Clinical trial NCT03328897
Conditions: Chronic Spontaneous Urticaria
Keywords: Chronic spontaneous urticaria ISS7 UAS7 omalizumab China
Sponsor: Novartis Pharmaceuticals
Start date: 2017-04-26; Completion date: 2019-09-24
Enrollment: 418 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to demonstrate the efficacy and safety of omalizumab, compared with placebo, as an add-on to H1 antihistamines (H1AH) therapy in adult patients suffering from Chronic Spontaneous Urticaria (CSU) who remained symptomatic despite H1AH therapy.

Detailed description:
This was a randomized, multicenteric, double-blinded, placebo-controlled, parallel-group study to evaluate the efficacy and safety of omalizumab as an add-on therapy for the treatment of patients of refractory CSU who remained symptomatic despite approved-dosed H1AH treatment.

The study consisted of three distinct epochs over 24 weeks: Screening epoch (Day -28 to Day -1), Randomized treatment epoch (Day 1 to Week 12) and Post-treatment follow-up epoch (Week 12 to Week 20). Patients were randomized into three treatment groups (omalizumab 300 mg s.c. omalizumab 150 mg s.c. and placebo) in a 2:2:1 ratio, stratified by latent tuberculosis (TB) status at Baseline (Yes/No).

On Day 1, eligible patients were randomly assigned to receive omalizumab (150 mg or 300 mg) or placebo by subcutaneous (s.c.) injection every 4 weeks (on Day 1, Week 4, and Week 8) during the 12-week double-blind randomized-treatment epoch. Patients visited the study center at 4-week intervals. Patients were instructed to stay on the same CSU H1AH treatment at stable dose that they were using during the pre-randomization period during the randomized treatment epoch. They were allowed to use diphenhydramine as rescue medication during all epochs. The last dose of the study drug during the randomized-treatment epoch was administered at Week 8 study visit, however, the last assessment was done at Week 12.

After the completion of the 12-week randomized-treatment epoch, all patients entered an 8-week post-treatment follow-up epoch.

Arms: arm 1: patients received a dose of omalizumab 300 mg which consisted of two injections of omalizumab 150 mg vials every 4 weeks (Day 1, Week 4 and Week 8) arm 2: patients received a dose of omalizumab 150 mg which consisted of one injection of omalizumab 150 mg vial and one injection of placebo 150 mg vial every 4 weeks (Day 1, Week 4 and Week 8) arm 3: patients received placebo which consisted of two injections of placebo 150 mg vials every 4 weeks (Day 1, Week 4 and Week 8)
Interventions: intervention 1: Omalizumab intervention 2: Placebo
Intervention descriptions: intervention 1: injection of 150mg or 300 mg intervention 2: Injection of placebo

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
CIGE025/Omalizumab
Clinical Trial Protocol CIGE025E2305 / NCT03328897 
A multicenter, randomized, double-blind, placebo-
controlled phase III study to evaluate the efficacy and 
safety of Xolair® (omalizumab) in Chinese patients with 
chronic spontaneous urticaria who remain symptomatic 
despite antihistamine treatment
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
00 (Original Protocol)
Clinical trial phase:
III 
Release date:
10-Aug-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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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.................................................................................................................8
Protocol summary................................................................................................................9
1
Introduction .......................................................................................................................13
1.1
Background............................................................................................................13
1.2
Purpose ..................................................................................................................14
2
Study objectives and endpoints .........................................................................................15
2.1
Objectives and related endpoints...........................................................................15
3
Investigational plan ...........................................................................................................17
3.1
Study design...........................................................................................................17
3.2
Rationale for study design .....................................................................................19
3.3
Rationale for dose/regimen, route of administration and duration of treatment....19
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................21
3.6
Risks and benefits..................................................................................................21
4
Population..........................................................................................................................23
4.1
Inclusion criteria ....................................................................................................24
4.2
Exclusion criteria...................................................................................................24
5
Treatment...........................................................................................................................26
5.1
Study treatment......................................................................................................26
5.1.1
Investigational and control drugs..........................................................26
5.1.2
Additional treatment..............................................................................27
5.2
Treatment arms ......................................................................................................27
5.3
Treatment assignment and randomization.............................................................27
5.4
Treatment blinding.................................................................................................28
5.5
Treating the patient................................................................................................29
5.5.1
Patient numbering, ................................................................................29
5.5.2
Dispensing the study drug.....................................................................29
5.5.3
Handling of study and additional treatment..........................................29
5.5.4
Instructions for prescribing and taking study treatment........................30
5.5.5
Permitted dose adjustments and interruptions of study treatment ........31
5.5.6
Rescue medication ................................................................................31


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5.5.7
Concomitant medication .......................................................................31
5.5.8
Prohibited medication ...........................................................................32
5.5.9
Emergency breaking of assigned treatment code..................................32
5.6
Study completion and discontinuation...................................................................33
5.6.1
Study completion and post-study treatment..........................................33
5.6.2
Discontinuation of study treatment .......................................................33
5.6.3
Withdrawal of informed consent...........................................................34
5.6.4
Loss to follow-up ..................................................................................35
5.6.5
Early study termination by the sponsor.................................................35
6
Visit schedule and assessments .........................................................................................35
6.1
Information to be collected on screening failures..................................................39
6.2
Patient demographics/other baseline characteristics .............................................39
6.2.1
Tuberculosis screening and management..............................................39
6.2.2
Other baseline characteristics................................................................42
6.3
Treatment exposure and compliance .....................................................................42
6.4
Efficacy..................................................................................................................42
6.4.1
eDiary assessments................................................................................42
6.4.2
Patient reported outcome assessment....................................................45
6.4.3
Appropriateness of efficacy assessments..............................................45
6.5
Safety.....................................................................................................................45
6.5.1
Physical examination ............................................................................45
6.5.2
Vital signs..............................................................................................46
6.5.3
Height and weight .................................................................................46
6.5.4
Laboratory evaluations..........................................................................46
6.5.5
Electrocardiogram (ECG) .....................................................................47
6.5.6
Pregnancy and assessments...................................................................47
6.5.7
Appropriateness of safety measurements..............................................47
47
47
7
Safety monitoring ..............................................................................................................48
7.1
Adverse events.......................................................................................................48
7.2
Serious adverse events...........................................................................................49
7.2.1
Definition of SAE .................................................................................49
7.2.2
SAE reporting........................................................................................50
7.3
Liver safety monitoring .........................................................................................51
7.4
Renal safety monitoring.........................................................................................51


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7.5
Reporting of study treatment errors including misuse/abuse ................................51
7.6
Pregnancy reporting...............................................................................................52
8
Data review and database management.............................................................................52
8.1
Site monitoring ......................................................................................................52
8.2
Data collection.......................................................................................................53
8.3
Database management and quality control............................................................53
8.4
Data Monitoring Committee..................................................................................54
8.5
Adjudication Committee........................................................................................54
9
Data analysis......................................................................................................................54
9.1
Analysis sets ..........................................................................................................54
9.2
Patient demographics and other baseline characteristics.......................................55
9.3
Treatments .............................................................................................................55
9.4
Analysis of the primary variable(s) .......................................................................56
9.4.1
Variable(s).............................................................................................56
9.4.2
Statistical model, hypothesis, and method of analysis..........................56
9.4.3
Handling of missing values/censoring/discontinuations.......................57
9.4.4
Sensitivity analyses ...............................................................................57
9.5
Analysis of secondary variables ............................................................................57
9.5.1
Efficacy variables..................................................................................57
9.5.2
Safety variables .....................................................................................61
9.5.3
Resource utilization...............................................................................63
9.5.4
Biomarkers ............................................................................................63
9.5.5
DNA......................................................................................................63
63
63
9.7
Interim analyses .....................................................................................................66
9.8
Sample size calculation..........................................................................................66
10 Ethical considerations........................................................................................................69
10.1
Regulatory and ethical compliance........................................................................69
10.2
Informed consent procedures.................................................................................69
10.3
Responsibilities of the investigator and IRB/IEC..................................................70
10.4
Publication of study protocol and results...............................................................70
10.5
Quality Control and Quality Assurance.................................................................70
11 Protocol adherence ............................................................................................................70
11.1
Protocol amendments.............................................................................................71
12 References .........................................................................................................................71


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13 Appendices ........................................................................................................................73
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................73
13.2
Appendix 2 Blood log............................................................................................73
13.3
Appendix 3 Dermatology Life Quality Index (DLQI) questionnaire....................74
List of tables
Table 2-1
Objectives and related endpoints ..........................................................15
Table 3-1
Number of study drug administrations at  Day 1 and at Weeks 4 
and 8......................................................................................................21
Table 5-1
Prohibited medication ...........................................................................32
Table 6-1
Assessment schedule.............................................................................36
Table 6-2
Urticaria Activity Score (UAS).............................................................42
44
44
44
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................52
Table 9-1 
Power analysis of primary and key secondary endpoints .....................67
73
Table 13-2
Blood log for immunogenicity..............................................................73
List of figures
Figure 3-1
Study design..........................................................................................18
Figure 6-1
Tuberculosis screening flowchart .........................................................40
Figure 9-1
Testing strategy for primary and secondary endpoints .........................59


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List of abbreviations
AE
Adverse Event
ALT 
Alanine Transaminase 
ANCOVA
Analysis of covariance
AR
Autoregressive
AST
Aspartate Transaminase 
ATA
Anti-Therapeutic Antibodies
AV
Atrioventricular
BMI 
Body Mass Index
BOCF
Baseline Observation Carried Forward
BUN 
Blood Urea Nitrogen
CFDA
China Food and Drug Administration
CI
Confidence Interval
CPO 
Country Pharma Organization
CQA
Clinical Quality Assurance
CRA 
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CSU
Chronic Spontaneous Urticaria
CT
Computed Tomography
DAR 
Dose Administration Record
DBP 
Diastolic Blood Pressure
DSM
Drug Supply Management
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA 
European Medicines Agency
EU
European Union
FAS 
Full Analysis Set
FcεRI
Fc Epsilon Receptor I
GCP
Good Clinical Practice
H1AH
H1 Antihistamines
HSS
Health Systems Specialist
IB 
Investigators Brochure
ICH 
International Conference on Harmonization
IEC   
Independent Ethics Committee  
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IN
Investigator Notification
INH
Isoniazid
ISS
Itch Severity Score
IUD
Intrauterine Device 
IUS
Intrauterine System 
J2R
Jump to Reference


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LDH 
Lactate Dehydrogenase
LFT
Liver Function Tests
LOCF
Last Non Missing Weekly Score
LSM
Least Squares Means
LTRA
Leukotrine Receptor Antagonist
MAR 
Missed At Random
MMRM
Mixed Effect Linear Model With Repeated Measures
MRI 
Magnetic Resonance Imaging
NHS
Number of Hives Score
PH
Proportional Hazard
PPD 
Purified Protein Derivative
PRO
Patient Reported Outcome
PSUR
Periodic Safety Update Report 
QFT
QuantiFERON Tuberculosis Gold Test
QM
Quality Management
QTcF 
Fridericia's Correction Formula
RAN
Randomized Set
RMP
Risk Management Plan
SAE
Serious Adverse Event
SAF
Safety Set
SBP 
Systolic Blood Pressure
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA query 
SOC
System Organ Class
TB
Tuberculosis
UNS 
Unscheduled Treatment Discontinuation Visit
US
United States
US CFR
United States Code of Federal Regulations
WOC
Withdrawl of Consent
β-hCG
Beta Human Chorionic Gonadotropin


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve blinding 
of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (eg. 100 mg 
once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent must be 
obtained (e.g. prior to starting any of the procedures described in the protocol)
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 pack 
number
A unique identifier on the label of each investigational drug package
Patient/subject ID 
A unique number assigned to each patient upon signing the informed consent 
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.
Randomization 
number
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment
Study drug/ 
treatment
Any single drug or combination of drugs administered to the patient as part of 
the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
UAS7
Sum of daily urticaria activity score (UAS) over 7 days prior to its assessment 
day. The daily UAS is average of the morning and evening UAS which is a 
composite score of the number of wheals (hives) and the intensity of itch.
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
Weekly itch severity 
score (ISS)
Sum of daily itch scores over 7 days prior to its assessment day. The daily itch 
score is average of the morning and evening itch scores. The intensity of itch 
score is recorded on a scale of 0 (none) to 3 (intense/severe).
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a patient does not 
want to participate in the study any longer, and does not want any further visits 
or assessments, and does not want any further study related contact, and 
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Protocol summary
Protocol 
number
CIGE025E2305
Title
A multicenter, randomized, double-blind, placebo-controlled phase III study 
to evaluate the efficacy and safety of Xolair® (omalizumab) in Chinese 
patients with chronic spontaneous urticaria (CSU) who remain symptomatic 
despite antihistamine treatment
Brief title
Study of efficacy and safety of Xolair® (omalizumab) in Chinese patients 
with chronic spontaneous urticaria
Sponsor and 
Clinical Phase
Novartis 
Phase III
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
To evaluate the efficacy of Xolair compared with placebo in patients with 
refractory CSU receiving concomitant H1 antihistamine therapy as measured 
by the ISS and the UAS7 instrument
Primary 
Objective(s)
The primary objective is to demonstrate the superiority of omalizumab 
300 mg or 150 mg administered subcutaneously every 4 weeks in patients 
with refractory CSU receiving concomitant H1AH therapy with respect to 
change from baseline in weekly itch severity score (ISS7) at Week 12 
compared to placebo.
Secondary 
Objectives
Objective 1: To demonstrate that patients with refractory CSU receiving 
concomitant H1AH who are treated with omalizumab 300 mg or 150 mg 
have a greater reduction from baseline in weekly urticaria activity score 
(UAS7) at Week 12, compared to placebo-treated patients
Objective 2: To demonstrate that patients with refractory CSU receiving 
concomitant H1AH who are treated with omalizumab 300 mg or 150 mg 
have a greater reduction from baseline in weekly number of hives score 
(NHS7) at Week 12 relative to placebo-treated patients
Objective 3: To demonstrate that a greater percentage of patients with 
refractory CSU receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have UAS7 ≤6 at Week 12 relative to 
placebo-treated patients
Objective 4: To demonstrate that a greater percentage of patients with 
refractory CSU receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg achieve UAS7 = 0 at Week 12 relative to 
placebo-treated patients 
Objective 5: To demonstrate that a greater percentage of patients with 


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refractory CSU receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg achieve ISS7 Minimally Important 
Difference (MID) response at Week 12 relative to placebo-treated patients
Objective 6: To demonstrate that patients with refractory CSU receiving 
concomitant H1AH who are treated with omalizumab 300 mg or 150 mg 
have a greater reduction from baseline in Dermatology Life Quality Index 
(DLQI) at Week 12 relative to placebo-treated patients
Objective 7: To evaluate the efficacy of omalizumab compared to placebo in 
patients with refractory CSU receiving concomitant H1AH therapy with 
regards to time to ISS7 MID response by Week 12
Objective 8: To evaluate the safety of omalizumab compared with placebo in 
patients with refractory CSU receiving concomitant H1AH therapy with 
regards to the incidence and severity of adverse events (AE) and serious 
adverse events (SAE), vital signs and clinical laboratory evaluation at the 
end of the study
Study design
Randomized, multicenter, double-blind, placebo-controlled, parallel-group 
study
Population
A total of approximately 600 patients aged 18 to 75 years old who have been 
diagnosed with refractory CSU and who remain symptomatic despite 
conventional H1AH treatment will be screened to allow 420 patients to be 
randomized into this study
Key Inclusion 
criteria
Diagnosis of CSU refractory to H1 antihistamines at the time of 
randomization, as defined by all of the following

Age 18-75 years

CSU diagnosis for ≥ 6 months.

The presence of itch and hives for ≥ 6 consecutive weeks at any time 
prior to randomization despite current use of H1AH treatment during this 
time period.

UAS7 score (range 0-42) ≥ 16 and itch component of UAS7 (range 0 to 
1) ≥ 8 during 7 days prior to randomization (Day 1).

In-clinic UAS ≥ 4 on at least one of the screening visit days (Day -14, 
Day -7, or Day 1).

Patients must have been on an approved dose of an H1AH for CSU for at 
least the 3 consecutive days immediately prior to the Day -14 screening 
visit and must have documented current use on the day of the initial 
screening visit.
Key Exclusion 
criteria
Clearly defined underlying etiology for chronic urticarias other than CSU 
(main manifestation being physical urticaria).
Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile 


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pruritus or other skin disease associated with itch
Urticarial 
vasculitis, 
urticaria 
pigmentosa, 
erythema 
multiforme, 
mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or 
generalized cancer
Study 
treatment
Omalizumab 150 mg, omalizumab 300 mg and placebo
2:2:1 randomization
Efficacy 
assessments
weekly itch severity score (ISS7) at Week 12 
weekly urticaria activity score (UAS7) at Week 12
weekly number of hives score (NHS7) at Week 12 
Percentage of patients who have UAS7 ≤6, UAS7 = 0, ISS7 MID at Week 
12 
DLQI 
Key safety 
assessments
Safety of omalizumab compared to placebo with regards to the incidence 
and severity of adverse events and serious adverse events, vital signs and 
clinical laboratory evaluation at the end of the study
Data analysis
Randomization will be stratified by latent tuberculosis (TB) at baseline 
(Yes/No).
The primary efficacy variable is change from baseline in weekly itch 
severity score (ISS7) at Week 12. The daily itch score is the average of the 
morning and evening itch severity scores. The baseline ISS7 is the sum of 
the daily itch severity scores over the 7 days prior to the randomization Day 
1 visit, and the ISS7 at Week 12 is the sum of daily itch scores over the 7 
days prior to the Week 12 visit.
A mixed-effect linear model with repeated measures (MMRM) will be used 
to obtain the least squares mean (LSM) estimate for each treatment group for 
change from baseline in ISS7 at Week 12. The MMRM model will include 
terms of treatment group, week (1 to 12), baseline score, baseline score-by-
week interaction, and treatment-by-week interaction as fixed effects. 
Treatment group and week will be fitted as categorical variables, and 
baseline score as a continuous covariate. The within-patient correlation will 
be modeled using the unstructured covariance matrix. The difference in 
LSM estimates between treatment groups, together with a 95% CI, will be 
presented.
The following secondary efficacy endpoints will be considered and analyzed 
accordingly.
-
Change from baseline in UAS7, NHS7, and overall DLQI at Week 12, 
respectively. For each endpoint, the treatment comparisons of 300 mg vs 


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placebo and 150 mg vs placebo will be made using an MMRM model 
with similar terms as the primary analysis but the corresponding baseline 
value as a covariate.
-
Percentage of patients with UAS7 ≤ 6, UAS7 = 0, and ISS7 MID 
response at Week 12, respectively.
For each endpoint, the treatment 
comparisons of 300 mg vs placebo and 150 mg vs placebo will be 
performed using a logistic regression model which will be fitted with 
treatment group as a factor and the corresponding baseline value as a 
covariate.
-
Time to ISS7 MID during the randomized-treatment epoch. Treatment 
comparisons of 300 mg vs placebo and 150 mg vs placebo will be 
performed using a Cox proportional hazard (PH) model with treatment 
group as a factor and baseline ISS7 as a covariate.
Multiplicity adjustment will be made for testing the primary and secondary 
hypotheses according to the type I error control plan.
Key words
Chronic spontaneous urticaria, ISS7, UAS7, omalizumab, China


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1
Introduction
1.1
Background 
Urticaria is a heterogeneous group of diseases characterized by hives and/or angioedema
(Zuberbier et al 2014). Chronic spontaneous urticaria (CSU) is defined as the spontaneous 
occurrence of daily, or almost daily, hives and itching for at least 6 weeks without an obvious 
cause (Zuberbier et al 2014). The prevalence of CSU is estimated as 0.5% - 1% of the 
population in Western countries. Women are affected twice as often as men and all age groups 
can develop CSU; the incidence peak of CSU is between 20 and 40 years (Maurer et al 2011).
In China, prevalence data for CSU are not available and an epidemiological survey conducted 
by China Dermatologist Association is ongoing. According to an epidemiological survey of 
urticaria conducted by Third Military Medical University in China, CSU accounted for about 
half of the total urticaria population. Distributions of gender and age among CSU patients 
were similar to those reported in Western countries (Luo Jie et al 2011). A recent 
hospital-based multicenter epidemiological study in the Chinese population found CSU to be 
the most common subtype in patients diagnosed with chronic urticaria (61% of all cases)
(Zhong et al 2014).
Among the proposed etiologies of CSU include those indicating an infectious origin (e.g.,
Helicobacter pylori), non-allergic hypersensitivity reactions to foods and drugs 
(pseudoallergic), and autoimmunity (Fiebiger et al 1995, Tong et al 1997, Zweiman et al 1998,
Fukuda et al 2004). In patients suspected of having an autoimmune etiology of CSU, urticaria 
symptoms are considered to result from mediator release following the cross-linking of high-
affinity immunoglobulin E (IgE) receptors (FcεRI) on mast cells and basophils. Chronic 
spontaneous urticaria is associated with immunoglobulin G (IgG) antibodies against IgE 
receptor α subunit in 35-40% of patients and against IgE in an additional 5-10% (Kaplan and 
Greaves et al 2009).
The currently recommended treatment for CSU in the EAACI/GA2LEN/EDF/WAO 
guidelines (Zuberbier et al 2014) is similar to that in the Chinese Society of Dermatology 
guideline (CSD 2007) in which non-sedating H1 antihistamines (H1AH) are recommended as 
first-line treatment. In case of inadequate response to H1AH, switching to another H1AH is 
recommended. As general practice, use of higher, off-label doses of H1AH is uncommon in 
China. Other off-label used treatment options in Chinese guidelines include leukotriene 
receptor antagonists or H2 antihistamine therapy. For some CSU patients refractory to H1AH, 
the guidelines recommend the use of systemic immunosuppressants, such as systemic 
corticosteroids or cyclosporine. However, these drugs are associated with poor tolerability and 
adverse events in many patients. Further treatment options include psoralen and ultraviolet A 
radiation, narrow-band ultraviolet phototherapy, dapsone, plasmapheresis, and intravenous 
immunoglobulin.
Although approximately half or more of CSU patients are considered to be well-controlled by 
H1AH at approved doses, the treatment options for those who remain symptomatic on 
treatment with H1AH are quite limited. Some patients benefit from the addition of LTRA or 
H2 antihistamines, systemic corticosteroids or immunosuppressants, but there is insufficient 


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evidence for these therapies and many are not approved for CSU. Because chronic 
spontaneous urticaria has a profound negative impact on patients’ quality of life (Choi WS et 
al 2016) there is a high unmet medical need for a new treatments in CSU patients refractory to 
H1AH.
Xolair® (omalizumab) is a humanized anti-IgE recombinant monoclonal antibody approved 
in 96 countries, including the US and the EU, to treat allergic asthma. Omalizumab binds to 
IgE, preventing its binding to FcεRI on the surface of mast cells and basophils. Reduction of 
free IgE also leads to reduced cell surface expression of FcεRI. Reduction in free IgE and in 
cell surface FcεRI limits the extent of release of mediators from mast cells and basophils in 
the allergic response.
The hypotheses for the mechanism of action of omalizumab in CSU patients are (1) lowering 
free IgE to near undetectable levels leads to down-regulation of IgE receptors, so that IgG 
autoantibody cannot cross-link the high-affinity receptor (FcεRI), and (2) the down regulation 
of FcεRI may be accompanied by an increase in the threshold above which degranulation of 
mast cells is triggered.
The main studies contributing to efficacy data for the CSU indication include a Phase II dose-
finding study Q4577g and 3 Phase III placebo-controlled studies (Q4881g, Q4882g, and 
Q4883g). Other sources of efficacy data include an initial placebo-controlled study (ADE05)
conducted locally in Germany prior to the Phase III program in CSU and small investigator -
initiated placebo-controlled pilot study (Kaplan et al 2008). The studies used for pooled 
efficacy analysis were Q4881g and Q4882g. Efficacy was assessed using well-established and 
validated endpoints, based on the Urticaria Activity Score (UAS). The Phase III studies were 
designed to select adult and adolescent patients (12 years and older) with severe, significant 
impairment of quality of life and refractoriness to current standard therapy. The pivotal 
efficacy studies, Q4881g and Q4882g, used doses of 75 mg, 150 mg and 300 mg administered 
every 4 weeks during 24 weeks and 12 weeks, respectively. A consistent dose response was 
observed across the primary and secondary endpoints. On the basis of the efficacy observed in 
the Phase III program, omalizumab 300 mg and 150 mg, given subcutaneously every 4 weeks, 
are recommended doses for the treatment of CSU.
The safety profile in CSU is consistent with that previously reported for the allergic asthma 
indication. Four studies, one Phase II (4577g) and three Phase III studies (Q4881g), (Q4882g), 
and (Q4883g), with a total of 1,068 patients, contributed data to the integrated evaluation of 
safety of omalizumab in CSU, including 802 patients who received one or more doses of 
omalizumab. There were no deaths or major organ toxicity and a similar incidence of adverse 
events and severe adverse events among the treatment groups was apparent, with no age-
specific safety concerns. Omalizumab is now approved for the treatment of CSU in 53 
countries worldwide including the US, the EU (counted as one), Canada, and Australia (as of 
April 2016). In the EU, only the 300 mg dose of omalizumab is approved whereas 300 mg 
and 150 mg are approved in most other regions.
1.2
Purpose 
The purpose of this study is to demonstrate the efficacy and safety of omalizumab, compared 
with placebo, as an add-on to H1AH therapy in adult patients suffering from CSU who remain 


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symptomatic despite H1AH therapy. The results of this study will support registration of 
omalizumab for adult patients suffering from CSU in China, and potentially in other countries.
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To demonstrate the superiority of omalizumab 
300 mg or 150 mg administered subcutaneously 
every 4 weeks in patients with refractory CSU 
receiving concomitant H1AH therapy with respect to 
change from baseline in weekly itch severity score 
(ISS7) at Week 12, compared to placebo
The primary efficacy variable 
is defined as the change 
from baseline of the ISS7 
score after 12 weeks of 
treatment
Section 9.4
Secondary
To demonstrate that patients with refractory CSU 
receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have a greater 
reduction from baseline in weekly urticaria activity 
score (UAS7) at Week 12,  compared to placebo-
treated patients
To demonstrate that patients with refractory CSU 
receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have a greater 
reduction from baseline in weekly number of hives 
score (NHS7) at Week 12 relative to placebo-treated 
patients
To demonstrate that a greater percentage of patients 
with refractory CSU receiving concomitant H1AH who 
are treated with omalizumab 300 mg or 150 mg have 
UAS7 ≤6 at Week 12 relative to placebo-treated 
patients
To demonstrate that a greater percentage of patients 
with refractory CSU receiving concomitant H1AH who 
are treated with omalizumab 300 mg or 150 mg 
achieve UAS7 = 0 at Week 12 relative to placebo-
treated patients 
To demonstrate that a greater percentage of patients 
with refractory CSU receiving concomitant H1AH who 
are treated with omalizumab 300 mg or 150 mg 
achieve ISS7 Minimally Important Difference (MID)
response at Week 12 relative to placebo-treated 
patients
To demonstrate that patients with refractory CSU 
receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have a greater 
Variables and timepoint:
UAS7

Change from 
Baseline of UAS7 
score after 12 weeks 
of treatment

Percentage of 
patients with UAS7
≤6 at Week 12

Percentage of 
patients with 
UAS7=0 at Week 12
NHS7

Change from 
Baseline of NHS7 
score after 12 weeks 
of treatment
ISS7

Percentage of 
patients with ISS7 
MID at week 12

Time to ISS7 MID 
response by Week 
12
DLQI

Change from 
Baseline of DLQI 
score after 12 weeks 
of treatment
Safety
Section 9.5


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Objective
Endpoint
Analysis
reduction from baseline in Dermatology Life Quality 
Index (DLQI) at Week 12 relative to placebo-treated 
patients
To evaluate the efficacy of omalizumab compared 
with placebo in patients with refractory CSU receiving 
concomitant H1AH therapy with regards to time to 
ISS7 MID response by Week 12
To evaluate the safety of omalizumab compared with 
placebo in patients with refractory CSU receiving 
concomitant H1AH therapy with regards to the 
incidence and severity of adverse events and serious 
adverse events, vital signs and clinical laboratory 
evaluation at the end of the study

Percentage of 
patients with AE, 
with SAE, and who 
discontinue due to 
an AE 

Exposure adjusted 
AE event rates

Percentage of 
patients with a 
clinically notable 
abnormality in Lab, 
ECG, and vital signs

Change from 
baseline in Lab, 
ECG, and vital signs


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3
Investigational plan
3.1
Study design
The study is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-
group study to evaluate the efficacy and safety of omalizumab administered subcutaneously as 
an add-on therapy for the treatment of patients aged 18-75 years with the diagnosis of 
refractory CSU and who remain symptomatic despite approved-dosed H1AH treatment. 
Patients will be randomized into three treatment arms (omalizumab 300 mg s.c., omalizumab 
150 mg s.c., and placebo) in a 2:2:1 ratio, stratified by latent TB status at baseline. 
Approximately 420 patients will be enrolled at approximately 30 study sites.
The study will consist of three distinct epochs over 24 weeks, as outlined below (see also
Figure 3-1).

Screening epoch: Day -28 to Day -1

Randomized-treatment epoch: Day 1 to Week 12

Post-treatment follow-up epoch: Week 12 to Week 20


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Figure 3-1
Study design
Eligible patients will be required to visit at Day -28~-14 and Day -7 during the 2-4 week 
screening epoch. Only in cases of outstanding laboratory results will an extended screening 
epoch be permitted. For the duration of the screening epoch, patients are recommended to stay 
on a stable CSU H1AH treatment. In addition, for patients requiring treatment for latent TB, 
screening epoch will be extended in order to allow for a 4-Week treatment period prior to 
randomization.
On Day 1, eligible patients will be randomly assigned (in a 2:2:1 ratio with an Interactive 
Response Technology [IRT]) to receive omalizumab (150 mg or 300 mg) or placebo by 
subcutaneous injection every 4 weeks (on Day 1, Week 4, and Week 8) during the 12-week 
double-blind randomized-treatment epoch. Approximately 168 patients will be randomized to 
the omalizumab 150 mg, approximately 168 patients to omalizumab 300 mg and 
approximately 84 patients will be randomized to receive placebo. For the duration of the 
randomized-treatment epoch, patients are recommended to stay on the same CSU H1AH 
treatment that they were using during the pre-randomization period. The last dose of study 
drug during the randomized-treatment epoch will be administered at Week 8 study visit. The 
primary endpoint will be assessed at Week 12. 
After the completion of the 12-week randomized-treatment epoch, all patients will enter an
8-week post-treatment follow-up epoch to allow for further characterization 
 
of omalizumab and collection of additional efficacy and safety data. All these evaluations will 


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also be done for those who withdraw from the study within 12 weeks of randomization.
During the post-treatment follow-up epoch, patients would be allowed to add one more H1AH 
therapy to their treatment regimen for CSU. This is expected to help limit patient dropout and 
ensure that patients return for safety evaluations during the post-treatment follow-up epoch.
For the duration of the study, patients will visit the study center at 4-week intervals. No study 
drug treatment will be given during the post-treatment follow-up epoch. The blind will be 
maintained for the full 20 weeks of the study (after randomization). For the duration of the 
study, all patients will be provided diphenhydramine (25 mg) tablets as rescue medication (see
Section 5.5.6) for additional itch relief on an as-needed basis (up to a maximum of three doses 
in 24 hours or less, based on local regulations). No other medication for itch relief will be 
allowed during the screening and treatment phases of the study.
3.2
Rationale for study design
This is a randomized, double-blind, parallel-group, placebo-controlled study to demonstrate 
the efficacy and safety of omalizumab in Chinese patients with CSU who remain symptomatic 
despite H1AH therapy compared with placebo. The study design is aligned with previous 
pivotal efficacy studies Q4881g and Q4882g. Efficacy is determined using the primary 
endpoint of change from baseline in the weekly itch severity score at Week 12 because itching 
is the symptom of greatest concern to patients, with the greatest impact on their quality of life 
(Mathias et al 2010). As CSU is both a disease of hives and intense itch, it is appropriate to 
evaluate clinical response assessing hives, as well as using a composite endpoint, UAS, which 
incorporates assessment of both  symptoms. Therefore the UAS will be incorporated as a 
secondary endpoint. The validity and reliability of UAS in CSU has been established in 
previous studies (Mylnek et al 2008, Mathias et al 2012).
The selection of Week 12 as the time point for primary efficacy assessment is consistent with 
previous studies conducted with omalizumab in CSU and is supported by the finding that 
response to omalizumab plateaued after 12 weeks in these studies. The reason for including 
only patients who are refractory to approved doses of H1AH therapy is that H1AH drugs are 
the approved first line therapy for CSU (Zuberbier et al 2009, Hide and Hiragun 2012), and 
the unmet medical need in CSU is highest in patients refractory to these drugs. Omalizumab 
will be used as an add-on therapy on top of H1AH treatment in this study.
3.3
Rationale for dose/regimen, route of administration and duration of 
treatment
The doses for this study are selected based on the results of the Phase III studies Q4881g and
Q4882g that tested omalizumab doses of 75 mg, 150 mg, 300 mg and placebo. The doses for
these Phase III studies were selected based on the results from the Phase II dose finding study 
Q4577g that tested a broad array of omalizumab doses (75, 300, and 600 mg) as a single 
subcutaneous injection in patients with CSU refractory to H1AH. Based on the results from 
these studies, 300 mg and 150 mg doses are the recommended doses and have been approved 
in most regions worldwide. Efficacy and safety with these doses is expected to be similar in 
the Chinese population.
The rationale for the dose/regimen chosen for this study is summarized as follows:


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
In the phase II study Q4577g, the 300 mg and 600 mg omalizumab dose groups both
demonstrated efficacy superior to the placebo group, but there was no additional benefit
observed for the 600 mg omalizumab group compared with the 300 mg omalizumab group. In 
exposure-response analysis, exposure levels at 300 mg appeared to approach the plateau of the 
exposure–response curve.

In studies Q4881g and Q4882g, on the primary endpoint (change from baseline to Week 12 in 
weekly itch severity score), omalizumab 150 mg and 300 mg given every 4 weeks
demonstrated consistent and statistically significant treatment effects relative to placebo. The 
75 mg dose did not show a consistent effect on the primary endpoint and most secondary 
endpoints.

The safety profile for omalizumab in CSU is consistent with the profile previously reported 
for the allergic asthma indication. The safety profile was similar for the 150 mg and 300 mg
doses in studies Q4881g and Q4882g, and consistent with the profile for the 300 mg dose 
used in the safety study Q4883g.

Based on exposure-response analysis of omalizumab in CSU, there was a dose response in
efficacy (itch improvement and percent complete UAS7 responders) across the dose range
tested (75 mg to 300 mg every 4 weeks), and no clear impact of body weight, body mass 
index (BMI) and baseline IgE on efficacy within each dose level. This result was again
confirmed in phase III studies. Flat dosing (ie., without adjustment for baseline body weight 
and/or IgE level) is therefore supported.

The 4 weeks dosing interval is selected because in the phase II study Q4577g maximum effect 
was observed 4 weeks post-dose. The appropriateness of the 4 week dosing interval was 
confirmed by PK/PD itch and hives time course modeling using the Phase III study data. An 
interval of 4 weeks is considered to minimize breakthrough CSU symptoms while avoiding 
accumulation resulting from dosing omalizumab more frequently than necessary.

There was no clinically significant difference found in PK and PD of omalizumab between
Chinese and Caucasian populations. Thus, Chinese subjects should respond similarly to
Caucasians when omalizumab is given with the same dose/regimen as used in the previous
studies (A2102, A2204 and A2206).

Flat dosing
Based on these findings, it is considered appropriate to select 150 mg and 300 mg doses for 
E2305 study. This study would attempt to further characterize the dose response profile for 
omalizumab in CSU with the objective of identifying the optimal dose in Chinese patients.
The rationale for a treatment (study drug administration) period of 12 weeks is described 
below:

Treatment with omalizumab results in a rapid reduction of CSU symptoms. The global phase 
III studies demonstrated that the time to achieve the minimally important difference response 
(decrease in UAS7 ≥5) was 1 to 2 weeks after the start of treatment.

The global phase III studies showed no clear differences in therapeutic efficacy after 12 and 
24 weeks of treatment, indicating that efficacy beyond Week 12 can be extrapolated from the 
Week 12 response.


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The rationale for establishing an 8-week follow-up epoch after the end of the treatment epoch
is that this is deemed sufficient to provide safety data and assessment of anti-therapeutic 
antibodies (ATA).
3.4
Rationale for choice of comparator
In this trial, omalizumab is investigated as add-on therapy to H1AHs and compared to placebo 
to determine the efficacy and safety of omalizumab as add-on therapy. 
During the 12 weeks of the treatment epoch, placebo will be given to the 150 mg group (150
mg omalizumab and 150 mg placebo) and placebo group (150 mg placebo x 2) (Table 3-1).
All patients must take study-defined H1AH medications at approved doses during the
screening, treatment, and post-treatment follow-up epochs, which is typical for placebo-
controlled trials where an add-on therapy is studied for a disease with a pre-existing standard 
of care.
Patients should remain on a stable H1AH treatment regimen throughout the study. 
Diphenhydramine will be allowed as rescue medication (see Section 5.5.6). Diphenhydramine 
25 mg will be provided and used on an as-needed basis (up to a maximum of three doses of 25 
mg in 24 hours according to the Chinese label) during the screening, randomized treatment, 
and post-treatment follow-up epochs. Patients will be permitted to add up to one additional 
H1AH therapy after the primary endpoint has been assessed at Week 12 to reduce patient 
dropout during the post-treatment follow-up epoch.
The use of placebo arm in this trial is deemed mandatory to demonstrate the efficacy and 
safety of Xolair in Chinese patients suffering from CSU. The 2:2:1 randomization serves to 
limit the proportion of patient that will receive placebo during the study to 20% of patients. 
Moreover, patients in the placebo arm will receive standard of care treatment with H1AH 
therapy throughout the study and will be allowed to receive rescue medication.
Table 3-1
Number of study drug administrations at  Day 1 and at Weeks 4 and 8
Treatment Arm
Omalizumab 300 mg
Omalizumab 150 mg
Placebo
Active drug (omalizumab 150 mg/vial)
2
1
0
Placebo (150 mg/vial)
0
1
2
3.5
Purpose and timing of interim analyses/design adaptations
Interim analyses or design adaptation are currently not planned.
3.6
Risks and benefits 
Based on results from multiple global studies, omalizumab treatment has a positive benefit-
risk ratio for severe, refractory CSU patients at either of the proposed doses. Patients treated 
with omalizumab can achieve a clinically relevant reduction in persistent and debilitating 
symptoms associated with the disease, while maintaining a safety profile consistent with the 
known safety profile in allergic asthma.


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Omalizumab has been approved for allergic asthma in 96 countries worldwide based on the 
positive benefit-risk ratio from the submitted clinical trials. Omalizumab was approved for the 
treatment of CSU in the EU and in the US in 2014. As of May 2016, omalizumab is approved 
for CSU in 83 countries worldwide including USA, EU, Switzerland, Canada, and Australia.
For CSU, significant and consistent results were apparent across all the Phase III studies. On 
the basis of the efficacy observed in the phase III program, omalizumab doses of 300 mg and 
150 mg administered every 4 weeks, result in a fast onset of treatment effect (within 1-2 
weeks) for the majority of patients, with significant improvement relative to placebo being
demonstrated for itch, hives and associated CSU symptoms. There were no reported deaths,
and few serious adverse events. Omalizumab was well-tolerated in all the clinical studies and
the observed adverse events were broadly similar across each treatment group. Overall no new
safety concerns were raised when these data are compared with the adverse reactions (AR)
listed in the current prescribing information for omalizumab.
The safety profile for omalizumab in CSU is consistent with the profile previously reported 
for the allergic asthma indication. There were no deaths or major organ toxicity in any SOC 
and a similar incidence of AEs and SAEs among the treatment groups with no age specific 
safety concerns. However, small imbalances were observed in some SOCs, as listed below 
with the event(s) that contributed to the imbalance bracketed:
General disorders and administration site disorders (injection site reactions), Infections and 
infestations (upper respiratory tract infection, urinary tract infection), Musculoskeletal and 
connective tissue disorders (arthralgia), Nervous system disorders (headache), and 
Respiratory, thoracic and mediastinal disorders (coughing, bronchospasm) were reported 
more frequently in the omalizumab treatment groups than in the placebo group. 
The preferred terms noted above are not necessarily the same events identified as adverse 
reactions (ARs). These were identified from candidate events where the incidence on any 
omalizumab dose was ≥2% higher than in the placebo group. The events noted as ARs in the 
pooled CSU safety database are nasopharyngitis, viral upper respiratory tract infection, 
sinusitis, arthralgia, and headache.
Apart from a few specific preferred terms, the other relatively small imbalances observed 
were in line with the well characterized safety profile of omalizumab in the severe allergic 
asthma indication, and with events listed in the adverse reaction (AR) table in the SmPC.
Among the more commonly reported AEs, headache was the only notable event that was 
reported more frequently relative to placebo in the omalizumab 150 mg and 300 mg dose 
groups. Most events seen were mild to moderate in severity, and no meaningful difference 
between treatment groups was seen for severe events during the treatment periods.
The percentage of patients with AEs suspected by the investigator to be related to study drug 
was slightly higher in the omalizumab groups (range 7.5% to 9.2%) compared to placebo 
(5.8%). The small imbalance with omalizumab 300 mg was partly due to preferred terms 
headache, and injection site reactions.
The incidence of SAEs, discontinuations from study due to an AE, and withdrawals from 
treatment were similar or lower with omalizumab treatment compared to placebo, so do not 
present an incremental risk to patients.


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Among a range of AEs of special interest examined, hypersensitivity, injection site reaction, 
and hematopoietic cytopenia were reported at higher rates with omalizumab 300 mg treatment, 
and were consistent with previous clinical experience with omalizumab.
There were no clinically relevant differences observed between treatment groups for 
hematology or vital signs, and no meaningful differences between treatment groups were 
observed for new abnormalities. 
During the follow-up period, imbalances were seen in the omalizumab groups compared to 
placebo in the SOCs of infections and infestations (150 mg and 300 mg omalizumab groups), 
and skin and subcutaneous tissue disorders (all omalizumab groups). An increase in skin and 
subcutaneous events was likely due to the re-emergence of symptoms present at baseline, 
while the imbalance in infections was similar or lower to the difference seen under active 
treatment, and showed no clear dose-dependence.
The safety profile is subject to regular review (PSUR 21, Feb 2016) and updates to the 
existing risk management plan omalizumab for allergic asthma and CSU. No new risks were 
identified in the latest version of the risk management plan (Core RMP 11, April 2016), 
Other treatment alternatives to omalizumab for patients that have failed the standard treatment
paradigm of H1 antihistamines at approved, or multiple doses include immunosuppressive
agents such as cyclosporine, or repeated exposure to oral glucocorticoids. There are
significant potential adverse effects associated with both of these alternatives and due to
safety concerns can only be administered over short periods of time.
Therefore, the benefit of treatment with omalizumab is that it could improve itch, hives and
associated CSU symptoms in a patient population that is refractory to current standard of care.
The risks for patients participating in this study include the potential for known safety issues 
associated with omalizumab, which includes anaphylaxis, with an estimated incidence of at 
least 0.2%, as well as the potential for additional risks outlined in the Investigator’s Brochure.
Based on the proposed mechanism of action of omalizumab, there is no clear scientific 
rationale to suspect a decrease in immunity to tuberculosis (TB) associated with its use, nor 
clinical data suggesting relapse or worsening of TB in patients treated with omalizumab. 
Nevertheless, given the high incidence of TB in China that is up to 20-fold as high as those in 
EU and US (WHO 2015), TB screening will be performed in the study. Patients screened with 
latent TB will need to receive tuberculosis prophylaxis for at least 4 weeks prior to study 
drugs (for details, see Section 6.2.1).
4
Population
A total of approximately 600 patients from approximately 30 sites in China mainland, aged 18 
to 75 years old who have been diagnosed with refractory CSU and who remain symptomatic 
despite conventional H1AH treatment will be screened to allow 420 patients to be randomized 
into this study. This accounts for approximately 30% screening failures. If the maximum early 
discontinuation rate of 10% is assumed for this study, then approximately 375 subjects are 
expected to be able to complete the 12-week randomized-treatment epoch with primary 
efficacy data available at the endpoint. 


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4.1
Inclusion criteria
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria:
1.
Written informed consent must be obtained before any assessment is performed. 
2.
Aged 18-75 years.
3.
Diagnosis of CSU refractory to H1AH at the time of randomization, as defined by all of the 
following:

CSU diagnosis for ≥ 6 months.

The presence of itch and hives for ≥ 6 consecutive weeks at any time prior to 
randomization despite current use of H1AH treatment during this time period.

UAS7 score (range 0-42) ≥ 16 and itch component of UAS7 (range 0-21) ≥ 8 during 7 
days prior to randomization (Day 1).

In-clinic UAS ≥ 4 on at least one of the screening visit days (Day -14, Day -7, or Day 1).

Patients must have been on an approved dose of an H1AH for CSU for at least the 3 
consecutive days immediately prior to the Day -14 screening visit and must have 
documented current use on the day of the initial screening visit.
4.
Willing and able to complete a daily symptom eDiary for the duration of the study.
5.
Patients must not have had any missing eDiary entries in the 7 days prior to randomization.
4.2
Exclusion criteria
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/subjects.
1.
Clearly defined underlying etiology for chronic urticarias other than CSU. This includes the 
following:

Acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure or contact urticarias;

Any of the following diseases, which may have symptoms of urticaria and/or angioedema:
urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary 
or acquired angioedema, lymphoma, leukemia, or generalized cancer
2.
Patients with a stool examination positive for ova or parasites (at screening) (patients should 
be cautioned and instructed to apply appropriate hygienic measurements when travelling to 
areas where helminthic infections are endemic).
3.
Any skin disease other than CSU with chronic itching that could confound the results of th e 
study (e.g., atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, or senile 
pruritus).
4.
Previous treatment with omalizumab.
5.
Contraindications to diphenhydramine:


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Hypersensitivity to diphenhydramine or other antihistaminic agents; acute bronchial asthma; 
acute angle-closure glaucoma; pheochromocytoma; hyperplasia of the prostate gland with 
formation of residual urine; epilepsy; hypokalemia; hypomagnesemia; bradycardia; a 
congenital long QT syndrome or other clinically significant cardiac disorders (especially 
coronary heart disease, disturbances in conduction, arrhythmias); the simultaneous application 
of drugs which prolong the QT interval (e.g., antiarrhythmic drugs Class IA or III, antibiotics, 
cisapride, malaria drugs, neuroleptic drugs) or lead to hypokalemia (e.g., certain diuretic 
drugs); the simultaneous application of monoamine oxidase inhibitors; the simultaneous 
uptake of alcohol.
6.
History of anaphylactic shock.
7.
Patients with platelet count ≤ 100,000 /μL at Visit 1.
8.
Patients who are sucrose-intolerant (e.g., the glucose-galactose malabsorption syndrome, 
fructose intolerance or sucrose-isomaltase deficiency).
9.
Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, 
hepatic, or other pathological conditions that could interfere with the interpretation of the 
study results and or compromise the safety of the patients.
10. Medical examination or laboratory findings that suggest the possibility of decompensation of 
co-existing conditions for the duration of the study. Any items that are cause for uncertainty 
will be reviewed with the investigator.
11. Inability to comply with study and follow-up procedures.
12. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to 
randomization.
13. Patients who have been previously randomized into this study.
14. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until 
the expected pharmacodynamic effect has returned to baseline, whichever is longer.
15. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
16. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients/subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
17. Patients taking medications prohibited by the protocol (see Section 5.5.8, Table 5-1)
18. History of malignancy of any organ system regardless of whether there is evidence of local 
recurrence or metastases (except basal cell carcinoma, actinic keratosis, or Bowen’s disease 
[squamous 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 treated or untreated, within the past 5 years)
19. Pregnant or nursing (lactating) women
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include:


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
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), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps). 

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS).
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
21. Patients with evidence of latent TB infection, as defined by a positive QuantiFERON 
TBGold Test (QFT), who are unwilling to be treated with TB treatment according to local 
country guidelines, or cannot, demonstrate documented compliance with prior treatment of 
latent TB infection according to local country guidelines. Patients with a positive QFT are 
required to have a chest X-ray, computerized tomography (CT scan), or MRI, obtained 
within 12 weeks prior to baseline, to evaluate for the potential for prior or current active TB
by a qualified physician. Patients with evidence of prior or current active TB cannot 
participate further in the trial.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs

Name: Omalizumab (IGE025)

Formulation: Lyophilized powder for solution for injection

Appearance: White cake, reconstituted solution: colorless to pale yellow and clear to slightly 
opalescent


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
Unit dose: 150 mg/vial

Packaging: Glass vial
The appearance of omalizumab vial differs from that of placebo vial, and the viscosity of 
omalizumab differs from that of placebo. Omalizumab matching placebo provided in 5ml 
glass vial.
5.1.2
Additional treatment
Except for the concurrent use of H1AH and diphenhydramine as rescue medication (see
Section 5.5.6), no additional treatment beyond investigational treatment is requested for this 
trial. The long-acting non-sedating H1AH agents are allowed during the study. 
Dosage and administration should follow local regulations
5.2
Treatment arms
Patients will be randomized to one of the following three treatment arms in a ratio of 2:2:1.

Omalizumab 300 mg arm will receive a dose of omalizumab 300 mg s.c. which consists of
two injections of omalizumab 150 mg vials every 4 weeks.

Omalizumab 150 mg arm will receive a dose of omalizumab 150 mg s.c. which consists of
one injection of omalizumab 150 mg vial and one injection of placebo 150 mg vial every 4
weeks.

Placebo arm will receive placebo s.c. which consists of two injections of placebo 150 mg vials 
every 4 weeks.
A detailed schedule of administration is described in Section 6. As this is a double-blind study,
the dispensing and administration of the study treatments will be performed by suitably
qualified personnel who are otherwise not involved in study conduct. Further details are
provided in Section 5.3,Section 5.4 and Section 5.5.
5.3
Treatment assignment and randomization 
At Visit “101,” all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The unblinded authorized staff will contact IRT at Visit 
101 after confirming that the patient fulfills all the inclusion/exclusion criteria. Also, the 
unblinded authorized staff will contact the IRT at Visits 102 and 103. The blinded staffs must 
not contact the IRT at the above visits. The IRT will assign a randomization number to the 
patient, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the first package of study drug to be dispensed to the patient. The 
randomization number will not be communicated to any of the site staff.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 


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responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified by latent TB at baseline (Yes/No).
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group.
5.4
Treatment blinding 
All data up to final database lock will be collected with the Novartis clinical trial team, 
investigator / site personnel evaluating subjects, and subjects blinded to treatment allocation. 
The Novartis clinical team will be blinded during the study until the final database is locked, 
and all site personnel including the assessor performing the study assessments, will also 
remain blinded to individual treatment allocation until after final database lock. This excludes 
the unblinded pharmacist and unblinded health care professional who will dispense and / or 
administer the study drug and not be involved in the study assessments. An unblinded 
pharmacist and an unblinded health care professional are required because they will be able to 
determine whether the study drug is active or not from the appearance of vial and the viscosity 
of the drug. Blinding will be maintained using the following methods:
1. Randomization data will be kept strictly confidential until the time of unblinding, and 
will not be accessible by anyone else involved in the study with the following 
exceptions:

Drug Supply Management (DSM), Drug Safety & Epidemiology (DS&E) and 
specific vendors whose role in trial conduct requires their unblinding

Unblinded pharmacist and unblinded health care professional at each site

Unblinded monitor
2. Placebo and active treatment will be dispensed by an unblinded pharmacist (or other 
authorized unblinded staff) who is independent of those involved in the assessment of 
study subjects. In addition, the unblinded pharmacist (or other authorized unblinded 
staff) will store study medication and keep medication records containing unblinded 
information in a secure area where blinded staff would not have access.
3. Study treatments will be administered by an unblinded suitably authorized individual 
(health care professional) who is not responsible for any aspect of subject assessment 
or follow-up.
4. The procedural details relating to treatment blinding and unblinded drug 
administration will be described in the Pharmacist Manual which will be provided 
separately.
In the event that the packaging of a study treatment has a broken seal, this information will be 
documented in the IRT, along with a reason (if applicable) and the medication number so that 
the vial will not be available to dispense to another subject.


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Unblinding will only occur in the case of subject emergencies (see Section 5.5.9) and at the 
conclusion of the study.
The appropriate personnel from the study site and Novartis will assess whether the study 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason. Study treatment must be discontinued after emergency 
unblinding.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering,
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. 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. The site must 
select the CRF book with a matching Subject Number from the EDC system to enter data. 
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 Screening 
epoch Study Disposition CRF.
5.5.2
Dispensing the study drug 
Each study site will be supplied with open-label study drug.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the omalizumab 150 mg or placebo. Unblinded 
site personnel will identify the investigational treatment package(s) to dispense to the patient 
by matching medication numbers obtained from IRT. Immediately before dispensing the 
package to the patient, unblinded site personnel will detach the outer part of the label from the 
packaging and affix it to the Investigational Product accountability log source document 
(Drug Label Form) for that patient’s unique subject number.
The study drugs will be dispensed by the unblinded pharmacist (or other unblinded authorized
site personnel) appointed at the study site.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 


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designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. The study drugs should be received by unblinded staff 
only. The blinded team should not have access to storage location or should not be involved in 
receipt of IP. 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 include Chinese and comply with the legal requirements of China. 
They will include storage conditions for the study 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 study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
The background treatment H1AH will be provided by the study site. For the use of H1AH 
please refer to Section 5.5.7.
5.5.4
Instructions for prescribing and taking study treatment 
Active or placebo omalizumab will be administered by subcutaneous injection. The first
administration of drug will take place at Visit 101 once all eligibility criteria have been
confirmed and all other assessments performed.
The lyophilized product takes 15-20 minutes to dissolve. The fully reconstituted product will
appear clear or slightly opalescent and may have a few small bubbles or foam around the edge
of the vial. Detailed instructions on how to reconstitute omalizumab vials can be found in the
separate Pharmacist Manual. Reconstituted omalizumab vials should be protected from direct
sunlight.
Administration
Study medication will be administered by an unblinded suitably authorized individual
(qualified health care professional) who is not responsible for any aspect of subject 
assessment or follow-up. This individual will be identified at site as the “independent study 
drug administrator”. The independent study drug administrator will administer the study 
treatment to the corresponding subject by s.c. injection during the study visit without 
engaging in any unnecessary interactions that may have the potential to unblind the subject or 
any of the site study personnel.
Study drug is administered to the patient using a disposable 25-gauge needle and a disposable
plastic tuberculin-type syringe. The injections are administered in the deltoid region on the
right arm and/or left arm, avoiding urticarial lesions. Alternatively, the injections can be
administered in the thigh if reasons preclude administration in the deltoid region. The
injections are administered subcutaneously after aspiration of the plunger of the syringe. If


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blood is withdrawn, the needle is removed without administration of the dose and the
injection site is changed.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment (omalizuamb, 
placebo, background H1AH or diphenhydramine) as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Investigational drug dose adjustments and/or interruptions are not permitted.
If a dose (omalizumab or placebo) was dispensed by IRT but not administered to a subject at a
visit at which the subject attended, this deviation event must be recorded on the Dosage
Administration Record eCRF.
5.5.6
Rescue medication
Diphenhydramine 10 mg or 25 mg tablet will be provided and used on an as -needed basis (up
to a maximum of 75 mg/day) during the screening, randomized-treatment, and post-treatment 
follow-up epochs.
Use of rescue medication must be recorded on the Concomitant medications form in the CRF.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions)
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
Permitted concomitant medications (for CSU)
Subjects should remain on a stable non-sedating H1AH treatment regimen throughout the 
study.
During the post-treatment follow-up epoch (after Week 12 visit) subjects are permitted to add 
up to one additional approved non-sedating H1AH or to up-dose the non-sedating H1AH 
within approved dose levels if multiple doses are available and a lower dose was used as a 
background therapy. 
Dosage and administration should follow local regulations.


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5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 that could confound the efficacy is NOT allowed 
during the study for indication and wash-out periods for these treatments are indicated in 
Table 5-1.
The investigator or authorized site staff must instruct the subject to notify them about any new
treatments he/she takes after enrollment. All prohibited treatments taken after enrollment must
be recorded in eCRF.
If a prohibited treatment listed in Table 5-1 was used during the study, the subject should
discontinue use of the prohibited treatment. At the discretion of the investigator or authorized
site staff, if the subject’s use during the study of a prohibited treatment listed in Table 5-1
presents undue safety risk for the subject, the subject should be discontinued from study
treatment as per Section 5.5.9.
Table 5-1
Prohibited medication
Medication
Wash out period
Anti-IgE therapy
No prior use allowed
Routine (daily or every other day during 5 or more consecutive 
days) doses of systemic corticosteroids 
30 days
Routine (daily or every other day during 5 or more consecutive 
days) doses of hydroxychloroquine
30 days
Routine (daily or every other day during 5 or more consecutive 
days) doses of immunosuppression (e.g. methotrexate, 
cyclosporine, tacrolimus, mycophenolate mofetil,  
cyclophosphamide, or triperygium wilfordii Hook)
30 days
Intravenous immunoglobulin G
30 days
Plasmapheresis
30 days
Regular (daily or every other day) doxepin (oral)
14 days
Any H2 antihistamine
7 days
Any leukotriene receptor antagonist (LTRA)
7 days
Any H1 antihistamine at greater than approved doses
3 days
vaccination with inactivated pathogen
48 hours prior to visits 101, 102, 
and 103
Oral Chinese traditional medicine prescribed for CSU *
30 days
Subjects taking either LTRAs or H2 antihistamine for disease other than CSU (e.g., asthma or
gastroesophageal reflux disease, respectively) will be permitted to continue their use during the 
study.  These diseases must be recorded as part of the medical history collected during the 
screening epoch. Inhaled asthma controllers, including corticosteroids, are also permitted during the 
study.
*Subject receiving oral Chines traditional medicine for another indication and for at least 2 months will 
be allowed to continue this treatment.
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 


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condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time. 
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish  

Pregnancy (see Section 6.5.6 and Section 7.6)

Use of prohibited treatment as per recommendations in Table 5-1

Any situation in which study participation might result in a safety risk to the patient

Individual serum creatinine increase ≥50% compared to baseline, unless the event is not 
drug related, related to disease progression, or if the benefit / risk assessment supports 
continuing study treatment.

Emergence of the following adverse events: adverse events that in the judgment of the 
investigator, taking into account the subject’s overall status, prevent the subject from 
continuing participation in the study (for example, sepsis)


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
Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study.
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of study drug, for a study treatment discontinuation visit. Treatment 
discontinuation visit assessments detailed in the “unscheduled treatment discontinuation visit” 
(UNS) in Table 6-1 should be completed and recorded in the eCRF. The investigator must 
determine the primary reason for the patient’s premature discontinuation of study treatment 
and record this information on the Dosage Administration eCRF. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone visits: 

new / concomitant treatments

adverse events / serious adverse events
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent 
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason 
at any time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g., telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.


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All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table below.
5.6.4
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the subject, e.g., dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed , 
an “s” indicates the data remain in the source documents only.
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients/subjects 
who prematurely discontinue the study for any reason should be scheduled for a visit as soon 
as possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, all dispensed investigational product should be reconciled and the adverse 
event and concomitant medications reconciled on the CRF.
Patients/subjects will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment. 


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Table 6-1
Assessment schedule
Epoch
Screening
Randomized treatment
Post-treatment follow-up
Visit Number
1
2
101
102
103
199a
201
299a
Visit Name
Week -4 
to -2 
Week -1 
Epoch 
disposition
Randomization 
Week 4 
Week 8 
Week 12
Epoch 
disposition
Week 16  Week 20 
Epoch 
disposi
tion
Day
Day -28 
to -14
Day -7
Day 1
Day 29
Day 57
Day 85
or DISC
Day 113
Day 141
or DISC
Obtain informed consent
x
Inclusion/ exclusion criteria
x
x
x
In-clinic assessment of UASb
x
x
x
Demographic data
x
Medical/surgical history 
including urticaria and 
angioedema history and prior 
treatments
x
Physical Examc
s
s
s
s
s
s
s*
Height
x
Weight
x
Vital signs
x
x
x
x
x
x
x
ECG
x
QuantiFERON®TB-Gold In-
Tube test
x
Chest X-rayk
x
Concomitant medication 
usage
x
x
x
x
x
x
x
x*
Adverse events
x
x
x
x
x
x
x
x*
Study drug/placebo 
administration
x
x
x
Randomization
x


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Epoch
Screening
Randomized treatment
Post-treatment follow-up
Visit Number
1
2
101
102
103
199a
201
299a
Visit Name
Week -4 
to -2 
Week -1 
Epoch 
disposition
Randomization 
Week 4 
Week 8 
Week 12
Epoch 
disposition
Week 16  Week 20 
Epoch 
disposi
tion
Day
Day -28 
to -14
Day -7
Day 1
Day 29
Day 57
Day 85
or DISC
Day 113
Day 141
or DISC
Contact IRT
x
x
x
x
x
Patients’ eDiaryd
x
x
x
x
x
x
x
x*
PROs
DLQI
x
x
x
x*
Laboratory tests
Serum pregnancy teste
x
Urine pregnancy teste
x
x
x
x
x*
Stool ova and parasite 
evaluationf
s
Hematologyg
x
x
x
x
x*
Chemistryh
x
x
x
x
x*
Urinalysis (local)i
x
x
x
Sample collection
Anti-omalizumab antibody
x
x
Epoch Depositionl
x
x
x
DLQI = Dermatology Life Quality Index
NOTE: PROs must be completed prior to other assessments.
NOTE: Unless otherwise indicated, all assessments should be performed pre-administration.
* These assessments are also to be conducted for patients who discontinue treatment.
a Subjects who discontinue study treatment early will be expected to perform 4 weeks after their last dose, the Day 85 (Visit 199) assessments. These subjects will 
subsequently be expected to perform Post-treatment follow-up the Day 113, 141 evaluations (Visit 201, and 299). Subjects who enter the Post-treatment follow-up epoch 
but wish to terminate early will be expected to perform the Day 141 (Visit 299) assessments.


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Epoch
Screening
Randomized treatment
Post-treatment follow-up
Visit Number
1
2
101
102
103
199a
201
299a
Visit Name
Week -4 
to -2 
Week -1 
Epoch 
disposition
Randomization 
Week 4 
Week 8 
Week 12
Epoch 
disposition
Week 16  Week 20 
Epoch 
disposi
tion
Day
Day -28 
to -14
Day -7
Day 1
Day 29
Day 57
Day 85
or DISC
Day 113
Day 141
or DISC
b In-clinic UAS is assessed by the investigator (for hives) and patient (for itch) at Day -14, Day -7 and Day 1.
c Physical exam on Day -14 is comprehensive but subsequent physical exams maybe limited.
d Includes UAS7 (itch score and number of hives), largest size of hives, 
, 
, rescue medication (diphenhydramine)
use, angioedema episodes, calls to doctor or nurse. Daily diary completed twice or once a day by the patient. The eDiary will be given to patients on Day -14, and the 
patients will be trained by the site staff how to use the eDiary
e All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test during the screening epoch and urine pregnancy 
test prior to randomization. If the serum pregnancy test during the screening epoch is positive, the patient will be a screening failure. If urine pregnancy test results are 
positive during the randomized-treatment epoch, dosing should be held and a serum pregnancy test will be performed by the central laboratory. If urine pregnancy test 
results are positive during the post-treatment follow-up epoch, a serum pregnancy test will be performed by the central laboratory. Urine pregnancy tests will be 
performed at the site.
f Note that stool ova and parasite examination should be performed on Day -7 in patients with an eosinophil count > 2 times the upper limit of normal on Day -14 AND 
risk factors for parasitic disease.
Stool ova and parasite examination will be performed at the site.
g Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count (neutrophils, bands, eosinophils, lymphocytes monocytes, 
basophils other cells).
h Sodium, potassium, chloride, bicarbonates, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, ALT, AST, 
LDH, alkaline phosphatase, creatinine phosphokinase, and uric acid.
i A midstream urine sample (approximately 30 mL) will be obtained, in order to avoid contamination with epithelial cells and sediments, and allow proper assessments. 
Semi quantitative ‘dipstick’ evaluation for the following parameters will be performed. Specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leucocyte and blood.
K Chest X ray will be performed only in case of positive QFT
l If the patient will continue into the next phase of the trial or if the study is terminated by the sponsor at any time for any reason, the patient are expected to perform the 
assessment at the last visit of each respective epoch. Epoch disposition page may look slightly different in the content depending the epoch.


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6.1
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next epoch 
will have the study completion page for the screening epoch, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include
date of birth, age, sex, race, ethnicity. Relevant medical history/current medical condition
present before signing the informed consent will be captured. Where possible, diagnoses, and
not symptoms, will be recorded. In addition, data on patient’s family history on malignancies
is collected on the respective CRF page to assess possible risk factors related to any
malignancies. 
6.2.1
Tuberculosis screening and management
6.2.1.1
QuantiFERON TB-Gold In-tube assay
A QFT to screen a population for latent tuberculosis infection (Doherty et al 2008) will be 
used at screening to evaluate the subjects’ eligibility for the study. This blood-based assay is 
specific for Mycobacterium tuberculosis and is not influenced by previous Bacillus Calmette-
Guérin vaccination or by exposure to other Mycobacteria species. Furthermore, this test, in 
contrast to the purified protein derivative (PPD) skin test, is also insensitive to a booster effect 
since the subject is not exposed to the vaccine. The assay measures the production of 
interferon-gamma and presents it relative to a negative and a positive control sample (Manuel 
and Kumar 2008). The QFT kit will be supplied by the central laboratory. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the study-specific laboratory manual.
6.2.1.2
Chest X-ray
For patients with a positive QFT, a chest X-ray is required; no new chest X-ray is needed in 
subjects with chest X-ray, chest CT scan and/or chest MRI performed within 12 weeks of 
screening. If the chest X-ray, chest CT scan, and/or chest MRI evaluated by a qualified health 
care professional reveals past or present active TB, the subject will not be enrolled into the 
study.
6.2.1.3
Protocol for tuberculosis screening
Screening for TB will be performed according to Figure 6-1, below. Positive or indeterminate 
QFTs must be entered on the Tuberculosis assessment eCRF.


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Figure 6-1
Tuberculosis screening flowchart
The approach to screening is as follows:

If the QFT result is negative, the subject may be randomized.

If the QFT result is positive, the investigator should perform further evaluation to rule out 
active TB, as per local procedures. If a TB workup was conducted prior to screening the 


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subject, results of the workup can be used to assess eligibility if the workup was 
conducted within 12 weeks prior to randomization.
o
Subjects with latent TB may be randomized if treatment for latent TB has been 
performed for 4 weeks prior to randomization and subject agrees to continuous 
treatment according to local guidelines.
o
Subjects positive for active TB per workup are not eligible for the study.

If the QFT result is indeterminate, the investigator may repeat the test once or may 
proceed directly to perform workup for TB as per local procedures. This action is at the 
discretion of the investigator. If a TB workup was conducted prior to the screening the 
subject, results of the workup can be used to assess eligibility if the workup was 
conducted within 12 weeks prior to randomization.
o
If the second test is negative, the subject may be randomized.
o
If the second test is positive or indeterminate, the investigator should perform 
further evaluation to rule out active TB, as per local guidelines. Subject positive 
for latent TB per workup may be randomized to the trial if treatment for latent TB 
has been performed for 4 weeks prior to randomization and subject agrees to 
continuous treatment according to local guidelines. Subjects positive for active TB 
per workup are not eligible for the study.

If eligibility is being assessed with only 1 test result and a TB workup (i.e., no second TB 
test will be performed), the TB test to assess eligibility must have been done via the 
central laboratory for the study within the screening epoch (within 4 weeks prior to 
randomization) and TB workup will only be considered if it was completed within 12 
weeks prior to randomization. Subjects positive for latent TB per workup may be 
randomized to the trial if sufficient treatment has been initiated according to local routine 
clinical practice for at least 4 weeks prior to randomization and will be maintained for the 
prescribed duration. Subjects positive for active TB per workup are not eligible for the 
study. Subjects negative for TB per workup (no signs of latent or active TB) may be 
randomized to the trial.
6.2.1.4
Treatment of latent TB and safety monitoring
In case of latent TB, patients who elect to remain in the trial will receive TB prophylaxis 
treatment according to local guidelines. The following recommendations are based on WHO 
guidelines and are considered guidance, unless local regulations suggest different approaches.
If a 6 month 5 mg/kg/per day INH TB prophylaxis is prescribed according WHO guidelines 
used in China (WHO 2015), patients are required to undergo monthly LFT monitoring. The 
INH treatment will be continued for 6 months.
The INH treatment should be halted in the following situations:

ALT ≥ 5 x ULN

ALT ≥ 3 x ULN and presence of symptoms (e.g. general malaise, fatigue, abdominal 
pain, nausea, or vomiting)


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
ALT ≥ 2-3 x ULN and AST ≥ 3 x ULN
In patients whose INH is discontinued, after ALT normalization, TB prophylaxis will be 
resumed with an alternative regimen (e.g., 10 mg/kg/per day rifampicin) for 3-4 months.
If regimens that don’t include INH are chosen to treat latent TB, then monitoring of LFTs will 
be necessary in the case of regimens including rifamycins (e.g., rifampicin, rifapentine, or 
rifabutine), pyrazinamide, or their analogs; in such cases, management of abnormal LFTs 
should be performed using the example for INH, above.
6.2.2
Other baseline characteristics
Baseline characteristic data to be collected on all subjects include (all laboratory results are 
central except where indicated): ECG, vital signs; hematology; clinical chemistry; local 
urinalysis; local stool ova and parasite evaluation; serum pregnancy test; medical history of 
anaphylactic; history of contraindications to diphenhydramine; immunogenicity; 
in clinic 
UAS; DLQI.
6.3
Treatment exposure and compliance 
All doses of study treatment administration will be recorded on the appropriate Dosage 
Administration Record eCRF page. Compliance will be assessed by unblinded field monitor 
at each visit using vials (omalizumab and omalizumab placebo) counts and information 
provided by the unblinded pharmacist or unblinded authorized site staff responsible for 
treatment dispensation and preparation. 
6.4
Efficacy
A number of efficacy variables will be assessed during the study. During each visit, the 
assessment will be started with patient reported outcomes (PRO) (DLQI) and then move to 
other assessments and laboratory assessment.
6.4.1
eDiary assessments
6.4.1.1
Number of hives, intensity of itch, and Urticaria Activity Score (UAS)
The number of hives, and intensity of itch score will be recorded by the patient twice daily 
(morning and evening) in their eDiary, on a scale of 0 (none) to 3 (intense/severe) (see
Table 6-2). The UAS is a composite score of the number of wheals (hives) (Hives Severity 
Scores, HSS); and the severity of the itch (Itch Severity Scores, ISS).
Table 6-2
Urticaria Activity Score (UAS)
Score
Wheals (Hives)
Pruritus (Itch)
0
None
None
1
Mild (1-6 hives/12 hours)
Mild (minimal awareness, easily 
tolerated)
2
Moderate (7-12/12 hours)
Moderate (definite awareness, 
bothersome but tolerable)
3
Severe (> 12 hives/12 hours)
Severe (difficult to tolerate)


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6.4.1.1.1 Hives Severity Score (HSS)
The wheals (hives) severity score (HSS), defined by number of hives, will be recorded by the 
patient twice daily in their eDiary, on a scale of 0 (none) to 3 (intense/severe) (see Table 6-2). 
A weekly score (HSS7) is derived by adding up the average daily scores of the 7 days 
preceding the visit. The possible range of the weekly score is therefore 0 – 21.
Complete hives response is defined as HSS7 = 0.
When either the morning or evening score is missing, the non-missing score for that day
(morning or evening) will be used as the daily score. When one or more of the daily scores are
missing, the following principles will be applied to handle the missing data: If a patient has at 
least 4 non-missing daily scores within the 7 days prior to the study visit, the weekly score is 
calculated as the sum of the available eDiary scores in that week, divided by the number of 
days that have a non-missing diary score, multiplied by 7. If there are less than 4 non-missing 
daily scores within the prior 7 days, then the weekly score is missing for the week.
6.4.1.1.2 Itch Severity Score (ISS)
The severity of the itch will be recorded by the patient twice daily in their eDiary, on a scale
of 0 (none) to 3 (intense/severe) (see Table 6-2). A weekly score (ISS7) is derived by adding
up the average daily scores of the 7 days preceding the visit. The possible range of the weekly
score is therefore 0 – 21. Partially missing diary entries will be handled in the same way as
described for the hives severity score.
Complete itch response is defined as ISS7 = 0.
Weekly itch severity score MID response is defined as a reduction from baseline in weekly 
itch severity score of at least 5 points.
Time to weekly itch severity score MID response is the time (in weeks) from the date of the 
first dose to the date where weekly itch severity score MID response is first achieved.
6.4.1.1.3 The weekly Urticaria Activity Score (UAS7)
The UAS7 is the sum of the HSS7 score and the ISS7 score. The possible range of the weekly
UAS7 score is 0 – 42.
Complete UAS7 response is defined as UAS7 = 0.
UAS7 MID response is defined as a reduction from baseline in UAS7 of at least 11 points.
Time to UAS7 MID response is the time (in weeks) from the date of the first dose to the date 
where UAS7 MID response is first achieved.
Week 12 responders are defined as patients who achieve an absolute UAS7 less than or equal 
to 6 at Week 12.


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6.4.1.6
Calls to doctor or nurse
Calls to doctor, nurse or nurse practitioner because of the patient’s skin condition will be 
recorded once daily in the eDiary by the patient.
6.4.2
Patient reported outcome assessment
6.4.2.1
Dermatology Life Quality Index (DLQI)
DLQI is a 10-item dermatology-specific health-related quality of life measure (Finlay and 
Khan 1994). Patients rate their dermatology symptoms as well as the impact of their skin 
condition on various aspects of their lives. An overall score will be calculated as well as 
separate scores for the following domains: Symptoms and Feelings, Daily Activities, Leisure, 
Work and School, Personal Relationships, Treatment. The minimally important difference of 
the overall DLQI score for patients with CSU has been estimated to be 2.24−3.10 (Shikiar et 
al 2005). DLQI questionnaire will be provided in Chinese language, and be assessed at the 
site; The questionnaire will be completed by the patients unobserved. 
6.4.3
Appropriateness of efficacy assessments 
Efficacy will be determined using the primary endpoint of change from baseline in the weekly 
itch severity score at Week 12. Assessment of itch is the symptom of greatest concern to 
patients, with greatest impact on their quality of life (Mathias et al 2010). Because the chief 
CSU symptoms are hives and intense itch, it is appropriate to evaluate clinical response 
through use of the UAS, a composite endpoint that measures both of these symptoms. UAS7 
is therefore incorporated as a secondary endpoint.
Time to onset of the clinical effect (ISS7 MID and UAS7 MID) of treatment with omalizumab 
will be evaluated during the treatment epoch. Time to onset of clinical effect is important to 
establish so that guidance can be given to patients regarding when a response should be 
expected.
Disease recurrence after study drug is withdrawn will be measured during this study. For all 
patients, symptom scores will be measured during both the treatment and post-treatment 
follow-up epochs. This important information will be used along with data from other studies 
to provide guidance for the duration of therapy.
6.5
Safety 
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
A short physical exam will include the examination of general appearance and vital signs 
(blood pressure [SBP and DBP] and pulse). A short physical exam will be at all visits starting 
from visit 3 except where a complete physical examination is required (see above). 


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Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be included in the Medical History part of the CRF. 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 using an automated validated device, e.g., OMRON, with an 
appropriately sized cuff. In case the cuff sizes available are not large enough for the patient’s 
arm circumference, a sphygmomanometer with an appropriately sized cuff may be used.
Clinically notable vital signs are defined in Appendix 1.
6.5.3
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. 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 counts, 
and platelet count will be measured.
6.5.4.2
Clinical chemistry
Sodium, potassium, chloride, bicarbonates, glucose, BUN, creatinine, calcium, phosphorus, 
magnesium, total and direct bilirubin, total protein, albumin, ALT, AST, LDH, alkaline 
phosphatase, creatinine phosphokinase, and uric acid will be measured.
6.5.4.3
Urinalysis
A midstream urine sample (approximately 30 ml) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. Semi 
quantitative 'dipstick' evaluation for the following parameters will be performed. Specific 
gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leucocyte and blood.
6.5.4.4
Anti-omalizumab antibodies
At Visit 101 an anti-omalizumab antibody level will be measured on all patients prior to first 
dosing. Patients are also instructed to return to the clinic for an anti-omalizumab antibody 
blood sample 12 weeks after their last administration (Visit 299). The 12-week waiting period 


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decreases the interference of anti-omalizumab antibody detection due to the presence of 
omalizumab. Refer to the blood log in Appendix 2, Table 13-2 for sample collection and 
volumes.
6.5.5
Electrocardiogram (ECG)
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula 
(QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs and a certified copy on non-heat 
sensitive paper, appropriately signed, must be collected and archived at the study site.
Each ECG tracing must be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs must be performed to confirm the safety finding. Clinically 
significant ECG findings at baseline must be discussed with the sponsor before administration 
of study treatment.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF / e(CRF) page as appropriate.
6.5.6
Pregnancy and assessments 
All pre-menopausal women who are not surgically sterile will have pregnancy testing.
Additional pregnancy testing might be performed if requested by local requirements.
Any females with a confirmed serum positive pregnancy test during screening are not eligible 
for randomization.
All pre-menopausal females who are not sterile at screening will also have a urine pregnancy 
test performed locally at Visits 101, 102, 103, 199 and 299.
A positive urine pregnancy test during the treatment epoch of the study requires immediate 
interruption of study treatment until serum β-hCG is performed and found to be negative. If 
the serum β-hCG test is positive, study treatment must be discontinued, as described in 
Section 5.5.9.
6.5.7
Appropriateness of safety measurements 
The safety assessments selected in this study are reliable and standard measured for a biologic 
immunomodulating agent in adult and adolescent subjects with CSU.


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7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must 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 findings, laboratory 
test findings, 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. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must 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 study treatment 

Yes

No

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.


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
whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE)
and which seriousness criteria have been met.

action taken regarding [investigational] treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only)

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition 
of SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must 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). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification (IN) or an Aggregate Safety Finding. New information might require an update to 
the informed consent and has then to be discussed with the patient.
The investigator must 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 must be recorded in the 
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:


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
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, e.g. 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 it were more severe (please refer to 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 (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day 
period after the last study visit should only be reported to Novartis if the investigator suspects 
a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE omalizumab and
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site. 


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Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Liver safety monitoring 
As omalizumab is not associated with hepatotoxic potential no specific liver safety monitoring 
is needed in this trial in patients who do not require treatment for latent TB.
7.4
Renal safety monitoring 
As omalizumab is not associated with kidney toxicity potential no specific renal safety 
monitoring is needed in this trial.
7.5
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record (DAR) 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.


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Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
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 a SAE
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
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 (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization. 
Additionally, a central analytics organization may analyze data, identify risks 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 


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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/subjects will be disclosed.
8.2
Data collection
Novartis will supply the investigator site with a computer loaded with Electronic Data 
Capture (EDC) software that has been fully validated and conforms to US CRF 21 Part 11 
requirements. Investigator site staff will not be given access to the EDC system until they 
have been trained by Novartis personnel. Designated investigator staff will enter the data 
required by the protocol into the Novartis CRFs using the Novartis-supplied computer. 
Automatic validation programs check for data discrepancies in the CRFs and, by generating 
appropriate error messages, allow the data to be confirmed or corrected by the investigator 
staff before transfer of the data to Novartis via a secure Virtual Private Network. The 
investigator must certify that the data entered are complete and accurate by signing a memo 
generated at the end of the trial that will be sent to him by Novartis personnel. After database 
lock, the investigator will receive copies of the patient data for archiving at the investigational 
site.
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).
Diary data will be entered into an electronic diary by the patient OR Patients/subjects will fill 
in their patient reported outcome (PRO) data in a site based tablet. The system will be 


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supplied by a vendor(s), who will also manage the database. The database will be sent 
electronically to Novartis personnel (or designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
Not required.
8.5
Adjudication Committee 
An independent adjudication committee will be used to monitor anaphylaxis. The events will 
be reviewed in a blinded manner and adjudicated as they occur during the conduct of the 
study. Details regarding the adjudication process are available in the relevant Anaphylaxis 
Adjudication Committee charter.
9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
9.1
Analysis sets 
Randomized population (RAN): The RAN will include all randomized subjects, regardless 
of whether they took any study medication. Patients in RAN will be analyzed according to the 
treatment assigned at randomization.
Full analysis set (FAS): The FAS will include all randomized subjects who receive at least 
one dose of study drug. Following the intent-to-treat principle, subjects will be analyzed 
according to the treatment they are assigned to at randomization. This analysis population will 
be used for all efficacy analyses unless otherwise specified.
Safety set (SAF): The SAF consists of all subjects in the FAS who take at least one dose of 
study medication. Subjects will be analyzed according to the actual treatment received during 
the randomized treatment epoch, as follows:


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
Placebo: Patients who received only placebo injections (i.e., no active treatment) during 
the randomized treatment epoch

150 mg omalizumab: Patients who received at least one 150 mg omalizumab injection but 
no higher active dose level (i.e., 300 mg) injections during the randomized treatment 
epoch

300 mg omalizumab: Patients who received at least one 300 mg omalizumab injection 
during the randomized treatment epoch.
9.2
Patient demographics and other baseline characteristics 
The analysis will be based on the RAN, unless otherwise specified.
Demographic and baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group. The number and percentage of patients in each category 
will be presented for categorical variables for each treatment group and all patients.
The randomized treatment groups will be summarized by the following demographic 
variables: gender, age, ethnicity, race, weight, height, and BMI.
Baseline disease characteristics will also be summarized for the following variables, including 
but not limited to: duration of CSU, previous number of CSU medications, previous use of 
systemic steroids for CSU, in-clinic UAS, weekly urticaria activity score (UAS7), weekly itch 
severity score (ISS7), weekly number of hives score (NHS7), weekly size of largest hive score 
(LHS7), and presence of angioedema.
Medical history
Any condition entered on the Medical history eCRF will be coded using the MedDRA 
dictionary. The number of patients with medical history will be summarized by primary 
system organ class, preferred term and treatment group for the RAN. Protocol solicited 
medical history will be also summarized.
9.3
Treatments 
The analysis of study treatment data will be based on the SAF, unless otherwise specified.
Study treatment
The duration of exposure to study treatment will be summarized by treatment group. In 
addition, the number of doses and total cumulative dosage will be presented.
Duration of exposure is defined as the date of the last treatment minus the date of first study 
drug administration plus 4 weeks (28 days).
Prior and concomitant medication
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized 


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study treatment and the date of the last study visit will be a concomitant medication, including 
those which were started pre-baseline and continued into the period where study treatment is 
administered.
Prior and concomitant medications will be summarized by treatment separately for CSU 
related and non-CSU related medications. CSU-related medications will be summarized by 
pre-specified categories, route of administration, and preferred term. Non-CSU related 
concomitant medications will be summarized by the preferred term. Concomitant medications 
will be also summarized by epoch; the randomized treatment epoch and newly onset during 
post-treatment follow-up epoch. 
Significant surgery and medical procedures will be summarized by primary system organ 
class and MedDRA preferred term.
9.4
Analysis of the primary variable(s)
Analyses will be based on the patients in FAS, unless otherwise specified. 
9.4.1
Variable(s)
The primary efficacy variable is change from baseline in weekly itch severity score (ISS7, a 
component of the UAS7, see Section 6.4.1.1) at Week 12. 
The daily itch score is the average of the morning and evening itch severity scores. The 
baseline ISS7 is the sum of the daily itch severity scores over the 7 days prior to the 
randomization Day 1 visit, and the ISS7 at Week 12 is the sum of daily itch scores over the 7 
days prior to the Week 12 visit. The same principles of calculating baseline and Week 12 
weekly scores will be applied to each weekly outcome unless otherwise stated.
9.4.2
Statistical model, hypothesis, and method of analysis
A mixed-effect linear model with repeated measures (MMRM) will be used to obtain the least 
squares mean (LSM) estimate for each treatment group for change from baseline in ISS7 at 
Week 12 (the primary endpoint). The MMRM model will include terms of treatment group, 
week (1 to 12), baseline score, baseline score-by-week interaction, and treatment-by-week 
interaction as fixed effects. Treatment group and week will be fitted as categorical variables, 
and baseline score as a continuous covariate. The within-patient correlation will be modeled 
using the unstructured covariance matrix (Mallinckrodt et al 2001). If the model does not 
converge, the compound symmetry covariance structure will be used. The occurrence of 
missing data will be assumed to be missing at random (MAR). 
The difference in LSM estimates between treatment groups, together with a 95% CI, will be 
presented.
A multiplicity adjustment for two primary efficacy comparisons based on above model will be 
made according to the overall study testing strategy provided in Section 9.5.1. The statistical 
analyses will test the null hypothesis of no difference between the placebo and each 
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9.4.3
Handling of missing values/censoring/discontinuations
The primary endpoint will be analyzed using an MMRM which is valid under the MAR 
(Missing-At-Random) assumption (Rubin 1976). Patients who have at least one post-baseline 
are included in the MMRM analysis. This includes not only the patients who have completed 
12 weeks of treatment (with a complete 12-week longitudinal data), but also those who 
discontinue from study treatment early (although only able to contribute to a partial time 
profile). This is under the assumption that dropouts would follow the similar data pattern like 
other patients who complete the treatment period in the same treatment group, as if they had 
not discontinued from the study treatment. 
Patients who discontinue from study treatment early will remain in the study and follow the 
procedures described in Section 5.5.9. Nevertheless, the data on and post the date of the last 
treatment + 4 weeks will be treated as missing in the primary analysis.
The ISS7 is the sum of the average daily itch scores over 7 days each week. The daily itch 
scores are calculated based on daily eDiary entries for itch. The daily itch score is then 
calculated as the average of the morning and evening itch scores. 
When either the morning or evening score is missing, the non-missing itch score for that day 
(morning or evening) will be used as the daily score. When one or more of the daily itch 
scores are missing, the following principles will be applied to handle the missing data:

If a patient has at least 4 non-missing daily itch scores within the 7 days prior to the study 
visit, the ISS7 score is calculated as the sum of the available eDiary itch scores in that 
week, divided by the number of days that have a non-missing diary itch score, multiplied 
by 7.

If there are less than 4 non-missing daily itch scores within the prior 7 days, then the ISS7 
score is missing for the week.
9.4.4
Sensitivity analyses 
The impact of missing data on the primary analysis results will be assessed by repeating the 
analysis using different missing data assumptions to handle missing data. The supportive 
analyses may include, but are not limited to:

An analysis of covariance (ANCOVA) model with missing Week 12 itch scores imputed 
by carrying forward the patients’ baseline scores (BOCF). The ANCOVA model would 
include treatment group as a factor, and baseline score as a covariate.

An ANCOVA model with missing Week 12 itch scores imputed by carrying forward the 
patients’ last non-missing weekly score (LOCF). The ANCOVA model would include 
treatment group as factors, and baseline score as a covariate.

Jump-to-Reference (J2R) multiple imputation approach
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
All of the secondary efficacy variables will be analyzed using the FAS unless otherwise 
specified.


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Testing strategy
The following primary and secondary hypotheses will be included in the testing strategy. To 
ensure the family-wise type I error rate (α) is kept at an overall level of less than 5%, a 
flexible gate-keeping procedure (Bretz et al 2009) will be employed as described below. The 
procedure allows the type-one error rate associated with a rejected hypothesis to be 
reallocated among the remaining (un-rejected) hypothesis tests according to a set of pre-
specified rules. The hypotheses are organized to describe the order in which different sets of 
hypotheses will be tested.
Primary objectives (as described in Section 9.4):
H1:
Omalizumab 300 mg is not different to placebo with respect to change from baseline 
in ISS7 (weekly itch severity score) at Week 12
H2:
Omalizumab 150 mg is not different to placebo with respect to change from baseline 
in ISS7 (weekly itch severity score) at Week 12
Secondary objectives:
H3:
Omalizumab 300 mg is not different to placebo with respect to change from baseline 
in UAS7 (weekly urticaria activity score) at Week 12
H4:
Omalizumab 150 mg is not different to placebo with respect to change from baseline 
in UAS7 (weekly urticaria activity score) at Week 12
H5:
Omalizumab 300 mg is not different to placebo with respect to change from baseline 
in NHS7 (weekly number of hives score) at Week 12
H6:
Omalizumab 150 mg is not different to placebo with respect to change from baseline 
in NHS7 (weekly number of hives score) at Week 12
H7:
Omalizumab 300 mg is not different to placebo with respect to the percentage of 
patients with UAS7 ≤6 response at Week 12
H8:
Omalizumab 150 mg is not different to placebo with respect to the percentage of 
patients with UAS7 ≤6 response at Week 12
H9: Omalizumab 300 mg is not different to placebo with respect to the percentage of patients 
with UAS7 = 0 response at Week 12
H10: Omalizumab 150 mg is not different to placebo with respect to the percentage of patients 
with UAS7 = 0 response at Week 12
H11: Omalizumab 300 mg is not different to placebo with respect to the percentage of patients 
with ISS7 MID response at Week 12
H12: Omalizumab 150 mg is not different to placebo with respect to the percentage of patients 
with ISS7 MID response at Week 12
H13: Omalizumab 300 mg is not different to placebo with respect to change from baseline in 
overall DLQI score at Week 12
H14: Omalizumab 150 mg is not different to placebo with respect to change from baseline in 
overall DLQI score at Week 12


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H15: Omalizumab 300 mg is not different to placebo with respect to the time to ISS7 MID 
during the randomized treatment epoch
H16: Omalizumab 150 mg is not different to placebo with respect to the time to ISS7 MID 
during the randomized treatment epoch
The graphical approach of (Bertz et al 2009) for sequentially rejective testing procedures is 
used to illustrate the testing strategy in Figure 9-1.
Figure 9-1
Testing strategy for primary and secondary endpoints
Note: As shown in the above graph, initially each H1 and H2 will be assigned α/2 to test the 
individual hypotheses simultaneously and move forward. 


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The family-wise error rate will be set to α = 5% (2-sided) and will be controlled using the 
proposed hierarchical testing strategy as illustrated in Figure 9-1. 
First, each of the hypotheses (H1 and H2) for the primary objective (based on change from 
baseline in ISS7 at Week 12) for omalizumab 300 mg and 150 mg versus placebo will be 
tested simultaneously at α/2.
If at least one of H1 and/or H2 is rejected, then H3 and/or H4, respectively, will be tested at α/2. 
If at least one of H3 and/or H4 is rejected, then H5 and/or H6, will be tested, respectively. A 
similar process applies until H15 and H16. Once all hypotheses for an omalizumab dose are 
rejected, then the respective α/2 can be passed on to the other dose’s hypotheses, if they are 
not already rejected at α/2. In the description above, rejection of a hypothesis refers to 
rejection of the two-sided hypothesis; however the significance level of a rejected hypothesis 
is only passed on according to the graphical procedure for the test of another hypothesis if the 
treatment effect is in favor of omalizumab. 
Change from baseline in weekly urticarial activity score (UAS7) at Week 12
The urticaria activity score (UAS) is a composite score (itch severity score and number of 
hives score) described in Section 6.4.1.1. For each of the morning and evening UAS score, it 
is calculated as the sum of the itch severity score and number of hives score according to 
eDiary entries. The daily UAS is the average of the morning and evening UAS scores, and 
UAS7 is the sum of daily UAS scores over 7 days. 
The missing data will be handled in the same way as described in Section 9.4.3.
Treatment comparisons of 300 mg vs placebo (H3) and 150 mg vs placebo (H4) in change 
from baseline to Week 12 in the UAS7 will be made using an MMRM model with similar 
terms as the primary analysis but baseline UAS7 as a covariate (Refer to Section 9.4.2). 
Change from baseline in weekly number of hives score (NHS7) at Week 12
The weekly number of hives score (NHS7) will be handled using the same principles as 
described for the primary endpoint in Section 9.4.1 and Section 9.4.3.
Treatment comparisons of 300 mg vs placebo (H5) and 150 mg vs placebo (H6) in change 
from baseline to Week 12 in the NHS7will be made using an MMRM model with similar 
terms as the primary analysis but baseline NHS7 as a covariate (Refer to Section 9.4.2). 
Percentage of patients with UAS7 ≤6 at Week 12
Treatment comparisons of 300 mg vs placebo (H7) and 150 mg vs placebo (H8) in the 
percentage of patients with UAS7 ≤6 at Week 12 will be made using a logistic regression 
model with treatment group as a factor and baseline UAS7 as a covariate. 
A patient with missing data at Week 12 will be imputed as a responder if the patient was a 
responder at Week 10 and Week 11, otherwise as a non-responder.


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Percentage of patients with UAS7 = 0 at Week 12
Treatment comparisons of 300 mg vs placebo (H9) and 150 mg vs placebo (H10) in the 
percentage of patients with UAS7 = 0 at Week 12 will be made using a logistic regression 
model with treatment group as a factor and baseline UAS7 as a covariate. 
A patient with missing data at Week 12 will be imputed as a responder if the patient was a 
responder at Week 10 and Week 11, otherwise as a non-responder.
Percentage of patients with ISS7 MID response at Week 12
The ISS7 MID response is defined as a reduction from baseline in ISS7 of ≥5 points. 
Treatment comparisons of 300 mg vs placebo (H11) and 150 mg vs placebo (H12) in the 
percentage of patients with ISS7 MID response at Week 12 will be made using a logistic 
regression model with treatment group as a factor and baseline ISS7 as a covariate.
A patient with missing data at Week 12 will be imputed as a responder if the patient was a 
responder at Week 10 and Week 11, otherwise as a non-responder.
Change from baseline in overall DLQI at Week 12
DLQI is a PRO instrument, described in Section 6.4.2.1. An overall score will be calculated 
according to the scoring manual given in Appendix 3. The baseline and up to Week 12 overall 
DLQI scores will be derived from the questionnaires assessed at the Day 1 and up to Week 12 
visits. 
Treatment comparisons of 300 mg vs placebo (H13) and 150 mg vs placebo (H14) in change 
from baseline to Week 12 in overall DLQI score will be made using an MMRM model with  
similar terms as primary analysis but baseline DLQI as a covariate (Refer to Section 9.4.2). 
Time to ISS7 MID response during the randomized treatment epoch
The ISS7 MID response is defined as a reduction from baseline in ISS7 of ≥5 points. Time to 
ISS7 MID response is the time (in weeks) from the date of the first dose to the date where 
ISS7 MID response is first achieved during the randomized treatment epoch. If no ISS7 MID 
response is achieved during the randomized treatment period, the patient will be treated as 
censored at the last dose date + 28 days – 1. 
Treatment comparisons of 300 mg vs placebo (H15) and 150 mg vs placebo (H16) will be 
performed using a Cox proportional hazard (PH) model with treatment group as a factor and 
baseline ISS7 as a covariate. The ratio of event rate and 95% CI will be reported. 
Kaplan-Meier analysis stratified by treatment group will be also presented with log-rank test 
and displayed graphically.
9.5.2
Safety variables 
All safety evaluations will be performed on the safety set (SAF).


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Adverse events
All the AEs occurring after providing written informed consent will be recorded on the 
Adverse Event eCRF page. AEs starting on or after the first dose of study treatment or events 
present prior to the first dose of study treatment but increased in severity based on preferred 
term will be classified as treatment emergent AEs. Overall AEs, SAEs, AEs by severity will 
be also summarized for each epoch (randomized-treatment and post-treatment follow-up)
when necessary. Non-treatment emergent AEs (occurring after providing written informed 
consent but before first dose of study treatment) will not be summarized but listed only.
Treatment emergent AEs will be summarized by presenting, for each treatment group, the 
number and percentage of patients having any AE, having an AE in each primary system 
organ class and having each individual AE (preferred term). Summaries will be also presented 
for treatment emergent AEs by severity and for study treatment related AEs. If a patient 
reported more than one AE with the same preferred term, the AE with the greatest severity 
will be presented. If a patient reported more than one AE within the same primary system 
organ class, the patient will be counted only once with the greatest severity at the system 
organ class level, where applicable. Separate summaries will be provided for death, serious 
adverse event, and adverse events leading to discontinuation.
Treatment emergent AEs of special interest for omalizumab treatment will be also 
summarized. AEs of special interest for omalizumab treatment will be specified as compound-
level risk factors defined in the Case Retrieval Strategy.
Summary tables that present numbers and percentages of patients with the AEs of special 
interest will be presented by standardized MedDra Query (SMQ) (if applicable), preferred 
term and treatment. In addition, the hepatic disorders events will be tabulated by latent TB at 
baseline (Yes/No).
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only 
be summarized for subjects with both baseline and post baseline values.
The hepatic-related laboratory tests will also be tabulated by latent TB at baseline (Yes/No).
Anti-omalizumab antibody
A summary of anti-omalizumab antibodies will be provided.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Subjects with notable vital signs as defined below 
will be listed.


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
Hypertension (systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure 
of ≥ 90 mmHg) or hypotension (systolic blood pressure or < 90 mmHg and/or 
diastolic blood pressure of < 60 mmHg).

Pulse rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia)
Other
Healthcare utilization (calling a doctor, nurse, or nurse practitioner) based on patient daily 
diary data will be summarized for each treatment group.
For patients reporting angioedema, the action(s) taken in response to their angioedema based 
on patient daily diary data will be summarized for each treatment group.
9.5.3
Resource utilization 
Not applicable.
9.5.4
Biomarkers 
Not applicable.
9.5.5
DNA
Not applicable.


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9.7
Interim analyses
No interim analysis is planned in this study.
9.8
Sample size calculation
The study is sized to ensure sufficient power to demonstrate meaningful efficacy based on the 
data from the full analysis set. In addition, for registration of a biologic compound the China 
health authority (China Food and Drug Administration, CFDA) requires at least 300 patients 
to be treated in the test drug as the minimum for safety evaluation. Assuming 10% dropout 
rate by week 12, the study will randomize 420 patients in a ratio of 2:2:1 to omalizumab 300 
mg, omalizumab 150 mg, and placebo to ensure 375 patients completing Week 12 with 300 
patients in the two omalizumab dose groups. 


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The below power evaluation for the planned hypothesis tests is based on a sample size of 375 
(2:2:1) patients who complete 12 weeks of treatment duration. The powers are examined 
according to the hierarchy order of the multiplicity type I error control plan with the overall 
alpha level controlled at 0.05 (2-sided) as outlined in Figure 9-1.  It is assumed Study E2305 
will repeat the performance of the previous pivotal studies (Q4881g, Q4882g, and E2306). 
Except for ethnicity, these 3 studies have a similar patient population with consistent results 
for the primary and secondary endpoints. There is no statistical evidence suggesting 
heterogeneity among the studies. A meta-analysis with fixed-effects model was performed 
based on summary data from these studies to combine the estimates of the treatment effect 
and standard deviation (SD). The obtained pooled estimates on the treatment effect size and 
SD are then used as the assumed values for the alternative hypotheses to evaluate the power 
for each endpoint. To understand the impact of the strength of dependency between endpoints 
on the power, the power was evaluated under 3 scenarios of correlation (0, 0.5, 0.9), i.e. 
completely independency, moderate dependency, and strong dependency. The results are 
summarized in Table 9-1.  
For the primary endpoint (change from baseline weekly itch score at Week 12), the study will 
offer 

a power of > 99.9% to detect a difference of 4.73 between 300 mg and placebo with the 
assumed SD of 5.28

a power of > 93% to detect a difference of 2.73 between 150 mg and placebo with the 
assumed SD of 5.55
The power was evaluated for the primary and secondary endpoints as a whole according to the 
testing strategy defined in Section 9.5.1 (Figure 9-1) using the gMCP package in the R 
software.   
According to Table 9-1, the power evaluation is summarized as follows. 

The power for 300 mg is maintained at nearly 95% and above for all testing 
hypotheses regardless of the strength of dependency between endpoints. 

The power for 150 mg is at least 80% for the testing hypotheses up to the endpoint of 
percentage of patients with UAS7 ≤ 6 at Week 12. The power for the rest of endpoints 
is decreased to 65% and below, and can be as low as 18% if the dependency between 
endpoints is none. 
By reviewing and using clinical data from previous studies in the power assessment for the 
targeted hypothesis tests for the current study, the total sample size of 420 (including 10%
dropout) with 2:2:1 assignment ratio is considered appropriate to allow sufficient power to 
achieve the primary objective and all the first four secondary objectives for both 300 mg and 
150 mg. The study also has high power to achieve the last four secondary objectives for 300 
mg, although the power is < 65% and below for 150mg.
Table 9-1 
Power analysis of primary and key secondary endpoints 
Endpoint
Hypo-
thesis
Comparison
Parameter 
assumptions1
Power2
Correlation between 
endpoints


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None 
(0)
Moderate 
(0.5)
Strong 
(0.9)
Change from 
baseline in 
ISS7 at W12
H1
300 mg vs 
Placebo
Δ=4.73
SD=5.28
>0.99
9
>0.999
>0.999
H2
150 mg vs 
Placebo
Δ=2.73
SD=5.55
0.933
0.931
0.932
Change from 
baseline in 
UAS7 at W12
H3
300 mg vs 
Placebo
Δ=11.16
SD=11.54
>0.99
9
>0.999
>0.999
H4
150 mg vs 
Placebo
Δ=6.31
SD=11.84
0.899
0.906
0.925
Change from 
baseline in 
NHS7 at W12
H5
300 mg vs 
Placebo
Δ=6.22
SD=6.82
>0.99
9
>0.999
>0.999
H6
150 mg vs 
Placebo
Δ=3.52
SD=6.77
0.859
0.880
0.917
% of patients 
with 
UAS7 ≤6 at 
W12
H7
300 mg vs 
Placebo
Log OR=2.09
SD=2.48
(~ p300=61%, p0=16%)
>0.99
9
>0.999
>0.999
H8
150 mg vs 
Placebo
Log OR=1.32
SD=2.46
(~ p150=41%, p0=16%)
0.830
0.864
0.914
% of patients 
with UAS7 = 
0 at W12
H9
300 mg vs 
Placebo
Log OR=2.27
SD=3.46
(i.e. p300=41%, p0=7%)
0.992
0.992
0.991
H10
150 mg vs 
Placebo
Log OR=1.21
SD=3.63
(~ p150=19%, p0=7%)
0.540
0.616
0.654
% of patients 
with ISS7 
MID at W12
H11
300 mg vs 
Placebo
Log OR=1.57
SD=2.34
(~ p300=81%, p0=47%)
0.986
0.986
0.989
H12
150 mg vs 
Placebo
Log OR=0.78
SD=2.09
(~ p150=65%, p0=47%)
0.408
0.537
0.631
Change from 
baseline in 
Overall DLQI 
at W12
H13
300 mg vs 
Placebo
Δ=3.55
SD=5.86
0.965
0.969
0.977
H14
150 mg vs 
Placebo
Δ=1.91
SD=6.25
0.237
0.404
0.536
Time to ISS7 
MID
H15
300 mg vs 
Placebo
Log HR=0.7
SD=1.14
(~ S300=6%, S0=25%)
0.947
0.955
0.970
H16
150 mg vs 
Placebo
Log HR=0.43
SD=1.15
(~ S150=12%, S0=25%)
0.179
0.372
0.530


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Endpoint
Hypo-
thesis
Comparison
Parameter 
assumptions1
Power2
Correlation between 
endpoints
None 
(0)
Moderate 
(0.5)
Strong 
(0.9)
1 Parameter assumptions are based on a meta-analysis of Studies Q4881g, Q4882g, and E2306 
Δ= Difference; OR=Odds Ratio; HR: Hazard Ratio (i.e. ratio of event rate)
p300, p150, p0: the probability of an event occurrence at Week 12 for Omalizumab 300mg, 150mg, and 
placebo
S300, S150, S0: the probability of not having an event at and prior to Week 12 for Omalizumab 300mg, 
150mg, and placebo
SD= Standard deviation for the data either normally distributed or on the scale with a normal 
approximation, e.g. logit(p) for binary data and log-log(S) for time-to-event data
2 Power is calculated based on the total sample size of 420 assigned to treatment group 300 mg, 150 
mg and placebo in ratio of 2:2:1 with 10% dropout rate during 12 weeks of treatment period, 
according to the hierarchy order of the multiplicity Type I error control scheme with overall alpha level 
controlled at 0.05 (2-sided).
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients/subjects 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(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 


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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 must be informed that taking the study treatment may
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.Audits are conducted to assess 
GCP compliance with global and local regulatory requirements, protocols and internal SOPs, 
and are performed according to written Novartis processes.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects 


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Protocol No. CIGE025E2305
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities 
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request
Bretz F, Maurer W, Brannath W, et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 284: 586-604.
Won-Sun Choi, Eun-Soo Lim, Ga-Young Ban, et al. (2016) Disease-specific impairment of 
the quality of life in adult patients with chronic spontaneous urticaria. Korean J Intern Med; 
Jun 1. [Epub ahead of print]
Doherty SD, Van Voorhees A, Lebwohl MG, et al. (2008) National Psoriasis Foundation 
consensus statement on screening for latent tuberculosis infection in patients with psoriasis 
treated with systemic and biologic agents. J Am Acad Dermatol; 59:209-17.
Fiebiger E, Maurer D, Holub H, et al. (1995) Serum IgG autoantibodies directed against the 
alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset 
of chronic urticaria patients? J Clin Invest; 96:2606-12.
Finlay AY and Khan GK (1994) Dermatology Life Quality Index (DLQI): a simple practical 
measure for routine clinical use. Clin Exp Dermatol; 19:210-6.
Fukuda S, Shimoyama T, Umegaki N, et al. (2004) Effect of Helicobacter pylori eradication 
in the treatment of Japanese patients with chronic idiopathic urticaria. J Gastroenterol; 
39:827-30.
Hide M and Hiragun T (2012) Japanese guidelines for diagnosis and treatment of urticaria in 
comparison with other countries. Allergol Int; 61(4):517-27.


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Protocol No. CIGE025E2305
Kaplan AP, Joseph K, Maykut RJ, et al. (2008) Treatment of chronic autoimmune urticaria
with omalizumab. J Allergy Clin Immunol; 122:569-73.
Kaplan AP and Greaves M (2009) Pathogenesis of chronic urticaria. Clin Exp Allergy; 
39:777-87.
Luo Jie, Song ZQ, Zhong H, et al. (2011) Clinical epidemiological characteristics of chronic 
urticaria: report of 535 cases. Journal of Third Military Medical University; 33(22):2421-24.
Mallinckrodt CH, Scott CW, David SR (2001) Accounting for dropout bias using mixed-
effects models. Journal of Biopharmaceutical Statistics; 119-21.
Manuel O, Kumar D (2008) QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev Mol Diagn; 8:247-56.
Mathias SD, Dreskin SC, Kaplan A, et al. (2010) Development of a daily diary for patients 
with chronic idiopathic urticaria. Ann Allergy Asthma Immunol; 105:142-8.
Mathias SD, Crosby RC, Zazzali JL, et al. (2012) Evaluating the minimally important 
difference of the urticaria activity score and other measurements of disease activity in patients 
with chronic idiopathic urticaria. Ann Allergy Asthma Immunol; 108:20-24.
Maurer M, Weller K, Bindslev-Jensen C, et al. (2011) Unmet clinical needs in chronic 
spontaneous urticaria. A GA2LEN task force report. Allergy; 66:317-30.
Mlynek A, Zalewska-Janowska A, Martus P, et al (2008) How to assess disease activity in 
patients with chronic urticaria? Allergy; 63:777-80.
Rubin DB (1976) Inference and Missing Data. Biometrika; 63:581-92.
Shikiar R, Harding G, Leahy M, et al. (2005) Minimal Important Difference (MID) of the 
Dermatology Life Quality Index (DLQI): results from patients with chronic idiopathic 
urticaria. Health Qual Life Outcomes; 3:36.
Tong LJ, Balakrishnan G, Kochan JP, et al. (1997) Assessment of autoimmunity in patients 
with chronic urticaria. J Allergy Clin Immunol; 99:461-5.
World Health organization (2015) Guidelines on the management of latent tuberculosis 
infection.
World Health organization (2015) Global tuberculosis report 2015.
Zhong H, Song Z, Chen W, et al. (2014) Chronic urticaria in Chinese population: a hospital-
based multicenter epidemiological study. Allergy; 69:359-64.
Zuberbier T, Asero R, Bindslev-Jensen C, et al. (2009) EAACI/GA2LEN/EDF/WAO 
guideline: definition, classification and diagnosis of urticaria. Allergy; 64:1417-26.
Zuberbier T, Aberer W, Asero R, , et al. (2014) EAACI/GA2LEN/EDF/WAO guideline for 
definition, classification, diagnosis, and management of urticaria: the 2013 revision and 
update. Allergy; 69:868-87.
Zweiman B, Valenzano M, Atkins PC (1998) Modulation of serum histamine releasing
activity in chronic idiopathic urticaria. Immunopharmacology; 39:225-34.


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Protocol No. CIGE025E2305
13
Appendices
13.1
Appendix 1: Clinically notable laboratory values and vital signs
The following criteria will be used to define expanded limit and notable abnormalities.
Hematology value
Platelet count: ≤ 100,000 /μL
No specific action is pre-defined within this protocol to respond to specific abnormal 
laboratory values, as it will be decided by the investigator /qualified site staff whether and 
which specific action needs to be taken to respond to any abnormal values, taking into account 
the overall status of the subjects.
For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outsides of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign off) and the investigator will report any values considered clinically 
significant in the CRF.
Vital signs
Notable values of vital signs are described in Section 9.5.2.
13.2
Appendix 2 Blood log
Table 13-2
Blood log for immunogenicity
Immunogenicity
Matrix
Serum
Visit
Sample No.
Volume (mL)
Visit 101 (pre-dose)
401
2
Visit 299
402
2
Sub total (mL)
4


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Protocol No. CIGE025E2305
13.3
Appendix 3
Dermatology Life Quality Index (DLQI)
questionnaire
DERMATOLOGY LIFE QUALITY INDEX
DLQI
Hospital No: N/A      
              Date:
Name: N/A
Score:
Address: N/A
Diagnosis:
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how itchy, sore, 
Very much

painful or stinging has your skin 
A lot

been? 
A little

Not at all

2.
Over the last week, how embarrassed
Very much

or self conscious have you been because 
              A lot

of your skin?
A little

Not at all

3.
Over the last week, how much has your 
Very much

skin interfered with you going
A lot

shopping or looking after your home or 
A little

garden?       
Not at all

Not relevant        
4.
Over the last week, how much has your 
Very much

skin influenced the clothes
A lot

you wear?
A little

Not at all

Not relevant       
5.
Over the last week, how much has your 
Very much

skin affected any social or 
A lot

leisure activities?
A little

Not at all

Not relevant       
6.
Over the last week, how much has your 
Very much

skin made it difficult for 
A lot

you to do any sport?
A little

Not at all

Not relevant        
7.
Over the last week, has your skin prevented
Yes



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Protocol No. CIGE025E2305
you from working or studying?
No

Not relevant       
If "No", over the last week how much has 
A lot

your skin been a problem at 
A little

work or studying?
Not at all

8.
Over the last week, how much has your 
Very much

skin created problems with your 
A lot

partner or any of your close friends
A little

or relatives? 
Not at all

Not relevant       
9.
Over the last week, how much has your 
Very much

skin caused any sexual
A lot

difficulties?
A little

Not at all

Not relevant        
10.
Over the last week, how much of a 
Very much

problem has the treatment for your
A lot

skin been, for example by making
A little

your home messy, or by taking up time? 
Not at all

Not relevant       
Please check you have answered EVERY question. Thank you.
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors.

SAP_001.pdf: 
Clinical Development
CIGE025/Omalizumab/Xolair®
CIGE025E2305 / NCT03328897
A multicenter, randomized, double-blind, placebo-
controlled phase III study to evaluate the efficacy and 
safety of Xolair® (omalizumab) in Chinese patients with 
chronic spontaneous urticaria who remain symptomatic 
despite antihistamine treatment
Statistical Analysis Plan (SAP)
Author:
, 
, 
,
 
Document type:
SAP Documentation
Document status:
Final version 3.0 Amendment 2
Release date:
11-Nov-2019
Number of pages:
49
Property of Novartis
For business use only


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CIGE025E2305
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
18-
Jan-
2017
Prior 
to 
FPFV
Creation of 
final version
1.0
N/A – First version
N/A
01-
Sep-
2017
Prior 
to DB 
lock
Final 
version 2.0
Systemic treatments list added
Typos correction
All
28-
Sep-
2018
Prior 
to DB 
lock
Final 
version 2.1
Updates on analysis sets definition
Adding of notable value for platelets count 
Adding of Protocol Deviations INCL03A and 
EXCL13 for FAS exclusion
Added of In-clinic at baseline
Precision on censoring of time to response 
in Time to ISS7 MID response
 
Updated ‘Change to protocol specified 
analyses’ section
Update on DLQI for study week to analysis
Section 2.2
Section 2.8.3
Section 5.6
Section 2.3.2
Section 2.7.2
Section 4
Section 5.1
21-
Mar-
2019
Prior 
to DB 
lock
Final 
version 2.2
Adding of population to use: FAS
Population updated by SAF
Precision added for Prior urticaria therapies
imputation
Precision added for latent TB status at 
baseline
Statistical methodology details added
Per-protocol set population added
Section 2.14
Section 2.10
Section 5.2.3
Section 5.8
Section 5.5.2
Section 2.2 / 5.6
Section 2.8.1.2


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SAP
CIGE025E2305
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Precision added for China requirement
11-
Nov-
2019
Prior 
to DB 
lock
Final 
version 3.0 
Amendment 
2
Duration of exposure updated for subjects 
who died.
Baseline definition updated for subjects 
who did not take any study medication.
On treatment period definition removed, 
since the definition is no longer required for 
the TFL shells.
Section 2.1.1 and 
2.4.1
PPS definition updated in order to exclude 
only Protocol Deviations with an impact on 
the primary endpoint. Also, 3 injections 
corrected to 3 doses of study drug.
SAF definition updated in order to include all 
subjects with one dose of study medication 
taken. Also, corrected actual treatment 
derivation as per PPS derivation, i.e. 300 
mg is two 150 mg injections at once (instead 
of one 300 mg injection).
Section 2.2
Concomitant 
medications 
will 
be 
summarized by ATC class and preferred 
term.
Prior medications not for CSU will be 
summarized by ATC class, preferred term 
and treatment group.
Section 2.4.2
Baseline ISS7 definition updated in order to 
use the first treatment intake date, rather 
than the randomization date since both 
dates can be different.
Added clarification that week 12 is derived 
from the 7 days prior the planned (not 
actual) day of the Week 12 visit (study days 
78 - 84).
Section 2.5.1
Rules for the primary endpoint updated in 
order to exclude all eDiary data collected on 
and after last dose +28 days for patients 
with less than three doses of study drug.
Clarified weekly score derivations apply to 
all weeks (not just the 7 days prior to a study 
visit).
Section 2.5.3
Removed ‘Analysis of the key secondary 
objective’ section, since there are no ‘key’ 
secondary objectives and added secondary 
endpoints.
Section 2.6.1


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SAP
CIGE025E2305
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Clarified time to ISS7 MID is ‘by Week 12’ 
instead of ‘during randomized treatment 
epoch’. 
Also, 
updated 
derivation 
for 
censoring subjects.
Corrected ‘ratio of event rate’ to ‘hazard 
ratio’.
Section 2.6.2 and 
2.11
Added clarification all safety evaluations will 
be performed on the safety set (SAF), 
‘unless otherwise specified’.
Section 2.7
Added 
exposure 
adjusted 
AE 
rates 
analysis.
Clarified ClinicalTrials.gov and EudraCT will 
be on treatment emergent adverse events.
Section 2.7.1
List of AE of Special Interest updated.
Section 2.7.1.1
Updated ‘China specific safety analysis’ to 
‘Other significant adverse events’.
Section 2.7.1.2
For hepatic-related laboratory tests (newly 
occurring liver enzyme abnormalities), even 
if few subjects in a certain group of latent TB 
status, a summary table will display split by 
latent TB status.
Section 2.7.3
Precision added in case there is some 
missing daily scores.
Section 2.7.4.4
 
Corrected first four secondary objectives to 
first three.
Section 3


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SAP
CIGE025E2305
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Corrected 
SAF 
definition 
and 
added 
updated 
baseline 
definition, 
updated 
concomitant medications analysis 
 
 
Section 4
Removed * and footnote, since study week 
is derived from study day, regardless of 
when study visits actually occur.
Update on DLQI in order to use Visit (not 
study week).
Section 5.1
Removed date imputation rules, since these 
are specified in the Programming Dataset 
Specifications.
Precisions added for some analysis.
Section 5.6.1.1
Section 5.6.2.2
Section 5.6.2.3
Section 5.6.2.5
Section 5.6.2.7
Added estimate and 95% CI to Multiple 
testing strategy.
G matrix updated and pre-processing of p-
values added in the multiple testing 
strategy.
Section 5.6.2.6
List of Protocol Deviations updated.
Section 5.7
Removed sensitivity analysis of patients 
with incorrect TB status, since this is not 
required.
Section 5.9


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SAP
CIGE025E2305
Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................8
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................10
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................15
2.3.2
Demographic and baseline characteristics ............................................15
2.3.3
Medical history......................................................................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary objective..........................................................................17
2.5.1
Primary endpoint...................................................................................17
2.5.2
Statistical hypothesis, model, and method of analysis..........................17
2.5.3
Handling of missing values/censoring/discontinuations.......................18
2.5.4
Supportive analyses...............................................................................18
2.6
Analysis of secondary efficacy objective(s)..........................................................19
2.6.1
Secondary endpoints .............................................................................19
2.6.2
Statistical hypothesis, model, and method of analysis..........................19
2.7
Safety analyses.......................................................................................................23
2.7.1
Adverse events (AEs)............................................................................24
2.7.2
Deaths....................................................................................................25
2.7.3
Laboratory data .....................................................................................25
2.7.4
Other safety data ...................................................................................26
27
2.9
Patient-reported outcomes .....................................................................................27
2.10
Biomarkers.............................................................................................................27
27
2.12
eDiary compliance analysis...................................................................................31


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2.13
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31
4
Change to protocol specified analyses ..............................................................................34
5
Appendix ...........................................................................................................................34
5.1
Study week definition............................................................................................34
5.2
Dermatology Life Quality Index (DLQI) ..............................................................35
5.3
Handling of duplicate/mistaken data in eDiary .....................................................37
5.4
AEs coding/grading ...............................................................................................37
5.5
Laboratory parameters derivations ........................................................................37
5.6
Statistical models...................................................................................................37
5.6.1
Primary analysis....................................................................................37
5.6.2
Other analysis........................................................................................38
5.7
Rule of exclusion criteria of analysis sets..............................................................45
5.8
Systemic treatments...............................................................................................48
5.9
Latent TB status at baseline...................................................................................48
6
Reference...........................................................................................................................48


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SAP
CIGE025E2305
List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
ANCOVA
Analysis of covariance
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Classification
BMI
Body Mass Index
BOCF
Baseline Observation Carried Forward
CDFA
China Food and Drug Administration
CI
Confidence Interval
CSR
Clinical Study report
CSU
Chronic Spontaneous Urticaria
DLQI
Dermatology Life Quality Index
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Strategy
eDiary
Electronic Diary
FAS
Full Analysis Set
GPS
Novartis Global Programming and Statistical environment
H1AH
H1 Antihistamines
HR
Hazard Ratio
IgE
Immunoglobulin E
IRT
Interactive Response Technology
ISS
Itch Severity Score
ISS7
Weekly Itch Severity Score
J2R
Jump to Reference
LHS7
Weekly size of largest hive score
LOCF
last observation carried forward
LSM
Least Squares Means
LTRA
Leukotrine Receptor Antagonist
MAR
Missing At Random
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MID
Minimally Important Difference
MMRM
Mixed Effect Linear Model With Repeated Measures
MNAR
Missing Not At Random
NHS
Number of Hives Score
NHS7
Weekly Number of Hives Score
NovDTD
Novartis Drug and Therapy Dictionary
OR
Odds Ratio
PPS
Per-Protocol Set


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PRO
Patient-reported Outcomes
RAN
Randomized Set
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMQ
Standardized MedDRA query
SOC
System Organ Class
TB
Tuberculosis
TFL
Table, Figure, Listing
UAS
Urticaria Activity Score
UAS7
Weekly Urticaria Activity Score
ULN
Upper limit of normal range


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1
Introduction
The purpose of Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol. The analysis planned in the SAP will be conducted 
on all subject data at the time the trial ends and the result will be described in the final Clinical 
Study Report (CSR). Protocol version 00 dated August, 10th 2016 has been referenced at the 
time of finalization of the SAP. 
1.1
Study design
The study is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-
group study to evaluate the efficacy and safety of omalizumab administered subcutaneously as 
an add-on therapy for the treatment of patients aged 18-75 years with the diagnosis of refractory 
CSU and who remain symptomatic despite approved-dosed H1AH treatment. Patients will be 
randomized into three treatment arms (omalizumab 300 mg s.c., omalizumab 150 mg s.c., and 
placebo) in a 2:2:1 ratio, stratified by latent TB status at baseline. The study will consist of three 
epochs over 24 weeks: 

Screening epoch: Day -28 to Day -1

Randomized-treatment epoch: Day 1 to Week 12

Post-treatment follow-up epoch: Week 12 to Week 20
Approximately 420 patients will be enrolled at approximately 30 study sites.
The primary analysis time point is when the final analysis is conducted at the end of the study. 
There is no interim analysis planned in the study. 
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To demonstrate the superiority of omalizumab 
300 mg or 150 mg administered subcutaneously 
every 4 weeks in patients with refractory CSU 
receiving concomitant H1AH therapy with respect to 
change from baseline in weekly itch severity score 
(ISS7) at Week 12, compared to placebo
The 
primary 
efficacy 
variable is defined as the 
change from baseline of the 
ISS7 score after 12 weeks of 
treatment
Section 2.5
Secondary
To demonstrate that patients with refractory CSU 
receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have a greater 
reduction from baseline in weekly urticaria activity 
score (UAS7) at Week 12,  compared to placebo-
treated patients
To demonstrate that patients with refractory CSU 
receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have a greater 
Variables and timepoint:
UAS7

Change from 
Baseline of UAS7 
score after 12 
weeks of treatment

Percentage of 
patients with 
Section 2.6


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Objective
Endpoint
Analysis
reduction from baseline in weekly number of hives 
score (NHS7) at Week 12 relative to placebo-treated 
patients
To demonstrate that a greater percentage of patients 
with refractory CSU receiving concomitant H1AH 
who are treated with omalizumab 300 mg or 150 mg 
have UAS7 ≤6 at Week 12 relative to placebo-
treated patients
To demonstrate that a greater percentage of patients 
with refractory CSU receiving concomitant H1AH 
who are treated with omalizumab 300 mg or 150 mg 
achieve UAS7 = 0 at Week 12 relative to placebo-
treated patients 
To demonstrate that a greater percentage of patients 
with refractory CSU receiving concomitant H1AH 
who are treated with omalizumab 300 mg or 150 mg 
achieve ISS7 Minimally Important Difference (MID) 
response at Week 12 relative to placebo-treated 
patients
To demonstrate that patients with refractory CSU 
receiving concomitant H1AH who are treated with 
omalizumab 300 mg or 150 mg have a greater 
reduction from baseline in Dermatology Life Quality 
Index (DLQI) at Week 12 relative to placebo-treated 
patients
To evaluate the efficacy of omalizumab compared 
with placebo in patients with refractory CSU receiving 
concomitant H1AH therapy with regards to time to 
ISS7 MID response by Week 12
To evaluate the safety of omalizumab compared with 
placebo in patients with refractory CSU receiving 
concomitant H1AH therapy with regards to the 
incidence and severity of adverse events and serious 
adverse events, vital signs and clinical laboratory 
evaluation at the end of the study
UAS7≤6 at Week 
12

Percentage of 
patients with 
UAS7=0 at Week 
12
NHS7

Change from 
Baseline of NHS7 
score after 12 
weeks of treatment
ISS7

Percentage of 
patients with ISS7 
MID at week 12

Time to ISS7 MID 
response by Week 
12
DLQI

Change from 
Baseline of DLQI 
score after 12 
weeks of treatment
Safety

Percentage of 
patients with AE, 
with SAE, and who 
discontinue due to 
an AE 

Exposure adjusted 
AE event rates

Percentage of 
patients with a 
clinically notable 
abnormality in Lab, 
ECG, and vital 
signs

Change from 
baseline in Lab, 
ECG, and vital 
signs


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2
Statistical methods
2.1
Data analysis general information
Data will be analyzed 
(Contracted Clinical Research Organization) according to the 
data analysis Section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR.  
Important information is given in the following sections and details are provided, as applicable, 
in Appendix 16.1.9 of the CSR.
SAS 9.4 will be used for generating study outputs used for clinical reports. 
Unless otherwise stated, summary tables/figures/listings will be on all subjects included in the 
population under consideration. Data will be summarized with respect to demographic and 
baseline disease characteristics, efficacy, and safety assessments. The analysis will be 
conducted on all subject data at the time the trial ends. 
The stratification factor latent TB status at baseline will be included in subgroup analysis where 
appropriate. 
2.1.1
General definitions
Study drug/treatment refers to the investigational drug Omalizumab and placebo. 
Date of first administration of study drug/treatment, or first date of study drug/treatment, refers 
to the date when the first dose of assigned treatment is administered. Date of last administration 
of study drug/treatment, or last date of study drug/treatment, refers to the date when the last 
dose of assigned treatment is administered. 
Duration of exposure is defined as last date of study drug/treatment minus the first date of study 
drug/treatment plus 4 weeks (28 days), except if the subject died before the date of the last 
treatment + 27 days, then duration of exposure in days is defined as date of death minus the 
date of first study drug administration + 1 day. 
Study day is defined as: if after first date of study drug, then Study Day = Date – first date of 
study drug + 1; if before first date of study drug, then Study Day = Date – first date of study 
drug; Study Day 1 is defined as the first date of study drug; there is no Study Day 0. 
Baseline is defined as the last non-missing result before or on first date of study drug. If a subject 
did not take any study drug, then the baseline is defined as the last non-missing result before or 
on randomization date.
2.2
Analysis sets
Screened set: All subjects who signed the informed consent.
Randomized population (RAN): The RAN will include all randomized subjects, regardless of 
whether they took any study medication. Patients in RAN will be analyzed according to the 
treatment assigned at randomization.
Full analysis set (FAS): The FAS will include all randomized subjects who receive at least one 
dose of study drug with the exception of those who have inadvertently been randomized into 
the study. Subjects who are randomized due to erroneous use of the IRT system (identified as 


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being randomized, having no dose administration records and who discontinue the study 
immediately) will be excluded. Following the intent-to-treat principle, subjects will be analyzed 
according to the treatment they are assigned to at randomization. This analysis population will 
be used for all efficacy analyses unless otherwise specified.
Per-protocol set (PPS): The PPS will include all patients in the FAS who have received 3 doses
of study drug during the treatment phase and without any major protocol deviations impacting 
the primary endpoint. Subjects will be analyzed according to the actual treatment received 
during the study as follows:

Placebo: Patients who received only placebo injections (i.e., no active treatment) during 
the study

150 mg omalizumab: Patients who received at least one 150 mg omalizumab injection but 
no higher active dose level (i.e., 300 mg) during the study

300 mg omalizumab: Patients who received at least two 150 mg omalizumab injections at 
once during the study
This supplementary efficacy population will be used to assess the robustness of the primary 
analysis results. For the PPS, major protocol deviations impacting the primary endpoint will be 
considered for the exclusion of subjects and are reported in the section 5.7 Rule of exclusion
criteria of analysis sets.
Safety set (SAF): The SAF consists of all subjects who take at least one dose of study 
medication. Subjects will be analyzed according to the actual treatment received during the 
randomized treatment epoch, as follows: 

Placebo: Patients who received only placebo injections (i.e., no active treatment) during 
the randomized treatment epoch

150 mg omalizumab: Patients who received at least one 150 mg omalizumab injection but 
no higher active dose level (i.e., 300 mg) during the randomized treatment epoch

300 mg omalizumab: Patients who received at least two 150 mg omalizumab injections at 
once during the randomized treatment epoch.
FAS, PPS, SAF: The protocol deviation codes leading to exclusion from the analysis sets 
defined above are presented in the section 5.7 Rule of exclusion criteria of analysis sets.
2.2.1
Subgroup of interest
Subgroup analyses will be performed by categories of the following demographic and baseline 
variable categories to evaluate the consistency of the primary efficacy results and key safety 
results. Summary analyses and the primary model will be applied repeatedly by the category of 
subgroup. Unless specified otherwise: 
Subgroup analysis for efficacy will be performed by: 

Gender (male vs female)

Age group (<65, >=65 years)

Body weight group (<40, 40-<80, >=80 kg)

Duration of CSU (<2, 2-10, >10 years at the time of Visit 1)


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
Previous use of systemic treatment (including steroids and other systemic treatment 
including cyclosporin) for CSU (Yes vs No)

Baseline ISS7 (<median, >=median)

Baseline UAS7 (<median, >=median)

Baseline total IgE (<median, >=median)

Baseline presence of angioedema (Yes vs No)
These subgroup analysis will be used for the primary analysis (change from baseline in ISS7 at 
Week 12) and repeated also for UAS7 at week 12 and for NHS7 at week 12 which will use the 
same statistical method (MMRM model).
Subgroup analysis for safety will be performed by: 

Gender (male vs female)

Age group (<65, >=65 years)

Body weight group (<40, 40-<80, >=80 kg)

Previous use of systemic treatment (including steroids and other systemic treatment 
including cyclosporin) for CSU (Yes vs No)

Baseline total IgE (<median, >=median)
These subgroup analysis will be used for AEs summaries.
2.3
Patient disposition, demographics and other baseline 
characteristics
The analysis will be based on the RAN, unless otherwise specified.
2.3.1
Patient disposition
The number of screened subjects who completed the screening epoch will be given and the 
reasons for not entering the randomized treatment epoch will be summarized. The number and 
percentage of subjects in the RAN who completed/discontinued the treatment epoch, and the 
reason for discontinuation will be presented by treatment group. The number and percentage of 
subjects in the RAN who completed/discontinued the follow-up epoch, and the reason for 
discontinuation will also be presented by treatment group. Patient disposition during the 
treatment and follow-up epochs will be listed.
2.3.2
Demographic and baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group. The number and percentage of patients in each category will 
be presented for categorical variables for each treatment group and all patients.
The randomized treatment groups will be summarized by the following demographic variables: 

Gender (Male, Female)

Age (years)

Age group (< 65, >= 65),


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
Ethnicity

Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other)

Weight (kg)

Weight group (<40, 40 - < 80, >= 80)

Height (cm)

Body Mass Index (BMI): (kg/m²)– calculated as weight (kg) / (height (m))^2 

BMI group (<25, 25 - < 30, >=30)
Baseline disease characteristics will also be summarized for the following variables, including: 

Duration of CSU (years)

Duration of CSU (<2, 2-10, > 10)

Previous number of CSU medications in classes (<= 3, >3)

Previous use of systemic treatment (including steroids and other systemic treatment 
including cyclosporin) for CSU (Yes, No). The list of systemic treatment is provided in 
the section 5.8.

Total IgE level (ng/mL)

Free IgE level (ng/mL)

Latent TB status (Yes, No) from laboratory data. Further information are provided in 
the section 5.9.

In-clinic UAS

Weekly urticaria activity score (UAS7)

Weekly itch severity score (ISS7)

Weekly number of hives score (NHS7)

Presence of angioedema (Yes, No)
2.3.3
Medical history
Any condition entered on the Medical history eCRF will be coded using the MedDRA 
dictionary. The number of patients with medical history will be summarized by primary system 
organ class, preferred term and treatment group for the RAN. Protocol solicited medical history 
will be also summarized.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The analysis of study treatment data will be based on the SAF, unless otherwise specified.
2.4.1
Study treatment / compliance
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of doses and total cumulative dosage will be presented.
Duration of exposure in days is defined as the date of the last treatment minus the date of first 
study drug administration plus 4 weeks (28 days), except if the subject died before the date of 
the last treatment + 27 days, then duration of exposure in days is defined as date of death minus 
the date of first study drug administration + 1 day.


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2.4.2
Prior, concomitant and post therapies
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered.
Prior and concomitant medications will be identified using Novartis Drug and Therapy 
Dictionary (NovDTD) including Anatomical Therapeutic Chemical (ATC) code.
Concomitant medications will be summarized by treatment separately for CSU related and non-
CSU related medications. CSU-related medications will be summarized by ATC class and 
preferred term. Non-CSU related concomitant medications will be summarized by the ATC 
class and preferred term. Concomitant medications will be summarized by epoch; the 
randomized treatment epoch and newly onset during post-treatment follow-up epoch. 
Prior medications not for CSU will be summarized by ATC class, preferred term and treatment 
group. Urticaria therapy prior to screening (entered on the Prior urticaria therapy eCRF page) 
will be summarized by type of therapy, preferred term and treatment group.
Significant surgery and medical procedures will be summarized by primary system organ class 
and MedDRA preferred term.
Rescue medication will be listed by treatment group. 
2.5
Analysis of the primary objective
Analyses will be based on the patients in FAS, unless otherwise specified. 
2.5.1
Primary endpoint
The primary efficacy variable is change from baseline in weekly itch severity score (ISS7, a 
component of the UAS7, see protocol Section 6.4.1.1) at Week 12. 
The daily itch score is the average of the morning and evening itch severity scores. The baseline 
ISS7 is the sum of the daily itch severity scores over the 7 days prior to the first study drug 
administration, and the ISS7 at Week 12 is the sum of daily itch scores over the 7 days during 
study days 78 – 84 (prior to the planned day of the Week 12 visit, study day 85). The same 
principles of calculating baseline and Week 12 weekly scores will be applied to each weekly 
outcome unless otherwise stated. See section 5.1 for details.
2.5.2
Statistical hypothesis, model, and method of analysis
A mixed-effect linear model with repeated measures (MMRM) will be used to obtain the least 
squares mean (LSM) estimate for each treatment group for change from baseline in ISS7 at 
Week 12 (the primary endpoint). The MMRM model will include terms of treatment group, 
week (1 to 12), baseline score, baseline score-by-week interaction, and treatment-by-week 
interaction as fixed effects. Treatment group and week will be fitted as categorical variables, 
and baseline score as a continuous covariate. The within-patient correlation will be modeled 
using the unstructured covariance matrix ([Mallinckrodt et al 2001]). If the model does not 


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converge, the compound symmetry covariance structure will be used. The occurrence of 
missing data will be assumed to be missing at random (MAR). 
The difference in LSM estimates between treatment groups, together with a 95% CI, will be 
presented.
A multiplicity adjustment for two primary efficacy comparisons based on above model will be 
made according to the overall study testing strategy provided in Section 2.6.2. The statistical 
analyses will test the null hypothesis of no difference between the placebo and each omalizumab 
dose group.
Even if latent TB status at baseline was a stratification variable for the randomization, it will 
not be included in the efficacy model. Indeed, this variable will have no influence on the 
efficacy analysis.
2.5.3
Handling of missing values/censoring/discontinuations
The primary endpoint will be analyzed using an MMRM which is valid under the MAR 
(Missing-At-Random) assumption ([Rubin 1976]). Patients who have at least one post-baseline 
are included in the MMRM analysis. This includes not only the patients who have completed 
12 weeks of treatment (with a complete 12-week longitudinal data), but also those who 
discontinue from study treatment early (although only able to contribute to a partial time profile). 
This is under the assumption that dropouts would follow the similar data pattern like other 
patients who complete the treatment period in the same treatment group, as if they had not 
discontinued from the study treatment. 
Patients who discontinue from study treatment early (have less than three doses of study drug)
will remain in the study and follow the procedures described in protocol Section 5.6.2. 
Nevertheless, the data on and post the date of the last treatment + 4 weeks (28 days) will be 
treated as missing in the primary analysis. This principle will be applied on all parameters from 
UAS questionnaire: ISS, UAS, NHS for the MMRM model.
The ISS7 is the sum of the average daily itch scores over 7 days each week. The daily itch 
scores are calculated based on daily eDiary entries for itch. The daily itch score is then 
calculated as the average of the morning and evening itch scores. 
When either the morning or evening score is missing, the non-missing itch score for that day 
(morning or evening) will be used as the daily score. When one or more of the daily itch scores 
are missing, the following principles will be applied to handle the missing data:

If a patient has at least 4 non-missing daily itch scores within the 7 days in a week, the ISS7 
score is calculated as the sum of the available eDiary itch scores in that week, divided by 
the number of days that have a non-missing diary itch score, multiplied by 7.

If there are less than 4 non-missing daily itch scores within the 7 days in a week, then the 
ISS7 score is missing for the week.
2.5.4
Supportive analyses
The primary efficacy analysis will be repeated on the PPS to assess the robustness of the primary 
result.


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The impact of missing data on the primary analysis results will be assessed by repeating the 
analysis using different missing data assumptions to handle missing data. The supportive 
analyses may include:

An analysis of covariance (ANCOVA) model with missing Week 12 itch scores imputed 
by carrying forward the patients’ baseline scores (BOCF). The ANCOVA model would 
include treatment group as a factor, and baseline score as a covariate.

An ANCOVA model with missing Week 12 itch scores imputed by carrying forward the 
patients’ last non-missing weekly score (LOCF). The ANCOVA model would include 
treatment group as a factor, and baseline score as a covariate.

Jump-to-Reference (J2R) multiple imputation (control-based pattern imputation) approach
2.6
Analysis of secondary efficacy objective(s)
All of the secondary efficacy variables will be analyzed using the FAS unless otherwise 
specified.
2.6.1
Secondary endpoints
The secondary endpoints are described below: 
UAS7

Change from Baseline in UAS7 score at Week 12 

Percentage of patients with UAS7≤6 at Week 12

Percentage of patients with UAS7=0 at Week 12
NHS7

Change from Baseline in NHS7 score at Week 12 
ISS7

Percentage of patients with ISS7 MID at week 12

Time to ISS7 MID by Week 12
DLQI

Change from Baseline in overall DLQI score at Week 12 
Analysis of secondary endpoints is described below.
2.6.2
Statistical hypothesis, model, and method of analysis
Testing strategy
The following primary and secondary hypotheses will be included in the testing strategy. To 
ensure the family-wise type I error rate (α) is kept at an overall level of less than 5%, a flexible 
gate-keeping procedure ([Bretz et al 2009]) will be employed as described below. The 
procedure allows the type-one error rate associated with a rejected hypothesis to be reallocated 
among the remaining (un-rejected) hypothesis tests according to a set of pre-specified rules. 
The hypotheses are organized to describe the order in which different sets of hypotheses will 
be tested.


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Primary objectives (as described in Section 2.5):
H1:
Omalizumab 300 mg is not different to placebo with respect to change from baseline in 
ISS7 (weekly itch severity score) at Week 12
H2:
Omalizumab 150 mg is not different to placebo with respect to change from baseline in 
ISS7 (weekly itch severity score) at Week 12
Secondary objectives:
H3:
Omalizumab 300 mg is not different to placebo with respect to change from baseline in 
UAS7 (weekly urticaria activity score) at Week 12
H4:
Omalizumab 150 mg is not different to placebo with respect to change from baseline in 
UAS7 (weekly urticaria activity score) at Week 12
H5:
Omalizumab 300 mg is not different to placebo with respect to change from baseline in 
NHS7 (weekly number of hives score) at Week 12
H6:
Omalizumab 150 mg is not different to placebo with respect to change from baseline in 
NHS7 (weekly number of hives score) at Week 12
H7:
Omalizumab 300 mg is not different to placebo with respect to the percentage of patients 
with UAS7 ≤6 response at Week 12
H8:
Omalizumab 150 mg is not different to placebo with respect to the percentage of patients 
with UAS7 ≤6 response at Week 12
H9: Omalizumab 300 mg is not different to placebo with respect to the percentage of patients 
with UAS7 = 0 response at Week 12
H10: Omalizumab 150 mg is not different to placebo with respect to the percentage of patients 
with UAS7 = 0 response at Week 12
H11: Omalizumab 300 mg is not different to placebo with respect to the percentage of patients 
with ISS7 MID response at Week 12
H12: Omalizumab 150 mg is not different to placebo with respect to the percentage of patients 
with ISS7 MID response at Week 12
H13: Omalizumab 300 mg is not different to placebo with respect to change from baseline in 
overall DLQI score at Week 12
H14: Omalizumab 150 mg is not different to placebo with respect to change from baseline in 
overall DLQI score at Week 12
H15: Omalizumab 300 mg is not different to placebo with respect to the time to ISS7 MID by 
Week 12
H16: Omalizumab 150 mg is not different to placebo with respect to the time to ISS7 MID by 
Week 12
The graphical approach of ([Bretz et al 2009]) for sequentially rejective testing procedures is 
used to illustrate the testing strategy in Figure 2-1.


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Figure 2-1
Testing strategy for primary and secondary endpoints
Note: As shown in the above graph, initially each H1 and H2 will be assigned α/2 to test the 
individual hypotheses simultaneously and move forward. 
The family-wise error rate will be set to α = 5% (2-sided) and will be controlled using the 
proposed hierarchical testing strategy as illustrated in Figure 2-1. 
First, each of the hypotheses (H1 and H2) for the primary objective (based on change from 
baseline in ISS7 at Week 12) for omalizumab 300 mg and 150 mg versus placebo will be tested 
simultaneously at α/2.


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If at least one of H1 and/or H2 is rejected, then H3 and/or H4, respectively, will be tested at α/2. 
If at least one of H3 and/or H4 is rejected, then H5 and/or H6, will be tested, respectively. A 
similar process applies until H15 and H16. Once all hypotheses for an omalizumab dose are 
rejected, then the respective α/2 can be passed on to the other dose’s hypotheses, if they are not 
already rejected at α/2. In the description above, rejection of a hypothesis refers to rejection of 
the two-sided hypothesis; however the significance level of a rejected hypothesis is only passed 
on according to the graphical procedure for the test of another hypothesis if the treatment effect 
is in favor of omalizumab. 
Change from baseline in weekly urticarial activity score (UAS7) at Week 12
The urticaria activity score (UAS) is a composite score (itch severity score and number of hives 
score) described in protocol Section 6.4.1.1. For each of the morning and evening UAS score, 
it is calculated as the sum of the itch severity score and number of hives score according to 
eDiary entries. The daily UAS is the average of the morning and evening UAS scores, and 
UAS7 is the sum of daily UAS scores over 7 days. 
The missing data will be handled in the same way as described in Section 2.5.3.
Treatment comparisons of 300 mg vs placebo (H3) and 150 mg vs placebo (H4) in change from 
baseline to Week 12 in the UAS7 will be made using an MMRM model with similar terms as 
the primary analysis but baseline UAS7 as a covariate (Refer to Section 2.5.2). 
Change from baseline in weekly number of hives score (NHS7) at Week 12
The weekly number of hives score (NHS7) will be handled using the same principles as 
described for the primary endpoint in Section 2.5.1 and Section 2.5.3.
Treatment comparisons of 300 mg vs placebo (H5) and 150 mg vs placebo (H6) in change from 
baseline to Week 12 in the NHS7 will be made using an MMRM model with similar terms as 
the primary analysis but baseline NHS7 as a covariate (Refer to Section 2.5.2).
Percentage of patients with UAS7 ≤6 at Week 12
Treatment comparisons of 300 mg vs placebo (H7) and 150 mg vs placebo (H8) in the 
percentage of patients with UAS7 ≤6 at Week 12 will be made using a logistic regression model 
with treatment group as a factor and baseline UAS7 as a covariate. 
A patient with missing data at Week 12 will be imputed as a responder if the patient was a 
responder at Week 10 and Week 11, otherwise as a non-responder.
Percentage of patients with UAS7 = 0 at Week 12
Treatment comparisons of 300 mg vs placebo (H9) and 150 mg vs placebo (H10) in the 
percentage of patients with UAS7 = 0 at Week 12 will be made using a logistic regression model 
with treatment group as a factor and baseline UAS7 as a covariate. 
A patient with missing data at Week 12 will be imputed as a responder if the patient was a 
responder at Week 10 and Week 11, otherwise as a non-responder.


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Percentage of patients with ISS7 MID response at Week 12
The ISS7 MID response is defined as a reduction from baseline in ISS7 of ≥ 5 points. 
Treatment comparisons of 300 mg vs placebo (H11) and 150 mg vs placebo (H12) in the 
percentage of patients with ISS7 MID response at Week 12 will be made using a logistic 
regression model with treatment group as a factor and baseline ISS7 as a covariate.
A patient with missing data at Week 12 will be imputed as a responder if the patient was a 
responder at Week 10 and Week 11, otherwise as a non-responder.
Change from baseline in overall DLQI at Week 12
DLQI is a PRO instrument, described in protocol Section 6.4.2.1. An overall score will be 
calculated according to the scoring manual given in protocol Appendix 3. The baseline and up 
to Week 12 overall DLQI scores will be derived from the questionnaires assessed at the Day 1 
and up to Week 12 visits. 
Treatment comparisons of 300 mg vs placebo (H13) and 150 mg vs placebo (H14) in change 
from baseline to Week 12 in overall DLQI score will be made using an MMRM model with 
similar terms as primary analysis but baseline DLQI as a covariate (Refer to Section 2.5.2). 
Time to ISS7 MID response by Week 12
The ISS7 MID response is defined as a reduction from baseline in ISS7 of ≥ 5 points. Time to 
ISS7 MID response is the time (in weeks) from the date of the first dose to the date where 
ISS7 MID response is first achieved during Week 1 to 12. If no ISS7 MID response is 
achieved by Week 12, then if the patient was a treatment completer (took 3 doses of study 
drug) they will be censored at the week of the last non-missing weekly score up to Week 12, 
and if the patient was not a treatment completer (took < 3 doses of study drug) they will be 
treated as censored at the maximum of (the last dose date + 28 days – 1)/7 and the last non-
missing weekly score, to a maximum of 12 weeks.
Treatment comparisons of 300 mg vs placebo (H15) and 150 mg vs placebo (H16) will be 
performed using a Cox proportional hazard (PH) model with treatment group as a factor and 
baseline ISS7 as a covariate. The hazard ratio and 95% CI will be reported. 
Kaplan-Meier analysis stratified by treatment group will be also presented with log-rank test 
and displayed graphically.
Subgroup analysis
All the sub-group analyses conducted for the primary efficacy variable (described in Section 
2.2.1) will be repeated for UAS7 at week 12 and NHS7 (weekly number of hives score) at week 
12. The primary model will be applied repeatedly by the category of subgroup. 
2.7
Safety analyses
All safety evaluations will be performed on the safety set (SAF), unless otherwise specified.


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2.7.1
Adverse events (AEs)
All the AEs occurring after providing written informed consent will be recorded on the Adverse 
Event eCRF page. AEs starting on or after the first dose of study treatment or events present 
prior to the first dose of study treatment but increased in severity based on preferred term will 
be classified as treatment emergent AEs. Overall AEs, SAEs, AEs by severity will be also 
summarized for each epoch (randomized-treatment and post-treatment follow-up) when 
necessary. Non-treatment emergent AEs (occurring after providing written informed consent 
but before first dose of study treatment) will not be summarized but listed only.
Treatment emergent AEs will be summarized by presenting, for each treatment group, the 
number and percentage of patients having any AE, having an AE in each primary system organ 
class and having each individual AE (preferred term). Summaries will be also presented for 
treatment emergent AEs by severity and for study treatment related AEs. If a patient reported 
more than one AE with the same preferred term, the AE with the greatest severity will be 
presented. If a patient reported more than one AE within the same primary system organ class, 
the patient will be counted only once with the greatest severity at the system organ class level, 
where applicable. Separate summaries will be provided for death, serious adverse event, and 
adverse events leading to discontinuation.
In addition, exposure adjusted AE rates (incidence rates) will be provided for each treatment 
group, by primary system organ class and preferred term.
Subgroup analysis will be performed for AE summaries, unless otherwise specified (see Section 
2.2.1 for subgroup definition). 
Clinicaltrials.gov and EudraCT 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 2% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.


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2.7.1.1
Adverse events of special interest / grouping of AEs
Treatment emergent AEs of special interest for omalizumab treatment will be also summarized. 
AEs of special interest for omalizumab treatment include the following, specified as compound-
level risk factors defined in the electronic Case Retrieval Strategy (eCRS): 

Anaphylaxis - anaphylactoid reactions (narrow)

Churg Strauss Syndrome - Hypereosinophilic syndrome 

Arterial Thromboembolic Events

Malignant neoplasms
Summary tables that present numbers and percentages of patients with the AEs of special 
interest will be presented by standardized MedDRA Query (SMQ) (if applicable), preferred 
term and treatment. In addition, the hepatic disorders events will be tabulated by latent TB at 
baseline (Yes/No). 
A sensitivity analysis will be done in order to summarize the hepatic disorders events among 
patients whose TB status may not be interpretable due to the incubation temperature violation
(as described in Section 5.9). The current version of eCRS is stored in GPS folder. 
2.7.1.2
Other significant adverse events
Treatment emergent AEs leading to treatment discontinuation will be summarized and listed. 
Treatment emergent AEs of special interest will be considered as treatment emergent other 
significant AEs as well.
2.7.2
Deaths
Overall death will be summarized and listed. 
2.7.3
Laboratory data
Laboratory values that the laboratory reports to be below or above the limit of quantification 
will be imputed by the respective limit of quantification.
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post baseline values.
The notable criteria for platelet count (≤ 100 x10E9/L) will be used to calculate number and 
percentage of patients with newly occurring or worsening notable abnormalities occurring while 
on study. A case will be considered as newly occurring if the value for a laboratory evaluation 
is not notable or missing at baseline but is notable thereafter; a case will be considered as 
worsening if the value for a laboratory evaluation is notable at baseline and at least one post-
baseline value is worse than baseline.
The hepatic-related laboratory tests (newly occurring liver enzyme abnormalities) will also be 
tabulated by latent TB at baseline (Yes/No). A sensitivity analysis will be done to summarize 
the hepatic-related laboratory tests among patients whose TB status may not be interpretable 
due to the incubation temperature violation (as described in Section 5.9).


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To evaluate potential drug-induced liver injury, newly occurring liver enzyme abnormalities at 
any time post-baseline will also be summarized while on study based on the event criteria given 
below:
-
3 x-, 5 x-, 8 x-, 10 x-, and 20 x upper limit of normal range (ULN) elevations of AST, 3 
x-, 5 x-, 8 x-, 10 x-, and 20 x upper limit of normal range (ULN) elevations of ALT, and 
either AST or ALT
-
elevation of TBL to > 1 x ULN,  > 1.5 x ULN,  and > 2 x ULN
-
elevation of ALP to > 1.5 x ULN,  > 2 x ULN,  > 3 x ULN,  and > 5 x ULN
-
elevation of AST or ALT to >3 x ULN accompanied by elevated TBL (>1.5 x ULN, > 2 x 
ULN)
-
elevation of ALP to (>3 x ULN, > 5 x ULN) accompanied by elevated TBL > 2 x ULN
-
Potential Hy’s Law: (AST or ALT > 3 x ULN) and TBL > 2 x ULN and ALP =< 2 x ULN 
For a criterion with combined components except for Hy’s Law, the elevations do not have to 
occur at the same post-baseline time point, which implies that the cases can be identified only 
by the highest post-baseline value. While for potential Hy’s Law case, all the elevations must 
occur at the same post-baseline time point. A case will be considered as newly occurring if a 
criterion is not met or missing at baseline but is met thereafter.
2.7.4
Other safety data
2.7.4.1
Anti-omalizumab antibody
A summary of anti-omalizumab antibodies will be provided by treatment group.
2.7.4.2
ECG and cardiac imaging data
Not applicable. 
2.7.4.3
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. Subjects with newly occurred notable vital signs 
as defined below will be listed.

Hypertension (systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure 
of ≥ 90 mmHg) or hypotension (systolic blood pressure of < 90 mmHg and/or 
diastolic blood pressure of < 60 mmHg).

Pulse rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia)
2.7.4.4
Other
Healthcare utilization (calling a doctor, nurse, or nurse practitioner) based on patient daily diary 
data will be summarized for each treatment group. In case of missing daily scores, observed 
data will be used.


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For patients reporting angioedema, the action(s) taken in response to their angioedema based 
on patient daily diary data will be summarized for each treatment group.
2.9
Patient-reported outcomes
Not applicable.
2.10
Biomarkers
Not applicable. 


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2.12
eDiary compliance analysis
To evaluate the compliance of eDiary completion, number of missing eDiary weekly scores of 
each patient will be summarized by treatment group and by study week. FAS will be used for 
this analysis.
2.13
Interim analysis
No interim analysis is planned in this study. 
3
Sample size calculation
The study is sized to ensure sufficient power to demonstrate meaningful efficacy based on the 
data from the full analysis set. In addition, for registration of a biologic compound the China 
health authority (China Food and Drug Administration, CFDA) requires at least 300 patients to 
be treated in the test drug as the minimum for safety evaluation. Assuming 10% dropout rate 
by week 12, the study will randomize 420 patients in a ratio of 2:2:1 to omalizumab 300 mg, 
omalizumab 150 mg, and placebo to ensure 375 patients completing Week 12 with 300 patients 
in the two omalizumab dose groups. 
The below power evaluation for the planned hypothesis tests is based on a sample size of 375 
(2:2:1) patients who complete 12 weeks of treatment duration. The powers are examined 
according to the hierarchy order of the multiplicity type I error control plan with the overall 
alpha level controlled at 0.05 (2-sided) as outlined in Figure 2-1.  It is assumed Study E2305 
will repeat the performance of the previous pivotal studies (Q4881g, Q4882g, and E2306). 
Except for ethnicity, these 3 studies have a similar patient population with consistent results for 
the primary and secondary endpoints. There is no statistical evidence suggesting heterogeneity 
among the studies. A meta-analysis with fixed-effects model was performed based on summary 
data from these studies to combine the estimates of the treatment effect and standard deviation 
(SD). The obtained pooled estimates on the treatment effect size and SD are then used as the 
assumed values for the alternative hypotheses to evaluate the power for each endpoint. To 
understand the impact of the strength of dependency between endpoints on the power, the power 
was evaluated under 3 scenarios of correlation (0, 0.5, 0.9), i.e. completely independency, 
moderate dependency, and strong dependency. The results are summarized in Table 3-1.  
For the primary endpoint (change from baseline weekly itch score at Week 12), the study will 
offer 

a power of > 99.9% to detect a difference of 4.73 between 300 mg and placebo with the 
assumed SD of 5.28

a power of > 93% to detect a difference of 2.73 between 150 mg and placebo with the 
assumed SD of 5.55


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The power was evaluated for the primary and secondary endpoints as a whole according to the 
testing strategy defined in Section 2.6.2 (Figure 2-1) using the gMCP package in the R software.   
According to Table 3-1, the power evaluation is summarized as follows. 

The power for 300 mg is maintained at nearly 95% and above for all testing hypotheses 
regardless of the strength of dependency between endpoints. 

The power for 150 mg is at least 80% for the testing hypotheses up to the endpoint of 
percentage of patients with UAS7 ≤ 6 at Week 12. The power for the rest of endpoints 
is decreased to 65% and below, and can be as low as 18% if the dependency between 
endpoints is none. 
By reviewing and using clinical data from previous studies in the power assessment for the 
targeted hypothesis tests for the current study, the total sample size of 420 (including 10% 
dropout) with 2:2:1 assignment ratio is considered appropriate to allow sufficient power to 
achieve the primary objective and all the first three secondary objectives for both 300 mg and 
150 mg. The study also has high power to achieve the last four secondary objectives for 300 
mg, although the power is < 65% and below for 150mg.
Table 3-1
Power analysis of primary and key secondary endpoints 
Endpoint
Hypo-
thesis
Comparison
Parameter 
assumptions1
Power2
Correlation between 
endpoints
None 
(0)
Moderate 
(0.5)
Strong 
(0.9)
Change from 
baseline in 
ISS7 at W12
H1
300 mg vs 
Placebo
Δ=4.73
SD=5.28
>0.99
9
>0.999
>0.999
H2
150 mg vs 
Placebo
Δ=2.73
SD=5.55
0.933
0.931
0.932
Change from 
baseline in 
UAS7 at W12
H3
300 mg vs 
Placebo
Δ=11.16
SD=11.54
>0.99
9
>0.999
>0.999
H4
150 mg vs 
Placebo
Δ=6.31
SD=11.84
0.899
0.906
0.925
Change from 
baseline in 
NHS7 at W12
H5
300 mg vs 
Placebo
Δ=6.22
SD=6.82
>0.99
9
>0.999
>0.999
H6
150 mg vs 
Placebo
Δ=3.52
SD=6.77
0.859
0.880
0.917
% of patients 
with 
UAS7 ≤6 at 
W12
H7
300 mg vs 
Placebo
Log OR=2.09
SD=2.48
(~ p300=61%, p0=16%)
>0.99
9
>0.999
>0.999
H8
150 mg vs 
Placebo
Log OR=1.32
SD=2.46
(~ p150=41%, p0=16%)
0.830
0.864
0.914
% of patients 
with UAS7 = 
0 at W12
H9
300 mg vs 
Placebo
Log OR=2.27
SD=3.46
(i.e. p300=41%, p0=7%)
0.992
0.992
0.991


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Endpoint
Hypo-
thesis
Comparison
Parameter 
assumptions1
Power2
Correlation between 
endpoints
None 
(0)
Moderate 
(0.5)
Strong 
(0.9)
H10
150 mg vs 
Placebo
Log OR=1.21
SD=3.63
(~ p150=19%, p0=7%)
0.540
0.616
0.654
% of patients 
with ISS7 
MID at W12
H11
300 mg vs 
Placebo
Log OR=1.57
SD=2.34
(~ p300=81%, p0=47%)
0.986
0.986
0.989
H12
150 mg vs 
Placebo
Log OR=0.78
SD=2.09
(~ p150=65%, p0=47%)
0.408
0.537
0.631
Change from 
baseline in 
Overall DLQI 
at W12
H13
300 mg vs 
Placebo
Δ=3.55
SD=5.86
0.965
0.969
0.977
H14
150 mg vs 
Placebo
Δ=1.91
SD=6.25
0.237
0.404
0.536
Time to ISS7 
MID
H15
300 mg vs
Placebo
Log HR=0.7
SD=1.14
(~ S300=6%, S0=25%)
0.947
0.955
0.970
H16
150 mg vs 
Placebo
Log HR=0.43
SD=1.15
(~ S150=12%, S0=25%)
0.179
0.372
0.530
1 Parameter assumptions are based on a meta-analysis of Studies Q4881g, Q4882g, and E2306 
Δ= Difference; OR=Odds Ratio; HR: Hazard Ratio
p300, p150, p0: the probability of an event occurrence at Week 12 for Omalizumab 300mg, 150mg, and 
placebo
S300, S150, S0: the probability of not having an event at and prior to Week 12 for Omalizumab 300mg, 
150mg, and placebo
SD= Standard deviation for the data either normally distributed or on the scale with a normal 
approximation, e.g. logit(p) for binary data and log-log(S) for time-to-event data
2 Power is calculated based on the total sample size of 420 assigned to treatment group 300 mg, 150 
mg and placebo in ratio of 2:2:1 with 10% dropout rate during 12 weeks of treatment period, 
according to the hierarchy order of the multiplicity Type I error control scheme with overall alpha level 
controlled at 0.05 (2-sided).


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4
Change to protocol specified analyses
Below changes from protocol specified analysis are made: 

Previous use of systemic treatments including steroids and other treatment (including 
cyclosporin) for CSU are summarized and used as subgroup analysis categories instead 
of previous use of systemic steroids for CSU. 

eDiary compliance analysis added to summarize the missing weekly eDiary scores. 

Weekly size of largest hive score (LHS7) is not summarize at baseline as not collected
in this study.

SAF definition updated in order to include all patients with at least one study medication 
intake.

ECG will be not listed as these data are collected only in source document.

Baseline ISS7 definition updated in order to consider the first study drug 
administration (rather than the randomization day) since a subject can have the first 
study medication intake after the randomization date.

CSU-related medications will be summarized by ATC class and preferred term. Also, 
non-CSU related concomitant medications will be summarized by ATC class and
preferred term.
 
5
Appendix
5.1
Study week definition
Definition of study week based on eDiary
A number of efficacy outcome measures (ISS7, NHS7, UAS7, 
) are in the form of weekly scores derived 
from patient daily diary data. The study weeks are defined based on the study days starting with 
Day 1 (see Table 5-1), which is the day the patient receives the first study treatment. The study 
day for a particular diary date is calculated as [Date of diary] – [Date of first dose] + 1.
Table 5-1
Study week definitions based on study days
Study Week
Study Day
Study 
Week
Study Day
1
2
3
4
1-7
8-14
15-21
22-28
13
14
15
16
85-91
92-98
99-105
106-112


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Study Week
Study Day
Study 
Week
Study Day
5
6
7
8
9
10
11
12
29-35
36-42
43-49
50-56
57-63
64-70
71-77
78-84
17
18
19
20
113-119
120-126
127-133
134-140
Furthermore, the baseline week is comprised of the 7 days prior to Day 1 (Day -7 to Day -1). 
Table 5-1 summarizes the time period (in study days) over which the data are used in the 
calculation of each weekly score. For most study weeks, weekly scores will be based on the 7 
study days given in Table 5-1.
Definition of study week based on DLQI on visit date
For efficacy variables collected by visit (DLQI), the reported visit will be used in the analysis.
No visit remapping will be applied.  
5.2
Dermatology Life Quality Index (DLQI)
The DLQI measures functional disability of subjects with dermatological disorders that are 17 
years or older of age and had been utilized as a relevant clinical measure in atopic dermatitis, 
as well as other dermatitis clinical trials. The DLQI is a simple, validated, self-administered 10-
item questionnaire. The instrument contains six functional scales (i.e., symptoms and feeling, 
daily activities, leisure, work and school, personal relationships, treatment). For the DLQI, each 
question will be answered with the following response: “not at all”, “a little”, “a lot”, or “very 
much”. “Not relevant” is also a valid response. Seven scores will be derived from DLQI: the 
total score of each of the six dimensions as well as the total score over all items. The higher the 
score, the more quality of life is impaired. 
The scoring of each question is as follows: 

Very much: Scored 3

A lot: Scored 2

A little: Scored 1

Not at all: Scored 0

Not relevant: Scored 0

Question unanswered: Scored 0

Question 7: “prevented work or studying”: Scored 3


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The DLQI total score will be calculated by summing the score of each question resulting in a 
maximum of 30 and a minimum of 0. The higher the score, the more Quality of Life is impaired. 
Meaning of DLQI Scores

0-1= no effect at all on subject’s life

2-5= small effect on subject’s life

6-10= moderate effect on subject’s life

11-20= very large effect on subject’s life

21-30= extremely large effect on subject’s life
The DLQI will be analyzed under six headings as follows: 

Symptoms and feelings: question 1 and 2, score maximum 6

Daily activities: question 3 and 4, score maximum 6

Leisure: question 5 and 6, score maximum 6

Work and school: question 7, score maximum 3

Personal relationships: question 8 and 9: score maximum 6

Treatment: question 10, score maximum 3
Interpretation of incorrectly completed questionnaires: 
There is a very high success rate of accurate completion of the DLQI. However, sometimes 
subjects do make mistakes. 
1. If one question is left unanswered this is scored 0. 
2. If two or more questions are left unanswered the questionnaire will not be scored. 
3. If question 7 is answered ‘yes’ this will be scored 3. If question 7 will be answered no 
or ‘relevant’ but then either ‘a lot’ or ‘a little’ is ticked this will then be scored 2 or 1. 
4. If two or more response options are ticked, the response option with the highest score 
will be recorded. 
5. If there is a response between two tick boxes, the lower of the two score options will be 
recorded. 
6. If one item is missing from a two-item subscale, that subscale will not be scored. 
Handling of missing values: 

If there is only one missing score per visit, it will be imputed with 0, and then the 
subscale including this item and the total score are derived accordingly. 

If there are two or more missing scores per visit, LOCF will be applied to the total score 
(i.e. LOCF is NOT applied to the 10 individual question scores for further derivation of 
the 6 subscale scores and 1 total score). 


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5.3
Handling of duplicate/mistaken data in eDiary
eDiary records are entered by subjects and if there are cases when more than one values are 
entered by subject for one entry due to technical reasons or by mistake, then the worst value 
will always be used in calculating weekly scores. 
Systemic erroneous data due to device malfunction are always excluded from the analysis. The 
impact of such issue if occurs will be evaluated by Novartis team and additional analysis may 
be considered if necessary. 
5.4
AEs coding/grading
Coding of AE will be done per MedDRA dictionary. 
5.5
Laboratory parameters derivations
Not applicable. 
5.6
Statistical models
5.6.1
Primary analysis
5.6.1.1
MMRM analysis
Change from baseline at Week 12 of ISS7 by treatment group is estimated using SAS procedure 
MIXED, and assuming unstructured covariance matrix. Compute least square means for change 
from baseline at Week 12 for each treatment group, and p-values are given with null hypothesis 
that there is no difference between active treatment group and placebo group. 
The following code will be used for this analysis:
ods output Lsmeans=lsmeans_est
           Diffs=diff
           ConvergenceStatus=conv;
proc mixed data=dataset order=internal;
class subject treatment week;
model <change from baseline> = treatment week baseline treatment*week 
baseline*week / s ddfm=kr;
repeated week / subject = subject type = un; 
  lsmeans treatment*week / cl pdiff;
run;
where change from baseline = change from baseline for the analysis parameter
baseline = baseline score of the analysis parameter
week = avisitn (from week 1 up to week 12 for Week 12 analysis / from week 1
up to week 20 for Week 20 analysis)
treatment = treatment group assigned in numeric (1 = 300 mg, 2 = 150 mg, 3 = 
Placebo)
subject = usubjid
Note that the diff dataset created will include all the treatment interactions for each week. The 
estimates for the right weeks, e.g. Week 12, and right treatment comparisons, e.g. 300 mg vs 
Placebo, should be subsetted by taking “week = 12 and _week=12” and “treatment=1 and 
_treatment=3”.
If the model with an unstructured covariance matrix does not converge, SAS will give a warning 
as “Unable to make hessian positive definite” or “Unable to Converge”. In this case, the 
compound-symmetry structure should be used instead: type=cs will be used in the above code.


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5.6.2
Other analysis
MMRM analysis are similar as defined for the primary analysis. 
5.6.2.1
Analysis of covariance (ANCOVA) model 
As a supportive analysis, change from baseline at Week 12 of ISS7 will be also estimated using 
analysis of covariance (ANCOVA) model using SAS procedure MIXED. Least square means 
for each treatment group are estimated, with p-values and confidence intervals generated under 
null hypothesis that no difference between active treatment group and placebo group. 
Baseline observation carried forward (BOCF) and last observation carried forward (LOCF) will 
be used separately to impute missing data at Week 12. 
The following code will be used for this analysis:
ods output LSMeans=lsmeans_est
    Estimates=diff_est;
proc mixed data=dataset order=internal;
class treatment;
model <change from baseline> = treatment baseline / s ddfm=kr;
  lsmeans treatment / cl pdiff;
  estimate "150 mg - Placebo" treatment 0 1 -1 / cl;
  estimate "300 mg - Placebo" treatment 1 0 -1 / cl;
run;
where change from baseline = change from baseline for the analysis parameter
baseline = baseline score of the analysis parameter
treatment = treatment group assigned in numeric (1 = 300 mg, 2 = 150 mg, 3 = 
Placebo)
5.6.2.2
Jump-to-reference (J2R) multiple imputation (control-based pattern 
imputation) for missing data
A multiple imputation for missing data approach will be performed to check the sensitivity of 
the primary analysis. As MMRM performed in the primary analysis is under MAR assumption, 
Jump-to-reference (J2R) multiple imputation also known as control-based pattern imputation 
under MNAR assumption for missing data will be performed. 
As the first step, SAS procedure MI is used to create a number of complete datasets using 
control-based pattern imputation. In step 2, each of these datasets is analyzed by the standard 
procedure (here it is PROC MIXED for MMRM model) and in step 3, the results of the multiple 
analyses are combined into a single analysis by using the SAS procedure MIANALYZE. 
The input dataset should have one record per subject with baseline score as well as all available 
ISS7 scores from Week 1 up to Week 12. The output dataset will contain a pre-specified number 
of concatenated imputed datasets and a new variable that identifies the imputation index. 
Once the imputation step is complete, the concatenated dataset can in turn be transposed back 
to the format with multiple records (weeks) per subject and then analyzed using PROC MIXED 
originally described in Section 5.6.1.1 with the additional by-variable of the index variable. The 
treatment differences (estimates and standard errors for 150 mg vs Placebo, 300 mg vs Placebo
and 150 mg vs 300 mg) at week 12 for each imputed dataset should be saved in a dataset for 
further analysis using PROC MIANALYZE.


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The imputation will be done in 2 steps:
1. To impute non-monotone missing data patterns – MAR assumption: in order to impute 
missing intermittent values.
2.  To perform the control-based imputation – MNAR assumption: in order to impute the 
missing values after subject’s discontinuation.
This method is based on the same methodology that was described by Ratitch, B. and O’Kelly, 
M. (2011).
The 1st step will be to impute all intermittent missing observations:
The following code will be used:
proc mi data=t_dat1b seed=1231 out=impdata_mono nimpute=1000;
   mcmc chain=multiple impute=monotone;
   var BASE _W1--_W12;
   by TRT01PN;
run;
where TRT01PN represents the planned treatment code (1: IGE 300 mg, 2: IGE 150 mg, 
3: Placebo)
     _W1 to _W12 represents all post-baseline scores (from Week 1 up to week 12)
      BASE is the ISS7 score at baseline.
In this step, only the non-monotone missing data will be imputed by using Markov Chain 
Monte Carlo methodology. So, our dataset will be partially imputed.
Note that 1000 imputations will be used. This number is much larger than the default in most 
software packages. This high number of imputations decreases at the best the uncertainty of the 
imputation.
And then, 2nd step will be to impute the monotone missing observations by using the control-
based imputation. This 2nd step will be done sequentially: one specific timepoint.
a) First, we will separate “impdata_mono“ dataset in 2 datasets:
o
One dataset containing all subjects with active treatments and with no missing data 
at Week 1: impdata_mono_rest1
o
One dataset containing all subjects with active treatments with missing data at 
Week 1 and all subjects in the control group: impdata_mono_imp1
data impdata_mono_imp1 impdata_mono_rest1;
set impdata_mono;
if trt01pn in(1,2) and lastweek>=1 then output impdata_mono_rest1; /*subjects 
taken active treatment and with non-missing values at Week 1*/
else output impdata_mono_imp1; /*subjects taken active treatment and with 
missing values at Week 1 or subjects in control group*/
run;
where TRT01PN represents the planned treatment code (1: IGE 300 mg, 2: IGE 150 mg, 
3: Placebo)
      LASTWEEK is the last week with a non-missing score (defined prior to any 
imputations).
b) Then, we will perform the imputation of missing data at Week 1 for the active treatments 
by using the control group:
proc sort data=impdata_mono_imp1; by _Imputation_ usubjid; run;


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proc mi data=impdata_mono_imp1 out=impdata_reg_imp1 nimpute=1 seed=234;
by _Imputation_;
var base _W1;
monotone reg(_W1=base);
run;
where _W1 represents the scheduled post-baseline scores Week 1
      BASE is the baseline score.
Since subjects from the active groups with non-missing values at time-point t are not included 
in the input dataset, they will not contribute to the estimation of an imputation model for time-
point t. The imputation model will be estimated using control subjects only, while this call to 
PROC MI will impute missing data at time-point t for all subjects who need imputation at that 
time-point. This way, subjects from active group will be imputed based on the control subjects’ 
model.
c) Then, we will assemble a dataset containing all subjects while including the just-imputed 
visit t data so that they can serve as predictors for the imputation of the next visit.
data impdata_mono1; 
set impdata_mono_rest1 impdata_reg_imp1; 
run;
d) The a), b) and c) steps will be repeated for all others timepoints sequentially up to Week 
12) using a reconstructed dataset (e.g., impdata_mono1) as a starting point in step (a). 
Once all missing data will be imputed, then the dataset will be transposed and the change 
from baseline will be recalculated. Then, a MMRM model will be done by using PROC 
MIXED with by “_Imputation_” and then, the results will be combining by using PROC 
MIANALYZE.
A MMRM model will be applied by _Imputation_ as per model below:
proc sort data=impfinal; by _imputation_ avisitn; run;
ods output Lsmeans=lsmeans_est
            Diffs=diff
            FitStatistics=FitStat
            ConvergenceStatus=conv;
proc mixed data=impfinal_ order=internal;
  by _Imputation_;
  class usubjid trt01pn avisitn;
  model chg = trt01pn avisitn base trt01pn*avisitn base*avisitn / s ddfm=kr;
  repeated avisitn / subject = usubjid type = un;  /*type = cs*/
  lsmeans trt01pn*avisitn / cl pdiff;
run;
where USUBJID represents the subject identifier
      TRT01PN represents the planned treatment code (1: IGE 300 mg, 2: IGE 150 mg, 
3: Placebo)
      AVISITN represents the study week from Week 1 up to Week 12
      BASE represents the baseline score
      CHG represents the change from baseline.


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Note that the diff dataset created will include all the treatment interactions for each week at 
each imputation and lsmeans_est dataset created will include all LS Mean for each week and 
each treatment at each imputation.
Then, all results will be pooled by using PROC MIANALYZE based on diff and lsmeans_est 
datasets:
proc sort data=diff; by avisitn trt01pn _trt01pn; run;
ods output ParameterEstimates= diffEstimates;
proc mianalyze data=diff;
   by avisitn trt01pn _trt01pn;
   modeleffects estimate;
   stderr stderr;
   where avisitn=12 and _avisitn=12;
run;
diffEstimates dataset created will contain all statistics related to the comparison of LS Mean.
proc sort data=lsmeans_est; by avisitn trt01pn; run;
ods output ParameterEstimates= LSmeansEstimates;
proc mianalyze data=lsmeans_est;
   by avisitn trt01pn;
  modeleffects estimate;
   stderr stderr;
run;
LSmeansEstimates dataset created will contain all LS Mean for each treatment and each visit.
5.6.2.3
Logistic regression model
Binary endpoints will be estimated using logistic regression model using SAS procedure 
GLIMMIX, specifying the distribution as binary and link function as logit. Compute least 
square means and confidence intervals by treatment group. Also odds ratios and their 
confidence intervals are estimated between active treatment group and placebo group. 
The following code will be used for this analysis:
ods output Estimates=diffor;
proc glimmix data=dataset order=internal;
   class treatment;
   model <response> (ref=first)= treatment baseline / dist=binary link=logit s ddfm=kr;
   lsmeans treatment / cl;
   estimate "150 mg - Placebo" treatment 0 1 -1 / cl exp;
   estimate "300 mg - Placebo" treatment 1 0 -1 / cl exp;
run; 
where response = response analysis value (1=Yes/0=No)
baseline = baseline score of the related parameter
treatment = treatment group assigned in numeric (1 = 300 mg, 2 = 150 mg, 3 = 
Placebo)
The odds ratios and their 95% CIs are given by the exponentiated variables in the diffor dataset 
(i.e. ExpEstimate, ExpLower, ExpUpper).
If the separation (at least one parameter estimate diverges to infinite, typically caused by zero 
or nearly zero response in the dichotomous covariates) happens, Firth’s method (Heinze and 


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Schemper, 2002) implemented in PROC LOGISTIC will be used with option firth 
clodds=pl specified. 
ods output Estimates=diffor;
proc logistic data=dataset order=internal;
  class treatment / param = glm;
  model <response> (ref=first)= baseline treatment / firth clodds=pl;
  estimate "150 mg - Placebo" treatment 0 1 -1 / cl exp;
  estimate "300 mg - Placebo" treatment 1 0 -1 / cl exp;
run;
5.6.2.5
Cox regression model
Time to event endpoints are analyzed using Cox regression model using SAS procedure PROC 
PHREG. Hazard ratios between active treatment group and placebo group and their confidence 
intervals will be generated by exponentially transforming the estimates and confidence intervals 
generated by the model. 
The following code will be used for this analysis:
ods output Estimates=Est;
proc phreg data=dataset;
  class treatment / order=internal param=glm;
  model time*censor(1)= treatment baseline;
  lsmeans treatment / cl diff;
  estimate "150 mg - Placebo" treatment 0 1 -1 / cl exp;
  estimate "300 mg - Placebo" treatment 1 0 -1 / cl exp;
run;
where time = time to event (e.g. time to first ISS7 MID response by week 12)
baseline = baseline score (e.g. of ISS7)
censor = censoring indicator variable (1 = censored, 0 = event)


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treatment = treatment group assigned in numeric (1 = 300 mg, 2 = 150 mg, 3 = 
Placebo)
The hazard ratios and their 95% CIs are given by the exponentiated variables in the Est dataset 
(i.e. ExpEstimate, LowerExp, UpperExp).
5.6.2.6
Multiple testing strategy
The results for multiple testing strategy will be presented as the example table below:  
Hypo-
thesis
Endpoint
Comparison
p-value
Outcome
Estimate
95% CI
unadjusted
adjusted
H1
ISS7 at 
Week 12
300 mg vs. 
Placebo
x.xx
(x.xx, 
x.xx)
0.007
0.014
Rejected
H2
ISS7 at 
Week 12
150 mg vs. 
Placebo
x.xx
(x.xx, 
x.xx)
0.049
0.098
Not 
rejected
H3
UAS7 at 
Week 12
300 mg vs. 
Placebo
x.xx
(x.xx, 
x.xx)
0.024
0.048
Rejected
H4~H1
4
H15
Time to 
ISS7 
MID 
response 
by Week 
12
300 mg vs. 
Placebo
x.xx
(x.xx, 
x.xx)
0.023
0.170
Not 
rejected
H16
Time to 
ISS7 
MID 
response 
by Week 
12
150 mg vs. 
Placebo
x.xx
(x.xx, 
x.xx)
0.010
0.230
Not 
rejected
The following SAS macro will be used to derive the adjusted p-values and testing outcomes:
START gmcp(p, w, g);
    n = NCOL(p);  padj = j(1,n,0);  pmax = 0;  crit = 0;
    DO UNTIL(crit = n);
      pos = LOC(w>0);  zero = LOC(w<=0); q = j(1,n,0);
      IF NCOL(pos)>0 THEN DO;
        q[pos] = p[pos]/w[pos];
        IF NCOL(zero)>0 THEN q[zero] = MAX(q[pos])+1;
      END;


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      ELSE RETURN('gMCP ERROR: Disconnected hypothesis with weight 0.');
      rej = MIN(LOC(q - MIN(q) <= 0));
      padj[rej] = MAX(q[rej], pmax);
      pmax = padj[rej];
      g1 = J(n, n, 0);
      DO i = 1 TO n; 
        w[i] = w[i] + w[rej]*g[rej,i];
        IF (g[i,rej]*g[rej,i]<1) THEN DO j = 1 TO n;
          g1[i,j] = (g[i,j] + g[i,rej]*g[rej,j])/(1 - g[i,rej]*g[rej,i]);
        END; 
        g1[i,i] = 0;
      END; 
      g = g1;  g[rej,] = 0;  g[,rej] = 0;  w[rej] = 0;  crit = crit + 1;
    END;
    padj = padj >< j(1,n,1);
    RETURN(padj);
FINISH;
The above macro used is published in Bretz et al (2011) and Alosh et al (2014), and is now a 
validated SAS macro that has been implemented in Novartis trials. 
Inputs for n hypotheses: 
•
p: Observed p values (1 x n vector) with n equals to the number of hypotheses 
which is 16 here. 
•
w: Weights for the hypotheses (1 x n vector)
= (0.5, 0.5, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0)
•
g: Transition weights for the directed edges (n x n matrix): 
=
⎝
⎜
⎜
⎜
⎜
⎜
⎜
⎜
⎜
⎜
⎜
⎜
⎜
⎛
0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ⎠
⎟
⎟
⎟
⎟
⎟
⎟
⎟
⎟
⎟
⎟
⎟
⎟
⎞


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The input p will contain two-sided unadjusted p-values, however if there are any comparisons 
that favor placebo, then the values of p will be adjusted in the following way before using the 
macro:

For the hypotheses on the left hand side of the graphical approach (H1, H3, ..., 
H15, for the 300mg dose), find the first hypothesis where the direction is in 
favor of placebo (no matter what the p value is), then in the vector p replace 
the unadjusted p-values of all the following hypotheses with 1.

For the hypotheses on the right hand side of the graphical approach (H2, 
H4, ..., H16, for the 150mg dose), find the first hypothesis where the direction 
is in favor of placebo (no matter what the p value is), then in the vector p
replace the unadjusted p-values of all the following hypotheses with 1.
This is because the significance level of a rejected hypothesis is only passed on according to 
the graphical procedure for the test of another hypothesis if the treatment effect is in favor of 
omalizumab (see section 2.6.2).
Outputs: 
•
padj: Adjusted p values (1 x n vector)
The source program is located in GPS (Global Programming and Statistics).
5.7
Rule of exclusion criteria of analysis sets 
Subject classification will be done by Protocol Deviation and non-Protocol Deviation criteria 
based on the tables below:


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Table 5-2
List of protocol deviations that cause subjects to be excluded
Deviation ID
Description of Deviation
Excluded from
INCL01A 
/ 
INCL01B
Informed consent missing or not signed 
prior to initiating study procedures.
FAS, SAF, PPS
INCL02
Age criteria not met
PPS
INCL03A
No diagnosis of CSU refractory to H1AH 
due to date of diagnosis not meeting criteria
PPS
INCL03B
No diagnosis of CSU refractory to H1AH 
due to lack of criteria on itch and hives
PPS
INCL03C
No diagnosis of CSU refractory to H1AH 
due to UAS7 score
PPS
INCL03D
No diagnosis of CSU refractory to H1AH 
due to UAS score
PPS
INCL03E
Criteria requirement at screening for prior 
use of H1AH at approved dose not met
PPS
INCL04  
Unwilling or unable to complete a daily 
symptom eDiary
PPS
INCL05
Missing one or more eDiary entries in the 7 
days prior to randomization
PPS
EXCL01
Underlying etiology for chronic urticarias 
other than CSU
PPS
EXCL03
Any other skin diseases than CSU with 
chronic itching
PPS
EXCL04
Previous treatment with omalizumab
PPS
EXCL05
Contraindications to diphenhydramine
PPS
EXCL06
History of anaphylactic shock
PPS
EXCL08
Patients who are sucrose intolerant
PPS
EXCL11
Inability to comply with study and follow-
up procedures
PPS
EXCL13
Patients previously randomized into this 
study
FAS, PPS
EXCL14
Use of other investigational drugs
PPS
EXCL15
History of hypersensitivity to study drug or 
similar chemical classes
PPS


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Deviation ID
Description of Deviation
Excluded from
EXCL17
Ongoing use of prohibited treatments at 
screening epoch
PPS
COMD01
Use of prohibited medication during 
randomized-treatment epoch.
PPS
TRT01
Incorrect dose of study medication
PPS
TRT02
Subject 
received 
the 
wrong 
study 
medication.
PPS
TRT03
Subject missed the administration
PPS
OTH01
Subject added new H1AH to the stable 
H1AH 
regimen during screening or 
randomized-treatment epoch.
PPS
OTH02  
Subject decreased H1AH regimen during 
screening 
and 
treatment 
epoch 
or 
discontinued stable H1AH regimen on any 
epoch
PPS
OTH02A
Subject 
received 
overdose 
of 
diphenhydramine rescue medication during 
screening or randomized-treatment epoch.
PPS
OTH06
Patient 
not 
compliant 
with 
eDiary 
completion requirements
PPS
OTH07
Inappropriate 
maintenance
of 
study 
medication
PPS
OTH09
Incorrect background treatment use of 
sedating H1AH
PPS
OTH10
Rescue medication mistakenly used as 
background medication
PPS
OTH11
Patient was Randomized but no study drug 
was taken
FAS, SAF, PPS
Table 5-3
Non-Protocol deviations that cause subjects to be excluded
Non-Protocol deviation criteria that 
cause a subject to be excluded
Excluded from
No treatment taken 
FAS, SAF, PPS


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Less than 3 doses of study drugs by 
Day 85
PPS
5.8
Systemic treatments
The list of the systemic treatment to use is: 

Systemic corticosteroids 

Hydroxychloroquine

Immunosuppression (e.g. methotrexate, cyclosporine, tacrolimus, mycophenolate 
mofetil, cyclophosphamide, or triperygium wilfordii Hook) 

Intravenous immunoglobulin G

H2 antihistamine

Leukotriene receptor antagonist (LTRA)

Oral Chinese traditional medicine prescribed for CSU
5.9
Latent TB status at baseline
An incubation issue has been identified which impacted the TB test samples in around 150
patients. The issue was that TB samples incubator temperature was fluctuating. EXCL21C
Protocol Deviation (Potential invalid QuantiFERON TB negative test result) has been created 
in order to identify these subjects.
In addition, several sites have not specified the correct TB status at the time of randomization, 
they wrote “Yes” while the correct TB status was “No”. For all analysis performed, the latent 
TB status at baseline from laboratory data will be used (rather than IRT data).
6
Reference
Alosh, M., Bretz, F., & Huque, M. (2014). Advanced multiplicity adjustment methods in 
clinical trials. Statistics in medicine, 33(4), 693-713.
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 284):586-604.
Bretz, F., Maurer, W., & Hommel, G. (2011). Test and power considerations for multiple 
endpoint analyses using sequentially rejective graphical procedures. Statistics in medicine, 
30(13), 1489-1501.
Heinze, G. and Schemper, M. (2002) A Solution to the Problem of Separation in Logistic 
Regression, Statistics in Medicine, 21, 2409–2419.
Mallinckrodt, CH, Scott CW, and David SR (2001) Accounting for dropout bias using mixed-
effects models. Journal of Biopharmaceutical Statistics; 11, 9-21.


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Ratitch, B. and O’Kelly, M. (2011), Implementation of Pattern-Mixture Models Using 
Standard SAS/STAT Procedures, in Proceedings of PharmaSUG 2011 (Pharmaceutical 
Industry SAS Users Group), SP04, Nashville.
Rubin DB (1976) Inference and Missing Data. Biometrika; 63:581-92.