Clinical trial NCT03437278
Conditions: Chronic Spontaneous Urticaria
Keywords: Anti-IgE Chronic spontaneous urticaria
Sponsor: Novartis Pharmaceuticals
Start date: 2018-08-01; Completion date: 2021-02-03
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical study was designed to evaluate the pharmacokinetics, safety and efficacy of ligelizumab in children from 12 to \< 18 years of age, with chronic spontaneous urticaria (CSU). The participants were treated with ligelizumab as an add-on therapy to approved doses of H1 antihistamines (H1AH) following the guideline on treatment of CSU.

Detailed description:
This was a Phase IIb dose-finding, randomized, double-blind, parallel-group, placebo-controlled, multicenter study in adolescent patients. The study consisted of 3 distinct study periods: Screening, Treatment and Follow-up period.

After the screening period (up to 4 weeks), at Day 1 participants were randomized into one of the three treatment arms in 1:2:1 fashion to ligelizumab high dose (120 mg every four weeks (q4w)) versus ligelizumab low dose (24 mg q4w) versus placebo. During the 24 weeks of treatment period, doses were administered on Day 1 then on weeks 4, 8, 12, 16, and 20 weeks after randomization. Participants randomized to placebo received placebo on Day 1, Weeks 4 and 8; thereafter they received 120 mg ligelizumab (high dose) on Weeks 12, 16 and 20 such that by the end of the study, the same number of participants received ligelizumab high dose as low dose. The treatment period was followed by a treatment-free follow-up period of 16 weeks to a maximum of Week 40.

Arms: arm 1: Participants received a dose of ligelizumab 120 mg (high dose) which consisted of one injection of 1 ml of ligelizumab 120 mg/ 1 ml vial every 4 weeks from Day 1 to Week 20 (inclusive). arm 2: Participants received a dose of ligelizumab 24 mg (low dose) which consisted of one injection of 0.2 ml of ligelizumab 120 mg/ 1 ml vial every 4 weeks from Day 1 to Week 20 (inclusive). arm 3: Participants received Placebo which consisted of one injection of 1 ml placebo every 4 weeks from Day 1 to Week 8 (inclusive). From week 12 to week 20 (inclusive), participants received a dose of ligelizumab 120 mg (high dose) which consisted of one injection of 1 ml of ligelizumab 120 mg/ 1 ml vial.
Interventions: intervention 1: Ligelizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Ligelizumab comes in 120 mg per 1 ml liquid vials. Participants received one injection every 4 weeks at a dose of 120 mg or 24 mg, high and low doses respectively. intervention 2: Placebo 0 mg per 1 ml liquid injection once every 4 weeks.

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
[QGE031/Ligelizumab]
Clinical Trial Protocol [CQGE031C2202 / NCT03437278]
A multicenter, randomized, double-blind, placebo-controlled phase 
2b dose-finding study to investigate the efficacy and safety of 
ligelizumab (QGE031) in adolescent patients with Chronic 
Spontaneous Urticaria (CSU)
Document type:
Clinical Trial Protocol
EUDRACT number:
2017-004207-52
(PIP number: EMEA-001811-PIP02-15)
Version number:
00 (Original Protocol)
Clinical trial phase:
2b
Release date:
18-Jan-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.4 (May 2017)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................17
2
Study objectives and endpoints .........................................................................................17
2.1
Objectives and related endpoints...........................................................................17
3
Investigational plan ...........................................................................................................19
3.1
Study design...........................................................................................................19
3.2
Rationale for study design .....................................................................................21
3.3
Rationale for dose/regimen, route of administration and duration of treatment....21
3.4
Rationale for choice of comparator .......................................................................22
3.5
Purpose and timing of interim analyses/design adaptations..................................23
3.6
Risks and benefits..................................................................................................23
4
Population..........................................................................................................................26
4.1
Inclusion criteria ....................................................................................................26
4.2
Exclusion criteria...................................................................................................26
5
Treatment...........................................................................................................................29
5.1
Study treatment......................................................................................................29
5.1.1
Investigational and control drugs..........................................................29
5.1.2
Additional treatment..............................................................................29
5.2
Treatment arms......................................................................................................29
5.3
Treatment assignment and randomization.............................................................29
5.4
Treatment blinding.................................................................................................30
5.5
Treating the patient................................................................................................31
5.5.1
Patient numbering .................................................................................31
5.5.2
Dispensing the study drug.....................................................................31
5.5.3
Handling of study and additional treatment..........................................32
5.5.4
Instructions for prescribing and taking study treatment........................32
5.5.5
Permitted dose adjustments and interruptions of study treatment ........33
33


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5.5.7
Concomitant medication .......................................................................33
5.5.8
Prohibited medication ...........................................................................34
5.5.9
Emergency breaking of assigned treatment code..................................35
5.6
Study completion and discontinuation...................................................................35
5.6.1
Study completion and post-study treatment..........................................35
5.6.2
Discontinuation of study treatment .......................................................35
5.6.3
Withdrawal of informed consent...........................................................37
5.6.4
Loss to follow-up ..................................................................................37
5.6.5
Early study termination by the sponsor.................................................37
6
Visit schedule and assessments .........................................................................................38
6.1
Information to be collected on screening failures..................................................46
6.2
Patient demographics/other baseline characteristics .............................................46
6.3
Treatment exposure and compliance .....................................................................46
6.4
Efficacy..................................................................................................................46
6.4.1
eDiary assessments for patient reported outcomes ...............................46
6.4.2
Children Dermatology Life Quality Index (CDLQI)............................50
6.4.3
Other assessments: In-clinic assessment of UAS..................................50
6.4.4
Appropriateness of efficacy assessments..............................................50
6.5
Safety.....................................................................................................................51
6.5.1
Physical examination ............................................................................51
6.5.2
Vital signs..............................................................................................51
6.5.3
Height and weight .................................................................................52
6.5.4
Laboratory evaluations..........................................................................52
6.5.5
Electrocardiogram (ECG) .....................................................................53
6.5.6
Pregnancy and assessments of fertility .................................................53
6.5.7
Anaphylaxis assessment........................................................................54
6.5.8
Assessment of cardiovascular events....................................................54
6.5.9
Assessment of pre-malignancies and malignancies ..............................54
6.5.10
Appropriateness of safety measurements..............................................54
6.6
Other assessments..................................................................................................54
6.6.1
Resource utilization...............................................................................54
6.6.2
Pharmacokinetics/Pharmacodynamics..................................................54
55
7
Safety monitoring..............................................................................................................56
7.1
Adverse events.......................................................................................................56
7.2
Serious adverse events...........................................................................................57


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7.2.1
Definition of SAE .................................................................................57
7.2.2
SAE reporting........................................................................................58
7.3
Liver safety monitoring .........................................................................................59
7.4
Renal safety monitoring.........................................................................................60
7.5
Reporting of study treatment errors including misuse/abuse ................................60
7.6
Pregnancy reporting...............................................................................................61
7.7
Other safety assessments .......................................................................................61
7.7.1
Immunogenicity assessments................................................................61
8
Data review and database management.............................................................................62
8.1
Site monitoring ......................................................................................................62
8.2
Data collection.......................................................................................................62
8.3
Database management and quality control............................................................63
8.4
Data Monitoring Committee..................................................................................63
8.5
Adjudication Committee........................................................................................64
9
Data analysis......................................................................................................................64
9.1
Analysis sets ..........................................................................................................64
9.2
Patient demographics and other baseline characteristics.......................................64
9.3
Treatments .............................................................................................................64
9.4
Analysis of the primary variables..........................................................................65
9.4.1
Primary Variables..................................................................................65
9.4.2
Statistical model, hypothesis, and method of analysis..........................65
9.4.3
Handling of missing values/censoring/discontinuations.......................65
9.4.4
Sensitivity analyses ...............................................................................65
9.5
Analysis of secondary
ariables ..................................................65
9.5.1
Efficacy variables..................................................................................65
9.5.2
Safety variables .....................................................................................67
9.5.3
Pharmacokinetics ..................................................................................68
68
9.5.5
PK/PD ...................................................................................................68
69
9.7
Interim analyses.....................................................................................................69
9.8
Sample size calculation..........................................................................................69
10 Ethical considerations........................................................................................................70
10.1
Regulatory and ethical compliance........................................................................70
10.2
Informed consent procedures.................................................................................70
10.3
Responsibilities of the investigator and IRB/IEC..................................................70


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10.4
Publication of study protocol and results...............................................................71
10.5
Quality Control and Quality Assurance.................................................................71
11 Protocol adherence ............................................................................................................71
11.1
Protocol amendments.............................................................................................72
12 References .........................................................................................................................73
13 Appendices ........................................................................................................................75
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................75
13.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................76
13.3
Appendix 3: Specific Renal Alert Criteria and Diagnosis.....................................78
13.4
Appendix 4 PRO tools...........................................................................................79
13.5
Appendix 5 PK/PD/ADA 
 log........................................................84
13.6
Appendix 6 World allergy organization grading system.......................................85
List of tables
Table 2-1
Objectives and related endpoints ..........................................................17
Table 3-1 
Number of study drug administrations..................................................23
Table 5-1
Prohibited treatment..............................................................................34
Table 6-1
Assessment schedule.............................................................................39
Table 6-2
Hives Severity Score.............................................................................47
Table 6-3
Itch Severity Score ................................................................................48
49
49
Table 6-6
Actions/treatments for Angioedema .....................................................49
Table 6-7
In-clinic UAS ........................................................................................50
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................61
Table 9-1
Secondary
efficacy variables.........................................66
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................76
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers...76
Table 13-3
Specific Renal Alert Criteria and Diagnosis.........................................78
List of figures
Figure 3-1
Study design..........................................................................................20
Figure 9-1
PK/PD exposure-response (E/R) concept .............................................69


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List of abbreviations
AC
Adjudication committee
ADA
Anti-drug antibodies
AE
Adverse event
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
AST
Aspartate aminotransferase
BP
Blood pressure
B-hCG
Beta Human Chorionic Gonadotropin 
BUN
Blood urea nitrogen
CDLQI
Children Dermatology Life Quality Index
CFR
United States Code of Federal Regulations
CINDU
Chronic Inducible Urticaria
CO
Country Organization
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CSU
Chronic Spontaneous Urticaria
DBP
Diastolic blood pressure
DMC
Data monitoring committee
DSM
Drug supply management
EC50
Concentration of a drug that gives half-maximal response.
ECG
Electrocardiogram
ECL
electrochemiluminescent
EDC
Electronic Data Capture
eDiary
Electronic diary
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
Emax
Maximum efficacy
EMEA
Europe Middle East ad Africa
EOT/TD
End of treatment/Study treatment discontinuation
ePRO
Electronic Patient Reported Outcome
ER
Exposure-response
EU
European Union
FAS
Full Analysis set


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FcɛRII
Low affinity Immunoglobulin E Receptor II
GCP
Good Clinical Practice
G-GT
Gamma-glutamyl transpeptidase
H1-AH
H1-antihistamines
H2-AH
H2-antihistamines
HSS
Hives Severity Score
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization 
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IN
Investigator notification
INR
International Normalized Ratio
IQS
Integrated Quantitative Sciences
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISS
Itch Severity Score
IU
Inducible urticarial
IUD
Intrauterine device
IUS
Intrauterine system
LDH
Lactate dehydrogenase
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)
LLOQ
lower limit of quantification
LTRA
Leukotriene Receptor Antagonist
mAb
Monoclonal antibody
MedDRA
Medical dictionary for regulatory activities
MoA
Mode of Action or mechanisim of Action
M&S
Modelling and Simulation
MSD
Meso Scale Discovery
NLME
Nonlinear mixed effect
PBO
Placebo
PCR
Protein to Creatinine Ratio
PD
Pharmacodynamics
PIP
Pediatric Investigational Plan


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PK
Pharmacokinetics
PKPD
Pharmacokinetics-pharmacodynamics
PRO
Patient Reported Outcome
PSD
Premature subject/patient discontinuation
PT
Prothrombin time
q4w
Every 4 weeks
QM
Quality Management
QTcF
Fridericia's Correction Formula
RAN
Randomized set
RBC
Red blood cells
REB
Research Ethic Board
RES
Reticuloendothelial system
SAE
Serious adverse event
SAF
Safety set
s.c.
Subcutaneous
SBP
Systolic blood pressure
SMQ
Standardized MedDRA Queries 
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
UAS
Urticaria Activity Score
ULN
Upper Limit of Normal
UPDD
Urticaria Patient Daily Diary
US
United States
WBC
White blood cells
WHO
World Health Organization
WoC
Withdrawal of study consent
XS
Third party data


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Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) 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 patient in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of 
clinical study data using data collection systems, such as Web-
based applications, interactive voice response systems and 
clinical laboratory interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) 
which are used to capture data transcribed from paper source 
forms used at the point of care.
eSource DDE
eSource Direct Data Entry (DDE) refers to the capture of clinical 
study data electronically, at the point of care. eSource 
Platform/Applications reduce the use of paper capture source 
data during clinical visits. 
eSource combines source documents and case report forms 
(eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate.
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (e.g. prior to starting any of the 
procedures described in the protocol)
Investigational drug
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.”
Medication number
A unique identifier on the label of each investigational drug 
package
Part 
A single component of a study which contains different 
objectives or populations within that single study. Common parts 
within a study are: a single dose part and a multiple dose part, or 
a part in patients/subjects with established disease and in those 
with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the 
informed consent 
Period
The subdivisions of the trial design (e.g. Screening, Treatment, 
Follow-up) which are described in the Protocol. Periods define 


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the study phases and will be used in clinical trial database setup 
and eventually in analysis
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Source Data/Document
Source data refers to the initial record, document, or primary 
location from where data comes. The data source can be a 
database, a dataset, a spreadsheet or even hard-coded data, such 
as paper or eSource.
Study drug/ treatment
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s), placebo/comparator active drug run-ins 
or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior 
to the defined study treatment completion date 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study is defined as when a 
patient does not want to participate in the study any longer, and 
does not want any further visits or assessments, and does not 
want any further study related contact, and does not allow 
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Protocol summary
Protocol number
CQGE031C2202
Full Title
A multicenter, randomized, double-blind, placebo-controlled phase 
2b dose-finding study to investigate the efficacy and safety of 
ligelizumab (QGE031) in adolescent patients with Chronic 
Spontaneous Urticaria (CSU) 
Brief title
A Phase 2b dose-finding study of QGE031 to investigate the 
efficacy and safety in adolescent patients with Chronic 
Spontaneous Urticaria (CSU)
Sponsor and 
Clinical Phase
Novartis 
Phase 2b
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
This clinical study is designed to evaluate the pharmacokinetics, 
safety and efficacy of ligelizumab in adolescent patients from 12 to 
< 18 years of age, with chronic spontaneous urticaria.
The study will generate data to be analyzed in a separate modelling 
and simulation study with the objective of i) estimating the relative 
potency of ligelizumab in adolescent patients compared with adults 
and ii) proposing a posology for the future treatment of adolescent 
patients.
Primary 
Objective(s) 
To evaluate the efficacy of QGE031 by assessing the change in the 
Urticaria Activity Score (UAS7) between baseline and Week 24. The 
primary endpoint will be change in UAS7 from baseline to Week 24. 
UAS7 is the sum of urticaria activity scores over a seven day period. 
Secondary 
Objectives

To evaluate the efficacy of ligelizumab doses with respect to 
UAS7 change from baseline at each protocol defined study 
visit

To evaluate the efficacy of ligelizumab doses on complete 
response in Urticaria Activity Score (UAS7=0), Hives Severity
Score (HSS=0), Itch Severity Score (ISS=0) at each protocol 
defined study visit

To investigate the effects on ISS7 and HSS7 when compared to 
baseline at each protocol defined study visit

To investigate the pharmacokinetics of ligelizumab 

To investigate the Pharmacodynamics
of ligelizumab by 
change in total IgE over time


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
Change from baseline in the Children Dermatology Life Quality 
Index at each protocol defined study visit

To evaluate the safety (including immunogenicity) and 
tolerability of ligelizumab.
Study design
This is a Phase 2b dose-finding, randomized, double-blind, parallel 
group, placebo controlled multicenter study in adolescent patients
Population
The study population will consist of approximately 48 adolescent 
males and females aged ≥ 12 and < 18 years who have been 
diagnosed with CSU and who remain symptomatic despite treatment 
with approved doses of H1-antihistamines. 
Key Inclusion 
criteria
- Parent or legal guardian’s written informed consent and 
child’s assent, if appropriate, must be obtained before any 
study related activity or assessment is performed. Of note, if 
the subject reaches age of consent (age as per local law) 
during the study, they will also need to sign the corresponding 
study ICF (Informed Consent Form) at the next study visit.
- Male and female adolescent patients aged ≥ 12 to <18 years 
at the time of screening.
- Diagnosis of CSU refractory to approved doses of H1-
antihistamines at the time of randomization, as defined by all 
of the following: 

The presence of itch and hives for at least 6 consecutive 
weeks at any time prior to enrollment despite current use 
of non-sedating H1-antihistamines during this time 
period

UAS7 score (range 0 - 42) ≥16 and HSS7 (range 0 -
21) ≥8 during 7 days prior to randomization (Day 1)

In-clinic UAS 4 on at least one of the screening visit 
days or Day 1 or  a medical record of the presence of 
hives (confirmed and  documented  by a physician); 
patients must have been on H1-antihistamines for 
treatment of CSU at the time of in-clinic UAS at 
screening visit and/or time of the medical record  of  
hives (for at least 3 days prior to the in-clinic UAS or 
medical record) 

CSU diagnosis for 6 months
-
Willing and able to complete a daily symptom eDiary for the 
duration of the study and adhere to the study visit schedules.


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-
Demonstration of compliance with the eDiary: patients 
should not have had any missing eDiary entries in the 7 days 
prior to randomization. Re-screening may be considered.
Key Exclusion 
criteria
-
Clearly defined underlying etiology for chronic urticarias 
other than CSU. This includes the following:

Inducible urticaria: urticaria factitia, cold-, heat-, solar-, 
pressure-, delayed pressure-, aquagenic-, cholinergic-, or 
contact-urticaria 

Diseases with possible symptoms of urticaria or 
angioedema such as urticarial vasculitis, erythema 
multiforme, 
cutaneous 
mastocytosis 
(urticaria 
pigmentosa), and hereditary or acquired angioedema 
(e.g. due to C1 inhibitor deficiency)
-
Any other skin disease associated with chronic itching that 
might confound the study evaluations and results (e.g. atopic 
dermatitis, bullous pemphigoid, dermatitis herpetiformis 
etc.) 
-
Previous exposure to omalizumab 
-
History of  anaphylaxis
Study treatment

Ligelizumab 120 mg per 1 mL liquid in vial

Placebo 
    0 mg per 1 mL liquid in vial
Efficacy assessments

Hives severity score (HSS)

Itch severity score (ISS)

Weekly Urticaria activity score (UAS7)
Key safety 
assessments
Safety evaluations include adverse events, physical examinations, 
laboratory values, vital signs and ECG
Other assessments

Patient reported outcome (
 CDLQI)

PK/PD
Data analysis
The primary variable is change in UAS7 from baseline to Week 24. 
UAS7 is the sum of HSS7 and ISS7. The primary variable will be 
analyzed descriptively in this protocol. In addition UAS7 from this 
study will be forwarded to a separate cross-study modelling and
simulation PKPD analysis study to establish the dose of ligelizumab 
in the age group to be confirmed in Phase 3.
Secondary variables will also be analyzed using descriptive 
statistics, no formal statistical testing will be applied. 


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Key words
Anti-IgE, chronic spontaneous urticaria, hives severity score, itch 
severity score, urticaria activity score


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1
Introduction
1.1
Background 
Chronic spontaneous urticaria (CSU) is defined as the spontaneous occurrence of itchy wheals, 
angioedema or both lasting for at least 6 weeks (Zuberbier et al 2014). The classic description 
of urticaria is a wheal and flare with a pale elevated lesion and surrounding erythema, ranging 
in size from a few millimeters to a few centimeters across, usually occurring in groups and often 
coalescing to form large confluent lesions. CSU can be debilitating and is associated with 
intense itching and has a major impact on patient’s well-being, suggested to be comparable to 
that of severe coronary artery disease (Greaves 2003, Powell et al 2007). The symptoms of 
urticaria and urticaria associated angioedema adversely affect daily activities and sleep 
(O'Donnell et al 1997). 
The lifetime prevalence of CSU is approximately 1.8%, and 20% of CSU patients still have the 
disease after 20 years (Zuberbier et al 2010, Greaves 2000). CSU is more common in adults 
than in children. The pathogenesis of CSU is not fully clear. Up to 50% of CSU cases are 
associated with histamine-releasing autoantibodies against either the high-affinity IgE receptor 
(FcεRI) or IgE antibodies; the clinical significance of these autoantibodies is unclear, though 
there are suggestions that they may be involved in disease pathogenesis (Kaplan 2002, Sabroe 
and Greaves 2006). It has also been suggested that CSU patients’ basophils may have distinct 
alterations in FcεRIα-mediated degranulation, independent of any potential role of 
autoantibodies (Eckman et al 2008). 
A majority of CSU patients can be treated with H1 antihistamine monotherapy, which is 
frequently used at doses up to four fold the approved dose (Zuberbier et al 2014). The use of H2
antihistamines and leukotriene receptor antagonist (LTRA) are not as well supported by clinical 
studies, although they have been recommended in treatment guidelines for patients who were 
symptomatic despite treatment with H1 antihistamines (Bernstein et al 2014). Systemic 
corticosteroids are sometimes added to the treatment regimens, however this is not 
recommended in treatment guidelines for long term treatment as patients are then at risk of 
adverse effects associated with chronic systemic corticosteroid exposure. 
Omalizumab has demonstrated efficacy in patients with CSU and has been approved in several 
countries including europe (EU), United States (US), Japan and Switzerland as add-on therapy 
in adult and adolescent patients with symptoms despite treatment with antihistamines. The 
completed Phase 2 and Phase 3 studies demonstrated that omalizumab improves the signs and 
symptoms of urticaria (e.g., itch, hives) in patients with CSU who have failed treatment with 
H1 antihistamines as well as those who have 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). The primary endpoint, reductions from baseline in mean weekly itch-severity scores 
(ISS7) and all pre-specified secondary end points (e.g., change from baseline in UAS7 (urticaria 
activity score over 7 days), weekly score for hive numbers (HSS7), proportion of patients with 
UAS7 ≤6) were dose-responsive. The exact mechanism for how omalizumab does work in CSU 
patients is still not completely understood. The understanding of the mode of action (MoA)
beyond suppression of free-IgE is evolving (Fine and Bernstein 2016, Chang et al 2015). 


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Revision of recent guidelines for the management of CSU patients confirmed that the 
therapeutic goal is complete remission of the signs and symptoms (i.e. UAS7 score of 0) 
(Zuberbier et al 2014); only about 40% of patients were free of symptoms at week 12 with the 
highest omalizumab dose tested (300 mg) in published Phase 3 studies (Maurer et al 2013,
Kaplan et al 2013). Therefore, an unmet medical need exists in the CSU patient population 
despite the availability of omalizumab (Xolair®).
Whilst the disease is less studied in pediatric patients its understanding in the pediatric 
population is also starting to evolve (Maurer et al 2017). Urticaria can occur in all age groups. 
The same disease classification with the distinction of acute and chronic urticaria, the latter 
distinguishing between CSU and chronic inducible urticaria (CINDU), is currently used to 
classify urticaria in infants, children and adolescents. Whilst there appears to be no conclusive 
epidemiologic data in children and adolescents, chronic urticaria may be less common in the 
pediatric and adolescent population. However, similar as in adults there is an unmet medical 
need in children. Recent studies indicated low rate of resolution in the pediatric age group of 
10% annually suggesting  that CSU is a long lasting disease in children as well (Netchiporouk 
2017).
Ligelizumab (QGE031) is a humanized monoclonal antibody (mAb) with higher affinity 
binding to human immunoglobulin E (IgE) than omalizumab. Upon binding, ligelizumab is able 
to block the interaction of IgE with both the high and low affinity IgE receptors (FcɛRI and 
FcɛRII). Ligelizumab is unable to mediate IgE receptor cross-linking and consequently 
histamine release (i.e. non-anaphylactogenic). When patients receive ligelizumab, circulating 
IgE is rapidly bound by the anti-IgE antibody and becomes inaccessible to IgE receptors on 
mast cells and basophils. IgE is necessary for the enhanced expression of the FcεRI seen in 
atopic patients, and a decrease in FcεRI expression on circulating basophils accompanies 
ligelizumab treatment. Other potentially beneficial effects from anti-IgE therapy include 
decreased IgE production, reduced B cell numbers and reduced cytokine production by T cells. 
Based upon the dose response observed in omalizumab CSU studies (Maurer et al 2013), 
superior affinity and pharmacodynamic outcomes of ligelizumab compared to omalizumab are 
anticipated to translate into superior clinical efficacy. Thus the ligelizumab development 
program in CSU aims to deliver a superior response compared with omalizumab with a similar 
safety profile in patients not adequately controlled with H1-antihistamines.
Whilst the disease presentation and medical need in adolescents appears to be the same as in 
adults there remains the question as to whether adolescent patients should receive the same dose 
as adults, as they do for Xolair®. Consequently, before enrolling adolescents in confirmatory 
Phase 3 studies, this small study will ascertain whether this age group benefits from ligelizumab
and, through administration of two active dose levels and a separate exposure-response data 
analysis study, determine the relative potency of ligelizumab compared with adults.
 
 
 
 


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1.2
Purpose
This clinical study is designed to evaluate the pharmacokinetics, safety and efficacy of 
ligelizumab in children from 12 to <18 years of age, with chronic spontaneous urticaria.
The study will generate data to be analyzed in a separate modelling and simulation study with
the objective of i) estimating the relative potency of ligelizumab in adolescent patients 
compared with adults and ii) proposing a posology for the future treatment of adolescent 
patients.
The patient population will be treated with ligelizumab as an add-on therapy to approved doses 
of H1-antihistamines following the guideline on treatment of CSU (Zuberbier et al 2014).
2
Study objectives and endpoints
2.1
Objectives and related endpoints
The study data will be forwarded to a separate modelling and simulation study which will utilize 
exposure (drug concentrations, PK) and UAS7 response data (pharmacodynamics, PD) over the 
full duration of the clinical study, both whilst on treatment and through follow-up periods 
(Section 9.5.5).
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective
Endpoint for primary objective

Change in the Urticaria Activity Score
(UAS7) between baseline and Week 24

The primary endpoint will be change in
UAS7 from baseline to Week 24.
UAS7 is the sum of urticaria activity
scores over a seven day period.
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the efficacy of ligelizumab
doses 24 mg and 120 mg with respect to
UAS7 change from baseline

To evaluate the efficacy of ligelizumab
doses 24 mg and 120 mg on complete
response in Urticaria Activity Score
(UAS7=0), 
Hives 
Severity
Score
(HSS=0), Itch Severity Score (ISS=0)

UAS7 change from baseline over time
(at each protocol defined study visit, in
addition to the primary endpoint)

Rate of complete responders (UAS7=0,
HSS7=0, ISS7 =0) over time (at each
protocol defined study visit)


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Objective(s)
Endpoint(s)

To investigate the effects on ISS7 and
HSS7 when compared to baseline

To investigate the pharmacokinetics of
ligelizumab

To investigate the pharmacodynamics of
ligelizumab

Change from baseline in the Children
Dermatology Life Quality Index

To evaluate the safety (including
immunogenicity) and tolerability of
ligelizumab (doses of 24 mg, 120 mg
s.c. every 4 weeks) versus placebo in
patients with CSU.

Itch symptom score change from
baseline over time (at each protocol
defined study visit)

Hives symptom score change from
baseline over time (at each protocol
defined study visit)

Model-based estimate of clearance and
volume of distribution using at least 7
samples

Summary statistics of change in Total
IgE over time.

Children Dermatology Life Quality
Index change from baseline over time
(each protocol defined study visit)

Adverse events, ECG-intervals and
interpretation, vital signs (blood
pressure, pulse rate) and clinical
laboratory evaluation


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Objective(s)
Endpoint(s)
3
Investigational plan
3.1
Study design
This is a Phase 2b dose-finding, randomized, double-blind, parallel group, placebo controlled 
multicenter study in adolescent patients. The study design has been agreed with the PDCO 
(Pediatric Committee (EU)). It consists of 3 distinct study periods, as outlined in Figure 3-1
below. After the screening period (up to 4 weeks), at Day 1 patients are randomized into one of 
the three treatment arms in 1:2:1 fashion to ligelizumab 120 mg q4w vs. ligelizumab 24 mg 
q4w vs. placebo. During the 24 weeks of treatment, doses are administered on Day 1 then 4, 8, 
12, 16, and 20 weeks after randomization. Subjects randomized to placebo will receive placebo 
on Day 1, Weeks 4 and 8; thereafter they will receive 120 mg ligelizumab on Week 12, 16 and 
20 such that the same number of patients will, by the end of the study, receive 120 mg as 24 
mg. Safety is assessed every 4 weeks; efficacy is primarily assessed using daily itch and hives 
scores summed into the weekly UAS7. The treatment period (24 weeks) is followed by a follow-
up period of 16 weeks to a maximum of Week 40.


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Figure 3-1
Study design
R: Randomization
Screening
Patients will have up to 4 weeks for screening to establish eligibility for the study. Patients will 
be required to attend two visits during the screening period: at Day −28 and Day −7. The Day-
7 can be brought forward depending on the availability of all laboratory results and the 
adherence to wash-outs related to non-allowed medication. Only in exceptional circumstances, 
when information concerning eligibility is outstanding (e.g. pending laboratory data), will an 
extended screening period be permitted. 
For certain Inclusion/Exclusion criteria, re-screening may be allowed for patients who fail 
initial screening (see Section 4.1 and 4.2). Only one re-screening will be allowed. If a patient 
rescreens for the study, the patient and their legal guardian (where applicable) must sign a new 
informed consent and child’s assent and he/she will be issued a new subject number. Informed 
consent for a rescreened patient must be obtained prior to performing any study-related 
assessments or collecting any data for the screening visit.
Double-blind treatment period
On Day 1, eligible patients will be randomly assigned to receive ligelizumab 24 mg, 120 mg or 
placebo s.c. q4w during the 24-week double-blind treatment period. It is planned to allocate 
approximately 12 patients to the ligelizumab 120 mg q4w, 24 patients to the ligelizumab 24 mg 
q4w and 12 patients to the placebo arm q4w. Patients are expected to attend all site visits based 
on the assessment schedule (Table 6-1).


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The last dose of study drug during the treatment period will be administered at the Day 141
(Week 20) study visit. As background medication, all patients in this study will continue to 
receive H1-antihistamines. Patients should remain on a stable treatment regimen throughout the 
study. 
Post-treatment follow-up period
After the completion of the double-blind treatment period, patients will enter a post-treatment 
follow-up period to allow for further characterization of the PK and response to ligelizumab as 
the drug washes out, collection of additional efficacy and safety data (e.g. relapse), and 
evaluation of the presence of anti-drug antibodies (ADAs). The follow-up period is 16 weeks 
with the last follow-up visit at day 281 (Week 40) corresponding to 20 weeks after the last 
treatment dose. No investigational treatment will be given during the post-treatment follow-up 
period, 
. Patients will be required 
to visit the study center every four weeks during post-treatment period.
 
 
3.2
Rationale for study design
The study uses a placebo-controlled parallel-group design to allow the assessment of the 
treatment effects in an unbiased fashion and to account for placebo effects. The duration of the 
placebo treatment is restricted to twelve weeks to reduce the time adolescents are having 
symptoms that would require a more effective treatment. Patients having received placebo will 
be rolled over to the 120 mg ligelizumab arm to collect further safety and efficacy data and give 
them an opportunity for a pronounced symptom improvement upon continuation of the study.
 
 
 
 
 
 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
 
 
 
 


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a 
 
 
 
 
 
 
 
 
3.4
Rationale for choice of comparator
The comparator treatment in this study is placebo. 
Placebo is used in this study for the following reasons:

to allow blinding of investigators and patients to their treatment and thereby minimize bias
in the evaluation of safety and efficacy assessments,

to allow assessment of the improvement in terms of CSU control for patients with disease
not controlled by background medication who are treated with ligelizumab, in comparison
to those continuing solely on background medication, and

to allow the assessment of safety of ligelizumab on top of background medication
compared to background medication alone
All patients, regardless of the treatment arm they are randomized to, will receive standard of 
care antihistamine therapy (approved doses) as background medication. 
 
 
Although the signs and symptoms of CSU are burdensome to patients, placebo 
trials have been safely and successfully conducted in this indication (Kaplan et al 2013, Maurer
et al 2013). Administration of placebo has been limited to 12 weeks while still allowing 
statistical comparison and maintenance of blinding to active versus placebo treatment. Patients 
having received placebo will be rolled over to the 120 mg ligelizumab arm to collect further 
safety and efficacy data and give them an opportunity for a pronounced symptom improvement 
upon continuation of the study. Patients have been allocated across the treatment arms according 
to the number needed to satisfy data requirements for optimal modeling and the number of 
placebo used has been kept to the minimum that still allows a meaningful analysis from the 
study data.


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Table 3-1 
Number of study drug administrations
Treatment
Ligelizumab
120 mg arm
Ligelizumab 
24 mg arm
Placebo/ligelizumab arm
Placebo 
period
Ligelizumab period
(120 mg dose)
Ligelizumab 
120 mg/mL 
liquid in vial
1 x 1.0 mL
1 x 0.2 mL
0
1 x 1.0 mL
QGE031 Placebo
0 mg/mL
liquid in vial
0
0
1 x 1 mL
0
Total 
# 
of 
injections
1
1
1
1
Total 
volume 
injected
1 mL
0.2 mL
1 mL
1 mL
3.5
Purpose and timing of interim analyses/design adaptations
No interim analysis is planned at the time of writing of this protocol, but may be added in case 
there is a need to provide information to health authorities, or to support program milestones.
3.6
Risks and benefits 
This study is investigating the exposure-response of ligelizumab in adolescent patients with 
Chronic Spontaneous Urticaria. This will allow to identify the best dose regimen that is used in 
adolescent patients. At the point of enrollment of adolescents substantial safety data supporting 
the safe use of ligelizumab has been collected in adult patient population. 
 
 
 
Overall ligelizumab is an investigational drug considered to be safe and 
well tolerated.
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria, 
study procedures and close clinical monitoring.
Potential risks for study participants
 
 
 
 


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Blood sampling and volumes
Blood volumes taken on single visit days and during the whole trial will be kept to a minimum 
to allow analyses of the key parameters specified for determining safety and pharmacodynamics 
effects and also to keep within the limits of health authority recommendations (EMA 2017).
Possible benefits for the study participants
In a Phase 2b study in adults, ligelizumab was very effective for the treatment of CSU. In 
comparison to omalizumab, another effective IgE targeted antibody, ligelizumab was superior 
in suppressing the cardinal symptoms of CSU, hives and itch and led to freedom of symptoms 
in a higher percentage of patients than with omalizumab. Patients that receive a dose of 120 mg 
in the current study could be expected to achieve such a response. Also the patients who receive 
placebo in the first part of the study and who will receive 120 mg ligelizumab from week 12 
onwards could expect a response as seen in adult patients with CSU. Whilst the patients who 
receive the lower dose of 24 mg may not achieve the same degree of symptom control as those 
who receive a 120 mg dose, they are, based on adult clinical data, expected to have a partial 
response. Note it is essential for the scientific integrity of the study that the lower dose (24 mg) 
is not fully effective as otherwise no dose-response analysis can be executed for the adolescent 
patient population. While all patients in the current study could achieve amelioration of their 
symptoms during the course of the study, it should however be noted that there may be patients 
who do not respond to ligelizumab treatment at all.


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4
Population
The study population will consist of approximately 48 adolescent males and females aged ≥ 12 
and < 18 years who have been diagnosed with CSU and who remain symptomatic despite 
treatment with approved doses of H1-antihistamines. 
It is anticipated that approximately 100 patients need to be screened in order to randomize 
approximately 48 into the 3 treatment arms due to an estimated screening failure rate of 
approximately 50% (see Figure 3-1).
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Parent or legal guardian’s written informed consent and child’s assent, if appropriate, 
must be obtained before any study related activity or assessment is performed. Of note, 
if the subject reaches age of consent (age as per local law) during the study, they will 
also need to sign the corresponding study ICF (Informed Consent Form) at the next 
study visit.
2. Male and female adolescent patients aged ≥ 12 to < 18 years at the time of screening.
3. Diagnosis of CSU refractory to approved doses of H1-antihistamines at the time of 
randomization, as defined by all of the following: 

The presence of itch and hives for at least 6 consecutive weeks at any time prior 
to enrollment despite current use of non-sedating H1-antihistamines during this 
time period

UAS7 score (range 0 - 42) ≥16 and HSS7 (range 0 - 21) ≥8 during 7 days prior 
to randomization (Day 1)

In-clinic UAS 4 on at least one of the screening visit days or Day 1 or a 
medical record of the presence of hives (confirmed and  documented by a 
physician); patients must have been on H1-antihistamines for treatment of CSU 
at the time of in-clinic UAS at screening visit and/or time of the medical record 
of  hives (for at least 3 days prior to the in-clinic UAS or medical record)

CSU diagnosis for 6 months
4. Willing and able to complete a daily symptom e-Diary for the duration of the study and 
adhere to the study visit schedules.
5. Demonstration of compliance with the eDiary: patients should not have had any missing 
eDiary entries in the 7 days prior to randomization. Re-screening may be considered.
4.2
Exclusion criteria
Patients/subjects fulfilling any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of the other investigational drugs prior to Visit 1, whichever is longer.
2. History of hypersensitivity to any of the study drugs or its components, or to drugs of 
similar chemical classes (i.e. to murine, chimeric, or human antibodies). 
3. Clearly defined underlying etiology for chronic urticarias other than CSU. This includes
the following:

Inducible urticaria: urticaria factitia, cold-, heat-, solar-, pressure-, delayed 
pressure-, aquagenic-, cholinergic-, or contact-urticaria 

Diseases with possible symptoms of urticaria or angioedema such as urticarial 
vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa), 
and hereditary or acquired angioedema (e.g., due to C1 inhibitor deficiency)
4. Patients with a stool examination positive for ova or parasites (at screening); re-
screening may be considered if absence of persisting infection has been demonstrated 
in repeat stool examinations.
5. Any other skin disease associated with chronic itching that might confound the study 
evaluations and results (e.g. atopic dermatitis, bullous pemphigoid, dermatitis 
herpetiformis etc.) 
6. Previous exposure to ligelizumab
7. Previous exposure to omalizumab
8. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to 
randomization 
9. Inability to comply with study and follow-up procedures 
10. Use of prohibited treatment detailed in protocol (Table 5-1)
11. Contraindications to or hypersensitivity to fexofenadine, loratadine,  cetirizine, 
rupatadine, bilastine or epinephrine or any of the ingredients
12. History of  anaphylaxis
13. History of malignancy of any organ system within the past 5 years (except for basal cell 
carcinoma or actinic keratoses or Bowen disease (carcinoma in situ) that have been 
treated with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the 
cervix or non-invasive malignant colon polyps that have been removed)
14. Presence of clinically significant cardiovascular (e.g. congenital heart diseases with 
significant persistent cardiac damage), 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 
patients, interfere with evaluation or interpretation of the study results, or preclude 
completion of the study


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15. 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
16. History or current treatment for hepatic disease including but not limited to acute or 
chronic hepatitis, cirrhosis or hepatic failure or AST/ALT levels or INR of more than 
1.5 x upper limit of normal (ULN) at Visit 1
17. History or presence of renal disease and/or estimated glomerular filtration (eGFR) rate 
of <35ml/min as calculated by the Schwartz formula at Visit 1
18. Platelets < 100 000/μL at Visit 1
19. History of long QT syndrome or whose QTcF (Fridericia) measured at Visit 1 is 
prolonged (> 450 ms for males or > 460 ms for females) and confirmed by a central 
assessor (these patients should not be re-screened).
20. Pregnant or nursing (lactating) females, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
B-hCG laboratory test
21. Women of child-bearing potential, defined as all females physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study medication and up to 20 weeks (5 times the terminal half-life) after 
stopping medication. Effective contraception methods include:

Total abstinence (when this is in line with the lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient

Barrier methods of contraception:

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide 

Use of oral, 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

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.


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5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs

Ligelizumab
120 mg per 1 mL liquid in vial

Placebo 
0 mg per 1 mL liquid in vial
During the 24 weeks of the treatment period, study drugs will be administered as per Table 3-1
at the clinic.
Novartis Drug Supply Management (DSM) will provide these investigational products as open-
label patient-specific supplies.
The investigational products will be supplied as a liquid in vial dosage form.
5.1.2
Additional treatment
No other additional treatment beyond investigational treatment (ligelizumab, placebo) is 
requested for this trial. Patients will continue to use their background medication (standard of 
care) with a stable regimen during the study.
 
 
 
 
5.2
Treatment arms
Patients will be assigned to one of the following three treatment arms in a ratio of 1:2:1. 
A. Ligelizumab 120 mg: 1 injection of ligelizumab (1mL) every 4 weeks from Day 1 to 
Week 20 (inclusive)
B. Ligelizumab 24 mg: 1 injection of ligelizumab (0.2mL) every 4 weeks from Day 1 to 
Week 20 (inclusive)
C. Placebo 0 mg: 1 injection of placebo (1 mL) at Day 1, Week 4, Week 8; followed by the 
same treatment as in Treatment A from week 12 onwards to week 20 (inclusive)
5.3
Treatment assignment and randomization
At Day 1, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will inform the independent 
unblinded site personnel (pharmacist or authorized delegate) to contact the IRT after confirming 
that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization 
number to the patient, which will be used to link the patient to a treatment arm and will specify 
a unique medication number for the package of investigational treatment to be dispensed to the 


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patient and will specify the volume of dose. The randomization number will not be 
communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding 
Patients, investigator staff and personnel performing the study assessments will remain blinded 
to the identity of the treatment from the time of randomization until final database lock. Data 
managers, programmers, statisticians, pharmacometricians and clinical experts of the Novartis 
trial team will also remain blinded until final database lock. An unblinded study monitor will 
visit the study site to monitor study drug related administration (see Section 8.1)
The following measures will be applied to keep the patient and study personnel blinded despite 
differences of the investigational treatments in appearance, viscosity and volume:
The study drug must be prepared by an independent unblinded pharmacist (or authorized 
delegate) and administered by an independent unblinded administrator. If an unblinded 
pharmacist is not available preparation and administration of drug may also be performed by a 
single independent unblinded site person if he/she is authorized to do both. Any site staff 
involved in the preparation and / or administration of study drug must not be involved in any of 
the study assessments.

Preparation of the investigational drug must be done in a separate space/room where 
patients and study personnel have no access.

To blind the liquid volume in the syringe, the syringe must be covered by a strip of 
opaque tape. The differences in length of the syringe plunger, related to the differences 
in the volume, should also be covered by the way of administration (see pharmacist 
manual).

The independent unblinded authorized site persons (pharmacist/administrator) should 
not communicate the appearance, the volume and any perceived sensation associated 
with the administration of the investigational drug.
The procedural details relating to treatment blinding and unblinded drug administration will be 
described in the Pharmacist Manual which will be provided separately.
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions:


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
Bioanalyst (PK): to enable identification of samples from the ligelizumab treatment 
arms of the study to facilitate bioanalysis.

Independent personnel (external to Novartis) involved in monitoring anaphylaxis and 
pre-malignancy/malignancy events (Adjudication Committee members) if such events 
would occur.
Unblinding during the conduct of the trial will only occur in the case of patient emergencies 
(Section 5.5.9). The patients, investigator staff and persons performing the assessments will 
remain blinded until after final database lock.
Health authorities will be granted access to unblinded data if needed.
The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason. Study treatment must be discontinued after emergency unblinding.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified in the study by a Subject Number (Subject No.), that is 
assigned when the patient is first enrolled for screening and is retained as the primary identifier 
for the patient 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 patient is numbered uniquely across the 
entire database. 
Once assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in the electronic data capture (EDC) system. The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the patient to register 
them into the IRT. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate CRF.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the “3” treatment arms and a specific visit or 
dose/dose level. Investigator staff will identify the study drug package(s) to dispense to the 
patient by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the package to the patient, investigator staff will detach the outer part of the label 
from the packaging and affix it to the source document (Drug Label Form) for that patient’s 
unique subject number. 


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5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by an independent unblinded designated person at the study 
site, handled and stored safely and properly, and kept in a secured location to which only the 
unblinded designees have access. Upon receipt, all study treatment must be stored according to 
the instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis 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 patient except for the medication number.
The independent unblinded site personnel must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by monitors during site visits or remotely and at the completion of the trial. 
Patients will be asked to return all unused study treatment and packaging at the end of the study 
or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the unblinded 
dedicated site staff member will return all unused study treatment, packaging, drug labels, and 
a copy of the completed drug accountability log to the unblinded monitor or to the appropriate
address provided in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
The
 concomitant medication allowed in the trial is described in 
Sections 5.5.6 and 5.5.7.
5.5.4
Instructions for prescribing and taking study treatment 
The independent study drug administrator will administer the study treatment to the patient 
during the study visit without engaging in any unnecessary interactions that may have the 
potential to unblind the patient or any of the study site personnel. All study treatments will be 
administered at the hospital/clinic.
The injection can be administered in the deltoid region on the right and/or left arm, and/or on 
the right and/or left thigh, or the abdomen as preferred by patient and/or site. The injection is
administered subcutaneously after aspiration of the plunger of the syringe. If blood appears at 
the hub or blood is withdrawn into a syringe, the needle is removed without administration of 
the dose and the injection site is changed. 
The guidelines for the preparation and administration of study medication are described in the 
pharmacist manual.
Patients will remain on-site for observation for a period of 2 h post-dose for all study drug 
administration visits. This observation period follows 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 


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Committees Joint task Force (Cox 2007) for the anti-IgE therapy currently available 
(omalizumab). As described in the Investigator’s Brochure (IB), the site needs to ensure 
readiness to react to anaphylactic events (e.g. have available injectable epinephrine, 
antihistamine, corticosteroids, intravenous supplies, oxygen, an oral airway, Ambu bag, and the 
ability to transport a patient rapidly to an emergency department/hospital).
The dosing schedule for individual patients will be the same within a treatment arm and will be 
assigned at randomization (Day 1).
All study drug dosages prescribed and dispensed to the patient and all dose changes or missed 
administrations during the study must be recorded on the appropriate CRF page. 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study drug dose adjustments and interruptions are not permitted. 
Any missed or altered study drug administrations must be recorded on the appropriate CRF 
page in order to reconstruct an accurate dosing history for each patient.
 
 
 
 
 
 
 
 
 
 
 
 
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the appropriate CRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. Approved doses of continuous 
H1-antihistamine therapy provided as concomitant medication should be kept stable during the 
study duration.


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5.5.8
Prohibited medication
Use of the class of treatments displayed in Table 5-1 is NOT allowed after start of first screening
visit. The minimum required period without prohibited treatment before the first screening visit 
(Visit 1) is listed in Table 5-1 as well. Each concomitant drug must be individually assessed 
against all exclusion criteria and the table below to see if it is allowed. If in doubt, the 
investigator should contact Novartis or delegate before randomizing a patient or allowing a new 
medication to be started.
Table 5-1
Prohibited treatment
Medication
Minimum required period 
without medications before 
Visit 1
Anti-IgE therapy
no prior use allowed
Routine (daily or every other day during more than 
one consecutive day /month) doses of systemic
corticosteroids
30 days
Beta-blocker therapy
7 days
Leukotriene antagonists
Stop at visit 1
H2-antihistamines
Stop at visit 1
H1-antistamines with sedative effects
Stop at visit 1
Constant use of H1-antihistamines at dose levels that 
are not labeled (approved)
Stop at visit 1
Routine (daily or every other day during 5 or more 
consecutive days) doses of hydroxychloroquine
30 days
Routine (daily or every other day during 5 or more 
consecutive days) doses of methotrexate, 
cyclosporine A, cyclophosphamide, tacrolimus and 
mycophenolate mofetil
30 days
Intravenous immunoglobulin G
30 days
Plasmapheresis
30 days
Regular (daily or every other day) doxepin (oral)
14 days
Inactivated virus vaccination
48 hours prior to Visit 110, 120, 
130, 140, 150 and 160, 
Live attenuated vaccine
30 days
If the prohibited treatment was used during the study for any indication, the patient must 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. If the 
patient received a live virus vaccination during the study, the patient must discontinue study 
treatment.
The table is not considered all inclusive. Medication should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.


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5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

subject number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. The appropriate personnel from the site and Novartis will assess 
whether investigational treatment should be discontinued for any patient whose treatment code 
has been broken inadvertently for any reason. 
Patients who discontinue investigational treatment should NOT be considered withdrawn from 
the study. They will be expected to perform the Visit 170 End of treatment/Study treatment 
discontinuation (EOT/TD) assessments four weeks after their last dose and will be expected to 
perform all follow-up assessments (Visit 180-210). If they fail to return for these assessments 
for unknown reasons, every effort (e.g., telephone, e-mail, letter) should be made to contact 
them.
The investigator must also contact the IRT to register the patient’s discontinuation from
investigational treatment.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol. The investigator must call or logon to the IRT system to record 
the patient completion. No post-study treatment is planned for this trial. 
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator at 
any time. 


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The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Investigational treatment must be discontinued under the following circumstances:

Patient/guardian wish 

Pregnancy (see Section 6.5.6 and Section 7.6)

Any situation in which study participation might result in a safety risk to the patient

Adverse events for which continued exposure to the study drug would be detrimental

Abnormal renal laboratory results requiring discontinuation (for guidance under which 
conditions a study drug discontinuation needs to be considered  see Appendix 3)

Abnormal liver laboratory results requiring discontinuation (for further guidance under 
which conditions study drug discontinuation should be considered see Appendix 2)

Platelets < 75000/µL

Unblinding of study treatment other than to authorized personnel (see Section 5.4) for any 
reason

If a patient develops a medical condition that requires use of prohibited treatment as per 
Section 5.5.8, or if patient exhibits a behavior of non-compliance regarding prohibited 
medications

Patient received a live virus vaccination during the study

If a patient experiences an unexpected hypersensitivity reaction of grade 4, as defined by 
the World Allergy Organization Grading System (Cox 2010), see Appendix 6.

Lower or upper respiratory organs: Respiratory failure with or without loss of 
consciousness

Or cardiovascular system: Hypotension with or without loss of consciousness

Requirement of emergency use of epinephrine (or a similar emergency intervention) due to 
anaphylactic or anaphylactoid reaction

Any other protocol deviation that results in a significant risk to the patient’s safety
The appropriate personnel from the site and Novartis will assess whether investigational
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.
Patients who discontinue investigational treatment should NOT be considered withdrawn from 
the study. They will be expected to perform the end of treatment/study treatment discontinuation
visit (EOT/TD) and all follow up visits. If they fail to return for these assessments for unknown 
reasons, every effort (e.g., telephone, e-mail, letter) should be made to contact them and their 
legal guardians.
The investigator must also contact the IRT to register the patient’s discontinuation from
investigational treatment.


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If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’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 patient 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 patient’s study withdrawal should be made as detailed in the 
assessment table below.
5.6.4
Loss 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 patient cannot be considered as lost to follow-up until the time 
point of his/her planned end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. 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 patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.


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6
Visit schedule and assessments
Table 6-1 lists all of the assessments. 
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed. At this final visit, all 
dispensed investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the CRF.
All patients who complete the treatment period will be expected to attend all follow-up visits 
(Week 28 – Week 40). Patients who withdraw early will be contacted for safety evaluations 
every 4 weeks following their last study drug administration until 20 weeks post withdrawal. 
Documentation of attempts to contact the patient should be recorded in the source 
documentation.


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Table 6-1
Assessment schedule
Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
Obtain Informed Consent
X
Inclusion/exclusion criteria
X
X
X
Demographic data
X
Relevant medical history
X
Family malignancy history – only to 
be completed if patient develops a 
malignancy event
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior urticaria treatment
X
Prior and Concomitant medication 
usage
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


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Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
Re-screening 
(re-screening 
CRF 
should be recorded if the patient is re-
screened)
X
Study drug/placebo administration
X
X
X
X
X
X
Randomization
XS
Contact IRT
XS
XS
XS
XS
XS
XS
XS
XS
XS
In-clinic assessment of UAS  and 
check of medical record for hives
X
X
X
ePROs should be completed prior to
any other assessment
Dispense Patients’ e-Diary
S


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Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
Patients’ e-Diary (download and 
review) Includes the urticaria patient 
daily 
diary 
(UPDD) 
 
 
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
CDLQI (Children Dermatology Life 
Quality Index)
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Laboratory tests
Stool ova and parasite evaluation; if 
clinical 
signs 
or 
symptoms 
of 
parasitosis develop at any time prior 
to the last study drug administration, 
additional assessments for parasitic 
conditions will be performed
X
X
Hematology (plus INR at 
all visits except Day -7, 
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS


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Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
Blood 
samplin
g
Day 1, Week 24 and Week 
40)
Clinical 
chemistry 
including
Bilirubin
(all 
indicated 
visits), 
 
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Serum pregnancy B-hCG 
test (for females of child 
bearing potential)
XS
XS
PK (ligelizumab)1
XS
XS
XS
XS
XS
XS
XS
XS
XS
PD (total IgE)1
XS
XS
XS
XS
XS
XS
XS
XS
XS
Anti-Drug/ligelizumab
antibodies (ADA)1
XS
XS
XS
XS
XS
XS


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Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
Urine 
samplin
g
Urinalysis
When 
a 
dipstick 
evaluation is abnormal, 
e.g. positive for WBC 
and/or 
blood, 
a 
microscopic examination 
including RBC and WBC 
XS
XS
XS
XS
XS


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Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
should be done by central 
lab
Urine Pregnancy Test if 
positive to be confirmed 
by serum B-hCG , should 
be done be central lab
S
S
S
S
S
S
S
S
S
S
S
S
S
Safety
Physical Exam
(Physical exam between Day -28 to 
Day -14 is a complete exam but 
subsequent physical exams maybe 
limited to a short  exam)
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
Height and Weight (at Visits 170 and 
210 only body weight will be 
measured)
X
X
X


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Period
Screening
Double-blind Treatment
Post-treatment Follow-Up 
Visit
1
2
110
120
130
140
150
160
170 or 
1998 
(EOT/
TD)
180
190
200
210 
or 
1999 
(EOS/P
SD)
Day
-28 to 
-14
-7
1
29
57
85
113
141
169
197
225
253
281
Week (R = randomization week)
-4 to -
2
-1
R
4
8
12
16
20
24
28
32
36
40
ECG (three ECG measurements to be 
taken at approximately 1 minute 
intervals at Visit 1 and 170, all other 
visits a single ECG measurement will 
be recorded)
XS
XS
XS
XS
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Others
Study disposition 
X
X
EOT/TD = End of treatment / Study treatment discontinuation; EOS / PSD = End of Study / Premature subject/patient discontinuation
X = assessment to be recorded on clinical data base
S = assessment to be recorded on source documentation only
XS =third party data
1 all samples to be taken pre-dose on dosing days


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6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next period will have 
reason for not being treated, demographics, inclusion/exclusion, and serious adverse event 
(SAE) data collected. Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include age, 
sex, race, ethnicity. Relevant medical history/current medical condition present before signing 
the informed consent will be captured. Where possible, diagnoses, and not symptoms, will be 
recorded. In addition, data on patient’s family history on malignancies is collected on the 
respective CRF page for those patients who during the trial experience an event related to any 
malignancies.
6.3
Treatment exposure and compliance 
Patients will receive one subcutaneous injection every 4 weeks at six visits during the double-
blind treatment period. Compliance is assured as study drug needs to be administered by 
independent unblinded study personnel via subcutaneous injection at the site. Administration 
of study drug should be recorded in the source documents and the corresponding CRF for each 
administration.
6.4
Efficacy
The efficacy assessments consist of Patient Reported Outcomes (PROs) that have been reported 
in the patient eDiary. The following efficacy variables will be assessed during the study:

Hives severity score (HSS)

Itch severity score (ISS)

Weekly Urticaria Activity score (UAS7)

Angioedema occurrence

Number of calls to doctor or nurse
6.4.1
eDiary assessments for patient reported outcomes
All patients will be provided with a handheld electronic device (eDiary) that consists of the 
Urticaria Patient Daily Diary (UPDD), 
and the Children 
Dermatology Life Quality Index (CDLQI) 


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The patients will receive clear instructions on the completion of the eDiary twice daily or once 
daily depending on the questions. Sites and patients will receive appropriate training and 
guidance on the use of the eDiary device.
Patients should be given sufficient space and time to complete all study PROs. If patients 
experience any difficulties with submission after they complete the PROs, the study staff should 
assist them with submitting their PRO responses.  Attempts should be made to collect responses 
to all PROs for all patients, including from those who prematurely discontinue prior to the study 
evaluation completion visit, however, if patients refuse to complete PROs, this should be 
documented in study source records. Patient’s refusal to complete study PROs are not protocol 
deviations.
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). The investigator should review not only the responses to the questions in the 
questionnaires but also for any unsolicited comments written by the patient. If AEs or SAEs are 
confirmed, then the physician must record the events as per instructions given in Section 7.1
and Section 7.2 of the protocol. 
6.4.1.1
Urticaria Patient Daily Diary (UPDD)
UPDD includes UAS7 (itch and hives) for clinical symptoms, 
 
 angioedema occurrence and its management (Appendix 3).
6.4.1.1.1 Hives Severity Score (HSS)
The wheals (hives) severity score, defined by number of hives, will be recorded by the patient 
twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe) (see Table 6-2). A weekly 
score (HSS7) is derived by adding up the average daily scores of the 7 days preceding the visit. 
The possible range of the weekly score is therefore 0 – 21.
Complete hives response is defined as HSS7 = 0.
Table 6-2
Hives Severity Score
Score
Wheals (Hives)
0
None
1
Mild (1-6 hives/12 hours)
2
Moderate (7-12/12 hours)
3
Severe (>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 one or more of the daily scores are 
missing, the following principles will be applied to handle the missing data:

If a patient has at least 4 non-missing daily scores within the 7 days prior to the study 
visit, the weekly score is calculated as the sum of the available eDiary scores in that 
week, divided by the number of days that have a non-missing diary score, multiplied by 
7. 


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
If there are less than 4 non-missing daily scores within the prior 7 days, then the weekly 
score is missing for the week.
6.4.1.1.2 Itch Severity Score (ISS)
The severity of the itch will be recorded by the patient twice daily in their eDiary, on a scale of 
0 (none) to 3 (intense/severe) (see Table 6-3). A weekly score (ISS7) is derived by adding up 
the average daily scores of the 7 days preceding the visit. The possible range of the weekly 
score is therefore 0 – 21. Partially missing diary entries will be handled in the same way as 
described for the hives severity score.
Complete itch response is defined as ISS7 = 0.
Table 6-3
Itch Severity Score
Score
Pruritus (Itch)
0
None
1
Mild (minimal awareness, 
easily tolerated)
2
Moderate (definite awareness, 
bothersome but tolerable)
3
Severe (difficult to tolerate)
6.4.1.1.3 The 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.
Complete UAS7 response is defined as UAS7 = 0.


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6.4.1.1.7 Angioedema occurrence
Table 6-6
Actions/treatments for Angioedema
Score
Action/treatments
0
Did nothing
1
Took some prescription or non-prescription medication
2
Called my doctor, nurse or nurse practitioner
3
Went to see my doctor, nurse or nurse practitioner
4
Went to the emergency room at the hospital
5
Was hospitalized


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6.4.1.1.8 Number of calls to doctor or nurse
The number of calls to doctor, nurse or nurse practitioner because of the patient’s skin condition 
will be recorded once daily in the eDiary by the patient.
6.4.2
Children Dermatology Life Quality Index (CDLQI)
The Children Dermatology Life Quality Index questionnaire is designed for use in children, i.e 
patients from age 4 to age 16. It will also be deployed to any 17 year olds participating in this 
trial. It is a 10-item dermatology-specific health-related quality of life measure. Patients rate 
their dermatology symptoms as well as the impact of their skin condition on various aspects of 
their lives. An overall score will be calculated as well as for the following domains: Symptoms 
and Feelings, Leisure, School or Holidays, Personal Relationships, Sleep, Treatment. The 
patient will complete this questionnaire on the eDiary at the hospital/clinic as per the assessment 
schedule in Table 6-1.
6.4.3
Other assessments: In-clinic assessment of UAS
The UAS will be recorded by the Investigator at the site by rating the patient’s number of 
urticaria lesion (hives) and interviewing the patient for the assessment of pruritus reflective of 
the patient’s condition over the 12 hours prior to the visit (Table 6-7).
Table 6-7
In-clinic UAS
Score
Wheals (Hives)
Score
Pruritus (Itch)
0
None
0
None
1
Mild (1-6 hives/ 12 hours)
1
Mild
2
Moderate (7-12/ 12 hours)
2
Moderate
3
Severe (>12 hives /12 hours)
3
Severe
6.4.4
Appropriateness of efficacy assessments 
The main CSU symptoms are hives and intense itch, therefore, it is appropriate to evaluate 
clinical response through use of the UAS, a composite endpoint that measures both of these 
symptoms. 
In the past literature has been noted that assessment of itch is the symptom of greatest concern 
to patients, with greatest impact on their quality of life (Mathias et al 2010). However, hives are 


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more objective since they can be counted on the body and thus are more easily quantifiable, 
whereas the itch is a subjective, non-specific sensation which could be of different origin. 
Thus, in this study, the primary efficacy endpoint will be the combination of both weekly hives 
and itch severity as covered by the UAS7 score. In addition each symptom score component 
(i.e. itch and hives score during the last seven days, ISS7 and HSS7 are analyzed as secondary 
endpoints.
Disease recurrence after study drug is withdrawn will be measured during the post-treatment 
follow-up period. For all patients, symptom scores will be measured during both the treatment 
and post-treatment follow-up periods. The assessment of onset and offset of effect is also 
important to inform the model based analysis that is planned based on the data set collected in 
this study.
6.5
Safety 
Main safety and tolerability assessments include:

AEs and SAEs. AEs leading to treatment discontinuation; Events of special interest 
are injection site reactions, anaphylaxis, pre-malignancy/malignancy, cardio-
cerebrovascular events

Physical examination

Vital signs

Laboratory evaluations

ECG
6.5.1
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, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
A short physical exam will include the examination of general appearance and vital signs (see 
section 6.5.2). A short physical exam will be at all visits starting from the first screening visit
except where a complete physical examination is required (see Table 6.1).
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the CRF. Significant findings made after signing the 
informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the CRF.
6.5.2
Vital signs 
Vital signs include blood pressure and pulse measurements. After the patient has been sitting 
for five minutes, with back supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured using a validated device with an appropriately sized cuff. In 
case the cuff sizes available are not large enough for the patient’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used.


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Clinically notable vital signs are defined in Appendix 1
6.5.3
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.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section unless 
noted otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual.
Clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential, and platelet count will be measured. Also coagulation will be assessed by
International Normalized Ratio (INR).
6.5.4.2
Clinical chemistry
Albumin, total bilirubin, alkaline phosphatase, AST, ALT, chloride, calcium, sodium, 
potassium, magnesium, LDH, creatinine, inorganic phosphorus, urea/BUN, 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.
6.5.4.3
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. If possible, a 
morning sample should be used to eliminate benign orthostatic (postural) proteinuria. Semi-
quantitative “dipstick” evaluation for specific gravity, glucose, protein, bilirubin, ketones, 
leukocytes and blood will be performed at site. When a dipstick evaluation is abnormal, e.g., 
positive for WBC and/or blood, a urine sample needs to 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.
6.5.4.4
Assessment of parasitic infections
Reduction in IgE levels may confer increased susceptibility to parasitic infections. The evidence 
of risk of acquiring or activating infections with helminthes is not confirmed and suspected to 
be low after treatment with anti-IgE such as ligelizumab and Omalizumab.
As indicated in Section 4.2 (exclusion criteria), all patients will need to have a stool sample 
collected at screening.
In case the patient is unable to provide a stool sample, they should take a sample pot home to 
bring or send in a stool sample as soon as possible after the visit, preferably the day after.


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Stool samples and additional assessment for parasitic disease will be examined for ova and 
parasites by the central laboratory. Negative tests must be documented before initiation of 
dosing.
If diarrhea or other clinical symptoms or signs of helminth infection develop at any time prior 
to the last study drug administration, additional assessments for parasitic conditions need to be 
performed.
A stool sample will also be collected at the end of study visit (EOS).
6.5.5
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. Triplicate ECGs (3 ECG 
measurements taken at approximately 1 min intervals) will be recorded at Visits 1 and 170; 
single ECGs will be recorded at all other visits where ECG is assessed. For each ECG performed, 
original traces and identical duplicate traces will be produced. The original trace will be sent 
electronically to the Contract Research Organization (CRO) directly from the provided ECG 
machine. Two “identical” duplicate print-outs will be generated 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 kept at the investigator site will be dated 
and signed and will be archived at the study site. The patient’s number, the date and actual time 
of the tracing, and Study Code (CQGE031C2202) must appear on each page of the ECG tracing. 
Clinically significant ECG findings prior to dosing with investigational treatment must be 
discussed with the sponsor. Clinically significant abnormalities should be recorded on the 
relevant section of the Medical history/Current medical conditions/AE CRF page, as 
appropriate. Full details of all procedures relating to the ECG collection and reporting will be 
contained in an investigator manual to be provided by the CRO to each investigator site.
6.5.6
Pregnancy and assessments of fertility 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female adolescent patients who have had their menarche or 
who experience their menarche during the study.
A urine pregnancy test and a serum B-hCG will be performed for all females of child-bearing 
potential according to the schedule in Table 6-1. A positive urine pregnancy test requires 
immediate interruption of study medication until serum B-hCG is performed and found to be 
negative. If positive, the patient must be discontinued from the investigational treatment. 
However, a patient may choose to remain in the study should she become pregnant, and be 
followed according to the protocol-defined study visits. Additional pregnancy tests may be 
performed at the investigator’s discretion during the study.
All female adolescents and their parents/caregivers should be informed about the potential risks 
of pregnancy and the need to prevent pregnancy during the study.
Urine pregnancy test kits will be provided to the sites by the Central Lab.


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6.5.7
Anaphylaxis assessment
An adjudication committee (AC) will be put in place to determine whether cases identified 
through a search algorithm based on the Standardized MedDRA Queries (SMQ) of 
hypersensitivity may represent cases of anaphylaxis. Further details regarding the AC will be 
documented in the AC charter. See Section 8.5 for details.
6.5.8
Assessment of cardiovascular 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 8.5 for details.
6.5.9
Assessment of pre-malignancies and malignancies
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of pre-malignancies and malignancies. The clinical 
presentation and association of these events with pre-existing risk factors will be part of the 
assessment. See Section 8.5 for details.
6.5.10
Appropriateness of safety measurements 
In addition to standard safety assessments that are commonly used in to assess the safety of 
patient populations, events of special interest that might possibly related to the mode of action 
of ligelizumab such as anaphylaxis, malignancies, and cardio-cerebrovascular events will be 
monitored and will be adjudicated by expert adjudication committees.
6.6
Other assessments
6.6.1
Resource utilization 
Healthcare utilization (calling a doctor, nurse, or nurse practitioner) will be reported by the 
patient in the daily diary. The action(s) taken by the patient in response to their angioedema will 
be also reported in the daily diary.
6.6.2
Pharmacokinetics/Pharmacodynamics
PK (ligelizumab) and PD (total IgE (free IgE plus IgE bound to ligelizumab)) will be measured 
in serum every 4 weeks during the treatment period and at selected visits during washout. A 
single blood collection will account for ligelizumab and total IgE. Where sample collections 
coincide with dosage administration then the blood sample must be taken immediately before 
the dose is administered.
Serum IgE levels will also be assessed prior to study drug administration at randomization visit
(Visit 110).
Blood collection and processing
All blood samples will be taken from the contra-lateral arm of the injection by either direct 
venipuncture or an indwelling cannula inserted in a forearm vein. All samples will be given a 


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unique sample number (as listed in Appendix 5). The actual sample collection date and time 
will be entered on the PK blood collection page of the CRF. 
Detailed instructions for blood sample collection, processing, storage and shipment are 
provided in the lab manual and flow charts prepared by the Central Laboratory.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic calculations
Due to the sparse nature of PK sampling in this study conventional non-compartmental analysis 
will not be conducted. Instead the data from this study will be added to a pooled dataset from 
different studies and analyzed with nonlinear mixed effect models based analysis (NLME) (see 
Section 9.5.5)
Further details on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manual


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7
Safety monitoring 
7.1
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 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 7.2):
1. The severity grade.
-
mild: usually transient in nature and generally not interfering with normal 
activities
-
moderate: sufficiently discomforting to interfere with normal activities
-
severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease 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.


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4. whether it constitutes a SAE (see Section 7.2 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
-
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.
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’s 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 
Appendix 1.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
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


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Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
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 Annex 
IV, ICH-E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
7.2.2
SAE reporting 
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 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. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 


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different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if 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 re-occurrence, 
complication, 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 study treatment a Drug Safety and Epidemiology 
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.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
7.3
Liver safety monitoring 
To ensure patient 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
Please refer to Table 13.1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 13.1 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 13.2. Repeat liver chemistry tests (ALT, AST, TBL, 
PT/INR, ALP and G-GT) to confirm elevation.


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
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
These investigations can include based on investigator’s discretion: serology tests, imaging 
and pathology assessments, hepatologist’s consultancy; obtaining more detailed history of 
symptoms and prior or concurrent diseases, history of concomitant drug use, exclusion of 
underlying liver disease
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
7.4
Renal safety monitoring 
Routine renal safety monitoring includes the assessment of creatinine, BUN, urine dipstick 
measurements. eGFR will be calculated using the Schwartz formula. For diagnosis and actions 
related to renal adverse events please refer to Appendix 3.
7.5
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, patient 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 collected in 
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.


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Table 7-1
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.
7.6
Pregnancy reporting 
To ensure patient 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. The newborn will be followed up to 3 months after the birth to 
collect any information on any development issue that would not be seen at birth. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
7.7
Other safety assessments
7.7.1
Immunogenicity assessments
The presence of anti-QGE031 antibodies will be determined in samples collected prior to the 
first dose and on Week 8, 16, 24, 32 and 40.
The presence of anti-QGE031 antibodies will be assayed using a MSD-based homogenous 
bridging assay. In this assay anti-QGE031 antibodies are captured in solution by combination 
of biotinylated and ruthenium-labeled forms of ligelizumab. Formed complex is subsequently 
detected by the ECL using streptavidin coated plates (MSD). Interference of endogenous IgE 
will be minimized by pre-treatment with an anti-IgE antibody coupled to magnetic beads to 
remove IgE and interference with ligelizumab will be minimized by an acid-treatment step to 
disrupt pre-existing anti-QGE031-QGE031 complexes. 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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8
Data review and database management 
8.1
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. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient 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 CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient 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 
patient's file. Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs. The investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient).
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 
patients/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.


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8.3
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to Novartis
(or a designated CRO).
Diary data will be entered into an electronic diary. The system will be supplied by a vendor(s), 
who will also manage the database. The database will be sent electronically to Novartis 
personnel (or designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The data will be sent electronically 
to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.


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8.5
Adjudication Committee 
The role of the Adjudication Committee (AC) is to ensure that all treatment outcomes are judged 
uniformly, using standard criteria and processes. The AC will be composed of clinical experts 
to evaluate disease progression and harmonize endpoint assessment criteria using data provided 
by the sponsor.
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial. Specific details regarding endpoint definitions can be found in the 
adjudication charter.
9
Data analysis 
The analysis will be conducted on all patient 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.
9.1
Analysis sets
The randomized set (RAN), which comprises all randomized patients, regardless of whether or 
not they actually received study medication, will be used for summaries of patient disposition 
and analysis sets.
The Full Analysis set (FAS) comprises all patients to whom study treatment has been assigned. 
Following the intent-to-treat principle, patients will be analyzed according to the treatment they 
were assigned to at randomization. FAS will be used for all efficacy variables, unless otherwise 
stated.
The safety set (SAF) will include all patients who received at least one dose of study drug 
whether or not being randomized. Patients will be analyzed according to the treatment they 
received. The safety set will be used in the analysis of all safety variables.
Note that the FAS and safety set are the same except that the safety set allows the inclusion of 
non-randomized patients who receive study drug in error. Also the FAS assigns randomized 
treatment and the safety set assigns received treatment.
9.2
Patient demographics and other baseline characteristics 
Demographics and baseline characteristics will be summarized using the safety set including 
disease characteristics, prior and background medications to treat urticaria, and relevant medical 
histories.
9.3
Treatments 
The number of patients and the length of time (in days) exposed to each study drug and dose 
will be summarized by treatment for the safety set.
Concomitant medications will be summarized by treatment for the safety set separated for 
urticaria related background medications and non-urticaria related medications. Urticaria 
related background medications will be summarized by pre-specified categories (including 


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dose) and preferred term. Non-urticaria related concomitant medications will be summarized 
by preferred term. 
9.4
Analysis of the primary variables
The primary variable will be analyzed descriptively in this protocol. In addition UAS7 from 
this study will be forwarded to a separate cross-study modelling and simulation PKPD analysis 
study (outlined in Section 9.5.5).
9.4.1
Primary Variables
The primary variable is change in UAS7 from baseline to Week 24. UAS7 is the sum of HSS7 
and ISS7 as described in Section 6.4.1. 
9.4.2
Statistical model, hypothesis, and method of analysis
No formal statistical testing will be applied for the primary variable. 
The primary variable will be summarized by treatment group in FAS, using descriptive statistics, 
which include arithmetic mean, standard deviation, minimum, maximum and median. The mean 
of the change from baseline by treatment group will be shown descriptively with 95% 
confidence intervals based on the t-distribution. 
9.4.3
Handling of missing values/censoring/discontinuations
As the primary analysis is to summarize the data descriptively, no imputation for the missing 
UAS7 will be applied. If ISS7 or HSS7 is missing, UAS7 will also be missing. 
To calculate ISS7/HSS7 score from daily score, missing daily score will be handled according 
to the rule described in Section 6.4.1. 
9.4.4
Sensitivity analyses
No sensitivity analysis is planned for the primary variable, as no statistical model is used.
9.5
Analysis of secondary
variables
9.5.1
Efficacy variables
Table 9-1 shows the list of efficacy variables. Unless otherwise specified, all efficacy variables 
will be analyzed in FAS. Summary tables will be presented by treatment group and visit (as 
applicable), using descriptive statistics, which include absolute and relative frequencies for 
categorical variables and arithmetic mean, standard deviation, minimum, maximum, median for 
continuous variables. Mean differences of the change from baseline in UAS7, HSS7 and ISS7
between groups will be shown descriptively with 95% confidence intervals based on two-
sample t-test. All analyses are shown descriptively and no formal statistical testing will be 
applied.


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Table 9-1
Secondary
efficacy variables
Domain
Variable
Treatment 
period: Weeks
12 and 24
Follow-up 
period: Week 
40
Clinical 
symptoms: total
Complete UAS7 response (UAS7 = 
0)
Y
Y
Change from Baseline in Urticaria 
Activity Score (UAS7)
Y
Y
Number of patients who have relapse 
(UAS7>=12) after achieving 
UAS7<=6
Y
Y
Clinical 
symptoms: hives
Complete hives response (HSS7 = 0)
Y
Y
Change from Baseline in HSS7
Y
Y
Clinical 
symptoms: itch
Complete itch response (ISS7 = 0)
Y
Y
Change from Baseline in Itch 
Severity Score (ISS7)
Y
Y
Clinical 
symptoms: 
angioedema
Number of days with angioedema 
according to the patient diary
Y
Y
Quality of life: 
CDLQI
Absolute and percentage change from 
baseline in total Children 
Dermatology life Quality Index 
(CDLQI) score
Y
Y
CDLQI individual domain scores
Y
Y
Achievement of CDLQI =0 or 1
Y
Y
Y: yes, N: no


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9.5.2
Safety variables
All safety variables will be analyzed by Safety Set (SAF).
Adverse events 
All adverse events which start after the first dose of study medication and within 16 weeks of 
the last dose will be considered as a treatment emergent adverse event. Treatment emergent 
adverse events may be presented in 2 sub-groups; those which started after first study drug dose 
and within 4 weeks after the last dose and those which started more than 4 weeks after the last 
dose. For the patients in the placebo arm, adverse events after switching to ligelizumab will be 
summarized separately.  
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: 

All adverse events 

Adverse events by maximum severity 

Adverse events suspected by the investigator as study drug-related 

Serious adverse events 

Adverse events leading to permanent discontinuation of study drug 
AEs of Special Interest 
Hypersensitivity assessment 
All hypersensitivity reactions that are possible cases of anaphylaxis will be adjudicated by 
independent committee. The adjudicated hypersensitivity reactions will be summarized by 
preferred term and severity. 
Cardio- and Cerebrovascular events
All cardio- and cerebrovascular events will be adjudicated by independent committee and 
summarized by preferred term and severity.
Malignancies 
Frequency of adjudicated newly detected malignancies will be reported. 
Laboratory data 
The following analyses will be performed, where appropriate, for measurements of urinalysis, 
hematology and blood chemistry tests: 

Standard descriptive statistics for values measured at baseline and post-baseline visits 
including changes from baseline, shift tables relative to the normal ranges between 
baseline and post-baseline visits, number (and percentage) of patients with clinically 
notable changes for selected tests. 


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Anti-QGE031 antibody
A summary of anti-QGE031 antibodies will be provided.
Vital signs 
Vital signs (i.e. blood pressure and pulse rate) will be summarized with standard descriptive 
statistics of raw data and changes from baseline for each visit separately. The numbers of 
patients with vital signs meeting the definition of notably abnormal will be presented by 
parameter. 
ECG 
ECG data will be summarized by treatment and visit. Changes from baseline will be 
summarized. 
Notable QTc values and change from baseline will be summarized. A notable value is defined 
as a QTc interval of greater than 450 ms. The categories used for the change (increase) in QTc 
are - less than 30 ms, 30 to 60 ms and greater than 60 ms. 
The Fredricia QT correction formula (QTcF) will be used for clinical decisions. 
9.5.3
Pharmacokinetics
PK data will be summarized descriptively and will be analyzed separately as part of the PK/PD 
analysis. 
9.5.5
PK/PD
PKPD modelling will be conducted in a separate modelling and simulation (M&S) study as the
data from this study, QGE031C2202, will be only one part of a pool from both adolescent and 
adult patients. 
 
 
 
 


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9.7
Interim analyses
No interim analyses is planned at the time of writing of this protocol, but may be added in case 
there is a need to provide information to health authorities, or to support program milestones.
In addition the DMC will receive on a regular basis safety information from the ongoing study.
9.8
Sample size calculation
The expected half-width of 95% confidence intervals for the change from baseline in UAS7 for 
each group is 5.2, assuming 24 patients in ligelizumab 24 mg arm and SD=13. If the mean 
change from baseline in UAS7 for ligelizumab group is -22.0 (based on C2201 adult study), the 
95% confidence interval of the mean change from baseline in UAS7 will be (-27.2, -16.8).    
 
 
 
 
 
 
 
 


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10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after the patient or a parent or legal guardian 
provides written (witnessed, where required by law or regulation), IRB/IEC/REB-approved
informed consent. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is capable 
of doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 
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 patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Females of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
patient recruitment procedures (e.g., advertisements) and any other written information to be 
provided to patients. 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.
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, 


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informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients/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.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures (SOP), and are performed according to 
written Novartis processes.
11
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 patients/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, 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. 


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11.1
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 intended to eliminate an apparent immediate hazard 
to patients/subjects 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 patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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12
References 
Bernstein JA, Lang DM, Khan DA, et al (2014) The diagnosis and management of acute and 
chronic urticaria: 2014 update. J Allergy Clin Immunol; 133(5):1270-7.
Chang TW, Chen C, Lin CJ, et al (2015) The potential pharmacologic mechanisms of 
omalizumab in patients with chronic spontaneous urticaria.J Allergy Clin Immunol;
135(2):337-42. 
Cox L, Larenas-Linnemann D, Lockey RF, et al (2010) Speaking the same language: The 
World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading 
System. J Allergy Clin Immunol; 125(3):569-74.
Cox L, Platts-Mills TA, Finegold I, et al (2007) American Academy of Allergy, Asthma & 
Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report 
on omalizumab-associated anaphylaxis. J Allergy Clin Immunol; 120(6):1373-7.
Eckman JA, Hamilton RG, Gober LM, et al (2008) Basophil phenotypes in chronic idiopathic 
urticaria in relation to disease activity and autoantibodies. J Invest Dermatol; 128(8):1956-63.
EMA 2014. Application II/0048 Assessment report, Section 2.3.4.2 page 10 and Section 2.3.5 
page 11. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Assessment_Report_-_Variation/human/000606/WC500164453.pdf accessed Nov.22nd 2017
EMA 2017 Ethical considerations for clinical trials on medicinal products conducted with 
minors Recommendations of the expert group on clinical trials for the implementation of 
Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf accessed Dec. 5th 2017
Fine LM, Bernstein JA, (2016) Guideline of Chronic Urticaria Beyond. Allergy Asthma 
Immunol Res.; 8(5):396-403
Gober MD, Fishelevich R, Zhao Y, et al (2008) Human natural killer T cells infiltrate into the 
skin at elicitation sites of allergic contact dermatitis. J Invest Dermatol; 128(6):1460-9.
Greaves MW (2003) Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol; 3(5):
363-8. Review.
Greaves M (2000) Chronic urticaria. J Allergy Clin Immunol; 105(4):664-72.
Kaplan A, Ledford D, Ashby M, et al (2013) Omalizumab in patients with symptomatic 
chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin 
Immunol; 132(1):101-9.
Kaplan AP (2002) Chronic urticaria-new concepts regarding pathogenesis and treatment. Curr 
Allergy Asthma Rep; 2(4):263-4.
Kaplan AP, Joseph K, Maykut RJ, et al (2008) Treatment of chronic autoimmune urticaria 
with omalizumab. J Allergy Clin Immunol; 122(3):569-73.
Maurer M, Church MK. Weller, K (2017) Chronic Urticaria in Children Still Itching for 
Insight JAMA Dermatol. Published online September 27, 2017 Chronic Urticaria in Children | 
Allergy and Clinical Immunology | JAMA Dermatology | The JAMA Network accessed Nov.
22nd 2017.


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Maurer M, Magerl M, Metz M, et al (2013) Revisions to the international guidelines on the 
diagnosis and therapy of chronic urticaria. J Dtsch Dermatol Ges.
Netchiporouk E, Sasseville D, Moreau L, Habel Y, Rahme E, Ben-Shoshan M (2017) 
Evaluating Comorbidities, Natural History, and Predictors of Early Resolution in a Cohort of 
Children With Chronic Urticaria. JAMA Dermatol. Published online Septmeber 27th 2017
https://jamanetwork.com/journals/jamadermatology/fullarticle/2653791 accessed Dec. 8th
2017
O'Donnell BF, Lawlor F, Simpson J, et al (1997) The impact of chronic urticaria on the 
quality of life. Br J Dermatol; 136(2):197-201.
Powell RJ, Du Toit GL, Siddique N, et al (2007) BSACI guidelines for the management of 
chronic urticaria and angio-oedema. Clin Exp Allergy; 37(5):631-50.
Sabroe RA, Greaves MW (2006) Chronic idiopathic urticaria with functional autoantibodies: 
12 years on. Br J Dermatol; 154(5):813-9. Review.
Shikiar R, Harding G, Leahy M, et al (2005) Minimal important difference (MID) of the 
Dermatology Life Quality Index (DLQI): results from patients with chronic idiopathic 
urticaria. Health Qual Life Outcomes; 3:36.
Zuberbier T, Aberer W, Asero R, et al (2014) The EAACI/GA(2) LEN/EDF/WAO Guideline 
for the definition, classification, diagnosis, and management of urticaria: the 2013 revision 
and update. Allergy; 69(7):868-87.
Zuberbier T, Balke M, Worm M, et al (2010) Epidemiology of urticaria: a representative 
cross-sectional population survey. Clin Exp Dermatol; 35(8):869-73.


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13
Appendices
13.1
Appendix 1: Clinically notable laboratory values and vital signs
Refer to Appendix 2 for clinically notable laboratory values for hepatotoxicity. 
Refer to Section 7.4 for clinically notable laboratory values for nephrotoxicity. 
The following other specific criteria have been identified for this study:

Platelets < 75 000/μL
Any patient who have platelets <75 000/μL after being randomized should discontinue study 
treatment.
For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outside of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the CRF.
Notable values for vital signs and change from baseline will be summarized. A notable value is 
defined as follows: heart rate of < 40 and > 90 bpm; systolic blood pressure of < 90 and > 140 
mmHg; diastolic blood pressure of < 65 and > 90 mmHg.
For ECGs a notable QTc value is defined as a QTc (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.


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13.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 13-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any 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
TBL: total bilirubin; ULN: upper limit of normal 
Table 13-2
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 liver events to the appropriate 
CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Record liver events to the appropriate 
CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Record liver events to the appropriate 
CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT 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
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Clinical Trial Protocol (Version 00)
Protocol No. CQGE031C2202
Criteria
Actions required
Follow-up monitoring

Establish causality

Record liver events to the appropriate 
CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Record liver events to the appropriate 
CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT 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)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Record liver events to 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 liver events to the appropriate 
CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT 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 liver events to the appropriate 
CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT 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 liver events to the appropriate 
CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution 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,  γGT : Gamma Glutamyl Transferase, LFT: Liver function tests


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Protocol No. CQGE031C2202
13.3
Appendix 3: Specific Renal Alert Criteria and Diagnosis
Ligelizumab is not a drug that has shown an increased risk for drug induced renal toxicity so 
far. However, when suspecting a drug induced renal event which could be related to the study 
medication please contact Novartis and do not continue to administer ligelizumab.
Table 13-3
Specific Renal Alert Criteria and Diagnosis
Serum Event
25% decrease in eGFR and eGFR ≤90ml/min/1.731
m2 compared to baseline
Note: Dependent on normal hydration status-
See list below2
Confirm finding after 24 h but within 5 days
1 Calculate the eGFR with “Schwartz formula” for use in children 1-18 years old
For height in cm and sCr in mg/dL: eGFR (mL/min/1.73 m2) = 0.413 x (height/sCr) 
For height in cm and sCr in µmol/L: eGFR (mL/min/1.73 m2) = 36.5 x (height/sCr) 
Urine Event
Protein-creatinine ratio (PCR)≥1g/g Cr
Confirm finding after 24h  but within 5 days
New dipstick glycosuria ≥3+ 
New dipstick hematuria ≥3+ 
Proteinuria is very common in children in a condition called benign orthostatic (postural) 
proteinuria. Thus, whenever assessing a positive dipstick for proteinuria in children, where 
feasible a first morning sample should be used to eliminate this potentially complicating 
variable.
2When assessing DIN renal events, also consider other causes of renal events and/or altered 
serum creatinine and BUN: 
• Hypovolemia 
• Major operations 
• Severe infections and sepsis 
• Co-medications affecting creatinine secretion (e.g., trimethoprim, cimetidine) 
• Change of antihypertensive treatment regimens 
• Acute or worsening heart failure 
• Rhabdomyolysis (monitor for increase in CPK) 
Cr : Creatinine,  sCr: : Serum Creatinine,  CPK : creatinine phosphokinase


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Clinical Trial Protocol (Version 00)
Protocol No. CQGE031C2202
13.4
Appendix 4 PRO tools
SAMPLES of questionnaire provided here are for illustrative purpose only. The text format and 
wording might slightly vary.


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Protocol No. CQGE031C2202


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Protocol No. CQGE031C2202


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Clinical Trial Protocol (Version 00)
Protocol No. CQGE031C2202


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Clinical Trial Protocol (Version 00)
Protocol No. CQGE031C2202


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Clinical Trial Protocol (Version 00)
Protocol No. CQGE031C2202
13.5
Appendix 5 PK/PD/ADA
 log
Analyte
Visit
1
2
110
120
130
140
150
160
170
180
190
200
210
Days
-28/-
14
-7
1
29
57
85
113
141
169
197
225
253
281
PK
x
x
x
x
x
x
x
x
x
Dose ref 
ID
1
2
3
4
5
6
6
6
6
Sample 
No
101
102
103
104
105
106
107
108
109
Total IgE
x
x
x
x
x
x
x
x
x
Sample 
no
201
202
203
204
205
206
207
208
209
Anti-drug/ 
QGE031 
antibodies
x
x
x
x
x
x
Sample 
no
401
402
403
404
405
406


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Protocol No. CQGE031C2202
13.6
Appendix 6 World allergy organization grading system

SAP_001.pdf: 


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Statistical Analysis Plan
CQGE031C2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
25-May-
2018
Prior 
to 
FPFV
Creation of 
final version
N/A - First version
NA
11-Sep-
2020
Prior 
to 
CSR 
DR
Interim 
analysis 
requested
Added interim analysis
Section 2.14 Interim 
analysis
Consistency 
with 
previous 
studies.
“Non-responder” imputation added
Section 
2.7.1 
Secondary endpoints
Include 
COVID 
19 
related 
impact.
Added Covid-19 impact related details
Section 
5: 
COVID 
related analysis
09-Oct-
2020
Prior 
to 
CSR 
DR
Interim 
analysis 
requested
Updated TEAE definition
Section 2.8.1 Adverse 
events (AEs)
Corrected upper limit for HR for age 
category 17 years
Section 2.8.4.2 Vital 
signs
09-Nov-
2020
Prior 
to 
CSR 
DR
Interim 
analysis 
requested
Updated COVID-19 related details
Section 5.0 COVID-
19 
Impact 
Assessment 
and 
related analysis
26-Jan-
2021
Prior 
to 
CSR 
DR
Final 
analysis 
request
Removed and updated interim analysis 
related details
Updated COVID-19 related details
Updated 
non-responder 
imputation 
related details
Section 2.14 Interim 
analysis
Section 5.0 COVID-
19 
Impact 
Assessment 
and 
related analysis
6.1 Scoring and data 
handling 
rules 
in 
eDiary


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Statistical Analysis Plan
CQGE031C2202
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
13_Feb-
2021
Prior 
to 
CSR 
DR
Final 
analysis 
request
Non-responder 
imputation 
related 
update
Section 
2.7.1 
Secondary endpoints, 
5.16.1 Scoring and 
data handling rules in 
eDiary
Updated for Placebo switcher related 
analysis information
Section 2.8.1 Adverse 
events (AEs), 2.8.3 
Laboratory data,
2.8.4.1 
Electrocardiogram 
(ECG), 2.8.4.2 Vital 
signs
Updated for time-period details
Section 2.8.1.1
Adverse 
events 
of 
special 
interest / grouping of 
AEs
 
 
Updated COVID-19 related analysis 
details
Section 5 COVID-19 
Impact 
Assessment 
and related analysis
05-Mar-
2021
Prior 
to 
CSR 
DR
Final 
analysis 
request
Added section for Other safety topics
Section 2.8.1.2 Other 
safety topics
11-Mar-
2021
Prior 
to 
CSR 
DR
Final 
analysis 
request
Added clarification population title will 
be ENR since the table also includes 
the number of patients screened
2.3 Analysis sets and 
2.4.1 Patient 
disposition
Added baseline ISS7, HSS7 score and 
duration of CSU (years)
Section 2.4 Patient 
disposition, 
demographics and 
other baseline 
characteristics
Prior medications will be based on 
SAF, to be consistent with protocol.
Added 
clarification 
about 
which 
Section 2.5.2 Prior, 
concomitant and post 
therapies


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Statistical Analysis Plan
CQGE031C2202
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
analysis are produced for which 
periods
Removed condition ‘for the week 12 
assessment of the placebo-ligelizumab 
group, only data before switching to 
ligelizumab will be used’, to follow in-
tent-to treat principle
Section 2.6.1 Primary 
endpoint
Added 95% CI of proportion of 
responses for UAS7, HSS7, ISS7 and 
CDLQI responses. Added 95% CI of 
mean 
for 
CDLQI.
Added 
mean 
differences of the change from baseline 
in UAS7, HSS7 and ISS7 between 
groups with 95% CI
Section 2.7.1 
Secondary endpoints
Added 
clarification 
about 
which 
analysis are produced for which 
periods. Added description of in-text 
tables and referenced section 6.5 for 
ClinicalTrials.gov and EudraCT tables
Section 2.8.1 
Adverse events (AEs)
Stool samples taken after the end of 
study visit will be flagged in the listing
Section 2.8.3 
Laboratory data
Added 
maximum/minimum 
post-
baseline value will be summarized
Section 2.8.4.2 Vital 
signs
Updated the changes comparing final 
SAP to protocol
Section 4 Change to 
protocol specified 
analyses
Added clarification for HSS7, ISS7 and 
UAS7 
daily 
score 
derivation 
for 
duplicate records
Section 6.1 Scoring 
and data handling 
rules in eDiary
Clarified ENR exclusion rule since 
disposition not done at screening per 
protocol, so not required
Section 6.7 Rule of 
exclusion criteria of 
analysis sets
Updated 
AE 
of 
special 
interest 
individual term related details
Section 2.8.1.1


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Statistical Analysis Plan
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Table of contents
Table of contents............................................................................................................................. 5
List of abbreviations ........................................................................................................................ 7
1
Introduction..................................................................................................................................... 9
1.1
Study design........................................................................................................................ 9
1.2
Study objectives and endpoints........................................................................................ 10
2
Statistical methods........................................................................................................................ 11
2.1
Data analysis general information.................................................................................... 12
2.2
General definitions ........................................................................................................... 12
2.2.1
Study day and Study Week............................................................................. 12
2.2.2
Baseline........................................................................................................... 12
2.3
Analysis sets...................................................................................................................... 13
2.3.1
Subgroup of interest....................................................................................... 14
2.4
Patient disposition, demographics and other baseline characteristics............................ 14
2.4.1
Patient disposition.......................................................................................... 15
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ...................................................................................................................... 15
2.5.1
Study treatment / compliance........................................................................ 15
2.5.2
Prior, concomitant and post therapies........................................................... 15
2.6
Analysis of the primary objective ..................................................................................... 16
2.6.1
Primary endpoint............................................................................................ 16
2.6.2
Statistical hypothesis, model, and method of analysis................................... 16
2.6.3
Handling of missing values/censoring/discontinuations................................ 16
2.6.4
Supportive analyses........................................................................................ 17
2.7
Analysis of secondary efficacy objective(s) ...................................................................... 17
2.7.1
Secondary endpoints ...................................................................................... 17
2.8
Safety analyses.................................................................................................................. 18
2.8.1
Adverse events (AEs) ...................................................................................... 18
2.8.2
Deaths............................................................................................................. 20
2.8.3
Laboratory data .............................................................................................. 20
2.8.4
Other safety data............................................................................................ 22
2.9
Pharmacokinetic endpoints.............................................................................................. 23
2.10
PD and PK/PD analyses..................................................................................................... 23
23
23


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Statistical Analysis Plan
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24
24
25
25
25
2.14
Interim analysis................................................................................................................. 26
3
Sample size calculation.................................................................................................................. 26
4
Change to protocol specified analyses.......................................................................................... 26
5
COVID-19 Impact Assessment and related analysis...................................................................... 27
6
Appendix........................................................................................................................................ 27
6.1
Scoring and data handling rules in eDiary ........................................................................ 27
6.2
Imputation rules ............................................................................................................... 28
6.2.1
Study drug....................................................................................................... 28
6.2.2
AE date imputation......................................................................................... 28
6.2.3
Concomitant medication (CM) date imputation ............................................ 30
6.3
Adverse event coding/grading.......................................................................................... 32
6.4
Laboratory parameters derivations.................................................................................. 32
6.5
Analysis for Clinicaltrials.gov and EudraCT....................................................................... 33
6.6
Statistical models.............................................................................................................. 33
6.6.1
Primary analysis.............................................................................................. 33
6.7
Rule of exclusion criteria of analysis sets ......................................................................... 34
7
Reference....................................................................................................................................... 34


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Statistical Analysis Plan
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List of abbreviations
AE
Adverse event
AESI
Adverse Events of Special Interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ATC
Anatomical Therapeutic Classification
AST
Aspartate aminotransferase
ATEs
Arterial thromboembolic events
BMI
Body Mass Index
BUN
Blood urea nitrogen
CDLQI
Children Dermatology Life Quality Index
CM
Concomitant medication
CRO
Contract Research Organization
CSR
Clinical Study report
CSU
Chronic Spontaneous Urticaria
DMC
Data Monitoring Committee 
DRP
Data Review Plan
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Strategy
eDiary
Electronic diary
eGFR
Estimated glomerular filtration rate
FAS
Full Analysis Set
FPFV
First Patient First Visit
HSS
Hive Severity Score
IgE
Immunoglobulin E
INR
International Normalized Ratio
IRT
Interactive Response Technology
ISS
Itch Severity Score
LDH
Lactate dehydrogenase
LLOQ
Lower Limit of Quantification
LOQ
Limit of Quantification
MedDRA
Medical Dictionary for Drug Regulatory Affairs
M&S
Modelling and Simulation
N/A
Not Applicable
PDev
Protocol Deviation
PD
Pharmacodynamics
PK
Pharmacokinetics


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Statistical Analysis Plan
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PRO
Patient-reported Outcomes
PT
Preferred Term
q4w
Every 4 weeks
QTcF
Fridericia QT Correction
RAN
Randomized set
RBC
Red Blood Cell
s.c.
Subcutaneous
SAE
Serious Adverse Event
SAF
Safety set
SAP
Statistical Analysis Plan
sCr
Serum Creatinine
SOC
System Organ Class
UAS
Urticaria Activity Score
ULN
Upper Limit of Normal
ULOQ
Upper Limit of Quantification
UPDD
Urticaria Patient Daily Diary
TBL
Total Bilirubin
WBC
White Blood Cell
WHO
World Health Organization


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Statistical Analysis Plan
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1
Introduction
The purpose of Statistical Analysis Plan (SAP) is to describe the statistical analysis planned in 
the protocol for the clinical study report.   
This SAP is based on the original version of protocol (i.e. version 00), dated 18-Jan-2018. 
1.1
Study design
This is a Phase 2b dose-finding, randomized, double-blind, parallel group, placebo controlled
multicenter study in adolescent patients. It consists of 3 distinct study periods, as outlined in 
Figure 1-1 below. After the screening period, at Day 1 patients are randomized into one of the 
three treatment arms in 1:2:1 fashion to ligelizumab 120 mg q4w vs. ligelizumab 24 mg q4w 
vs. placebo. No stratification will be considered for the randomization. 
During the 24 weeks of treatment, doses are administered on Day 1, then on week 4, 8, 12, 16, 
and 20 after randomization. Subjects randomized to placebo will receive placebo on Day 1, 
Week 4 and 8; thereafter they will receive 120 mg ligelizumab on Week 12, 16 and 20 such that 
the same number of patients will, by the end of the study, receive 120 mg as 24 mg. The 
treatment period (24 weeks) is followed by a follow-up period of 16 weeks to a maximum of 
Week 40.
The planned number of patients is 48. Week 24 is considered as primary endpoint in the study.
Data from both the treatment and follow-up periods, will be forwarded to a separate modelling 
study.
Figure 1-1
Study design


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Statistical Analysis Plan
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R: randomization
1.2
Study objectives and endpoints
Table 2-2
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective
Endpoint for primary objective

Change in the Urticaria Activity Score 
(UAS7) between baseline and Week 24

The primary endpoint will be change in 
UAS7 from baseline to Week 24. 
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the efficacy of ligelizumab 
doses 24 mg and 120 mg with respect to 
UAS7 change from baseline 

To evaluate the efficacy of ligelizumab 
doses 24 mg and 120 mg on complete 
response in Urticaria Activity Score 
(UAS7=0), 
Hives 
Severity
Score 
(HSS=0), Itch Severity Score (ISS=0)

To investigate the effects on ISS7 and 
HSS7 when compared to baseline

To investigate the pharmacokinetics of 
ligelizumab

To investigate the pharmacodynamics of 
ligelizumab

UAS7 change from baseline over time 
(at each protocol defined study visit, in 
addition to the primary endpoint)

Rate of complete responders (UAS7=0, 
HSS7=0, ISS7 =0) over time (at each 
protocol defined study visit)

Itch severity score change from 
baseline over time (at each protocol 
defined study visit)

Hives severity score change from 
baseline over time (at each protocol 
defined study visit)

Model-based estimate of clearance and 
volume of distribution using at least 7 
samples

Summary statistics of change in Total 
IgE over time.


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Statistical Analysis Plan
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Objective(s)
Endpoint(s)

Change from baseline in the Children 
Dermatology Life Quality Index 

To evaluate the safety 
(including 
immunogenicity) and tolerability of 
ligelizumab (doses of 24 mg, 120 mg s.c. 
every 4 weeks) versus placebo in patients 
with CSU.

Children Dermatology Life Quality 
Index change from baseline over time 
(each protocol defined study visit)

Adverse events, ECG-intervals and 
interpretation, 
vital 
signs 
(blood 
pressure, pulse rate) and clinical 
laboratory evaluation 
2
Statistical methods
This section contains information that will be used to draft Clinical Study Report (CSR) Section 
9.7 on statistical analysis.


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Statistical Analysis Plan
CQGE031C2202
2.1
Data analysis general information
Data will be analyzed by 
, using SAS version 9.4 or above. 
DMC analysis will be done by the independent statistician and programmers in the separate 
Contract Research Organization (CRO) (
). Statistical Analysis Plan for the DMC analysis 
will be prepared separately.  
In general, summary tables will be presented by treatment group and visit/week (as applicable), 
using descriptive statistics, which include absolute and relative frequencies for categorical 
variables and arithmetic mean, standard deviation, minimum, maximum, median for continuous 
variables.
2.2
General definitions
2.2.1
Study day and Study Week 
The first day of administration of study treatment (first dose) is defined as Day 1. All other 
study days will be labeled relative to Day 1. 
Data from eDiary, the study weeks are defined based on the study days starting with Day 1 (see 
Table 2-1), which is the day the patient receives the first study treatment.
Table 2-1
Study Week definition based on Study Day
Study Week
Study Days
Baseline
(-7)-(-1)
1
1-7
2
8-14
w
7×(w−1)+1 - 7×w
40
274 – 280
Where w is all other remaining study weeks: Between Week 2 and 40, (e.g. 3, 4, 5, 6, 7, 8,..)
For the other data taken by scheduled visit, all by-visit summaries will be performed according 
to the scheduled reported visit. 
2.2.2
Baseline
Unless otherwise specified, baseline is the last assessment (including unscheduled visits) 
obtained on the day of or before the first dose of study treatment. For patient without any 
administration of study dose, the baseline assessment will be their last assessment under the 
study. All assessments obtained after the first dose of study drug are considered as post-
baseline. 
For eDiary score corresponding to a score on the 7 days prior to the visit assessment, the 
baseline will be defined as the baseline week (see Table 2-1).
For ECG numeric measurements, baseline will be defined as the mean of the measurements 
taken on the last date on or before the date of first dose of study treatment. For ECG overall 


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Statistical Analysis Plan
CQGE031C2202
interpretation, baseline will be the most common interpretation (normal/abnormal) of the 
assessments taken on the last date on or before the date of first dose of study treatment (if there 
are an equal number of normal and abnormal assessments on the same date, then baseline will 
be set to ‘abnormal’).
For CDLQI, if the questionnaire was completed more than once on the same date, on the last 
date on or before treatment start date, then the worst outcome (i.e. the highest score) of the 
duplicate observations on that date will be used for baseline. 
For PK/PD, baseline will include assessments on the date of first dose of study treatment, unless 
they are excluded by the inclusion flag derived by the PK analyst.
2.3
Analysis sets
The enrolled set (ENR) will include all patients who had signed an informed consent form and 
had a screening visit. 
The randomized set (RAN), which comprises all randomized patients, regardless of whether or 
not they actually received study medication.
For summaries of patient disposition and analysis sets RAN will be used for deriving 
percentages. ENR will be used for treatment epoch disposition and analysis sets tables 
population title since those tables will also include number of patients screened. 
The Full Analysis set (FAS) comprises all patients to whom study treatment has been assigned. 
Following the intent-to-treat principle, patients will be analyzed according to the treatment they 
were assigned to at randomization. Mis-randomized patients (mis-randomized in IRT) will be 
excluded. Mis-randomized patients are defined as cases where IRT contacts were made by the 
site either prematurely or inappropriately prior to confirmation of the patient’s final 
randomization eligibility and no study medication was administered to the patient. FAS will be 
used for all efficacy variables, unless otherwise stated.
The safety set (SAF) will include all patients who received at least one dose of study drug 
whether or not being randomized. Patients will be analyzed according to the treatment they 
actually received. The safety set will be used in the analysis of all safety variables. 
Note that the FAS and safety set are the same except that the safety set allows the inclusion of 
non-randomized patients who receive study drug in error, and the FAS may include patients 
that were randomized but not treated unless mis-randomization. Also the FAS assigns 
randomized treatment and the safety set assigns received treatment.
Rule of exclusion criteria of analysis set is described in Appendix 6.7.
Protocol deviations will be summarized by deviation category and treatment group for the 
RAN. The deviation categories defined in the DRP for the study are presented below: 

SELECTION CRITERIA NOT MET


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
SUBJECT NOT WITHDRAWN AS PER PROTOCOL

TREATMENT DEVIATION 

PROHIBITED CONCOMITANT MEDICATION

OTHER 
For COVID-19 related Protocol deviation summary report include all those categories and 
they will be further classified based on available COVID related sub-categories. This report 
will be on Safety set population.
2.3.1
Subgroup of interest
Not applicable for the CSR analysis considering the number of subjects.
2.4
Patient disposition, demographics and other baseline 
characteristics
Demographics and baseline characteristics will be summarized using the SAF by treatment 
group, including disease characteristics, prior and background medications to treat urticaria, 
and relevant medical histories.
Demographics (collected at Visit 1)

Age (years)

Sex (Male, Female)

Race (White, Black or African American, Asian, Native Hawaiian or Other Pacific 
Islander, American Indian or Alaska Native)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Not reported)

Weight (kg)

Height (cm)

Body Mass Index (BMI) – calculated as weight (kg) / (height (m))2

BMI group (< 25, 25 - < 30, >= 30 kg/m**2)
Baseline characteristics (baseline is defined in section 2.2.2) 

Total IgE level (IU/mL) 

In-clinic UAS score

Baseline ISS7, HSS7, UAS7 score

Baseline UAS7 score category (see Table 2-2) 

Duration of CSU (years)


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Table 2-2
Category of disease status based on UAS7 score
Disease status
UAS7 value
Free (0)
0
Well-controlled (1-6)
0<UAS7=<6
Mild (7-15)
6<UAS7<16
Moderate (16-27)
16=<UAS7<28
Severe (28-42)
28=<UAS7=<42
In-clinic assessment of UAS
The UAS will be recorded by the Investigator at the site by rating the patient’s number of 
urticaria lesion (hives) and interviewing the patient for the assessment of pruritus reflective of 
the patient’s condition over the 12 hours prior to the visit. In-clinic UAS score (0-6) will be 
summarized using summary statistics.
Medical history or current medical conditions
Medical history or current medical condition will be coded using MedDRA and summarized by 
SOC and PT. Protocol solicited medical history will be summarized separately. 
2.4.1
Patient disposition
The number and percentage of patients who completed each study phase (treatment, post 
treatment follow-up) will be summarized by treatment group and percentages will be based on 
the RAN. The reason for discontinuation of each phase will also be summarized by treatment 
group. For the treatment epoch disposition table the population title will be ENR since the table 
also includes the number of patients screened. 
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
Study treatment / compliance
Summary tables for exposure will be presented using the SAF. 
The duration of exposure to study treatment in weeks will be summarized by treatment group.
Duration of exposure is defined as the date of the last treatment minus the date of first study 
drug administration plus 4 weeks (28 days).
The number of injections per patient which are correctly administered as per protocol will be 
summarized by treatment.
2.5.2
Prior, concomitant and post therapies
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Urticaria related prior medications will be summarized for the SAF by treatment 
group, pre-specified categories, preferred term and symptom treated. 


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Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the date of the last study visit. Concomitant medications will 
be summarized by treatment for the SAF, for urticaria related medications and non-urticaria 
related medications (taken from eCRF). Background medication for urticaria selected for the 
patient will be summarized separately using the pre-specified drug name. Other urticaria related 
concomitant medication will be listed together with non-urticaria related medications. 
Medications will be coded using Anatomical Therapeutic Chemical (ATC) code and 
summarized by treatment, ATC class and preferred term. Concomitant medications will be 
summarized for the entire study and for up to week 12 separately. Background medication for 
urticaria will be summarized for the treatment epoch and for up to week 12 separately.
Concomitant non-drug therapies and medical procedures will be summarized by primary system 
organ class and MedDRA preferred term. Concomitant non-drug therapies and medical 
procedures will be summarized for the entire study and for up to week 12 separately.
For analysis “up to Week 12”, for the ligelizumab groups concomitant medications up  to Week 
12 will be included and for the placebo-ligelizumab arm concomitant medications prior to 
ligelizumab switch will be included. 
 
 
2.6
Analysis of the primary objective
2.6.1
Primary endpoint
The primary variable is absolute change in UAS7 from baseline to Week 24. UAS7 is the sum 
of HSS7 and ISS7. 
HSS and ISS will be recorded by the patient twice daily in their eDiary, on a scale of 0 (none) 
to 3 (severe). A weekly score (HSS7/ISS7) is derived by summing the average daily scores of 
the 7 days preceding the planned visit date. The possible range of UAS7 is therefore 0-42.
The primary variable will be summarized by treatment group in the FAS using descriptive 
statistics.  
2.6.2
Statistical hypothesis, model, and method of analysis
No formal statistical testing will be applied for the primary variable. 
The mean of the change from baseline by treatment group will be shown descriptively with 95% 
confidence intervals based on the t-distribution.
2.6.3
Handling of missing values/censoring/discontinuations
As the primary analysis is to summarize the data descriptively, no imputation for the missing 
UAS7 will be applied. If ISS7 or HSS7 is missing, UAS7 will also be missing. 


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To calculate ISS7/HSS7 score from daily score, missing daily score will be handled according 
to the rules defined in the SAP appendix Section 6.1.  
2.6.4
Supportive analyses
No sensitivity analysis is planned for the primary variable, as no statistical model is used.
2.7
Analysis of secondary efficacy objective(s)
All secondary efficacy analysis will be based on FAS. 
2.7.1
Secondary endpoints
Urticaria Activity Score 
The number and proportion of patients who achieve the complete UAS7 response (UAS7 = 0),
hives response (HSS7 = 0), itch response (ISS7 = 0), and patients who achieve UAS7 <= 6, 
will be summarized by treatment and week. The 95% Clopper and Pearson confidence interval 
of the proportion will also be displayed. Non-responder imputation will be applied to missing 
data as described in SAP appendix section 6.1. 
Change from baseline in UAS7, HSS7 and ISS7 will also be summarized by treatment and week. 
The mean of the change from baseline by treatment group will be shown descriptively with 95% 
confidence intervals based on the t-distribution. 
The number and proportion of patients who have UAS7<=6 at Week 12 and Week 24 then have 
relapse (UAS7>=12) will be summarized by treatment and week after Week 12/ Week 24.   
Mean differences of the change from baseline in UAS7, HSS7 and ISS7 between treatment 
groups (ligelizumab 24 mg q4w vs. placebo - ligelizumab 120 mg q4w), (ligelizumab 120 mg 
q4w vs. placebo - ligelizumab 120 mg q4w) and (ligelizumab 24 mg q4w vs. ligelizumab 120 
mg q4w) will be shown descriptively with 95% confidence intervals based on two sample t-test,
at Week 12 and Week 24.
CDLQI assessment 
The Children Dermatology Life Quality Index questionnaire (CDLQI) is designed for use in 
children, i.e. patients from age 4 to age 16. It will also be deployed to any 17-18 year olds 
participating in this trial. It is a 10-item dermatology-specific health-related quality of life 
measure. Patients rate their dermatology symptoms as well as the impact of their skin condition 
on various aspects of their lives. The CDLQI is calculated by summing the score of each 
question resulting in a maximum of 30 and a minimum of 0 according to Table 2-3. The higher 
the score, the more quality of life is impaired. An overall score will be calculated as well as for 
the following domains according to Table 2-4: Symptoms and Feelings, Leisure, School or 
Holidays, Personal Relationships, Sleep, and Treatment. 


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Absolute and percentage change from baseline in total Children Dermatology Life Quality 
Index (CDLQI) score will be summarized by treatment and visit. The mean of the change from 
baseline by treatment group will be shown descriptively with 95% confidence intervals based 
on the t-distribution.
The number and proportion of patients who achieve CDLQI=0 or 1 will be summarized by 
treatment and visit. The 95% Clopper and Pearson confidence interval of the proportion will 
also be displayed. Non-responder imputation will be applied to missing data as described in 
section 6.1.
Table 2-3
CDLQI scoring
Score
Answer
0 
Question unanswered
Not at all
1
Only a little 
2
Quite a lot
3
Very much
Question 7: “Prevented School”
Table 2-4
CDLQI domains
Domain
Relevant Question
Maximum score
Symptoms and feelings
Questions 1 and 2
6
Leisure
Questions 4, 5 and 6
9
School or holidays
Questions 7
3
Personal relationships
Question 3 and 8
6
Sleep
Questions 9
3
Treatment
Question 10
3
2.8
Safety analyses
All safety parameters will be summarized based on the SAF. 
2.8.1
Adverse events (AEs)
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. Treatment emergent adverse events will be summarized by 
treatment groups in the following study period:


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
Treatment period up to Week 12 for the ligelizumab groups and prior to ligelizumab 
switch in the placebo-ligelizumab arm. 

Treatment period. 

Post-treatment follow up period

Entire study period.
Treatment emergent adverse events will be summarized by the actual treatment group.   
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: 

All adverse events (entire study, up to week 12, treatment epoch, follow-up epoch)

Adverse events by maximum severity (up to week 12, entire study, treatment epoch)

Adverse events suspected by the investigator as study drug-related (up to week 12, entire 
study, treatment epoch)

Serious adverse events (entire study, treatment epoch)

Adverse events leading to permanent discontinuation of study drug (treatment epoch)
In addition an overview of adverse events will be produced to summarize the number and 
percentage of patients with AEs, TEAES (overall and treatment related), treatment emergent 
SAEs (overall and treatment related), treatment emergent SAEs leading to death (overall and 
treatment related) and treatment emergent SAEs leading to treatment discontinuation (overall 
and treatment related).
Also, a separate summary table for most frequently reported TEAEs during the study, by PT 
will be produced. Most frequent TEAEs will be those with their PT representing at least 10% 
of subjects in any treatment group.
For the legal requirements of ClinicalTrials.gov and EudraCT, two additional tables of 
adverse events will be provided as described in section 6.5.
2.8.1.1
Adverse events of special interest / grouping of AEs
Adverse events of special interest
The following adverse events of special interest (AESI) will be summarized separately by each 
category standardized MedDRA query / PT for entire study, up to week 12 and treatment epoch. 
Details will be provided in the separate document, called electronic Case Retrieval Strategy
(eCRS). The search criteria in the latest eCRS corresponding the MedDRA version at the 
database lock will be used and reported in the CSR. 


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Adjudicated AEs
In addition to the AESI listed above, the following AEs will be adjudicated by the independent 
committee. The adjudicated events will be listed.   

Hypersensitivity assessment 

Cardio- and Cerebrovascular events

Malignancies 
2.8.1.2
Other safety topics
The following other safety topics will be listed:

COVID 19 infection

Pregnancy

Immunogenicity (anti-drug antibodies / ADA)

Liver Toxicity
2.8.2
Deaths
No separate listing or table will be provided from the database. Death will be reported as part 
of SAE which cause death. 
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis) and by treatment. 
The change from baseline to each study visit with maximum/minimum post-baseline value will 
be summarized by visit presented for quantitative parameters. For the parameters with normal 
range, shift tables value will be provided based on the normal range assigned by the central lab. 

Ligelizumab groups: from baseline to the worst post-baseline.

Placebo-ligelizumab:  
1.
from baseline to the worst post-baseline up to treatment switch
2.
from baseline to the worst post-baseline after treatment switch
For categorical parameters, frequencies by categories at each visit will be summarized. 
The number of patients with newly occurring or worsening abnormality during the study will 
be summarized and listed by treatment based on the notable criteria specified in the protocol
(See SAP section 6.4). For the placebo-ligelizumab group, the number of patients with newly 
occurring or worsening abnormality, prior to and after the treatment switch will be summarized 


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separately. A case is considered as newly occurring abnormality if the value is not notable or 
missing at baseline but is notable thereafter during the study. A case is considered as worsening 
abnormality if the value is notable at baseline and at least one post-baseline value during the 
study is worse than baseline. 
To evaluate potential drug-induced liver injury, newly occurring liver enzyme abnormalities at 
any time post-baseline will also be summarized according to Table 5-1. For the placebo-
ligelizumab group, the number of patients with newly occurring or worsening abnormality, 
prior to and after the treatment switch will be summarized separately.
Stool ova for assessment of parasitic infections and urine serum pregnancy test will be listed 
separately. Samples taken after the end of study visit will be flagged in the listing.
For laboratory test values below Lower Limit of Quantification (LLOQ) or above Upper Limit 
of Quantification (ULOQ) will be imputed as LLOQ or ULOQ value, respectively. The 
numerical part of the reported result will be treated as the actual LLOQ or ULOQ. These 
laboratory values will be displayed in listings using the standard unit with reported sign i.e. “<” 
or “>”.
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential (Neutrophils, Basophils, Monocytes, Lymphocytes and Eosinophils), platelet count, 
will be summarized by treatment and visit. Coagulation will be assessed by International 
Normalized Ratio (INR) and listed only.
Chemistry
Albumin, total bilirubin, alkaline phosphatase, AST, ALT, chloride, calcium, sodium, 
potassium, magnesium, LDH, creatinine, inorganic phosphorus, urea/BUN and uric acid will 
be summarized by treatment and visit. If the total bilirubin concentration is increased above 1.5 
times the upper limit of normal, direct and indirect reacting bilirubin will be differentiated and 
listed only.
Urinalysis 
Semi-quantitative “dipstick” evaluation for specific gravity, glucose, protein, bilirubin, ketones, 
leukocytes and blood will be performed at site. When a dipstick evaluation is abnormal, e.g., 
positive for WBC and/or blood, a urine sample needs to be sent to the Central Lab for 
microscopic examination. 
The categorical results of the dipstick at site will be summarized by treatment and visit. Results 
examined by the Central Lab will be listed only.    


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2.8.4
Other safety data
2.8.4.1
Electrocardiogram (ECG)
A shift table from baseline to the worst post-baseline value will be presented based on the
overall ECG interpretation. 
For ECG parameters, the number and percentage of patients with newly occurring or worsening 
notable abnormalities occurring post-baseline will be listed by treatment group. The definition 
of newly occurring or worsening is the same as laboratory values. For the placebo-ligelizumab 
group, the number of patients with newly occurring or worsening abnormality, prior to and after 
the treatment switch will be summarized separately.
The following were considered as notable values: QTcF >450 msec (males), QTcF >460 msec 
(females); QTcF change from baseline >30 msec, >60 msec; PR >250 msec.
2.8.4.2
Vital signs
Vital signs (blood pressure and pulse rate) and changes from baseline will be summarized by 
treatment group and visit, also maximum/minimum post-baseline value will be summarized. 
The number and percentage of patients with newly occurring or worsening notable 
abnormalities occurring post-baseline will be summarized by treatment group. For the placebo-
ligelizumab group, the number of patients with newly occurring or worsening abnormality, 
prior to and after the treatment switch will be summarized separately. The definition of newly 
occurring or worsening is the same as laboratory values. 
A notable value is defined as follows: heart rate of < 40 and > 90 bpm; systolic blood pressure 
of < 90 and > 140 mmHg; diastolic blood pressure of < 65 and > 90 mmHg.
The vital signs will be also summarized according to the Table 2-5 and notable values defined 
for each age:
Table 2-5
Criteria for notable vital sign for pediatric patients (age 12 to 17 years)
Age
Systolic
BP  
(mmHg)
Diastolic 
BP
(mm Hg)
HR (bpm)
12 years
101-135
59-91
60-110
13 years
104-137
60-91
60-110
14 years
106-140
60-92
60-110
15 years
107-142
61-93
60-110


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16 years
108-145
63-94
60-110
17 years
108-147
64-97
60-100
A notable value is one that falls outside the above ranges.
 
 
 
2.9
Pharmacokinetic endpoints
All subjects with a PK sample will be included in the pharmacokinetic (PK) data analysis.  
Concentrations will be given in mass per volume units. Drug concentration of ligelizumab will 
be summarized descriptively by treatment and visit using SAF. Missing values or those below 
the limit of quantification (LOQ) will be indicated in the data listings and treated as zero in data 
presentations and calculations. 
2.10
PD and PK/PD analyses
PK/PD modelling will be conducted in a separate modelling and simulation (M&S) study as the 
data from this study will be only one part of a pool from both adolescent and adult patients. Full 
details are available in a separate M&S study protocol and results will be provided in a separate 
PK/PD report. 
 
 
  
 
 
 
 


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2.14
Interim analysis
No interim analyses is planned other than the analyses for the independent DMC. DMC
meeting will be held at least once during the 6 months for periodical safety review. 
To maintain the blind the outputs for the DMC will be conducted in a semi-blinded manner 
(using dummy treatment code) by the independent statistician and programmer in the separate 
CRO (
) who are not involved in CSR reporting. Details will be provided by the DMC 
charter. 
Outputs to be provided to the DMC will be specified in the separate document.
3
Sample size calculation
The expected half-width of 95% confidence intervals for the change from baseline in UAS7 for 
each group is 5.2, assuming 24 patients in ligelizumab 24 mg arm and SD=13. If the mean 
change from baseline in UAS7 for ligelizumab group is -22.0 (based on C2201 adult study), the 
95% confidence interval of the mean change from baseline in UAS7 will be (-27.2, -16.8).    
 
 
 
 
 
 
 
 
4
Change to protocol specified analyses

Add enrolled set (ENR) to summarize all patients after informed consent including 
screening failure.

Change the notable criteria for QTc to be used for the analysis, to be consistent with the 
definition in other section of the protocol and project standard.

Treatment emergent adverse events definition was made more comprehensive by 
removing the restriction of events starting within 16 weeks of the last dose. i.e. definition
is now all 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.

Adjudicated AEs will only be listed and not summarized, since few adjudicated AEs are 
expected.


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
CDLQI individual domain scores will only be listed and not summarized, since it was not 
medically relevant.

Exposure to study drug will be summarized in weeks rather than days, for easier
interpretation.
5
COVID-19 Impact Assessment and related analysis 
The trial began in Jul 2018 and completed in Feb 2021, which included the period during 
which the COVID-19 pandemic was occurring globally. When the pandemic disruption 
occurred, most participants in the trial have been enrolled, no changes have been made to trial 
conduct, study design or planned statistical analyses, and as such, the impact of the pandemic
was limited on the trial.
A summary table will be provided for COVID-19 related protocol deviations. 
6
Appendix
6.1
Scoring and data handling rules in eDiary
Missing morning or evening score in UPDD
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. 
Missing daily score in UPDD 
When one or more of the daily scores are missing, the following principles will be applied to 
handle the missing data:

If a patient has at least 4 non-missing daily scores within the 7 days prior to the study 
visit, the weekly score is calculated as the sum of the available eDiary scores in that 
week, divided by the number of days that have a non-missing diary score, multiplied by 
7. 

If there are less than 4 non-missing daily scores within the prior 7 days, then the weekly 
score is missing for the week.
The rule will be applied for HSS7, ISS7, Angioedema occurrence score, 
 
 
Missing weekly score in UPDD
For the response rate analysis, for patients with missing data either due to discontinuation or 
due to insufficient eDiary data during that week, imputation of the response will be done 
using the worst-case scenario (i.e. non-responder). For the patients completing the study, there 


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will be no more imputation applied after the end of study visit. For the patients discontinuing 
the study early, the imputation will be applied up to Week 40.
Missing CDLQI score
For the CDLQI total score derivation, if there is only one missing score per visit, then it will be 
imputed to 0 then subscale including this item and total score will be calculated accordingly. If 
there are two or more missing scores per visit, then the total score for the visit will be missing. 
For the response rate analysis, for patients with missing data either due to discontinuation or 
due to insufficient information during that visit, imputation of the response will be done using 
the worst-case scenario (i.e. non-responder). The imputation will be applied up to Week 40.  
Duplicate data handling of questionnaires
For HSS7, ISS7 and UAS7, the daily score is derived from the average of morning and evening 
scores, even if there is more than one score during the morning or evening, the average of all 
available scores during the day is used for the daily score. 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, if there is more than one score during the morning/evening then the average of those 
scores will be used. All other questionnaires are completed either daily or at visits. If any of 
those questionnaires are completed more than once per day or visit (depending on the 
questionnaire schedule), then the worst outcome (i.e. the highest score) of the duplicate 
observations will be used in the analysis.
6.2
Imputation rules
6.2.1
Study drug
No imputation of missing/partial start or study end date drug. If missing the time of study drug 
end date will be imputed to 23:59:59.
6.2.2
AE date imputation
Rules for imputing the AE end date:

If the AE end date month is missing, then the imputed end date should be set to the 
earliest of the (study end date, 31DECYYYY, date of death).

If the AE end date day is missing, then the imputed end date should be set to the 
earliest of the (study end date, last day of the month, date of death).

If AE year is missing, then the end date will not be imputed.
Rules for imputing the AE start date:




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b. Else if AE month is not missing, then the imputed AE start date is set to the mid-
month point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, then the 
AE started after treatment.  Therefore:
a.
If the AE month is missing, then the imputed AE start date is set to the year start 
point (01JanYYYY).
b. Else if the AE month is not missing, then the imputed AE start date is set to the later 
of (month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing, then the imputed AE start date is set to the AE 
reference start date + 1 day.
b. Else if the AE month is less than the treatment start month, then the imputed AE 
start date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, then the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to (imputed) AE end date.
6.2.3
Concomitant medication (CM) date imputation
No imputation of numeric date will be performed for the dates of medication recorded on the 
Trial Rescue Medication CRF page or the Prior urticaria therapy CRF page. All therapies on 
the Prior urticaria therapy CRF page will be considered as prior.
Rules for imputing the CM end date (including on-going records):

If imputing end dates, this should be done prior to calculating imputed start dates.

When the medication is ongoing at the end of the study, no numeric end date is 
derived.

If the end date is completely missing no numeric end date is derived.
a) If CM end day is missing and CM month/year are non-missing, then impute CM date 
as the minimum of study end date and the last day of the month.
b) If CM end day/month are missing and CM year is non-missing, then impute CM date 
as the minimum of study end date and the end of the year (31DECYYYY).
c) If imputed CM end date is less than the complete CM start date, use the complete CM 
start date as the imputed CM end date.




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4. If the CM start date year value is equal to the Treatment start date (TR01SDT) year 
value;
a) And the CM month is missing or the CM month is equal to the Treatment start 
date (TR01SDT) month, then the imputed CM start date is set to one day prior
Treatment start date (TR01SDT).
b) Else if the CM month is less than the Treatment start date (TR01SDT) month, 
then the imputed CM start date is set to the mid-month point (15MONYYYY).
c) Else if the CM month is greater than the Treatment start date (TR01SDT) month, 
then the imputed CM start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the complete (imputed) CM end date, then imputed CM start date should be set to the complete 
(imputed) CM end date.
6.2.3.1
Prior therapies date imputation
Same as concomitant medication. 
6.3
Adverse event coding/grading 
Not applicable.
6.4
Laboratory parameters derivations
Clinically notable criteria
The following notable criteria will be used in the study: 

Platelets < 75 000/μL

25% decrease in eGFR and eGFR ≤ 90ml/min/1.731 m2 compared to baseline

New dipstick glycosuria ≥3+

New dipstick hematuria ≥3+
eGFR is calculated with Schwartz formula for use in children 1-18 years old:

For height in cm and sCr in mg/dL: eGFR (mL/min/1.73 m2) = 0.413 x (height/sCr) 

For height in cm and sCr in µmol/L: eGFR (mL/min/1.73 m2) = 36.5 x (height/sCr)


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Liver-enzyme abnormalities
Table 6-1
Liver- enzyme abnormalities
Parameter
Notable criterion
ALT
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
(ALT or AST) & TBL
>3xULN & (TBL>1.5xULN; >2xULN)
(ALT or AST) & INR
>3xULN & INR>1.5
TBL 
>1xULN; >1.5xULN; >2xULN
ALP
>1.5xULN, >2xULN, >5xULN
ALP & TBL
>3xULN; >5xULN & TBL>2xULN
(ALT or AST) & TBL & ALP
ALT or AST>3xULN & (TBL)>2xULN & 
ALP≤2xULN (potential Hy’s Law case)
AST = Aspartate aminotransferase; also known as SGOT, ALT = Alanine aminotransferase; also known as SGPT, 
INR=International Normalized Ratio, ALP = Alkaline phosphatase, TBL = Total bilirubin
6.5
Analysis for Clinicaltrials.gov and EudraCT
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and on treatment emergent serious adverse events and SAE suspected to be 
related to study treatment, will be provided by system organ class and preferred term on the 
safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block. If 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
6.6
Statistical models
6.6.1
Primary analysis
Not applicable. 


Novartis
For business use only
Page 34
Statistical Analysis Plan
CQGE031C2202
6.7
Rule of exclusion criteria of analysis sets 
No PD will be used for excluding from any analysis set. 
Table 6-2
Subject Classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
ENR
NA
Not having informed consent;
Not having screening epoch
RAN
NA
Not randomized
FAS
NA
Not in RAN;
Mis-randomized
SAF
NA
No double-blind study drug taken
7
Reference
There is no statistical reference for the study..