reduced/increased
!
Drug interrupted/withdrawn
6. its outcome i.e., its recovery status or whether it was fatal.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment or end of study visit, whichever is longer.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
!
they induce clinical signs or symptoms
!
they are considered clinically significant
!
they require therapy
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. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.1 Appendix 1.
For lab values provided without related clinical information, the Common Terminology Criteria 
for Adverse Events (CTCAE) scale must be used to determine the seriousness. Any value of 
Grade 4 and above on this CTCAE scale must be considered serious.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [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
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!
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
!
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
!
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
!
social reasons and respite care in the absence of any deterioration in the subject’s 
general condition
!
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
!
is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred or not. 
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30 day period after the last study visit should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment. Any SAEs reported up to the 
subject’s last visit will be reported in the eCRF. SAEs beyond that date will only be 
recorded in the Novartis Safety database.
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess the relationship of each SAE to each specific 
component of the study treatment (if the study treatment consists of several components) 
complete the SAE Report Form in English and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the investigator folder provided to each site.
Follow-up information is submitted as instructed in the investigator folder. Each reoccurrence, 
compilation, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the investigational treatment, a Chief Medical Office 
and Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
Consider the following 3 categories (as applicable) to determine SAE reporting timeframes:
1. To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence.
2. Any SAEs experienced after the 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment.
3. Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An 
SAE that is considered completely unrelated to a previously reported one should be 
reported separately as a new event.
10.1.4
Pregnancy reporting
Pregnancies
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
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Pregnancy should be recorded and reported by the investigator to the Novartis/ Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any
pregnancy outcome. The follow-up should be for up to 12 months following the birth of the 
baby. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):
!
Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter
!
Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
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Please refer to Table 16-1 in Section 16.2 Appendix 2 for complete definitions of liver 
laboratory triggers and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e. ALT, AST, total 
bilirubin (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 the Discontinuation of study 
treatment section), if appropriate
!
Hospitalization of the subject if appropriate
!
Causality assessment of the liver event
!
Thorough follow-up of the liver event should include (based on investigator’s 
discretion) serology tests, imaging and pathology assessments, gastroenterologist 
or hepatologist’s consultancy, obtaining more detailed history of symptoms and prior 
or concurrent diseases, history of concomitant drug use, exclusion of underlying liver 
disease, imaging such as abdominal ultrasound, Computerized 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.
10.2.2
Renal safety monitoring
The following base monitoring for renal laboratory values, as per the Novartis Drug-Induce 
Nephrotoxicity Guidelines (July 2013; 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 ≥ 48 h 
after last dose
Urine Dipstick (Spot urine sample)
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-4.
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10.2.3
Adjudication committee
To enhance the safety assessment, more specifically relative to 1) anaphylactic events, 2) 
neoplastic events, and 3) major cardio-cerebrovascular events, 3 Adjudication Committees, 
independent panels of experts external to Novartis, will provide reviews of identified potential 
events in a blinded manner. Adjudication will be performed on a regular basis.
All the details of the adjudication processes including the committee members are included in 
the adjudication committee charters.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Designated investigator site 
staff will not be given access to the Electronic Data Capture (EDC) system until they have been 
trained. Automatic validation programs check for data discrepancies in the eCRFs, allow 
modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered into the CRFs by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Laboratory samples except for stool samples and other locally processed laboratory samples 
will be processed centrally and the results will be sent electronically to Novartis. Stool samples 
will be processed by local labs and the results will be collected by Novartis via eCRFs. 
ECG readings will be processed centrally and results will be sent electronically to Novartis. 
Patients will fill in their daily diary data on a  device at home. PROs will be completed by 
patients on site on the day of applicable visits. The system will be supplied by a vendor(s) who 
will also manage the database. The database will be sent electronically to Novartis.
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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 and made available for data analysis. Any changes to the database after that 
time can only be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis
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. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
12.1
Analysis sets
The following analysis sets will be used in this trial:
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Safety Set includes all subjects who received at least one dose of study treatment. Subjects will 
be analyzed according to the study treatment received. Safety Set will be used for all safety 
analyses and also for efficacy analyses.
 
 
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be listed and summarized descriptively for the Safety 
set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. Summary for urticaria specific medical history will also 
be provided.
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 patients and the length of time in weeks exposed to ligelizumab will be 
summarized by means of descriptive statistics. 
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. Prior medications for CSU will be summarized 
separately by pre-specified categories and preferred term. 
12.4
Analysis of the primary endpoint(s)
The primary variable will be analyzed descriptively. No formal statistical analysis will be 
provided. 
12.4.1
Definition of primary endpoint(s) 
As the study objective is to assess the safety with no specific safety hypothesis, treatment 
emergent adverse events during the study will be considered as a primary variable. Treatment 
emergent adverse events are defined as adverse events which start after the first dose of study 
medication, or events present prior to the first dose of study medication but increased in severity 
based on preferred term. All adverse events onset in the follow-up period will also be considered 
as treatment emergent.
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12.4.2
Statistical model, hypothesis, and method of analysis
The number of subjects who had a treatment-emergent adverse event will be summarized 
overall, by system organ class (SOC) and preferred term descriptively. No statistical model will 
be applied for the primary endpoints.
12.4.3
Handling of missing values/censoring/discontinuations
For the subject who discontinued treatment or study, no imputation or adjustment will be 
considered for counting the number of subjects who have a treatment emergent AE/SAE. All 
subjects will be treated equally when the data is summarized, regardless of the treatment 
duration and/or study duration of each subject.
12.4.4
Sensitivity and Supportive analyses
No sensitivity or supportive analyses are planned.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
All efficacy variables listed below will be analyzed in Safety Set. Summary tables will be 
presented by visit or week using descriptive statistics. Categorical variables will be presented 
as frequencies and percentages. For continuous variables, mean, standard deviation, median, 
minimum, and maximum will be presented. Mean differences of the change from baseline 
(UAS7, HSS7, ISS7 and DLQI) will be shown descriptively with 95% confidence interval based 
on one-sample t-test. Proportion of subjects (UAS7=0, HSS7=0, ISS7=0 and DLQI=0/1) will 
also be shown with 95% confidence interval based on Fisher's exact test. All analyses will be 
provided descriptively and no formal statistical testing will be applied. 
!
Absolute change from baseline of UAS7, ISS7 and HSS7
!
Proportion of subjects with HSS7 = 0, ISS7 =0 and UAS7=0 response
!
Absolute change from baseline of DLQI
!
Proportion of subjects with DLQI = 0/1
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used.
Adverse events
All information obtained on adverse events will be displayed by subject.
All treatment emergent adverse events which started after first drug dose and within 4 weeks 
after the last dose will also be summarized as adverse events in the treatment phase. In addition 
to what is described in the primary endpoints section, treatment emergent adverse events with 
the number and percentage of patients having any adverse event overall, by system organ class 
and preferred term will be provided for: 
!
Serious adverse events
!
Adverse events by maximum severity
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!
Adverse events suspected by the investigator as study drug related
!
Adverse events leading to permanent discontinuation of study drug
The number of subjects with adverse events of special interest will be listed.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by subject and visit with the abnormalities flag based on the 
notable criteria. The number of patients with notable abnormal vital signs will be summarized.
12-lead ECG
All ECG data will be listed by subject and visit with abnormalities flag based on the notable 
criteria. The number of patients with notable abnormal vital signs will be summarized.
Clinical laboratory evaluations
All laboratory data will be listed by subject and visit with abnormalities flag based on normal 
ranges. Shift tables using the low/normal/high classification will be used to compare baseline 
to the worst on-treatment value. For the parameters with clinically notable abnormal criteria, 
newly occurred or worsening abnormality will also be summarized.
Anti-ligelizumab antibody
All data of anti-ligelizumab antibodies will be listed. Number of patients who have positive 
anti-ligelizumab antibodies will be summarized by visit.
 
 
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12.7
Interim analyses
Not Applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
No formal statistical power calculations to determine sample size were performed for this study. 
The sample size is determined based on the regulatory requirement by Pharmaceuticals and 
Medical Devices Agency (PMDA) to fulfill the long term safety data for Japanese patients. 
Considering 10% drop out rate based in the QGE031C2201 study, the planned sample size 
(N=65) in this study will have 58 patients with 1 year exposure, and it is expected to have 100 
Japanese patients exposed to ligelizumab with 1 year in the total ligelizumab CSU program, 
together with QGE031C2201/E1 and QGE031C2303 studies. With the total sample size 
(N=100) exposed to ligelizumab in Japanese patients, one can expect to see at least one patient 
with a specific AE with 95% probability, assuming the occurrence rate of an AE is 3%, aligned 
with ICH E1 guideline. Safety data from the study will also be evaluated together with Japanese 
patients from other ligelizumab studies in the submission dossier.
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12.8.2
Secondary endpoint(s)
The expected half-width of 95% confidence interval for the change from baseline in UAS7 
would be 3.3, assuming 58 patients (10% missing) are available of post-baseline UAS7 data 
and SD=13. If the mean change from baseline in UAS7 for ligelizumab group is -22.0 (based 
on C2201 study at Week 12), 95% confidence interval of the mean change from baseline in 
UAS7 will be (-25.3, -18.7).
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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol,
written informed consent form, 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 his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
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Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.
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15
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Zuberbier T, Aberer W, Asero R, et al (2018) The EAACI/GA²LEN/EDF/WAO guideline for 
the definition, classification, diagnosis and management of urticaria. Allergy p. 1393-1414.
Zuberbier T, Asero R, Bindslev-Jensen C, et al (2009) EAACI/GA(2)LEN/EDF/WAO 
guideline: management of urticaria. Allergy p. 1427-43.
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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Refer to Section 16.2 Appendix 2 for clinically notable laboratory values for hepatotoxicity.
Refer to Section 16.3 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 has platelets < 75,000/μL after being randomized should discontinue study 
treatment.
For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outside of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the CRF.
Notable values for vital signs and change from baseline will be summarized.
Notable values for adults are defined as follows: heart rate of < 60 and > 100 beats per minute 
(bpm); systolic blood pressure of < 90 and ≥ 140 mmHg; diastolic blood pressure of < 60 and 
≥ 90 mmHg.
For ECGs a notable QTc value is defined as a QTcF (Fridericia’s) interval of greater than 450 
ms for males or greater than 460 ms for females – all such ECGs will be flagged by the Central 
CRO’s cardiologist and require assessment for clinical relevance by the investigator. For 
adolescent subjects, the Central CRO will use age-and gender-specific reference values.
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16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS
!
3 x ULN < ALT / AST ≤ 5 × ULN
!
1.5 x ULN < TBL ≤ 2 × ULN
LIVER EVENTS
!
ALT or AST > 5 × ULN
!
ALP > 2 × ULN (in the absence of known bone 
pathology)
!
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome)
!
ALT or AST > 3 × ULN and INR > 1.5
!
Potential Hy’s Law cases defined as 
!
subjects showing ALT or AST > 3 x ULN, combined 
with elevation of serum TBL to > 2 x ULN, without 
initial findings of cholestasis (no ALP elevation), and
!
Absence of any alternative cause likely explaining 
the combination of increased ALT or AST and TBL, 
such as viral hepatitis A, B, C, or E; preexisting or 
acute liver disease; or another drug capable of 
causing the observed injury 
!
Any clinical event of jaundice (or equivalent term)
!
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, right upper quadrant 
pain or tenderness, fever, nausea, vomiting, rash and/or 
eosinophilia(5%)
!
Any adverse event potentially indicative of a liver toxicity*
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea
!
Discontinue the study 
treatment immediately
!
Hospitalize, if clinically 
appropriate
!
Establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
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Criteria
Actions required
Follow-up monitoring
> 8 × ULN
!
Discontinue the study 
treatment immediately
!
Hospitalize if clinically 
appropriate
!
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 resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and  (TBL > 2 x ULN 
or INR > 1.5 )
!
Discontinue the study 
treatment immediately
!
Hospitalize, if clinically 
appropriate
!
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 resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN
!
Repeat LFT within 48 
hours
!
If elevation persists, 
continue follow-up 
monitoring
!
If elevation persists for 
more than 2 weeks, 
discontinue the study drug
!
Establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied by 
symptomsb
!
Discontinue the study 
treatment immediately
!
Hospitalize if clinically 
appropriate
!
Establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)
!
Repeat LFT within the next 
week
!
If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
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Criteria
Actions required
Follow-up monitoring
> 2 × ULN (in the absence of 
known bone pathology)
!
Repeat LFT within 48 
hours
!
If elevation persists, 
establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)
!
Repeat LFT within 48 
hours
!
If elevation persists, 
discontinue the study drug 
immediately
!
Hospitalize if clinically 
appropriate
!
Establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic)
!
Repeat LFT within the next 
week
!
If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice
!
Discontinue the study 
treatment immediately
!
Hospitalize the patient
!
Establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*
!
Consider study treatment 
interruption or 
discontinuation
!
Hospitalization if clinically 
appropriate
!
Establish causality
!
Record the AE and 
contributing factors (eg, 
conmeds, med hx, lab) in 
the appropriate CRF
Investigator discretion
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Criteria
Actions required
Follow-up monitoring
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN b (General) malaise, fatigue, abdominal pain, right upper quadrant pain or tenderness fever,  
nausea, vomiting, rash and/or eosinophilia(5%) c Resolution is defined as an outcome of one of the 
following: (1) return to baseline values, (2) stable values at three subsequent monitoring visits at 
least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver 
transplantation, and (5) death.
Alb: Albumin; LFT: Liver function test
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.
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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Refer to Section 10.2.2
Table 16-3
Specific Renal Alert Criteria and Actions
Renal Event
Confirmed serum creatinine increase 25% –
49%
Consider causes and possible interventions
Follow up within 2-5 days
Serum creatinine increase ≥ 50% +
Consider causes and possible interventions
Repeat assessment within 24-48 h 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)≥1 g/gCr (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 study drug interruption or 
discontinuation unless other causes are 
diagnosed and corrected
New onset hematuria ≥3+ on urine
Dipstick
+ Corresponds to KDIGO criteria for Acute Kidney 
Injury
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
Whenever a renal event is identified, a detailed patient history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event:
!
Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)
!
Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema
!
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output
!
Concomitant events or procedures such as trauma, surgical procedures, cardiac or 
hepatic failure, contrast media or other known nephrotoxin administration, or other 
diseases or causes, e.g., dehydration due to delirium, tumor lysis
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Table 16-4
Renal event follow-up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF
!
Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells
!
Blood pressure and body weight
!
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid
!
Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until:
!
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio <1 g/g Cr, or ACR <300 
mg/g Cr) or
!
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months
!
Analysis of urine markers in samples collected over the course of the DIN event
sCR: serume creatinine
16.4
Appendix 4: PRO tools
Samples of questionnaire provided here are for illustrative purpose only. The text format and 
wording might slightly vary.
Patient Diary: Urticaria Patient Daily Diary (UPDD)
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Dermatology Life Quality Indec (DLQI):
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16.5
Appendix 5 
/ADA Log
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16.6
Appendix 6: World allergy organization grading system
World allergy organization subcutaneous immunotherapy systemic reaction grading 
system
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