An Open Label, Multicenter, Extension Study to Evaluate the Long-term Safety of QGE031 240 mg s.c. Given Every 4 Weeks for 52 Weeks in Chronic Spontaneous Urticaria Patients Who Completed Study CQGE031C2201
Phase: PHASE2
Conditions: Chronic Spontaneous Urticaria
Sponsor: Novartis Pharmaceuticals

Global Clinical Development - General Medicine 
QGE031/Ligelizumab 
Clinical Trial Protocol CQGE031C2201E1 / NCT02649218
An open label, multicenter, extension study to evaluate the 
long-term safety of QGE031 240 mg s.c. given every 4 
weeks for 52 weeks in Chronic Spontaneous Urticaria 
patients who completed study CQGE031C2201 
Document type: 
Protocol 
EUDRACT number: 
2015-003636-13 
Version number: 
Final v00 
Clinical trial phase: 
IIb 
Release date: 
7-Oct-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0, August, 2015 

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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 ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Purpose .................................................................................................................. 15 
2 
Study objectives ................................................................................................................. 15 
2.1 
Primary objective(s) ............................................................................................... 15 
2.2 
Secondary objectives ............................................................................................. 15 
 
 15 
3 
Investigational plan ........................................................................................................... 16 
3.1 
Study design ........................................................................................................... 16 
3.2 
Rationale of study design ....................................................................................... 17 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 18 
3.4 
Rationale for choice of comparator ....................................................................... 18 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 18 
3.6 
Risks and benefits .................................................................................................. 18 
4 
Population .......................................................................................................................... 19 
4.1 
Inclusion criteria .................................................................................................... 20 
4.2 
Exclusion criteria ................................................................................................... 20 
5 
Treatment ........................................................................................................................... 22 
5.1 
Protocol requested treatment ................................................................................. 22 
5.1.1 
Study treatment ..................................................................................... 22 
5.1.2 
Additional study treatment .................................................................... 22 
5.2 
Treatment arms ...................................................................................................... 22 
5.3 
Treatment assignment, randomization ................................................................... 22 
5.4 
Treatment blinding ................................................................................................. 23 
5.5 
Treating the patient ................................................................................................ 23 
5.5.1 
Patient numbering ................................................................................. 23 
5.5.2 
Dispensing the investigational treatment .............................................. 23 
5.5.3 
Handling of study treatment .................................................................. 24 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 24 

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5.5.5 
Permitted dose adjustments and interruptions of study treatment ......... 25 
5.5.6 
Rescue medication ................................................................................ 25 
5.5.7 
Concomitant treatment .......................................................................... 25 
5.5.8 
Prohibited Treatment ............................................................................. 26 
5.5.9 
Emergency breaking of assigned treatment code .................................. 26 
5.6 
Study completion and discontinuation ................................................................... 27 
5.6.1 
Study completion and post study treatment .......................................... 27 
5.6.2 
Discontinuation of study treatment ....................................................... 27 
5.6.3 
Withdrawal of consent .......................................................................... 28 
5.6.4 
Loss to follow-up .................................................................................. 28 
5.6.5 
Early study termination ......................................................................... 28 
6 
Visit schedule and assessments ......................................................................................... 29 
6.1 
Information to be collected on screen/ roll-over failures ....................................... 34 
6.2 
Patient demographics/other baseline characteristics .............................................. 34 
6.3 
Treatment exposure and compliance ..................................................................... 34 
6.4 
Efficacy .................................................................................................................. 34 
6.4.1 
eDiary Assesments ................................................................................ 34 
 
 37 
6.4.3 
Appropriateness of efficacy assessments .............................................. 38 
6.5 
Safety ..................................................................................................................... 38 
6.5.1 
Physical examination ............................................................................ 38 
6.5.2 
Vital signs .............................................................................................. 38 
6.5.3 
Height and weight ................................................................................. 39 
6.5.4 
Laboratory evaluations .......................................................................... 39 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 40 
6.5.6 
Pregnancy .............................................................................................. 41 
6.5.7 
Anaphylaxis assessment ........................................................................ 41 
6.5.8 
Assessment of cardio-cerebrovascular events ....................................... 41 
6.5.9 
Assessment of pre-malignancies and malignancies .............................. 41 
6.5.10 
Appropriateness of safety measurements .............................................. 41 
 
 41 
 
 41 
 
 41 
 
 43 
7 
Safety monitoring .............................................................................................................. 43 
7.1 
Adverse Events ...................................................................................................... 43 

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7.2 
Serious adverse events ........................................................................................... 45 
7.2.1 
Definition of SAE ................................................................................. 45 
7.2.2 
SAE reporting........................................................................................ 46 
7.3 
Liver safety monitoring ......................................................................................... 47 
7.4 
Renal safety monitoring ......................................................................................... 48 
7.5 
Reporting of study treatment errors including misuse/ abuse ................................ 49 
7.6 
Pregnancy reporting ............................................................................................... 49 
7.7 
Prospective suicidality assessment ........................................................................ 49 
8 
Data review and database management ............................................................................. 50 
8.1 
Site monitoring ...................................................................................................... 50 
8.2 
Data collection ....................................................................................................... 50 
8.3 
Database management and quality control ............................................................ 51 
8.4 
Data Monitoring Committee .................................................................................. 51 
8.5 
Adjudication Committees ...................................................................................... 51 
9 
Data analysis ...................................................................................................................... 52 
9.1 
Analysis sets .......................................................................................................... 52 
9.2 
Patient demographics and other baseline characteristics ....................................... 52 
9.3 
Treatments ............................................................................................................. 52 
9.4 
Analysis of the primary variable(s) ....................................................................... 52 
9.4.1 
Variable(s) ............................................................................................. 52 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 54 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 54 
9.4.4 
Supportive analyses ............................................................................... 55 
9.5 
Analysis of secondary variables ............................................................................ 55 
9.5.1 
Efficacy variables .................................................................................. 55 
9.5.2 
Safety variables ..................................................................................... 56 
 
 56 
 
 56 
9.6 
Interim analyses ..................................................................................................... 57 
9.7 
Sample size calculation .......................................................................................... 57 
10 Ethical considerations ........................................................................................................ 58 
10.1 
Regulatory and ethical compliance ........................................................................ 58 
10.2 
Informed consent procedures ................................................................................. 58 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 58 
10.4 
Publication of study protocol and results ............................................................... 59 
11 Protocol adherence ............................................................................................................ 59 

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11.1 
Protocol Amendments ............................................................................................ 59 
12 References ......................................................................................................................... 59 
13 Appendices ........................................................................................................................ 62 
13.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 62 
13.2 
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ......................................................................................................... 63 
13.3 
Appendix 3 World Allergy Organization Grading System .................................... 66 
13.4 
Appendix 4 Blood log ............................................................................................ 67 
 
 69 
 
 
List of tables 
Table 5-1 
Prohibited Treatment ............................................................................. 26 
Table 6-1 
Assessment Schedule ............................................................................ 30 
Table 6-2 
Hives Severity Score ............................................................................. 35 
Table 6-3 
Itch Severity Score ................................................................................ 35 
 
 36 
 
 36 
 
. 37 
Table 7-1 
Specific Renal Alert Criteria and Actions ............................................. 48 
Table 7-2 
Reporting of study treatment errors ...................................................... 49 
Table 9-1 
Secondary 
 efficacy variables ......................................... 55 
Table 13-1 
Liver Event and Laboratory Trigger Definitions .................................. 63 
Table 13-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 63 
 
 
List of figures 
Figure 3-1 
Study design ......................................................................................... 17 
Figure 9-1 
Probability of observing adverse events with given incidence ............. 57 

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List of abbreviations 
 
 
AC 
Adjudication committee 
ACR 
Albumin to Creatinine Ratio 
 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CFR 
US Code of Federal Regulations 
CIU 
Chronic Idiopathic Urticaria 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSU 
Chronic Spontaneous Urticaria 
CTC 
Common Toxicity Criteria 
DBP 
Diastolic blood pressure 
 
 
DMC 
Data monitoring committee 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
ePRO 
Electronic Patient Reported Outcome 
FcɛRII 
High affinity Immunoglobulin E Receptor II 
FcεRI 
High affinity Immunoglobulin E Receptor I 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GTL 
Global trial lead 
GWAS 
Genome-wide association studies 
H1-AH 
H1-antihistamines 
H2-AH H2-antihistamines 

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hCG 
Human Chorionic Gonadotropin 
hsCRP 
High sensitivity C-reactive protein 
HSS 
Hive Severity Score 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
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) 
LTRA 
Leukotriene Receptor Antagonist 
MedDRA 
Medical dictionary for regulatory activities 
OC/RDC 
Oracle Clinical/Remote Data Capture 
PCR 
Protein to Creatinine Ratio 
 
 
 
 
 
 
PSW 
Premature study withdrawal 
q2/4w 
Every 2/4 weeks 
SAE 
Serious adverse event 
s.c. 
Subcutaneous 
SBP 
Systolic blood pressure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 

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UAS 
Urticaria Activity Score 
ULN 
Upper Limit of Normal 
UPDD 
Urticaria Patient Daily Diary 
WHO 
World Health Organization 
 
 

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Glossary of terms 
 
 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Epoch 
A portion of the study which serves a specific purpose. Typical 
Epochs are: screening/recruitment, wash-out, treatment, and 
follow-up 
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.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include protocol- 
specified concomitant background therapies when these are 
standard treatments in that indication 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 
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 with established disease and in those with newly- 
diagnosed disease. 
Period 
A subdivision of a cross-over study 
Premature subject/ patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
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), active drug run-ins or background therapy 

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Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment for any reason; may or may not 
also be the point/time of premature patient withdrawal 
Subject Number 
A number assigned to each patient who enrolls into the study 
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 

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Protocol summary 
 
 
Protocol number 
CQGE031C2201E1 
Title 
An open label, multicenter, extension study to evaluate the long-term 
safety of QGE031 240 mg s.c. given every 4 weeks for 52 weeks in 
patients with Chronic Spontaneous Urticaria who completed study 
CQGE031C2201 
Brief title 
A long-term safety study for QGE031 as an add-on therapy for adults with 
CSU who have completed study CQGE031C2201 
Sponsor and Clinical 
Phase 
Novartis 
Phase 2b, long-term safety study 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to evaluate the safety of QGE031 given to 
CSU patients over a long term treatment period 
Primary Objective 
The primary objective of this study is to assess the long-term safety of 
QGE031 (240 mg s.c.) given every 4 weeks for 12 months in patients 
who completed study CQGE301C2201 by evaluation of: 
• 
Incidence and severity of all adverse events 
• 
Changes in vital signs, laboratory assessments, and ECGs 
Secondary Objectives 
To evaluate long-term treatment outcomes of QGE031 in adult patients 
with CSU by evaluation of: 
• 
Sustained remission defined as maintaining UAS7 ≤ 6 over 48 weeks 
post-treatment follow up epoch among the subjects achieving 
remission at the end of treatment epoch 
Study design 
This study is an open label, single arm, long-term safety extension to 
study CQGE031C2201: a 52 week treatment followed by a 48 week 
follow up 
Population 
Adults CSU patients who completed the core study. Approximately 240 
patients may enroll into this extension study 
Key Inclusion criteria 
• 
Patients who complete study treatment epoch and at least visit 203 in 
the follow-up epoch in study QGE031C2201 
• 
Present with active disease 
Key Exclusion criteria 
• 
New onset of chronic urticaria other than CSU 
Investigational and 
reference therapy 
QGE031 240 mg s.c. q4w 
Efficacy assessments 
• 
Urticaria Activity Score (UAS7) 
• 
Hives Severity Score (HSS7) 
• 
Itch Severity Score (ISS7) 
Safety assessments 
• 
Incidence and severity of adverse events including serious adverse 

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events, adverse events leading to study treatment discontinuation 
and any events of special interest 
• 
Changes in vital signs, laboratory assessments, and ECGs 
Data analysis 
Summary statistics will be provided for adverse events, laboratory 
parameters and efficacy parameters over time. Time to event variables 
will be summarized by Kaplan-Meier estimates. 
Key words 
, chronic spontaneous urticaria, long-term safety 

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1 
Introduction 
1.1 
Background 
Urticaria is a heterogeneous group of diseases characterized by itchy hives and/or angioedema. 
Chronic urticaria is defined as urticaria that has  been continuously or intermittently present  
for more than 6 weeks (Maurer, et al 2013, Bernstein, et al 2014). Chronic urticaria is then 
further divided into two subgroups: Chronic Spontaneous Urticaria (CSU) and Inducible 
Urticaria (IU) the latter including physical urticaria such as heat-, cold-, or pressure-urticaria, 
and special variants such as cholinergic urticaria. CSU is defined as spontaneous appearance  
of itchy wheals, angioedema, or both ≥ 6 weeks due to known or unknown causes (Zuberbier, 
et al 2014). A combination of both the CSU and an inducible form of urticaria is possible,  
such as the frequently observed combination of asymptomatic dermographic urticaria and 
CSU. 
Previously, all chronic urticaria forms without a known trigger were named “chronic 
idiopathic urticaria” (CIU). Due to medical progress it is now known that in some of the 
previously considered “idiopathic” urticaria forms in fact auto-antibodies may be detected. 
However, the daily fluctuating appearance of the symptoms in this chronic urticaria with auto- 
antibodies still remains unpredictable and is not induced by a demonstrable trigger, hence 
appear spontaneously. In order to reflect in the terminology correctly that some of the former 
“idiopathic” forms in fact may have detectable auto-antibodies, this population is now  
referred to as chronic spontaneous urticaria (CSU) according to the international guideline 
(Maurer, et al 2013, Zuberbier, et al 2014). The use of the expression “chronic idiopathic 
urticaria” in medical practice is no longer recommended. However, this new naming 
convention is not implemented in all parts of the world and in countries such as the United 
States and Canada the patient population with chronic urticaria with a non-specific etiology, 
or unknown triggers is still referred to as chronic idiopathic urticaria (CIU). Following the 
International Guideline, the disease entity will be referred to as CSU throughout this 
document for consistency. 
The lifetime prevalence of CSU is approximately 1.8%, and 20% of CSU patients still have 
the disease after 20 years (Greaves 2000, Zuberbier, et al 2010). Affected patients experience 
frequent pruritic hives with associated erythema and/or episodes of angioedema. Angioedema 
is reported to be associated with approximately 33-67% of CSU cases (Juhlin 1981, Toubi, et 
al 2004, Zuberbier, et al 2010, Maurer, et al 2011). The classic skin lesion in 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. 
 
 
 
 
 
 

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Treatment of CSU is a challenge and non-sedating (second generation) H1-antihistamines 
(H1-AH) are the mainstay of symptomatic therapy of CSU. While H1-AH at approved doses 
provide relief for some patients, more than 50% of patients do not respond to H1-AH at 
regular doses. Even when up-dosing up to fourfold of the approved dose according to the 
second step of the treatment algorithm of the current International Guideline (Zuberbier, et al 
2014), a substantial part of patients do not experience control of urticaria symptoms (Maurer, 
et al 2011, Marrouche, et al 2014). For patients without disease control at fourfold doses of 
H1-AH, the third step of the treatment algorithm of the International Guideline foresees the 
addition of omalizumab, or ciclosporin A, or montelukast to the H1-AH. 
The level of evidence for the efficacy of leukotriene receptor antagonists (LTRA) in urticaria 
is low but best for montelukast which consequently led to only a weak recommendation from 
experts for this off-label treatment. Short courses (max. 10 days) of systemic corticosteroids 
can be added to the 3rd level treatment regimens, if exacerbations demand this. Due to the 
adverse effects associated with chronic systemic corticosteroid exposure, a longer duration of 
treatment is not advisable. Other treatment options that were previously used such as 
intravenous immunoglobulin G, dapsone, hydroxychloroquine, H2-antihistamines (H2-AH), 
methotrexate, and cyclophosphamide, have an unfavorable benefit risk profile or significant 
side-effect profile and are no longer recommended for therapy of CSU (Kaplan 2002, Powell, 
et al 2007, Zuberbier, et al 2014). However, given that H2-AH is still used in certain countries, 
in this protocol, we allow the use of H2-AH as background therapy. 
Omalizumab (Xolair®), a humanized monoclonal antibody against human IgE, has recently 
been approved for the treatment of CSU among subjects whose symptoms cannot be 
adequately controlled by H1-AHs.
 
 
 
 
 
 
 
 
 
 
 
 

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The ongoing core study CQGE031C2201 is a dose-range finding, double blind, active and 
placebo controlled parallel group study to characterize the dose response relationship for 
QGE031 doses 24, 72 and 240 mg sc q4w administered for 20 weeks with respect to 
achievement of complete hives response after 12 weeks of treatment. The active comparator 
in the core study is 300 mg omalizumab administered sc q4w. 
As an open-label extension to study CQGE031C2201, study CQGE031C2201E1 will assess 
the long-term safety and tolerability as well as explore long-term efficacy of QGE031 during 
52-week treatment and 48-week post-treatment follow-up among patients who completed 
CQGE031C2201. For those subjects who received placebo or lower doses of QGE031 in the 
core study, this study presents a chance to be treated with a higher dose of QGE031 240 mg. 
In addition, this study also provides an opportunity to collect safety and efficacy data related 
to re-treatment with QGE031. 
 
1.2 
Purpose 
The purpose of this study is to evaluate long-term safety as well as efficacy outcome of 
QGE031 240 mg sc administered every 4 weeks for 12 months in patients with chronic 
spontaneous urticaria (CSU) who completed the CQGE031C2201 study. Safety and efficacy 
assessments will be conducted during the treatment epoch and the 48-week post-treatment 
epoch and the latter allows an assessment of sustained remission among responders. The 
efficacy of retreatment among subjects who were exposed to different dose levels of QGE031 
in the core study will also be assessed. In this study, QGE031 is administered as an add-on 
therapy to H1-AH alone at approved or increased doses or in combination with H2-AH and/or 
a LTRA. 
 
2 
Study objectives 
2.1 
Primary objective(s) 
The primary objective of this study is to assess the long-term safety of QGE031 in adult CSU 
patients who completed the core study CQGE031C2201 using the following evaluations: 
• Incidence and severity of non-serious and serious adverse events including any events of 
special interest 
• Changes in vital signs, laboratory assessments, and ECGs 
2.2 
Secondary objectives 
The secondary objective of this study is to assess the long-term efficacy of QGE031 in adult 
CSU patients who completed the CQGE031C2201 study using the following evaluations: 
• Sustained remission defined as maintaining UAS7 ≤ 6 over 48 weeks post-treatment 
follow up epoch among the subjects achieving remission at the end of treatment epoch 
 
 

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3 
Investigational plan 
3.1 
Study design 
This study is an open label, single arm, long-term safety extension for all patients who 
completed the core study CQGE031C2201 and fulfil the enrollment criteria for the extension 
study. 
Among the 360 patients expected to participate in the core study, it is estimated that 
approximately 240 subjects may enroll in this extension study. Enrollment criteria require 
subjects to complete the treatment epoch and atleast visit 201 - 203 in the follow-up epoch in 
study CQGE031C2201 and present with active disease, as defined by UAS7≥12. The study 
consists of two epochs: open-label treatment and post-treatment follow up epoch. At or after 
visit 203, when the subjects become eligible to enroll in this extension study, they will 
complete all assessments associated with Visit 206 as a part of core study completion. The 
treatment epoch of this extension study will consist of 52 weeks of QGE031 240 mg s.c. at 4- 
week intervals. During the post-treatment follow-up epoch, the patients will be followed at 
12-week intervals for 48 weeks. See Figure 3-1 for study design. 
As in the core study, patients will continue using their background medication i.e H1-AH at 
approved or increased doses alone or in combination with H2-AH and/or a LTRA. 
 
 
Open-label study Treatment Epoch: 
• Visit 301 - 313 
• This treatment epoch consists of 52 weeks of open label treatment with QGE031 240 mg 
sc every 4 weeks. 
• All lab assessments done as a part of end of core study visit (Visit 206) will be used to 
determine eligibility to enroll into the extension study. 

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• The informed consent will be signed at visit 206 
• The subjects will continue to complete eDiary assessments between visits 206 and 301 
• Visit 301 should occur approximately 14 - 21 days after visit 206 core study assessments. 
Only in exceptional circumstances, when information concerning eligibility is outstanding 
(e.g., pending laboratory data), visit 301 can be extended. 
• Subjects relevant medical conditions and concomitant medications will be reviewed at 
visits 206 
• Subjects receive their first dose of QGE031 at visit 301 and last dose of QGE031 at visit 
313 
 
Post-treatment follow-up Epoch: 
• Visit 401 – 405 
• 48 weeks of post-treatment follow up consisting of visits every 12 weeks. 
• No study treatment will be given during the post-treatment follow-up epoch; however, 
patients are allowed to take background medication and rescue medication. If a subject 
relapses i.e. develops symptoms with an UAS7 ≥12, the investigator should be contacted 
for an ad-hoc visit to consider treatment with standard of care or other therapy. 
 
Figure 3-1 
Study design 
 
 
 
3.2 
Rationale of study design 
An open-label study design was chosen to obtain information on the long-term safety and 
efficacy of QGE031 (240 mg) given s.c. q4w for 52 weeks in patients with chronic 
spontaneous urticaria patients completing study CQGE031C2201. An open-label design 
avoids exposing patients to placebo for an extended period of time and administration of 
QGE031 240 mg allows for maximum exposure to the study drug. The 48-week post- 
treatment follow-up epoch will assess safety following treatment discontinuation, as well as to 
evaluate 
 including sustained remission. 

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3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
Given that the primary goal of this study is to assess the long-term safety of QGE031 in 
chronic spontaneous urticaria patients, the highest dose tested in the core study - 240 mg 
QGE031 administered sc q4w for 52 weeks is used for this extension study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The subcutaneous (s.c.) route of administration is selected since this is the route of 
administration in the core study, favorable bioavailability demonstrated with QGE031 in 
previous studies and its ease for both patients and caregivers. 
 
3.4 
Rationale for choice of comparator 
Not applicable. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
An interim analysis of safety and efficacy data will be performed at the end of open-label 
treatment epoch to collect information that might be relevant for the planning of other trials. 
Of note, the study procedures will not be modified as a result of this interim analysis. 
 
3.6 
Risks and benefits 
The inclusion and exclusion criteria are selected to enroll patients with CSU most likely to 
benefit from participating in the study and are consistent with the criteria used in the core 
study CQGE031C2201. The overall risk to patients will be minimized by compliance with the 
inclusion/exclusion criteria and clinical monitoring. 

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The investigators will provide the patient with written instructions to contact them if 
symptoms of CSU worsen. Investigators will be instructed on acceptable treatments for 
worsening CSU to allow patients to continue on the study. 
Other treatment alternatives to QGE031 for patients that have failed the standard treatment 
with H1-AH at approved or increased doses include omalizumab and immunosuppressive 
agents such as cyclosporine A, or repeated exposure to oral glucocorticoids. There are 
potential adverse effects associated with both of these alternatives. Omalizumab is an 
approved therapy for treatment of CSU refractory to standard of care treatment, and exhibits a 
favorable benefit-risk profile. It is a recombinant humanized IgG1 monoclonal antibody that 
binds to IgE-specific epitopes within the C3 (FcεRI binding) region of the IgE molecule and is 
indicated in many countries for the treatment of CSU refractory to standard therapy. 
QGE031, although similar in principle to omalizumab, is still in clinical development. The 
risks associated with QGE031 are not fully characterized; however it is expected that the risk 
will be similar to Xolair. As of 31-Jan 2015, approximately 390 patients have been exposed to 
QGE031 across 8 studies (up to 6 SC administrations of 280 mg q2w and a single IV 
administration of 10 mg/kg). About 115 patients have completed 16 weeks treatment in the 
ongoing CQGE031B2201 asthma study 
 
 and have entered into the one year open label extension study (QGE031 dose 240 mg sc 
q4w). In all the completed and currently ongoing clinical studies with QGE031, no deaths 
related to QGE031 have been reported. QGE031 administration has been safe and well- 
tolerated with the most commonly reported adverse events being procedure-related adverse 
events, such as injection-site pain, swelling, bruising, or redness and other hypersensitivity 
reactions (e.g. rash, swelling of throat and/or tongue) including anaphylaxis. 
One case of anaphylaxis has been observed with QGE031 in study CQGE031B2201E1 as of 
31 July 2015. The risk of significant hypersensitivity reactions is mitigated by administering 
study medication only at the study site and observing patients for extended period after 
administration at the study site. (please refer to the Investigator Brochure (IB) for the 
complete safety summary). In addition, epinephrine is provided to the study participants in 
case needed. 
Although the clinical benefits and safety profile of QGE031 in patients with CSU have not yet 
been established, given the similar mode of action as omalizumab, the benefit to the patient 
from study participation is that treatment with QGE031 will likely improve itch, hives and 
angioedema. The risk for patients participating in this study includes the potential for known 
safety issues such as hypersensitivity reactions including anaphylaxis, as well as for any 
unknown safety effects that could occur. 
 
4 
Population 
The study population will consist of male and female adult patients (≥18 years old, ≤ 75 years 
old at the time of enrollment into the core study). All patients who received either various 
doses of QGE031 or Xolair or placebo in the core study and present active disease defined as 
UAS ≥ 12 at visit 203 or subsequent visits of the follow-up epoch of the core study will be 
offered the possibility to enter this study. Among 360 patients expected to participate in the 

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core CQGE031C2201 study, approximately 240 are estimated to enroll into this extension 
study. 
 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Patients who complete the treatment epoch in study CQGE031C2201 and complete at 
least Visit 203 (Week 32 of the follow-up epoch, ≥16 weeks after last injection) and 
present with active disease as defined by UAS7 ≥12. 
3. Patients must not have any missing eDiary entries in the 7 days prior to Visit 301 (patients 
are allowed to repeat until this criterion is met). 
4. Willing and able to complete a daily symptom eDiary for the duration of the study and 
adhere to the study visit schedules. 
 
4.2 
Exclusion criteria 
As in the core study CQGE031C2201, patients 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. 
1. Use of other investigational drugs at the time of enrollment into the extension study or 
within 30 days or 5-half-lives prior to visit 206, whichever is longer 
2. Patients with a stool examination positive for ova and parasites (stool sample taken at visit 
206). 
3. New onset or signs and symptoms of any form of chronic urticaria other than CSU during 
the follow-up epoch of study CQGE031C2201. This includes the following: 
• Inducible urticaria: urticaria factitia, cold, heat, solar, pressure, delayed pressure, 
aquagenic, cholinergic, or contact urticarial per investigator’s evaluation 
• 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. Any other skin disease associated with chronic itching that might confound the study 
evaluations and results (e.g. atopic dermatitis, bullous pemphigoid, dermatitis 
herpetiformis, senile pruritus etc.) 
5. Onset or ongoing alcohol or drug abuse, within the last 6 months 
6. Unable to comply with study and follow-up procedures during the entire treatment and 
follow-up period 
7. Use of prohibited treatment as detailed in protocol (Table 5-1) 
8. Hypersensitivity to any of the study drugs i.e. QGE031, fexofenadine, loratidine, cetirizine, 
or epinephrine or any of the ingredients or its components, or to drugs of similar chemical 
classes (i.e. to murine, chimeric, or human antibodies) 
9. History of anaphylactic shock 

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10. Onset of malignancy of any organ system within the past 1 year (except for basal cell 
carcinoma or actinic keratoses or Bowen disease (carcinoma in situ) that have been treated 
with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or 
non-invasive malignant colon polyps that have been removed) 
11. Onset of clinically significant cardiovascular (such as but not limited to myocardial 
infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure 
arrhythmia, uncontrolled hypertension within 12 months prior to visit 206), 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 the 
compromise the safety of the patients, interfere with evaluation or interpretation of the 
study results, or preclude completion of the study 
12. Medical examination or laboratory findings that suggest the possibility of decompensation 
of co-existing conditions for the duration of this study. Any items that are cause for 
uncertainty will be reviewed with the investigator 
13. 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 1.5x 
upper limit of normal (ULN) 
14. History of renal disease or creatinine level above 1.5x ULN at visit 206 
15. Platelets < 100,000/µL at visit 206 
16. Long QT syndrome or whose QTcF (Fridericia) measured at end of core study visit (Visit 
206) is prolonged (> 450 ms for males or > 460 ms for females) and confirmed by a 
central assessor (ECG measurement should not be repeated in these patients to confirm 
eligibility) 
17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test 
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. 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 m prior to screening in core study). For female subjects 
on the study, the vasectomized male partner should be the sole partner for that subject 
• Barrier methods of contraception: 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 

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• 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. 
Note: Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation atleast 6 weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow-up hormone level assessment is she considered not of child bearing potential. 
 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Study treatment 
The following will be prepared by Novartis and supplied to the Investigative site as open-label 
medication of liquid formulation vials: 
• QGE031 120mg/mL solution for subcutaneous injection is provided in 2mL glass vials 
each containing 1mL QGE031 solution at 120mg/mL.
 
The solution is clear to 
opalescent, colorless to yellowish in 2mL glass vials with rubber stopper and aluminum 
flip-off cap and is ready-to-use for subcutaneous injection. 
 
5.1.2 
Additional study treatment 
No additional treatment beyond study treatment is requested for this trial. 
Patients will continue to use their background medication i.e H1-AH at approved or increased 
doses alone or in combination with H2-AH and/or a LTRA (standard of care) with a stable 
regimen during the study. 
 
5.2 
Treatment arms 
Patients will all be treated with QGE031 240 mg sc q 4 weeks for 52 weeks (13 treatments) in 
this open label study. 
 
5.3 
Treatment assignment, randomization 
This is a single-arm study and all patients will receive QGE031 treatment. 
At Visit 301, all eligible patients will be enrolled via Interactive Response Technology (IRT). 
The investigator or his/her delegate will contact the IRT system after confirming that the 
patient fulfills all the inclusion/exclusion criteria. The IRT will assign a unique medication 

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number for the first package of study treatment (QGE031) to be dispensed to the patient. 
There will be no randomization. 
 
5.4 
Treatment blinding 
In this extension study, treatment is open-label; patients, investigator staff, persons 
performing the assessments, the sponsor and data analysts will know that all patients receive 
QGE031 q4w. 
Randomization/treatment assignment data from the study CQGE031C2201 will be kept 
strictly confidential and will not be unblinded to the extension study sites at least until the 
core study CQGE031C2201 is fully completed. The site staff including the unblinded 
pharmacist who prepared the study treatment in the core study CQGE031C2201 must ensure 
that blinding for the core study is strictly maintained. To avoid any biased assessments in the 
extension study, the unblinded pharmacist or designee from the core study cannot be involved 
in the extension study other than to prepare and/or administer the open-label QGE031 in the 
extension study. 
 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient was uniquely identified by a Subject Number in the core study CQGE031C2201, 
which is composed by the site number assigned by Novartis and a sequential number assigned 
by the investigator. In this extension study, the subject numbers will remain the same as 
assigned during the core study CQGE031C2201; no new subject numbers will be assigned. 
The same RDC database will be used for both the core and the extension study. Study visits 
related to the extension study will become available once the patient has completed the core 
study and the site has indicated in the eCRFs that the patient will continue into the extension 
study. 
Upon signing the informed consent for the extension study, 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 system. 
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 Treatment 
Epoch Disposition form. 
 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
All patients will receive QGE031 240mg (2 vials) at each study drug administration and 
supplies will be provided in 2 boxes (1 vial in one box). Each vial is 120mg/1ml. The 
investigational treatment packaging has a 2-part label. A unique medication number is printed 
on each part of this label. Investigator staff will identify the investigational treatment 
package(s) to dispense to the patient by contacting the IRT and obtaining the medication 

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number. Immediately before dispensing the medication 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. 
 
5.5.3 
Handling of study treatment 
 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should 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 CPO 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 investigational treatment but no 
information about the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits or remotely and at the completion of the 
trial. Patients will be asked to return all unused investigational treatment and packaging 
throughout, at the end of the study or at the time of discontinuation of investigational 
treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site. 
 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
 
5.5.4 
Instructions for prescribing and taking study treatment 
All study drug administrations can be done in an outpatient ambulatory clinic setting. Study 
drug will be administered by a pharmacist or designee. Blinded personnel involved in core 
study can prepare and administer drug in this extension study. Subjects will remain on-site for 
observation for a period of 2 hours for the first 3 study drug administrations (Visit 301, 302 
and 303) and 30 minutes for subsequent drug administration visits (304 to 313). 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 Committees Joint Task 
Force (Cox et al 2007) for the anti IgE therapy currently available (omalizumab). 
Two injections are required to administer the dose of 240 mg. The injections 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 injections are administered 

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subcutaneously after aspiration of the plunger of the syringe. If blood appears at his hub or 
blood is withdrawn into a syringe, the needle is removed without administration of the dose 
and the injection site is changed. Each injection must be administered at a different site (e.g., 
right arm and left thigh). 
The guidelines for the preparation and administration of study medication are described in the 
pharmacist manual. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Study drug dose adjustments are not permitted. Study drug interruption is only permitted if  
the investigator considers an interruption necessary for the treatment of an adverse event. An 
interruption of two (2) consecutive study drug administrations or three or more 
administrations in total should be discussed with Novartis or delegate regarding the patient’s 
eligibility to continue investigational treatment. 
Any missed or altered study drug administrations must be recorded on the Dosage 
Administration Record CRF in order to reconstruct an accurate dosing history for each patient. 
 
5.5.6 
Rescue medication 
Fexofenadine, loratadine, and cetirizine (H1-AH), in addition to being used as background 
medication will be allowed as rescue medication and used on an as needed basis during 
treatment and follow-up epochs. The selection of any one rescue medication should be made 
once for an individual patient. A switch of the rescue medication for an individual patient or 
between the core and extension study is not permitted. The patients will use the rescue 
medication at the indicated dose. If required for symptomatic relief, patients may take up to  
4x the approved dose of the rescue medication, depending on local clinical practice and 
guideline. H1-AH rescue medication will be sourced locally. 
 
 
As an additional safety precaution for the treatment of anaphylactic reactions, patients will be 
supplied with epinephrine, either via an auto-injector (if available) or as per other local 
standard of care. The investigator will train the patients on how to detect such reactions and 
how to use epinephrine. After any use of epinephrine, patients will need to seek immediate 
medical attention to ensure that the initial reaction has been successfully controlled and/or to 
trigger additional therapeutic steps. 
The use of epinephrine will be recorded on the concomitant medication CRF page. 
 
5.5.7 
Concomitant treatment 
This study requires concurrent use of H1-AH alone (at approved doses as per local health 
authority guidance or at increased doses up to four-fold) or in combination with H2-AH 
and/or LTRA (montelukast, zafirlukast, pranlukast) as background medication. 

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It is recommended that patients should remain on a stable treatment regimen (H1-AH alone or 
in combination with H2-AH and/or LTRA) throughout the study. 
The investigator should 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 on the respective 
CRF pages. 
 
5.5.8 
Prohibited Treatment 
Consistent with the core study CQGE031C2201, the use of the treatments displayed in Table 
5-1 is NOT allowed after the start of study treatment. The minimum required period without 
prohibited treatment before Visit 206 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. 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 
 
Table 5-1 
Prohibited Treatment 
Medication 
Minimum required period without 
medication before Visit 301 
 
Beta-blocker therapy 
7 days 
Routine (daily or every other day during 5 or more 
consecutive days) doses of systemic corticosteroids 
Routine (daily or every other day during 5 or more 
consecutive days) doses of hydrochloroquine 
Routine (daily or every other day during 5 or more 
consecutive days) doses of methotrexate, cyclosporine A, 
cyclophosphamide, tacrolimus and mycophenolate mofetil) 
30 days 
 
30 days 
 
30 days 
Intravenous immunoglobulin G 
30 days 
Plasmapheresis 
30 days 
Regular (daily or every other day) doxepin (oral) 
14 days 
Inactive vaccination 
48 hours prior to any visit 
Live attenuated vaccine 
30 days 
 
 
 
5.5.9 
Emergency breaking of assigned treatment code 
Not applicable 

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5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post study treatment 
Study completion for individual patients will be when he/she has completed the extension 
study 52 weeks of treatment and the full follow-up epoch up to and including Visit 405. 
Treatment completion will be when the patient completed the full 52-week treatment epoch. If 
patients relapse during the follow-up epoch of the extension study as defined by a UAS7 ≥ 12, 
they will be allowed to exit the study if desired and receive conventional therapy at the 
discretion of the investigator. 
Completion of the study will be considered when all patients will have completed 52 weeks of 
treatment epoch and the full follow up epoch or have prematurely withdrawn from the study. 
Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Epoch Completion 
eCRF page. 
When the patient has completed all scheduled study assessments, the investigator must call or 
logon to the IRT system to record the patient completion as per above completion definitions. 
The following is recommended for initiating other treatment outside or post study: 
• A wash-out of QGE031 of at least 4 months is advised prior to commencing Xolair® 
treatment 
 
5.6.2 
Discontinuation of study treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. 
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
As in study CQGE031C2201E1, study treatment must be discontinued under the following 
circumstances: 
• Adverse events for which continued exposure to the study drug would be detrimental 
• Abnormal renal laboratory results requiring discontinuation (see Section 7.4) 
• Abnormal liver laboratory results requiring discontinuation (see Appendix 2) 
• Platelets < 75000/ µL 
• Pregnancy 
• 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 3 
• Lower or upper respiratory: Respiratory failure with or without loss of consciousness 

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• Or cardiovascular: Hypotension with or without loss of consciousness 
• Emergency use of epinephrine due to anaphylactic or anaphylactoid reaction 
• Any protocol deviation that results in a significant risk to the patient’s safety 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They will be expected to perform the Visit 313 (PSW) assessments four weeks after 
their last dose (except receiving study drug as a part of visit 313) and will be expected to 
perform all follow-up assessments (Visit 401-405). 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 provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
 
 
5.6.3 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs only 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. 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Investigational treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
 
5.6.4 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until his/her 
scheduled end of study visit (Visit 405) would have occurred. 
 
5.6.5 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 

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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. 
Given that this is a safety extension study to the core CQGE031C2201 study, if the core study 
is terminated for any reason including the outcome of interim analysis or the program is 
terminated, then the current study will also be terminated. 
 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments. All data obtained from the assessments listed in Table 6- 
1 must be supported in the patient’s source documentation. The table indicates which data are 
entered into the CRF from the source data (D), remain in the source documents only (S) or are 
loaded into the database from separate source documents, i.e. outside vendors (DS). 
Patients should be seen for all visits on the designated day or as close to it as possible. The 
patient should be instructed to contact the investigator if he/she is unable for any reason to 
attend the visit as planned and the visit should be rescheduled as close as possible to the 
original date. 
All patients who complete the treatment epoch will be expected to attend all follow-up visits 
(Visits 401-405). Patients who withdraw early will also be contacted every 4 weeks following 
final study drug administration until 12 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 
 
Epoch 
Core 
study 
*, 1, a 
Treatment Epoch 
Post-treatment follow up epoch 
Visit 
206 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
PSW 
401 
402 
403 
404 
405 
PSW 
Week 
-3/-2 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
64 
76 
88 
100 
Day 
-21/- 
14 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
449 
533 
617 
701 
Obtain informed 
consent 
D 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion/ 
Exclusion Criteria 
D 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Relevant Medical 
history 
D 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Family Malignancy 
history 
D 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Ongoing Concomitant 
medication usage 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Surgery and 
procedures 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Dispense H1-AH 
rescue medication 
- 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Rescue medication 
usage 
- 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Dispense epinephrine 
- 
S 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Study drug 
administration 
- 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
- 
- 
- 
- 
- 
Contact IRT 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
- 
- 
- 
- 
DS 

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Epoch 
Core 
study 
*, 1, a 
Treatment Epoch 
Post-treatment follow up epoch 
Visit 
206 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
PSW 
401 
402 
403 
404 
405 
PSW 
Week 
-3/-2 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
64 
76 
88 
100 
Day 
-21/- 
14 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
449 
533 
617 
701 
Patient eDiary 
UPDD 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
Laboratory tests/ Safety 
Stool ova and parasite 
evaluation 
DS 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DS 
- 
- 
- 
- 
Blood 
sample 
Hematology 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
Clinical 
Chemistry 
including 
bilirubin, 
hsCRP 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 
DS 

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Epoch 
Core 
study 
*, 1, a 
Treatment Epoch 
Post-treatment follow up epoch 
Visit 
206 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
PSW 
401 
402 
403 
404 
405 
PSW 
Week 
-3/-2 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
64 
76 
88 
100 
Day 
-21/- 
14 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
449 
533 
617 
701 
Urine 
Urinalysis 
D 
D 
- 
- 
- 
D 
- 
- 
- 
D 
- 
- 
- 
D 
- 
- 
D 
- 
D 
sample 
dipstick (if 
abnormal 
submit 
sample to 
central lab) 
Pregnancy 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
test 
Physical Exam 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Vital signs 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Weight 
D 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
D 
ECG 
D 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
D 
- 
- 
- 
- 
D 
Adverse events 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Liver safety monitoring 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Renal safety 
monitoring 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 

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Epoch 
Core 
study 
*, 1, a 
Treatment Epoch 
Post-treatment follow up epoch 
Visit 
206 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
PSW 
401 
402 
403 
404 
405 
PSW 
Week 
-3/-2 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
64 
76 
88 
100 
Day 
-21/- 
14 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
449 
533 
617 
701 
Others 
Screening epoch 
completion form 
D 
Treatment epoch 
completion form 
D 
Post treatment follow 
up epoch completion 
form 
D 
*Visit 301 can occur approximately 14 to 21 days after visit 206 of the core study. 
1: Patients who become eligible to enroll into the extension study at or after visit 203 of the core study must complete all lab assessments related to the 
end of core study (visit 206). The current version of the core protocol is to be referred regarding assessments related to visit 206. 
a Subjects must complete all assessments associated with visit 206 as a part of core study to determine eligibility for enrollment into the extension 
study. The informed consent must be signed at visit 206. Subjects will continue using eDiary between visit 206 and 301. 
 
 
PSW = Premature subject/patient withdrawal. Patients who discontinue study treatment will be expected to perform the Visit 313 (PSW) assessments 
(except receive the study drug dose associated with visit 313) four weeks after their last dose and will be expected to perform all follow-up 
assessments (Visit 401-405). 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. 
S = assessment to be recorded on clinical data base, 
D= assessment to be recorded on the CRF based on source documentation, 
DS=assessment to be loaded into the database from separate source documents i.e. outside vendors 

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6.1 
Information to be collected on screen/ roll-over failures 
All patients who have signed informed consent but are not administered study drug will have 
the study phase completion page for the screening epoch, patient visit dates, 
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 including date of birth, age, sex, race and 
ethnicity that was collected as a part of the core study will be used for this extension study. 
Relevant medical history/ medical condition will be reviewed at Visit 206 prior to signing the 
informed consent. Data on patient’s family history on malignancies will also be collected at 
Visit 206 on the respective CRF page. 
 
6.3 
Treatment exposure and compliance 
Patients will receive two subcutaneous injections every 4 weeks at 13 visits during the open 
label treatment epoch. 
Compliance is assured as study drug needs to be administered by study personnel every 4 
weeks via subcutaneous injection. Administration of study drug, date, time and injection site 
will be recorded in the source documents and on the Drug Administration Record eCRF for 
each injection. 
 
6.4 
Efficacy 
A number of efficacy variables will be assessed during the study. Efficacy will be assessed for 
each patient individually based on the baseline data collected between Visit 206 and Visit 301. 
 
6.4.1 
eDiary Assesments 
All patients will be provided with an electronic device (eDiary). Similar to the core study, the 
eDiary will consist of two components: Urticaria Patient Daily Diary (UPDD) 
 
. The patients will receive clear instructions on the 
completion of the eDiary twice daily or once daily depending on the questions. The patients 
will continue using the eDiary between visit 206 and 301. 
 
6.4.1.1 
Urticaria Patient Daily Diary (UPDD) 
UPDD includes UAS7 (itch and hives) for clinical symptoms, use of rescue medication, sleep 
and activity interference, angioedema occurrence and its management, and number of calls 
 
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 

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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. 
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 atleast 4 non-missing daily scores within the 7 days prior to 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 ediary 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. 
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 hives/ 12 hours) 
3 
Severe (> 12 hives/ 12 hours) 
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 ediary 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) 

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6.4.1.1.3 Weekly Urticaria Activity Score (UAS7) 
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly 
UAS7 score is 0 – 42. Complete UAS7 response is defined as UAS7 = 0. Clinical remission is 
defined as UAS7 ≤ 6, and the status of “remission” and “sustained remission” will be assessed 
during treatment and post-treatment epoch, respectively. Clinical relapse is defined as 
UAS7≥12. 
 
 
 
 
 
 
 

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6.4.3 
Appropriateness of efficacy assessments 
In the past literature it 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, based on the current experts’ feedback, the hives are more objective and specific to 
underlying condition being studied, whereas the itch is very subjective, non-specific and can 
be of different origin. 
Disease recurrence after study drug is withdrawn will be measured during the post-treatment 
follow-up epoch. For all patients, symptom scores will be measured during both the treatment 
and post-treatment follow-up epochs. 
 
6.5 
Safety 
Main safety and tolerability assessments include: 
• AEs and SAEs, including AEs leading to treatment discontinuation and events of interest 
such as 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 at Visit 301. 
A short physical exam will include the examination of general appearance and vital signs 
(blood pressure [SBP and DBP] and pulse). A short physical exam will be at all visits starting 
from Visit 302. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings made after first administration of investigational drug 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 BP 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 three times using an automated validated device, e.g. OMRON, 

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with an appropriately sized cuff. The repeat sitting measurements will be made at 1 - 2 minute 
intervals and the mean of the three measurements will be used. 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. 
Clinically notable vital signs are defined in Appendix 1. 
 
6.5.3 
Height and weight 
Body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured. Height will be taken from the baseline assessment in the core study and will not be 
repeated for the extension study. 
 
6.5.4 
Laboratory evaluations 
A central laboratory will be used to analyze and report blood chemistry/hematology, urine (if 
abnormal dip stick at site), and any stool samples. 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 count, white blood cell 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 and hs- 
CRP 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 
Semi-quantitative “dipstick” evaluation will be performed at site including but not limited to 
specific gravity, glucose, protein, bilirubin, ketones, leukocytes and blood. Only 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 further examination including but not limited to RBC and WBC. 
Please refer to Section 7.4 and Table 7-1 for, specific actions and assessments needed in case 
of any abnormal findings related to renal function. 
Dipsticks will be provided to the sites by the Central Lab. 

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6.5.4.4 
Assessment of parasitic infections 
 
 
 
All subjects will have a stool sample collected at Visit 206 and 401. In case the patient is 
unable to provide a stool sample they should take the sample pot home to bring in a stool 
sample as soon as possible after the visit, preferable the day after. Stool samples and 
additional assessment for parasitic disease will be examined for ova and parasites by the 
central laboratory. Negative test results must be documented before initiation of study 
treatment. In case diarrhea develops at any time prior to the last dose of study drug 
administration, additional assessments for parasitic infections would be performed and study 
treatment would not be resumed until results are obtained. 
 
6.5.5 
Electrocardiogram (ECG) 
Standard 12 lead ECGs must be performed only after subjects have been resting in the supine 
position for at least 10 minutes. The preferred sequence of cardiovascular data collection 
during study visits is to perform the ECG prior to vital signs, and blood sampling. The 
Fridericia’s 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 206, 313 and 405. For patients whose ECG is abnormal at Visit 206 due to 
technical/mechanical faults, a repeat ECG may be performed. All electrocardiograms must be 
performed using a 12 standard lead. For those patients who prematurely discontinue from the 
study, an ECG tracing will be taken at Visit 405. 
For each ECG performed original traces and identical duplicate traces will be produced. The 
original trace will be sent electronically to the 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 subject's number, subject initials, 
the date, actual time of the tracing, and Study Code (CQGE031C2201E1) must appear on 
each page of the ECG tracing. 
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. 
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 if present at visit 206 or on the AE eCRF page as 
appropriate. 

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6.5.6 
Pregnancy 
Women of child-bearing potential only will have a urine pregnancy test at the visits specified 
in Table 6-1. A positive urine pregnancy test requires a serum sample to be sent to the Central 
Lab and, during treatment epoch, immediate interruption of study medication until serum β- 
hCG is performed and found to be negative. If positive, the patient must be discontinued from 
the study drug but remain on the trial for the safety evaluation. Urine pregnancy test kits will 
be provided to the sites by the Central Lab. 
 
6.5.7 
Anaphylaxis assessment 
An adjudication committee (AC) is in place to determine whether cases identified through a 
search algorithm based on the Standardized MedDRA Queries 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 cardio-cerebrovascular events 
An AC is 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 
Events of special interest such as suspected anaphylaxis, neoplastic events, and cardiovascular 
events will be monitored and will be adjudicated by expert adjudication committees. 
 
 

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7 
Safety monitoring 
7.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient 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 
an investigational product. 
For all patients who have signed informed consent and are entered into the next epoch 
(Extension 1 Treatment epoch) of the study, all adverse events occurring after informed 
consent is signed will be recorded on the Adverse Event CRF. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. 
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. 

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Clinically significant abnormal laboratory values or test results should 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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1 and will be described in the laboratory manual. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• 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 
• its relationship to the investigational treatment (no/yes), or 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
• whether it constitutes a SAE (see Section 7.2.1 for definition of SAE) 
• action taken regarding investigational treatment. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: 
• no action taken (i.e. further observation only) 
• investigational treatment dosage adjusted/temporarily interrupted 
• investigational treatment permanently discontinued due to this adverse event 
• concomitant medication given 
• non-drug therapy given 
• patient hospitalized/patient’s hospitalization prolonged 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 

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investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
 
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: 
• is fatal or life-threatening 
• 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 (specify what this includes) 
• 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 
• 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 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient 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 more severe (see Annex IV, ICH-E2D Guideline). 
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 
patient or might require intervention to prevent one of the other outcomes listed above. 
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 (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per section 7.2.2 

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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 (Visit 405) must be 
reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 30 day period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow-up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the Oracle Clinical/Remote Data Capture (OC/RDC) system (where 
available). The investigator must assess the relationship to each specific component of the 
study treatment (if the study treatment consists of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department. The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow-up to a previously reported SAE. 
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first. 
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated and whether the patient continued or withdrew from study 
participation. Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a 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 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 

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relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries. 
 
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: 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Table 13-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 in Appendix 2. 
For the liver laboratory trigger: 
• Repeating the LFT within the next week to confirm elevation. 
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages. 
• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 

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7.4 
Renal safety monitoring 
To ensure patient safety and enhance reliability in determining the nephrotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
renal events has to be followed. 
The following two categories of renal adverse events have to be considered during the course 
of the study: 
1. Serum event: 
• confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status 
2. Urine event: 
• New onset (≥ 1+) proteinuria, hematuria or glucosuria; or 
• Doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine 
ratio (PCR) (if applicable). 
Every renal laboratory trigger or renal event as defined in Table 7-1 should be followed-up by 
the investigator or designated personnel at the trial site as summarized below. 
 
Table 7-1 
Specific Renal Alert Criteria and Actions 
Serum Event 
 
Serum creatinine increase 25-49% compared to baseline 
Confirm 25% increase after 24-48h 
Follow-up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase ≥ 50% 
compared to baseline 
 
 
Urine Event 
New dipstick proteinuria ≥ 1+ 
Albumin- or Protein-creatinine ratio increase ≥ 2-fold 
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 3 mg/mmol 
Protein-creatinine ratio (PCR) ≥ 150 mg/g or >15 mg/mmol 
Follow-up within 24-48h if possible 
Consider drug interruption 
Consider patient hospitalization/specialized 
treatment 
 
Confirm value after 24-48h 
Perform urine microscopy 
Consider drug interruption/discontinuation 
New dipstick glucosuria ≥ 1+ not due to diabetes 
Blood glucose (fasting) 
Perform serum creatinine, ACR 
New dipstick hematuria ≥ 1+ not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR 
 
For all renal events: 
1. 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
2. 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 
Event stabilization: sCr level with ± 10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ± 50% variability over last 6 months. 
 

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7.5 
Reporting of study treatment errors including misuse/ abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of study drug while under the control of a healthcare professional, patient or 
consumer 
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 DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE 
 
Table 7-2 
Reporting of study treatment errors 
Treatment error type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/ No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/ Abuse 
Yes 
Yes 
Yes even if not 
associated with an SAE 
 
 
 
7.6 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed-up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded 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 
Prospective suicidality assessment 
All SAEs relating to suicidal behavior should be reviewed by the Safety Management Team 
or early project teams. 

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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 CRFs 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 entries on the eCRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment. The study monitor will 
also ensure that study drug 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 
and identify risks and trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight. 
The investigator must maintain source documents for each 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. 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 CRF entries. 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 will be disclosed. 
 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. Data from both the core study (CQGE031C2201) and extension study 
(CQGE031C2201E1) will be entered into the same database. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 

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8.3 
Database management and quality control 
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site. 
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 by the patient. The system will be supplied 
by a vendor, who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO). 
Data about study treatment administered to the patient will be tracked using an Interactive 
Response Technology (IRT). The system will be supplied by a vendor, who will also manage 
the database. The database will be sent electronically to Novartis (or a designated CRO). 
The occurrence of relevant protocol deviations will be determined. Prior to the final analysis, 
after these actions have been completed and the database has been declared to be complete, it 
will be locked. Data cleaning and determination of protocol deviations will also be performed 
on an ongoing basis, with particular effort before the planned interim analyses. However, sites 
are able to change data until the final database lock. Any changes to the database after that 
time can only be made after written agreement by Novartis Development management. 
 
8.4 
Data Monitoring Committee 
A DMC is not required. 
 
8.5 
Adjudication Committees 
To enhance the safety assessment, more specifically relative to anaphylactic events, neoplastic 
events and major cardio-cerebrovascular events, three independent panels of experts external 
to Novartis will provide independent reviews of potentially identified events in a blinded 
manner and adjudicated on a regular basis. 
All the details of the adjudication processes including the committee members are included in 
the adjudication committee charters. 

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9 
Data analysis 
9.1 
Analysis sets 
Safety Set (SS): The SS consists of all patients who received at least one dose of open-label 
study drug during this open-label study and who had at least one post-baseline (Visit 301) 
safety assessment. 
All safety and efficacy analyses will be performed on the safety analysis set and for the total 
population (not broken down by treatment) unless otherwise specified. 
 
9.2 
Patient demographics and other baseline characteristics 
Demographic and background information will be summarized and be presented based on the 
Safety Set. Medical history/current medical condition before the start of open-label extension 
study will be summarized by system organ class and preferred term according to MedDRA 
dictionary. 
 
9.3 
Treatments 
The number of patients and the length of time (in days) exposed to study drug will be 
summarized by treatment for the safety set. 
Concomitant medications will be summarized 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 dose) and preferred 
term. Non-urticaria related concomitant medications will be summarized by preferred term. 
Use of rescue medication will be summarized as well. 
 
9.4 
Analysis of the primary variable(s) 
Descriptive safety analyses will be conducted using the Safety Set. 
 
9.4.1 
Variable(s) 
The primary objective of this study is to obtain additional data on the long-term safety and 
tolerability of QGE031 for 12 months of treatment in CSU patients. 
The primary variables are: for AEs/SAEs, ECGs, laboratory assessments, vital signs data and 
events of special interest such as hypersensitivity reactions, anaphylaxis, cardio- 
cerebrovascular events, and pre- and malignancies. 
Baseline for the safety analysis is the last visit (Visit 206) of the core study CQGE031C2201, 
except for parameters which are newly assessed at Visit 301, in which case Visit 301 is the 
baseline visit. 
 
Adverse events 
All adverse events which start after the first dose of study medication in the extension study 
and within 52 weeks of the last dose will be considered as a treatment emergent adverse event. 

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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. Adverse events that started during the follow-up epoch of the 
core study will be reported and analyzed in the core study and will not be included in tables of 
the extension study unless they become more severe. They will, however, be included in 
listings with additional collected information (e.g., outcome) as applicable. Adverse events 
that started in the core study but became more severe in the extension study will be reported 
and analyzed as new events. 
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 malignancies whether newly detected or worsening of existing 
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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Vital signs 
Vital signs (i.e. blood pressure, pulse rate and) 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. 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
No hypotheses will be tested. 
Adverse events will be summarized by presenting the number and percentage of patients 
having any AE by primary system organ class and/or preferred term. AE by severity, drug 
related AEs, AEs leading to premature discontinuation of study drug, death and serious AEs 
will be presented in a similar format as all AEs. 
AEs related to potential anaphylaxis will be summarized separately. 
Laboratory and vital sign data will be summarized by presenting summary statistics of values 
and change from baseline by visit, and by presenting frequency of patients with clinically 
notable changes. 
ECG intervals will be summarized by presenting summary statistics for change from baseline 
values by visit. Count and frequency of clinically notable ECG abnormalities or changes will 
be presented. The (uncorrected) QT interval will be corrected according to the Fridericia’s 
formulae. 
Laboratory data, vital sign data and ECG data will be listed with abnormal value flagged 
based on normal ranges or clinically notable ranges. 
Other safety data will be summarized and listed as appropriate. 
 
9.4.3 
Handling of missing values/censoring/discontinuations 
All available data for the endpoints outlined in Section 9.4.1 will be reported. Missing data 
will not be imputed. 

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9.4.4 
Supportive analyses 
The analysis of subgroups of patients for safety parameters is not foreseen. If deemed 
necessary based on, for example, results obtained in the core study, such subgroups may be 
predefined and specified in the statistical analysis plan. 
 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Secondary efficacy variables will be summarized by visit with descriptive statistics, which 
include absolute and relative frequencies for categorical variables and arithmetic mean, 
standard deviation, minimum, maximum, median and first and third quartile for continuous 
variables. Baseline measurements are those taken in the week preceding the first dose 
administered in the extension study. Time to event variables will be summarized using 
Kaplan-Meier estimates. 
 
Table 9-1 
Secondary 
 efficacy variables 
 
 
Domain 
Variable 
Analyzed in 
treatment epoch 
Analyzed in 
follow-up epoch 
Clinical symptoms: 
total 
Complete UAS7 response (UAS7 = 0) 
Y 
Y 
Change from Baseline in Urticaria 
Activity Score (UAS7) 
Y 
Y 
Time to achievement of complete UAS7 
response 
Y 
N 
Time to loss of complete UAS7 response 
for patients having achieved complete 
UAS7 response at Week 52 
N 
Y 
Clinical symptoms: 
hives 
Complete hives response (HSS7 = 0) 
Y 
Y 
Change from Baseline in HSS7 
Y 
Y 
Time to achievement of complete hives 
response 
Y 
N 
Time to loss of complete hives response 
for patients having achieved complete 
hives response at Week 52 
N 
Y 
Clinical symptoms: 
itch 
Complete itch response (ISS7 = 0) 
Y 
Y 
Change from Baseline in Itch Severity 
Score (ISS7) 
Y 
Y 

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Domain 
Variable 
Analyzed in 
treatment epoch 
Analyzed in 
follow-up epoch 
Y: yes, N: no 
Achievement of UAS7=0 response, HSS7 = 0 response and ISS7 = 0 response will also been 
summarized by treatment received in the core study, and by response status achieved at week 
20 of the core study. 
 
 
9.5.2 
Safety variables 
See section 9.4. 
 
 

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9.6 
Interim analyses 
An interim summary of safety and efficacy data will be prepared when all patients have 
completed the treatment epoch. In particular, the summary will include baseline 
characteristics, adverse events, safety laboratory data and the weekly symptom scores and 
derived responder status. Additional parameters may be added as deemed necessary and will 
be defined in more detail in an interim analysis plan. Study procedures will not be modified as 
a result of this interim analysis. 
 
9.7 
Sample size calculation 
It is expected that approximately 240 patients will enter the extension study. The following 
graph shows the binomial probability of observing at least one event for a range of true 
incidences from 0.001 (0.1%) to 0.05 (5%) in samples of 200, 250 and 300 patients. 
 
Figure 9-1 
Probability of observing adverse events with given incidence 
 

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10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented 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 providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
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 (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should 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. 
Women of child bearing potential should 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 
should 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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 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 Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 

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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 
Novartis assures that 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. 
 
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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
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 it cannot be implemented. All significant protocol deviations 
will be recorded and reported in the CSR. 
 
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. 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, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations. 
 
12 
References 
References are available upon request 
Bernstein JA, Lang DM, Khan DA, et al (2014) The diagnosis and management of acute and 
chronic urticaria: 2014 update. J Allergy Clin Immunol; 133(5):1270-7. 
Biagtan MJ, Viswanathan RK, Evans MD, et al (2011) Clinical utility of the Chronic Urticaria 
Index. J Allergy Clin Immunol; 127(6):1626-7. 
Bretz F, Pinheiro JC, Branson M, et al (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics; 61(3):738-48. 

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Chang TW, Chen C, Lin CJ, et al (2014) The potential pharmacologic mechanisms of 
omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol; pii: 
S0091-6749(14)00657-5. [Epub ahead of print] 
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) Qualification Opinion on MCP-Mod as an efficient statistical methodology for 
model-based design and analysis of Phase II dose finding studies under model uncertainty. 
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. 
Juhlin L (1981) Recurrent urticaria: clinical investigation of 330 patients. Br J Dermatol; 
104(4):369-81. 
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. 
Marrouche N, Grattan C (2014) Update and insights into treatment options for chronic 
spontaneous urticaria. Expert Rev Clin Immunol; 10(3):397-403. 
Mathias SD, Dreskin SC, Kaplan A, et al (2010) Development of a daily diary for patients 
with chronic idiopathic urticaria. Ann Allergy Asthma Immunol; 105(2):142-8. 
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. 
Maurer M, Weller K, Bindslev-Jensen C, et al (2011) Unmet clinical needs in chronic 
spontaneous urticaria. A GA2LEN task force report. Allergy; 66(3):317-30. 
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. 
Pinheiro J, Bornkamp B, Glimm E, et al (2013) Model-based dose finding under model 
uncertainty using general parametric models. Stat Med; 33(10):1646-61. 

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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. 
 
 
Toubi E, Kessel A, Avshovich N, et al (2004) Clinical and laboratory parameters in predicting 
chronic urticaria duration: a prospective study of 139 patients. Allergy; 59(8):869-73. 
Wang DD, Zhang S, Zhao H, et al (2009) Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol;49(9):1012-24. 
WAO Guidelines in Urticaria. World Allergy Organ J;5 Suppl:S1-5. 
Zuberbier T (2012) A Summary of the New International EAACI/GA2LEN/EDF/WAO 
Guidelines in Urticaria. World Allergy Organ J; 5 Suppl 1:S1-5. 
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 serum blood chemistry tests for hepatotoxicity. 
The following specific criteria have been identified for this study: 
• AST, ALT or INR above 1.5x ULN 
• Creatinine above ULN 
• Platelets <75,000μL. 
• Stool test result positive for ova or parasites 
Any patient that has AST, ALT, INR or creatinine levels above the limits specified above or a 
stool test result positive for ova or parasites at Visit 206, should be excluded from the study. 
Any patients that have AST, ALT, INR or creatinine levels above the limits specified above, 
after the patient has started treatment in the extension study, should have regular laboratory 
assessments to monitor those laboratory parameters, until they return to baseline values (or 
within normal range), or the investigator indicates that post baseline values are sufficiently 
close to baseline that no further follow-up is warranted for patient safety. 
Any patients that have platelets <75,000μL after the patient has started treatment should be 
discontinued from study drug. 
For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outside of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically 
significant in the eCRF. 
Notable values for vital signs and change from baseline will be summarized. 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 and > 460 for females – all such ECGs require assessment for clinical relevance 
by the Investigator. Patients with a heart rate of >100 bpm measured on 2 occasions, 
approximately 10 minutes apart, while resting, should be discontinued from study treatment. 

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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 x ULN 
ALP > 2 x ULN (in the absence of known bone pathology) 
TBL > 2 x ULN (in the absence of known Gilbert 
syndrome) 
ALT or AST > 3 x ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 x 
ULN and TBL > 2 x ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 x ULN) 
Any clinical event of jaundice (or equivalent term) 
ALT or AST > 3 x ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia 
Any adverse event potentially indicative of a liver toxicity * 
 
 
 
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 drug 
immediately 
• Hospitalize, if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 x ULN 
• Discontinue the study drug 
immediately 
• Hospitalize if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
> 3 x ULN and INR > 1.5 
• Discontinue the study drug 
immediately 
• Hospitalize, if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 

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Criteria 
Actions required 
Follow-up monitoring 
> 5 to ≤ 8 x ULN 
• Repeat LFT within 48 hours 
• If elevation persists, continue 
follow-up monitoring 
• If elevation persists for more 
than 2 weeks, discontinue 
the study drug 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 x ULN accompanied by 
symptomsb 
 
 
 
 
> 3 to ≤ 5 x ULN 
(patient is asymptomatic) 
 
 
 
ALP (isolated) 
> 2 x ULN (in the absence of 
known bone pathology) 
 
 
TBL (isolated) 
> 2 x ULN (in the absence of 
known Gilbert syndrome) 
 
 
 
 
 
 
> 1.5 to ≤ 2 x ULN 
(patient is asymptomatic) 
• Discontinue the study drug 
immediately 
• Hospitalize if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
• Repeat LFT within the next 
week 
• If elevation is confirmed, 
initiate close observation of 
the patient 
 
• Repeat LFT within 48 hours 
• If elevation persists, 
establish causality 
• Complete liver CRF 
 
• Repeat LFT within 48 hours 
• If elevation persists, 
discontinue the study drug 
immediately 
• Hospitalize if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
• Repeat LFT within the next 
week 
• If elevation is confirmed, 
initiate close observation of 
the patient 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
 
 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
 
 
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) 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
Jaundice 
• Discontinue the study drug 
immediately 
• Hospitalize the patient 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
Any AE potentially indicative of 
•    Consider study drug 
Investigator discretion 

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Criteria 
Actions required 
Follow-up monitoring 
a liver toxicity* 
 
interruption or 
discontinuation 
• Hospitalization if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
 
*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 
aElevated ALT/AST > 3 x ULN and TBL > 2 x ULN but without notable increase in ALP to > 2 x 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. 
 

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13.3 
Appendix 3 World Allergy Organization Grading System 
World Allergy Organization subcutaneous immunotherapy systemic reaction grading 
system 
Source: Cox 2010 

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13.4 
Appendix 4 Blood log 
Sample 
Sample 
type 
Visit 
206* 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
401 
402 
403 
404 
405 
Day 
-21/- 
14 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
421 
477 
533 
701 
Chemistry 
Serum 
1.5mL 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
3.5 
Haem+ 
PT(INR) 
Blood 
4.5+2m 
L 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
6.5 
Total blood volume for 
labs/ 
 per 
visit 
16.1 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 

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Protocol No. CQGE031C2201E1 
 
 
Sample 
Sample 
type 
Visit 
206* 
301 
302 
303 
304 
305 
306 
307 
308 
309 
310 
311 
312 
313 
401 
402 
403 
404 
405 
Day 
-21/- 
14 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
421 
477 
533 
701 
Total blood 
Volume/ 
visit 
26.1 
10 
10 
10 
10 
10 
10 
20 
10 
10 
10 
10 
10 
20 
10 
16 
10 
16 
20 
Total blood volume from Visit 301 - 405 
222 mL 
*: Blood volume from assessments done as a part of Visit 206 not included in Total blood volume for this extension study 

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13.5 
Appendix 5 ePRO tools 
Samples of questionnaire provided here are for illustrative purposes only. The text format and 
wording might slightly vary. 
Patient Diary: Urticaria Patient Daily Diary (UPDD) 
 
 

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