Clinical trial NCT03369704
Conditions: Seasonal Allergic Rhinitis
Keywords: cryptomeria, omalizumab, seasonal allergic rhinitis
Sponsor: Novartis Pharmaceuticals
Start date: 2017-12-15; Completion date: 2018-10-20
Enrollment: 337 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, on top of SoC (anti-histamine and nasal corticosteroid) in adult and adolescent patients with severe Japanese cedar pollinosis, whose symptoms were inadequately controlled despite the current recommended therapies (nasal corticosteroids plus one or more medications out of anti-histamine, leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 receptor antagonist) in the previous 2 Japanese cedar pollen seasons.

Detailed description:

Arms: arm 1: Eligible patients randomized to this arm received omalizumab subcutaneously for 12 weeks arm 2: Eligible patients randomized to this arm received placebo subcutaneously for 12 weeks
Interventions: intervention 1: Omalizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Omalizumab were administered by subcutaneous injection. Dose (75 to 600 mg) and dosing frequency (every 2 or 4 weeks) were determined by serum total IgE level (IU/mL) and body weight (kg) measured at the screening epoch according the dosing table. intervention 2: Placebo were administered by subcutaneous injection. Dose (75 to 600 mg) and dosing frequency (every 2 or 4 weeks) were determined by serum total IgE level (IU/mL) and body weight (kg) measured at the screening epoch according the dosing table.

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
CIGE025/Omalizumab 
Clinical Trial Protocol CIGE025F1301 / NCT03369704
A 12 week, multi-center, randomized, double-blind, 
placebo-controlled phase III study to evaluate the efficacy 
and safety of omalizumab in adult and adolescent patients 
with inadequately controlled severe Japanese cedar 
pollinosis despite the current recommended therapies 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2017-002154-36 
Version number: 
00 (Original Protocol) 
Clinical trial phase: 
III 
Release date: 
07-Jun-2017
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.3 (February 2017) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 10 
1 
Introduction ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Purpose .................................................................................................................. 14 
2 
Study objectives and endpoints ......................................................................................... 14 
2.1 
Objectives and related endpoints ........................................................................... 14 
3 
Investigational plan ........................................................................................................... 16 
3.1 
Study design........................................................................................................... 16 
3.2 
Rationale for study design ..................................................................................... 18 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 18 
3.4 
Rationale for choice of comparator ....................................................................... 19 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 20 
3.6 
Risks and benefits .................................................................................................. 20 
4 
Population .......................................................................................................................... 22 
4.1 
Inclusion criteria .................................................................................................... 22 
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 .............................................................................. 26 
5.2 
Treatment arms ...................................................................................................... 26 
5.3 
Treatment assignment and randomization ............................................................. 27 
5.4 
Treatment blinding ................................................................................................. 27 
5.5 
Treating the patient ................................................................................................ 28 
5.5.1 
Patient numbering ................................................................................. 28 
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 ....................................................................... 32 
5.5.8 
Prohibited medication ........................................................................... 33 
5.5.9 
Emergency breaking of assigned treatment code .................................. 35 
5.6 
Study completion and discontinuation ................................................................... 35 
5.6.1 
Study completion and post-study treatment .......................................... 35 
5.6.2 
Discontinuation of study treatment ....................................................... 35 
5.6.3 
Withdrawal of informed consent ........................................................... 36 
5.6.4 
Loss to follow-up .................................................................................. 37 
5.6.5 
Early study termination by the sponsor ................................................. 37 
6 
Visit schedule and assessments ......................................................................................... 37 
6.1 
Information to be collected on screening failures .................................................. 40 
6.2 
Patient demographics/other baseline characteristics ............................................. 40 
6.3 
Treatment exposure and compliance ..................................................................... 40 
6.3.1 
Omalizumab/Placebo ............................................................................ 40 
6.3.2 
Concomitant medications for Japanese cedar pollinosis ....................... 40 
6.4 
Efficacy .................................................................................................................. 40 
6.4.1 
e-Diary assessment ................................................................................ 41 
6.4.2 
Japanese Rhino-conjunctivitis Quality of Life Questionnaire 
(JRQLQ) ................................................................................................ 43 
6.4.3 
Appropriateness of efficacy assessments .............................................. 43 
6.5 
Safety ..................................................................................................................... 43 
6.5.1 
Physical examination ............................................................................ 43 
6.5.2 
Vital signs.............................................................................................. 43 
6.5.3 
Height and weight ................................................................................. 44 
6.5.4 
Laboratory evaluations .......................................................................... 44 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 44 
6.5.6 
Pregnancy and assessments of fertility ................................................. 45 
6.5.7 
Appropriateness of safety measurements .............................................. 45 
6.6 
Other assessments .................................................................................................. 45 
 
 45 
 
 
 45 
6.6.3 
Resource utilization ............................................................................... 46 
6.6.4 
Pharmacokinetics and pharmacodynamics ........................................... 46 
 
 46 
7 
Safety monitoring .............................................................................................................. 46 
7.1 
Adverse events ....................................................................................................... 46 


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7.2 
Serious adverse events ........................................................................................... 48 
7.2.1 
Definition of SAE ................................................................................. 48 
7.2.2 
SAE reporting........................................................................................ 49 
7.3 
Liver safety monitoring ......................................................................................... 49 
7.4 
Reporting of study treatment errors including misuse/abuse ................................ 50 
7.5 
Pregnancy reporting ............................................................................................... 51 
8 
Data review and database management ............................................................................. 51 
8.1 
Site monitoring ...................................................................................................... 51 
8.2 
Data collection ....................................................................................................... 52 
8.3 
Database management and quality control ............................................................ 52 
8.4 
Data Monitoring Committee .................................................................................. 53 
8.5 
Adjudication Committee ........................................................................................ 53 
9 
Data analysis ...................................................................................................................... 53 
9.1 
Analysis sets .......................................................................................................... 53 
9.2 
Patient demographics and other baseline characteristics ....................................... 54 
9.3 
Treatments ............................................................................................................. 54 
9.4 
Analysis of the primary variable(s) ....................................................................... 54 
9.4.1 
Primary Variable(s) ............................................................................... 54 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 55 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 55 
9.4.4 
Sensitivity analyses ............................................................................... 55 
9.5 
Analysis of secondary variables ............................................................................ 55 
9.5.1 
Efficacy variables .................................................................................. 56 
9.5.2 
Safety variables ..................................................................................... 56 
9.5.3 
Resource utilization ............................................................................... 57 
9.5.4 
Pharmacokinetics .................................................................................. 57 
9.5.5 
DNA ...................................................................................................... 57 
9.5.6 
Biomarkers ............................................................................................ 57 
9.5.7 
PK/PD ................................................................................................... 58 
 
 58 
9.7 
Interim analyses ..................................................................................................... 58 
9.8 
Sample size calculation .......................................................................................... 58 
10 Ethical considerations ........................................................................................................ 59 
10.1 
Regulatory and ethical compliance ........................................................................ 59 
10.2 
Informed consent procedures ................................................................................. 59 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 60 


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10.4 
Publication of study protocol and results............................................................... 60 
10.5 
Quality Control and Quality Assurance ................................................................. 60 
11 Protocol adherence ............................................................................................................ 60 
11.1 
Protocol amendments ............................................................................................. 61 
12 References ......................................................................................................................... 62 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 63 
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 64 
15 Appendix 3: Patient e-Diary (sample) ............................................................................... 66 
16 Appendix 4: Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ) ...... 68 
 
 
 70 
18 Appendix 6: Blood log ...................................................................................................... 72 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 14 
Table 4-1 
Severity of nasal symptoms .................................................................. 23 
Table 4-2 
Severity of ocular symptoms ................................................................. 23 
Table 5-1 
Dosing table (mg/dose) ......................................................................... 27 
Table 5-2 
Prohibited medication ........................................................................... 33 
Table 6-1 
Assessment schedule ............................................................................. 38 
Table 6-2 
Severity of nasal symptoms .................................................................. 41 
Table 6-3 
Severity of ocular symptoms ................................................................. 42 
Table 6-4 
Score for medication use ....................................................................... 42 
Table 6-5 
Severity of impairment of daily activities ............................................. 42 
 
 45 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 51 
Table 9-1 
Sensitivity of power to change in assumptions for N=346 ................... 59 
Table 14-1 
Liver Event and Laboratory Trigger Definitions .................................. 64 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 64 
Table 18-1 
Blood log for PK and PD Samples ........................................................ 72 
Table 18-2 
Blood log for immunogenicity .............................................................. 72 
 


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List of figures 
Figure 3-1 
Study design .......................................................................................... 17 
 


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List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AR 
Adverse reactions 
AST 
Aspartate Aminotransferase 
AV 
Atrioventricular 
BMI 
Body mass index 
CABG 
Coronary artery bypass graft 
CPO 
Country Pharma Organization 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organisation 
DAR 
Dosage administration record 
DSM 
Drug Supply Management 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
JRQLQ 
Japanese Rhinoconjunctivitis Quality of Life Questionnaire 
LFT 
Liver function test 
MAR 
Missing at Random 
MedDRA 
Medical dictionary for regulatory activities 
MI 
myocardial infarction 
MMRM 
mixed model for repeated measure 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
QM 
Quality Management 
QoL 
quality of life 
QTcF 
Fridericia QT correction formula 
RAN 
Randomized set 


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RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAF 
Safety set 
SAP 
Statistical analysis plan 
SC 
subcutaneous 
SMQ 
Standardized MedDRA Query 
SoC 
Standard of cares 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TD 
Study treatment discontinuation 
UNS 
Unscheduled treatment discontinuation visit 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
β-hCG 
Beta Human Chorionic Gonadotropin 


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Glossary of terms 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 
100 mg once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care. 
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.” 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT (Interactive 
Response Technology) system 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource. 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Withdrawal of consent 
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material 
 


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Protocol summary 
Protocol number 
CIGE025F1301 
Full Title 
A 12 week, multi-center, randomized, double-blind, placebo-controlled 
phase III study to evaluate the efficacy and safety of omalizumab in adult 
and adolescent patients with inadequately controlled severe Japanese 
cedar pollinosis despite the current recommended therapies 
Brief title 
Study of efficacy and safety of omalizumab in severe Japanese cedar 
pollinosis adult and adolescent patients 
Sponsor and  
Clinical Phase 
Novartis / Phase III 
Investigation type 
Drug 
Study type 
Investigational 
Purpose and rationale 
To demonstrate the efficacy and safety of omalizumab compared with 
placebo, on top of standard of cares (SoC, anti-histamine and nasal 
corticosteroid) in adult and adolescent patients with severe Japanese 
cedar pollinosis, whose symptoms were inadequately controlled despite 
the current recommended therapies (nasal corticosteroids plus one or 
more medications out of anti-histamine, leukotriene receptor antagonist, or 
prostaglandin D2/thromboxane A2 receptor antagonist) in the previous 2 
Japanese cedar pollen seasons. 
Primary Objective(s) 
To demonstrate the efficacy of omalizumab compared with placebo with 
respect to mean nasal symptom score during the severe symptom period 
Secondary Objectives 
Objective 1: To evaluate the efficacy of omalizumab compared with 
placebo with respect to the following endpoints during the severe symptom 
period. 
• Mean ocular symptom score and mean nasal ocular symptom score 
• Mean nasal symptom medication score, mean ocular symptom 
medication score, and mean nasal ocular symptom medication score 
• Mean score for severity of sneezing, rhinorrhea and nasal congestion 
• Mean score for severity of itchy and watery eye 
• Mean score for impairment of daily activities 
• Symptom free days 
• Use of rescue medication 
• Japanese Rhino-conjunctivitis Quality of Life Questionnaire score 
Objective 2: To evaluate the safety of omalizumab compared with placebo 
with respect to adverse events, serious adverse events, adverse events of 
special interest, physical examinations, laboratory assessments, vital signs 
and anti-omalizumab antibodies. 
Objective 3: To evaluate the PK/PD of omalizumab with respect to serum 
omalizumab concentration, free IgE concentration and total IgE 
concentration at evaluation visits. 
Study design 
Randomized multi-center, double-blind, placebo-controlled study 
Population 
The study population consist of adult and adolescent (≥ 12 - < 75 years) 
patients with severe Japanese cedar pollinosis whose symptoms were 
inadequately controlled despite the nasal corticosteroid plus one or more 
medications out of anti-histamine (second generation), leukotriene 
receptor antagonist, or prostaglandin D2/thromboxane A2 receptor 
antagonist in the previous 2 Japanese cedar pollen seasons. 


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In the study, a total of 346 patients will be enrolled in Kanto-area of Japan. 
Approximately 10% of the total patients enrolled will be the patients aged 
≥ 12 - < 15 years at the screening epoch. Since a 10% screen failure rate 
is expected, approximately 390 patients will be screened. 
Key Inclusion criteria 
• Aged ≥ 12 - < 75 years at the screening epoch. 
• A clinical history of Japanese cedar pollinosis defined by the following: 
• Took nasal corticosteroid plus one or more medications out of anti-
histamine (second generation), leukotriene receptor antagonist, or 
prostaglandin D2/thromboxane A2 receptor antagonist in Japanese 
cedar pollen seasons in 2016 and 2017.  
• Had inadequately controlled symptoms of Japanese cedar pollinosis 
lasting at least one week in the Japanese cedar pollen season in 
2017 despite the intranasal corticosteroid plus one or more 
medications out of anti-histamine (second generation), leukotriene 
receptor antagonist, or prostaglandin D2/thromboxane A2 receptor 
antagonist (regardless of having perennial allergic rhinitis or not). 
• Serum cedar pollen-specific Immunoglobulin E (IgE) levels of ≥ score 
of 3 by CAP-RAST/FEIA, ImmunoCAP or MAST at the screening 
epoch. 
• Developing a symptom of Japanese cedar pollinosis during the period 
from first observational day* in cedar pollen in Kanto area to initial drug 
administration (Visit 101), as defined by the following: 
• Having any nasal or ocular symptom (≥ score of 1 in sneezing, 
rhinorrhea, nasal congestion, itchy eye or watery eye) in at least 2 
days 
or 
• Having both any nasal symptom (≥ score of 1 in sneezing, 
rhinorrhea, nasal congestion) and any eye symptom (≥ score of 1 in 
itchy eye or watery eye) in at least one day, 
which is confirmed by patient e-diary (unless a symptom is clearly 
consider to take place due to other than Japanese cedar 
pollinosis/allergic rhinitis (e.g., upper respiratory tract infection, or 
common cold)). 
*It will be notified to the investigator in writing by the sponsor. 
• Body weight and serum total IgE level at screen epoch within the 
dosing table range; body weight of ≥ 20 to ≤ 150 kg and serum total IgE 
levels of ≥ 30 to ≤ 1500 IU/mL at a maximum. 
Key Exclusion criteria 
• With an active rhinitis other than allergic rhinitis (e.g., acute or chronic 
rhinitis, idiopathic rhinitis) 
• With an active nose disease other than allergic rhinitis (e.g., acute or 
chronic rhinosinusitis or deflected septum) which is expected to affect 
the evaluation of efficacy of the study drug judged by the investigator 
• With elevated serum IgE levels for reasons other than allergy (e.g. 
parasite infections, hyperimmunoglobulin E syndrome, Wiskott-Aldrich 
Syndrome or clinical allergic bronchopulmonary aspergillosis). 
• With a severe asthma treated with high dose inhaled corticosteroid 
(≥ 800 µg/day fluticasone propionate or an equivalent for aged ≥ 16 to 
< 75 years, > 200 µg/day for aged ≥ 12 to < 16 years) 
• Who are receiving operative treatment for allergic rhinitis (e.g., 
electrocoagulation, laser surgery, 80% trichloroacetic acid 


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chemo-surgery, inferior turbinectomy or posterior nasal neurectomy) 
within 1 years prior to the screening epoch 
Study treatment 
Omalizumab 150 mg, placebo 
Efficacy assessments 
• e-Diary assessment 
• Nasal symptom 
• Ocular symptom 
• Medication use 
• Impairment of daily activities 
• JRQLQ (Japanese Rhino-conjunctivitis Quality of Life Questionnaire) 
Key safety 
assessments 
Safety of omalizumab compared with placebo with respect to adverse 
events, serious adverse events, adverse events of special interest, 
physical examinations, laboratory assessments, vital signs and 
anti-omalizumab antibodies 
Other assessments 
• 
 
• The pharmacokinetics(PK)/pharmacodynamics(PD) of Omalizumab 
• 
 
 
• 
 
Data analysis 
The mean nasal symptom score during the severe symptom period will be 
compared between treatments using an analysis of variance model with 
treatment group, dosing schedule (two-weekly or four-weekly) and 
randomization strata for the Full analysis set (FAS) based on hypotheses: 
H0: Omalizumab is not different to placebo with respect to mean nasal 
symptom score over the severe symptom period, H1: Omalizumab is 
different to placebo with respect to mean nasal symptom score over the 
severe symptom period. Adverse events will be summarized with 
descriptive statistics for the Safety set (SAF). The secondary efficacy 
variables will be basically analyzed using the same model as the primary 
variable for the FAS. 
Key words 
Add-on to standard of care, Nasal symptom score, Omalizumab, Patients 
aged ≥ 12 to < 75 years, Placebo-controlled, Uncontrolled severe 
Japanese cedar pollinosis 


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1 
Introduction 
1.1 
Background 
Japanese cedar pollinosis (Japanese cedar pollen-induced seasonal allergic rhinitis) is a 
substantial medical problem in Japan, afflicting approximately 30% of the Japanese people. It 
is a type I allergic disease of the nasal mucosa, characterized by paroxysmal repetitive sneezing, 
watery rhinorrhea, and nasal congestion, frequently coexisting with eye symptoms (e.g., itchy 
eye and watery eye). It is mainly classified with two disease types of “Sneezing and rhinorrhea 
type” and “nasal blockage type” based on the main symptom. Japanese cedar pollen season 
generally starts end-January/ early-February and lasts until the end of April, in which March is 
the most severe (Practical guideline for the management of allergic rhinitis in Japan 2016, 
Okubo et al 2017). 
Treatment for Japanese cedar pollinosis consists of elimination/avoidance of cedar pollen (e.g., 
mask, glasses), pharmacotherapy, specific immunotherapy and operative treatment (for 
morphological abnormality). Pharmacotherapy is chosen based on the severity and disease type 
of the patients. When cedar pollens begin to scatter (or when symptoms develop), treatment is 
initiated commonly with anti-histamine or leukotriene receptor antagonist (or prostaglandin 
D2/thromboxane A2 receptor antagonist) and when the symptoms are exacerbated as cedar 
pollens scattering increases, nasal corticosteroid is added. During the peak season, patients with 
severe Japanese cedar pollinosis are treated with the combination of nasal corticosteroid and 
anti-histamine (Sneezing and rhinorrhea type) or of nasal corticosteroid, anti-histamine, and 
leukotriene receptor antagonist (nasal blockage type). In case of severe nasal blockage, nasal 
vasoconstrictor is added (Practical guideline for the management of allergic rhinitis in Japan 
2016). 
However, these standard of cares (SoC) are not effective enough. According to the internet 
survey by Okubo (Okubo and Okuda 2012), about half of the Japanese cedar pollinosis patients 
developed severe symptoms and even after treated with SoC, 25% of the patients still had 
symptoms. In addition, 10% of the patients were strongly unsatisfied with the efficacy of SoC. 
Such symptoms can affect quality of life (QoL) by causing fatigue, headache, cognitive 
impairment, and result in loss of work productivity and school days. According to the survey, 
70% of cedar pollinosis patients had significantly reduced QoL. Thus, significant unmet needs 
are thought to remain in the treatment with Japanese cedar pollinosis. 
Omalizumab (Xolair®) is a humanized monoclonal anti-Immunoglobulin E (IgE) antibody 
currently approved for treating inadequately controlled allergic asthma and chronic spontaneous 
urticaria worldwide including Japan, which selectively binds to the Ce3 domain of IgE that 
interacts with IgE receptors on effector cells (Presta et al 1993). This antibody blocks the 
binding of IgE to high-affinity receptors (FceRI), thereby preventing the IgE-mediated (type I 
allergic) cellular responses (Shields et al 1995, Beck et al 2004). We previously conducted 
randomized controlled studies with omalizumb against placebo (CIGE025A1303, Okubo et al 
2006) and suplatast tosilate (CIGE025A1305, Nagakura et al 2008), which showed that 
omalizumab was effective and safe in patients with moderate to severe Japanese cedar pollinosis. 
Patients treated with omalizumab achieved a clinically relevant suppression in nasal and eye 
symptoms associated with the disease. The safety profile for omalizumab was consistent with 
the profile previously reported for the allergic asthma indication and no new safety concerns 


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were raised. In addition, administration of omalizumab in two consecutive Japanese cedar 
pollen seasons was shown to be well-tolerated and loss of efficacy was not observed 
(CIGE025A1306, Ogino et al 2009). Based on available data of omalizumab, it is postulated 
that omalizumab will have a favorable benefit to risk profile and represent a new promising 
treatment in patients with Japanese cedar pollinosis. 
In this study, we will evaluate the efficacy and safety of omalizumab on top of SoC in patients 
with severe Japanese cedar pollinosis, which reflects the positioning of omalizumab expected 
in the treatment with Japanese cedar pollinosis. 
1.2 
Purpose 
The purpose of this study is to demonstrate the efficacy and safety of omalizumab compared 
with placebo, on top of SoC (anti-histamine and nasal corticosteroid) in adult and adolescent 
patients with severe Japanese cedar pollinosis, whose symptoms were inadequately controlled 
despite the current recommended therapies (nasal corticosteroids plus one or more medications 
out of anti-histamine, leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 
receptor antagonist) in the previous 2 Japanese cedar pollen seasons. 
The results of this study will support registration of omalizumab for Japanese cedar pollinosis 
in Japan. 
2 
Study objectives and endpoints 
2.1 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
• To demonstrate the efficacy of 
omalizumab compared with placebo 
• Mean nasal symptom score during the severe 
symptom period 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
• To evaluate the efficacy (symptoms, 
quality of life impairment) of omalizumab 
compared with placebo 
• Mean score of the following endpoints during the 
severe symptom period 
• Ocular symptom score and nasal ocular 
symptom score 
• Nasal symptom medication score, ocular 
symptom medication score, and nasal ocular 
symptom medication score 
• Score for severity of sneezing, rhinorrhea and 
nasal congestion 
• Score for severity of itchy and watery eye 
• Score for impairment of daily activities 
• Symptom free days (days with all nasal symptoms 
are not more than mild in severity) during the 
severe symptom period 


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Objective(s) 
Endpoint(s) 
• Use of rescue medication (tramazoline 
hydrochloride, levocabastine hydrochloride) during 
the severe symptom period 
• Rescue medication score 
• Number of days with no rescue medication 
• Amount of rescue medication used 
• Japanese Rhinoconjunctivitis Quality of Life 
Questionnaire (JRQLQ, No1) score at evaluation 
visit 
• To evaluate the safety of omalizumab 
compared with placebo 
• Adverse events, serious adverse events, adverse 
events of special interest, physical examinations, 
laboratory assessments, vital signs and 
anti-omalizumab antibodies 
• To evaluate the PK/PD of omalizumab 
• Serum omalizumab concentration, free IgE 
concentration and total IgE concentration at 
evaluation visit 
Severe symptom period: The three weeks where the cumulative value of the mean daily nasal 
symptom score will be the maximum. 
Severe pollen period: The period between the first and last days when ≥ 50 grains/cm2 of Japanese 
cedar pollen are counted. 
Pollen period: The start day of the pollen period is defined as the first of 2 consecutive days when 
≥ 1 grain/cm2 of Japanese cedar pollen is counted; the end day of the pollen period is the first of 3 
consecutive days when no grain is counted. 
Japanese cedar pollen count: The data at Chiyoda-Ku, Tokyo, which will be provided from 
 
, will be used in the study. 


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3 
Investigational plan 
3.1 
Study design 
This is a Phase III multi-center, randomized, double-blind, placebo-controlled study in patients 
with severe Japanese cedar pollinosis, whose symptoms were inadequately controlled despite 
the current recommended therapies (nasal corticosteroid plus one or more medications out of 
anti-histamine (second generation), leukotriene receptor antagonist, or prostaglandin 
D2/thromboxane A2 receptor antagonist) in the previous 2 Japanese cedar pollen seasons. 
Approximately 346 patients will be enrolled in Kanto-area of Japan. 
The study consists of 3 distinct study epochs: 
- 
Screening epoch: Day -35 to Day -1 (1 - 5 weeks) 
- 
Treatment epoch: Day 1 to Day 85 (12 weeks) 
- 
Post-treatment follow-up: Day 225/239 (24 weeks after the last dosing) 
Screening epoch 
Informed consent for a patient must be obtained prior to performing any study-related 
assessments or collecting any data for the screening visit. For patients aged ≥ 12 - < 20 years at 
the screening epoch, parent or legal guardian has given written informed consent and the patient 
has given assent consent, if applicable. 
Each patient’s eligibility based on the inclusion and exclusion criteria will be determined during 
the screening period. 
The patients should carefully record their nasal symptoms, ocular symptoms, usage of 
medications and impairments of daily activities on their e-diaries everyday. Only medications 
indicated in Section 5.5.6 and Section 5.5.7 are permitted to use for Japanese cedar pollinosis 
(allergic rhinitis). Fexofenadine hydrochloride and tramazoline hydrochloride for nasal 
symptoms, and levocabastine hydrochloride for eye symptoms are allowed to use as rescue 
medications. 
Only one re-screening will be allowed for patients who have failed initial screening. If a patient 
rescreens for the study, the patient must sign a new informed consent prior to performing any 
study-related assessments or collecting any data and he/she will be issued a new patient number. 
Treatment epoch 
On Day 1, eligible patients will be randomly assigned in a 1:1 ratio to receive omalizumab or 
placebo by subcutaneous injection. Patients will be stratified using Interactive Response 
Technology (IRT), based on the age group (≥ 12 to < 15 years and ≥ 15 to < 75 years), 
coexisting of perennial allergic rhinitis (Yes/No), dose frequency (every 2 weeks and 4 weeks) 
and having cedar pollinosis symptom at the initial drug administration (Yes / No). 
Doses (mg) and dosing frequency (every 2 or 4 weeks) of the study drug will be determined by 
serum total IgE level (IU/mL) and body weight (kg) measured at the screening epoch according 
to the dosing table (Table 5-1) and must not be changed during the treatment epoch. Initial 
administration of the study drug will be conducted in approximately 3 weeks between 
mid-January and mid-February in 2018, which will be determined by the sponsor based on the 


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forecast of cedar pollen scattering and be notified to the investigator by the end of 2017. 
Allowable range of study drug administration recommended is the designated day ± 7 days. In 
addition, at least one-week interval will be kept between administrations. 
Patients are expected to attend all site visits based on the assessment schedule (Table 6-1) and 
to complete the entire 12 weeks duration. Patients should carefully record their nasal symptoms, 
ocular symptoms, usage of medications and impairments of daily activities on their e-diaries 
everyday. 
Only medications indicated in Section 5.5.6 and Section 5.5.7 are permitted to use for Japanese 
cedar pollinosis (allergic rhinitis). During the treatment epoch, fexofenadine hydrochloride 
(oral, 60 mg/time, twice per day) should be used as a concomitant medication irrespective of 
patient’s symptoms. In addition, in approximately 2 - 4 weeks around in March, fluticasone 
propionate (1 spray (50 µg for patients aged ≥ 15 to < 75 years, 25 µg for patients aged ≥ 12 to 
< 15 years)/nostril, twice per day) should be used as a concomitant medications irrespective of 
patient’s symptoms, as well in ALL patients. Start date of fluticasone propionate use and 
duration of fluticasone propionate use (2 - 4 weeks) will be determined by the sponsor based on 
the forecast of cedar pollen scattering and be notified to the investigator in writing by mid-
February 2018. Tramazoline hydrochloride for nasal symptom, and levocabastine 
hydrochloride for eye symptoms are allowed to use as rescue medications. 
Post treatment Follow-up 
Blood 
sampling 
for 
the 
follow-up 
assessments 
(anti-omalizumab 
antibody 
and 
Pharmacokinetics (PK)/ Pharmacodynamics (PD)) will be conducted 24 weeks after the last 
dosing. After the end of the treatment period, no limitation on concomitant/rescue/prohibited 
medications should be set. 
Figure 3-1 
Study design 
 
*Start date of fluticasone propionate use and duration of fluticasone propionate use (2 - 4 weeks) will 
be determined by the sponsor based on the forecast of cedar pollen scattering. 


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3.2 
Rationale for study design 
This randomized, double-blind, parallel-group, placebo-controlled study design supports the 
assessment of efficacy as well as safety of omalizumab in patients with severe Japanese cedar 
pollinosis, whose symptoms were inadequately controlled despite the current recommended 
therapies (nasal corticosteroid plus one or more medications out of anti-histamine, leukotriene 
receptor antagonist, or prostaglandin D2/thromboxane A2 receptor antagonist) in the previous 2 
Japanese cedar pollen seasons. These patients have a significant unmet medical need and 
represent the target population for omalizumab. 
To reflect the current recommended treatment algorithm for severe Japanese cedar pollinosis 
(Practical guideline for the management of allergic rhinitis in Japan 2016), this study allows to 
use the following treatment on the top of study treatment: 
• 
fexofenadine hydrochloride as a concomitant medication 
• 
fluticasone propionate as a concomitant medications in approximately 2 - 4 weeks around 
in March 
• 
Tramazoline hydrochloride for nasal symptom, and levocabastine hydrochloride for eye 
symptoms as rescue medications. 
The endpoints included in this study measure symptomatic and objective parameters of 
Japanese cedar pollinosis; symptomatic parameters: nasal symptoms, ocular symptoms, rescue 
medication use, quality of life, 
; objective parameters: 
 
, which allow assessment of the suppression of Japanese cedar pollinosis symptoms 
by omalizumab. 
The primary analysis will be performed on all the data during the screening epoch and the 
treatment epoch after all patients complete the treatment epoch to support the registration. See 
Section 3.5 and Section 9.7 for more details. 
The key elements of the study were discussed and agreed with Pharmaceuticals and Medical 
Devices Agency in Japan. 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
Dose/regimen, route of administration 
In this study, Investigational drug (omalizumab/placebo) will be administered subcutaneously 
according to the dosing table, which is approved for severe allergic asthma in Japan. The 
rationale for using the dosing table in the study is summarized as follows; 
• Allergic rhinitis and allergic asthma are both type-I allergic diseases, so same mode of 
action of omalizumab is expected. 
• The dosing table was made based on the results of clinical studies in early phase in 
allergic population including asthma and rhinitis. 
• There was no clinically significant difference found in PK and PD of omalizumab between 
allergic asthma and allergic rhinitis populations (Hayashi et al 2007). 


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• The dosing table (at that time) was used in all previous omalizumab studies 
(CIGE025A1303 (Okubo et al 2006), CIGE025A1305 (Nagakura et al 2008), 
CIGE025A1306 (Ogino et al 2009)) in patients with Japanese cedar pollinosis, which 
showed that omalizumab was effective and safe in patients with moderate to severe 
Japanese cedar pollinosis. 
Start date of initial treatment 
Japanese cedar pollen generally begins to scatter in early-mid February indicated as Japanese 
cedar pollen dispersal day, defined as the first of 2 consecutive days when ≥ 1 grain/cm2 of 
Japanese cedar pollen is counted (average date of Japanese cedar pollen dispersal day in recent 
10 years in Tokyo area is 16th February. But please note that very small amount pollen scatters 
sporadically before the Japanese cedar pollen dispersal day), scatters severely from early March 
to early April, and ends scattering by the end of April. On the other hand, based on the results 
of the nasal challenge test (Lin et al 2004), omalizumab requires approximately 1 - 2 weeks to 
start to show its efficacy and ≥ 4 weeks to maximize it because omalizumab can’t inhibit 
Immunoglobulin E (IgE), already bound to FceRI on the cell surface. 
So, by setting the period of initial study drug administration in approximately 3 weeks between 
mid-January and mid-February in 2018, adequate time for omalizumab to exert its effect can be 
secured and approximately 350 study patients can initiate study treatment, as well. Because 
Japanese cedar pollen dispersal varies a little among years, actual period of initial treatment will 
be determined by the sponsor based on the forecast of cedar pollen scattering and be notified to 
the investigator by the end of 2017. 
In addition, because omalizumab should be categorized as a “treatment drug”, not “prophylactic 
drug”, omalizumab should be administered to the patients who have already developed any 
symptom of Japanese cedar pollinosis defined in the inclusion criteria. 
Duration of treatment 
Treatment duration of 12 weeks is selected to cover peak season for Japanese cedar pollinosis 
which will generally be expected from early-March to early April (and to cover almost all of 
the Japanese cedar pollen season (February to April)). 
3.4 
Rationale for choice of comparator 
All patients will receive standard of care treatments as concomitant medications. Omalizumab 
or placebo will be administered as add-on therapy. 
Placebo is used as comparator in this study for the following reasons: 
• to allow blinding of investigators and patients to their treatment and thereby minimize bias 
in the evaluation of safety and efficacy assessments, 
• to allow assessment of the suppression of Japanese cedar pollinosis symptoms for patients 
with uncontrolled disease who are treated with omalizumab, in comparison to those 
treated solely with standard of care treatments, 
• to allow the assessment of safety of omalizumab on top of standard of care treatments 
compared to standard of care treatments alone. 


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3.5 
Purpose and timing of interim analyses/design adaptations 
There will be no interim analysis in this study. A primary analysis will be performed on all the 
data during the screening epoch and the treatment epoch after all patients complete the treatment 
epoch to support the registration. The database lock for this analysis will be done after 30 days 
safety evaluation following the end of the treatment epoch will be completed for all patients. 
After completion of post-treatment follow-up visit for all patients, PK analysis for the follow-
up epoch will be performed separately. 
3.6 
Risks and benefits 
The inclusion and exclusion criteria are selected to enroll patients with Japanese cedar pollinosis 
most likely to benefit from participating in the study. The overall risk will be minimized by 
compliance with the eligibility criteria and study procedures, close clinical monitoring 
including the use of an electronic diary at home to monitor symptoms and the use of 
concomitant and recue medications permitted, which are in line with current medical treatment 
guidelines. 
Omalizumab (Xolair®), an anti-IgE recombinant DNA-derived humanized monoclonal 
antibody, represents a unique therapeutic approach for Immunoglobulin E (IgE)-mediated 
disease by reducing the concentration of free IgE in blood by selectively binding to human IgE. 
Omalizumab has been approved for allergic asthma and chronic spontaneous urticaria 
worldwide including US, EU and Japan. 
Identified/potential risks to omalizumab include anaphylaxis/anaphylactoid reactions, serum 
sickness syndrome/serum sickness like disease, antibody formation to omalizumab, 
Churg-Strauss 
syndrome/hypereosinophilic 
syndrome, 
thrombocytopenia, 
arterial 
thromboembolic events and malignant neoplasms. In clinical trials, the most commonly 
reported adverse reactions are injection site reactions, headaches and abdominal pain upper. 
Additional information on risks associated with omalizumab will be found in the local medical 
health authority approved product information and Investigator Brochure (IB). The risk of 
significant hypersensitivity reactions is mitigated by having the drug administration taking 
place only at the study site and requiring observation of patients at the study site after drug 
administration. 


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In summary, the benefit to the patient from study participation is that treatment with 
omalizumab could suppress nasal and eye symptoms of Japanese cedar pollinosis, which would 
be inadequately controlled despite the current recommended therapies. The risk for patients 
participating in this study includes the potential for known safety issues associated with 
omalizumab, which includes anaphylaxis, as well as for any unknown safety risks (which may 
be serious) that could occur. Based on available data of omalizumab, it is anticipated that 
omalizumab will have a favorable benefit to risk profile in patients with severe Japanese cedar 
pollinosis. 


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4 
Population 
The study population consist of adult and adolescent (≥ 12 to < 75 years) patients with severe 
Japanese cedar pollinosis whose symptoms were inadequately controlled despite the nasal 
corticosteroid plus one or more medications out of anti-histamine (second generation), 
leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 receptor antagonist in the 
previous 2 Japanese cedar pollen seasons. 
In the study, a total of 346 patients will be enrolled in Kanto-area of Japan. Approximately 10% 
of the total patients enrolled will be the patients aged ≥ 12 to < 15 years at the screening epoch. 
Since a 10% screen failure rate is expected, approximately 390 patients will be screened. 
4.1 
Inclusion criteria 
Patients 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. For 
patients aged ≥ 12 to < 20 years at the screening epoch, parent or legal guardian has given 
written informed consent and the patient has given assent consent, if applicable. 
2. Aged ≥ 12 to < 75 years at the screening epoch. 
3. A clinical history of Japanese cedar pollinosis defined by the following: 
• Took nasal corticosteroid plus one or more medications out of anti-histamine (second 
generation), leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 
receptor antagonist in Japanese cedar pollen seasons in 2016 and 2017. 
• Had inadequately controlled symptoms of Japanese cedar pollinosis lasting at least 
one week in the Japanese cedar pollen season in 2017 despite the use of nasal 
corticosteroid plus one or more medications out of anti-histamine (second generation), 
leukotriene receptor antagonist, or prostaglandin D2/thromboxane A2 receptor 
antagonist (regardless of having perennial allergic rhinitis or not). 
Inadequately controlled symptoms are defined as presentation of all symptoms of sneezing, 
rhinorrhea, and nasal congestion, at least one of which is ≥ score of 3 according to the practical 
guideline for the management of allergic rhinitis in Japan 2016 below (Table 4-1). 
Medications for Japanese cedar pollinosis in 2016 and 2017 should be confirmed by medical 
records or “prescription records (book)” and symptoms of Japanese cedar pollinosis in 2017 
should be confirmed by questionnaire, which should be completed by the patients at screening 
epoch. 


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Table 4-1 
Severity of nasal symptoms 
Score 
4 
3 
2 
1 
0 
Paroxysmal sneezing  
(number of episodes 
of paroxysmal 
sneezing in a day) 
≥ 21 times 
20-11 times 
10-6 times 
5-1 times 
0 
Rhinorrhea 
(number of episodes 
of nose blowing a day) 
≥ 21 times 
20-11 times 
10-6 times 
5-1 times 
0 
Nasal congestion 
Completely 
obstructed all 
day 
Severe nasal 
congestion 
causing 
prolonged oral 
breathing in a 
day 
Severe nasal 
congestion 
causing 
occasional oral 
breathing in a 
day 
Nasal 
congestion 
without oral 
breathing 
Less 
severe 
degree than 
score of 1 
4. Serum cedar pollen-specific IgE levels of ≥ score of 3 by CAP-RAST/FEIA, ImmunoCAP 
or MAST at the screening epoch. 
5. Developing a symptom of Japanese cedar pollinosis during the period from first 
observational day* in cedar pollen in Kanto area to initial drug administration (Visit 101), 
as defined by the following; 
• Having any nasal or ocular symptom (≥ score of 1 in sneezing, rhinorrhea, nasal 
congestion, itchy eye or watery eye (Table 4-1 and Table 4-2)) in at least 2 days 
or 
• Having both any nasal symptom (≥ score of 1 in sneezing, rhinorrhea, or nasal 
congestion (Table 4-1)) and any eye symptom (≥ score of 1 in itchy eye or watery eye 
(Table 4-2)) in at least one day, 
 
which is confirmed by patient e-diary (unless a symptom is clearly consider to take 
place due to other than Japanese cedar pollinosis/allergic rhinitis (e.g., upper 
respiratory tract infection, or common cold)). 
*It will be notified to the investigator in writing by the sponsor. 
Table 4-2 
Severity of ocular symptoms 
Score (/day) 
4 
3 
2 
1 
0 
Itchy eye 
More severe 
degree than 
score of 3 
Frequently 
rubbing eye(s) 
Occasionally 
rubbing eye(s) 
Not to the extent 
of rubbing eye(s) 
None 
Watery eye 
More severe 
degree than 
score of 3 
Frequently 
wiping tears 
Occasionally 
wiping tears 
Not to the extent 
of wiping tears 
None 
6. Body weight and serum total IgE level at screen epoch within the dosing table range; body 
weight of ≥ 20 to ≤ 150 kg and serum total IgE levels of ≥ 30 to ≤ 1500 IU/mL at a 
maximum. 
7. ≥ 70% compliance with e-diary daily entries during the last 7 days in the screening epoch 


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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. 
1. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected 
pharmacodynamic effect has returned to baseline, whichever is longer. 
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes. 
3. History of anaphylactic shock or severe anaphylactic reaction that in the clinical judgment 
of the investigator might compromise patient safety. 
4. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade Atrioventricular (AV) block (e.g., bifascicular block, 
Mobitz type II and third degree AV block)  
5. Patients taking medications prohibited by the protocol (see Section 5.5.8, Table 5-2) 
6. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases. 
7. Pregnant or nursing (lactating) women 
8. 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 and 30 days following the last dosing of investigational drug. Basic 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), 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) 


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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. 
9. With platelet level ≤ 100 000/µL (100 × 109/L) at the screening epoch 
10. With an active rhinitis other than allergic rhinitis (e.g., acute or chronic rhinitis, idiopathic 
rhinitis) 
11. With an active nose disease other than allergic rhinitis (e.g., acute or chronic rhinosinusitis 
or deflected septum) which is expected to affect the evaluation of efficacy of the study 
drug judged by the investigator 
12. With elevated serum IgE levels for reasons other than allergy (e.g. parasite infections, 
hyperimmunoglobulin E syndrome, Wiskott-Aldrich Syndrome or clinical allergic 
bronchopulmonary aspergillosis). 
13. With a severe asthma treated with high dose inhaled corticosteroid (≥ 800 µg/day 
fluticasone propionate or an equivalent for aged ≥ 16 to < 75 years, >200 µg/day for aged 
≥ 12 to < 16 years) 
14. Who are receiving operative treatment for allergic rhinitis (e.g., electrocoagulation, laser 
surgery, 80% trichloroacetic acid chemo-surgery, inferior turbinectomy or posterior nasal 
neurectomy) within 1 years prior to the screening epoch 
15. Who are taking methotrexate, gold salts, cyclosporine, tacrolimus (with the exception of 
topical product) or other immunosuppressant within 3 months prior to the screening epoch 
16. Who are taking systemic (oral or intravenous (IV)) corticosteroids or intra-muscular 
depo-steroids within 4 weeks prior to the screening epoch 
17. Who are receiving desensitization immunotherapy within 1 years prior to the screening 
epoch (excluding patients with not less than 2 years of stable maintenance doses at the 
screening epoch) 
18. With clinically significant uncontrolled systemic disease or a history of such disease (eg., 
infection, hematological disease, renal, hepatic, coronary heart disease or other 
cardiovascular disease, cerebro-vascular, endocrinologic or gastrointestinal disease) within 
the previous 3 months prior to the screening epoch 
19. Who have a plan to travel to Okinawa or Hokkaido in Japan or travel abroad for more than 
5 days between February and April in 2018 
20. Who have used omalizumab including marketed product (Xolair®). 
21. Contraindications to fexofenadine hydrochloride (oral), fluticasone propionate (nasal), 
tramazoline hydrochloride (nasal), or levocabastine hydrochloride (ocular). 


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5 
Treatment 
5.1 
Study treatment 
The sponsor will provide the following investigational treatment to the study sites in open-label 
manner: 
• Omalizumab (IGE025) 150 mg 
• Placebo matching to Omalizumab (IGE025) 150 mg 
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 
• 
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 5 ml glass 
vial. 
5.1.2 
Additional treatment 
No additional treatment beyond investigational drug is included in this trial, except for 
fexofenadine hydrochloride and fluticasone propionate as concomitant medications and 
fexofenadine hydrochloride, tramazoline hydrochloride and levocabastine hydrochloride as 
rescue medications. 
5.2 
Treatment arms 
Patients will be assigned at Visit 101 to omalizumab arm or placebo arm in a ratio of 1:1. 
Dose (75 to 600 mg) and dosing frequency (every 2 or 4 weeks) of the study drug will be 
determined by serum total IgE level (IU/mL) and body weight (kg) measured at the screening 
epoch according the dosing table (Table 5-1). 
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. 


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Table 5-1 
Dosing table (mg/dose) 
 
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 investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study drug to be dispensed 
to the patient. The randomization number will not be communicated to the 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 and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).  
Randomization will be stratified by the age group (≥ 12 to < 15 years and ≥ 15 to < 75 years), 
coexisting of perennial allergic rhinitis (Yes/No), dose frequency (every 2 weeks and 4 weeks) 
and having cedar pollinosis symptom at the initial drug administration (Yes/No)*.  
*It is estimated that approximately ≥ 70% of the randomized patients will have any symptom 
(≥ score of 1 in sneezing, rhinorrhea, nasal congestion, itchy eye or watery eye (Table 4-1 and 
Table 4-2)) at least one day of three days before initial drug administration (including the day 
of administration). 
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group. 
5.4 
Treatment blinding 
Patients, investigator staff and personnel performing the study assessments will remain blinded 
to the identity of the treatment from the time of randomization until final database lock. Data 
 


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managers, programmers, statisticians, pharmacometricians and clinical experts of the Novartis 
clinical trial team will remain blinded until the primary analysis. An unblinded study monitor 
will visit the study site to monitor study drug related administration (see Section 8.1). 
Blinding will be maintained using the following methods: 
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions: 
• Specific vendors whose role in trial conduct requires their unblinding (e.g., IRT) 
• Drug Supply Management (DSM) 
• Unblinded pharmacist and unblinded health care professional at each study site 
• Unblinded monitor 
• Bioanalyst for PK/PD 
2. The following measures will be applied to keep the patient and study personnel blinded 
despite differences of the investigational treatments in appearance, viscosity: 
• Study treatment will be dispensed by an unblinded pharmacist (or other authorized 
unblinded staff) who is independent of those involved in the assessment of study 
patients. 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. 
• 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. 
• The independent unblinded authorized site persons (pharmacist/administrator) should 
not communicate the appearance, the volume and any perceived sensation associated 
with the administration of the investigational drug. 
The procedural details relating to treatment blinding and unblinded drug administration will be 
described in the Pharmacist Manual and the protocol mandate tools which will be provided 
separately. 
Unblinding will only occur in the case of patient emergencies (see Section 5.6), at the time of 
the primary analysis (see Section 9.7) and at the PK analysis for the follow-up epoch. 
The randomization codes associated with patients/subjects from whom PK samples are taken 
will be disclosed to PK analysts who will keep PK results confidential until data base lock. 
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. 


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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 study drug in packaging of identical appearance. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the omalizumab or placebo. Unblinded site 
personnel will identify the study drug package(s) to dispense to the patient by contacting the 
IRT and obtaining the medication number(s). Immediately before dispensing the package to the 
patient,unblinded site personnel will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) for that patient’s unique subject number. 
5.5.3 
Handling of study 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 in refrigerated conditions at 2°C to 8°C, and kept in a secured location to 
which only the investigator and designees have access. Upon receipt, all study treatment must 
be stored according to the instructions specified on the labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
respective Novartis CPO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number. 
The unblinded site personnel must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by unblinded 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 unblinded 
site personnel will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis unblinded monitor or to the Novartis address 
provided in the investigator folder at each site. 
5.5.3.2 
Handling of additional treatment 
The following concomitant/rescue treatments has to be monitored specifically: 
• Fexofenadine hydrochloride 
• Fluticasone propionate 


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• Tramazoline hydrochloride  
• Levocabastine hydrochloride 
For the use of the above please refer to Section 5.5.6 and Section 5.5.7.1. Details are described 
in the CRF completion guidelines. 
5.5.4 
Instructions for prescribing and taking study treatment 
Omalizumab or placebo 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. Dose (75 to 600 mg) and dosing frequency 
(every 2 or 4 weeks) of the study drug will be determined by serum total IgE level (IU/mL) and 
body weight (kg) measured at the screening epoch according the dosing table (Table 5-1), which 
must not be changed during the treatment epoch. Initial administration of the study drug 
(Visit 101) will be conducted in approximately 3 weeks between mid-January and 
mid-February in 2018, which will be determined by the sponsor based on the forecast of cedar 
pollen scattering and be notified to the investigator in writing by the end of 2017. Allowable 
range of study drug administration recommended is the designated day ± 7 days. In addition, at 
least one-week interval will be kept between administrations. The last administration of the 
study drug should be at Visit 105 (Day 57) for 4-weekly dosing and at Visit 106 (Day 71) for 
2-weekly dosing, respectively. 
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 
patient by s.c. injection during the study visit without engaging in any unnecessary interactions 
that may have the potential to unblind the patient 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 blood is withdrawn, 
the needle is removed without administration of the dose and the injection site is changed. Study 
drug should be used immediately after reconstitution. If not used immediately, in-use storage 
times and conditions prior to use are not longer than 8 hours at 2°C to 8°C. Detailed instructions 
on how to administrate study drug can be found in the separate Pharmacist Manual. 
After administration, patients will be observed carefully for potential adverse events of 
anaphylaxis at study sites (for recommendation, 2 hour observation for initial administration 


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and at least 30 minutes observation for administrations afterward). In addition, for a delayed 
onset of anaphylaxis, patients and the investigator should ensure communication means. 
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, as well as fexofenadine hydrochloride 
(concomitant), fluticasone propionate (concomitant), tramazoline hydrochloride (rescue), or 
levocabastine hydrochloride (rescue) 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) is dispensed by IRT but not administered to a patient at a 
visit at which the patient attends, this deviation event must be recorded on the Dosage 
Administration Record CRF. 
5.5.6 
Rescue medication 
Screening epoch 
Only the following rescue medications are allowed to use for nasal symptoms of Japanese cedar 
pollinosis (allergic rhinitis) during the screening epoch; 
• Fexofenadine hydrochloride (oral, 60 mg/time, twice a day at maximum) 
• Tramazoline hydrochloride (nasal, 2 to 3 drops/time, 4 times a day at maximum) 
Patients should use these rescue medications along with the following instruction by the 
investigator; 
If symptom of sneezing, rhinorrhea or nasal congestion not less than moderate (≥ score of 2 in 
Table 4-1) in severity take place, use fexofenadine hydrochloride first, then followed by 
tramazoline hydrochloride in case that nasal congestion doesn’t improved. 
For eye’s symptoms (itchy and watery eye) of Japanese cedar pollinosis (allergic rhinitis), only 
levocabastine hydrochloride is allowed to use as a rescue medication; 
• Levocabastine hydrochloride (ocular, 1 to 2 drops/time, 4 times a day at maximum) 
Patients should use the medication along with the following instruction by the investigator; 
If symptom of itchy eye or watery eye not less than moderate (≥ score of 2 in Table 4-2) in 
severity take place, use levocabastine hydrochloride. 
Treatment epoch 
During the treatment epoch, only tramazoline hydrochloride is allowed to use for nasal 
symptoms of Japanese cedar pollinosis (allergic rhinitis) as a rescue medication. 
• Tramazoline Hydrochloride (nasal, 2 or 3 drops/time, 4 times a day at maximum) 
Patients should use the medication along with the following instruction by the investigator; 


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If symptom of nasal congestion not less than moderate (≥ score of 2 in Table 4-1) in severity 
takes place despite concomitant use of fexofenadine hydrochloride or fexofenadine 
hydrochloride and fluticasone propionate (see Section 5.5.7), use tramazoline hydrochloride. 
For eye’s symptoms (itchy and watery eye) of Japanese cedar pollinosis (allergic rhinitis), only 
levocabastine hydrochloride is allowed to use as a rescue medication; 
• Levocabastine hydrochloride (ocular, 1 to 2 drops/time, 4 times a day at maximum) 
Patients should use the medication along with the following instruction by the investigator; 
If symptom of itchy eye or watery eye not less than moderate (≥ score of 2 in Table 4-2) in 
severity take place despite concomitant use of fexofenadine hydrochloride, use levocabastine 
hydrochloride. 
Use of rescue medication must be recorded both on the e-diary and on the Concomitant 
medications 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. 
5.5.7.1 
Concomitant medications for Japanese cedar pollinosis (allergic 
rhinitis) 
Screening epoch 
No concomitant medications are allowed. 
Treatment epoch 
During the treatment epoch, fexofenadine hydrochloride should be used as a concomitant 
medication irrespective of patient’s symptoms. 
• Fexofenadine hydrochloride (oral, 60 mg/time, twice per day) 
In addition, in approximately 2 - 4 weeks around in March, fluticasone propionate should be 
used as a concomitant medications irrespective of patient’s symptoms, as well. Start date of 
fluticasone propionate use and duration of fluticasone propionate use (2 - 4 weeks) will be 
determined by the sponsor based on the forecast of cedar pollen scattering and be notified to 
the investigator in writing by mid-February 2018. 
• Fluticasone propionate (nasal, 1 spray (50 µg)/nostril, twice per day) for patients aged 
≥ 15 to < 75 years 


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• Fluticasone propionate (nasal, 1 spray (25 µg)/nostril, twice per day) for patients aged 
≥ 12 to < 15 years 
Use of concomitant medication above must be recorded both on the e-diary and on the 
Concomitant medications in the CRF. 
For patients with asthma, long-term controlled medications should be kept constant during the 
screening and treatment epoch, if at all possible. 
5.5.8 
Prohibited medication 
Use of the treatments displayed in the below table (Table 5-2) is NOT allowed during the period 
as indicated. The investigator or authorized site staff should instruct the patient to notify them 
about any new/additional treatments he/she takes after enrollment. All prohibited treatments 
taken after enrollment must be recorded in eCRF. 
Table 5-2 
Prohibited medication 
Prohibited treatments 
Time period when 
treatment is prohibited 
Action to be taken in case of use 
during prohibited period 
• Nasal corticosteroids other than 
fluticasone propionate 
a. Screening epoch 
b. Treatment epoch 
a. Discontinue patient from the trial - 
rescreen patient if eligible. 
b. Discontinue study treatment if the 
prohibited treatments taken for 
more than 3 days and move to 
post-treatment follow-up. If not, 
discontinue use the prohibited 
treatments and continue in 
treatment epoch. 
• Fluticasone propionate (nasal) 
a. Screening epoch 
b. Treatment epoch 
without in 
approximately 2 - 4 
weeks around in 
March determined by 
the sponsor, when 
fluticasone propionate 
should be used as a 
concomitant 
medication 
a. Discontinue patient from the trial - 
rescreen patient if eligible. 
b. Discontinue study treatment if the 
prohibited treatments taken for 
more than 3 days outside the 
period of concomitant use and 
move to post-treatment follow-up. 
If not, discontinue use the 
prohibited treatments and 
continue in treatment epoch. 


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Prohibited treatments 
Time period when 
treatment is prohibited 
Action to be taken in case of use 
during prohibited period 
• Anti-histamines other than 
fexofenadine hydrochloride 
(oral) or levocabastine 
hydrochloride (ocular) 
• Leukotriene receptor 
antagonists 
• Mast cell stabilizer 
• Th2 cytokine inhibitor 
• Prostaglandin D2/thromboxane 
A2 receptor antagonist 
• Anti-cholinergic medication 
(with the exception of topical 
product) 
• Combination tablet between 
fexofenadine hydrochloride and 
pseudoephedrine hydrochloride 
• Nasal vasoconstrictor other 
than tramazoline hydrochloride 
• Chinese traditional medicine 
prescribed for Japanese cedar 
pollinosis 
a. Screening epoch 
b. Treatment epoch 
a. Discontinue patient from the trial - 
rescreen patient if eligible. 
b. Discontinue study treatment if the 
prohibited treatments taken for 
more than 3 days and move to 
post-treatment follow-up. If not, 
discontinue use the prohibited 
treatments and continue in 
treatment epoch. 
• Systemic corticosteroids (e.g., 
oral, IV, SC) 
Note: inhaled corticosteroids 
are permitted but dose should 
be kept constant if possible 
a. 4 weeks prior to 
screening epoch and 
screen epoch 
b. Treatment epoch 
a. Discontinue patient from the trial - 
rescreen patient after wash-out if 
eligible. 
b. Discontinue study treatment and 
move to post-treatment follow-up. 
• Methotrexate, gold salts, 
cyclosporine, tacrolimus (with 
the exception of topical product) 
or other immunosuppressant 
a. 3 months prior to 
screening epoch and 
screen epoch 
b. Treatment epoch 
a. Discontinue patient from the trial. 
b. Discontinue study treatment and 
move to post-treatment follow-up. 
• Operative treatment for allergic 
rhinitis (e.g., electrocoagulation, 
laser surgery, 80% 
trichloroacetic acid 
chemo-surgery, inferior 
turbinectomy or posterior nasal 
neurectomy) 
a. 1 year prior to 
screening epoch and 
screen epoch 
b. Treatment epoch 
a. Discontinue patient from the trial. 
b. Discontinue study treatment and 
move to post-treatment follow-up. 
• Desensitization immunotherapy 
(excluding patients with not less 
than 2 years of stable 
maintenance doses at the 
screening epoch) 
a. 1 years prior to 
screening epoch and 
screen epoch 
b. Treatment epoch 
a. Discontinue patient from the trial. 
b. Discontinue study treatment and 
move to post-treatment follow-up. 
SC: subcutaneous, IV: intravenous 
 
In case of undue safety risk for the patient, the patient should discontinue study treatment at the 
discretion of the Investigator (please see Section 5.6.2). 


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After the end of the treatment period, no limitation on concomitant/rescue/prohibited 
medications should be set. 
5.5.9 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/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. 
For all patients a safety follow-up should be conducted (e.g. by telephone) 30 days following 
the end of the treatment epoch. The information to be collected at this follow up includes serious 
adverse events. 
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: 


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• Patient wish 
• Pregnancy (see Section 6.5.6 and Section 7.5) 
• Use of prohibited treatment as per recommendations in Table 5-2 
• Any situation in which study participation might result in a safety risk to the patient 
• A confirmed platelet level ≤ 75 000/µL (75 × 109/L) 
• 
Unsatisfactory therapeutic effect 
• Emergence of the following adverse events: Consider any 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 
• 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 to 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 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 


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• 
Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table below. 
5.6.4 
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her 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 discontinued patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed, 
and an “s” indicates the data remain in the source document only. 
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed. At this final visit, all 
dispensed investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the CRF. 
Patients will be contacted for safety evaluations during the 30 days following the end of the 
treatment epoch. 


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Table 6-1 
Assessment schedule 
Epoch 
Screening 
Treatment 
Post-treatment 
follow-up 
Visit 
1 
101 
102 a 
103 
104 
105 
106a 
199 or 
TD 
299 or  
TD b 
Day 
Day-35 to -7 
Day 1 
Day 15 
Day 29 
Day 43 
Day 57 
Day 71 
Day 85 
Day 225 or  
Day 239 
Allowed visit window recommended (day) 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
+28 
Obtain informed consent c 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography, medical/surgical history 
X 
 
 
 
 
 
 
 
 
Complete physical exam 
S 
 
 
 
 
 
 
S 
 
Short physical exam 
 
S 
S 
S 
S 
S 
S 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
12 lead ECG 
S 
 
 
 
 
 
 
 
 
Total IgE, specific IgE (central lab) 
X 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
PROs (JRQLQ, 
) 
 
X 
 
X 
X 
X 
 
X 
 
Review patients’ e-diary d 
 
S 
S 
S 
S 
S 
S 
S 
 
Laboratory test 
 
 
 
 
 
 
 
 
 
Pregnancy test (Urine) e 
X 
X 
 
X 
 
X 
 
X 
 
Hematology 
X 
 
 
X 
 
X 
 
X 
 
Chemistry 
X 
 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 


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Epoch 
Screening 
Treatment 
Post-treatment 
follow-up 
Visit 
1 
101 
102 a 
103 
104 
105 
106a 
199 or 
TD 
299 or  
TD b 
Day 
Day-35 to -7 
Day 1 
Day 15 
Day 29 
Day 43 
Day 57 
Day 71 
Day 85 
Day 225 or  
Day 239 
Allowed visit window recommended (day) 
 
 
±7 
±7 
±7 
±7 
±7 
±7 
+28 
Sample collection 
 
 
 
 
 
 
 
 
 
PK/PD f 
 
X 
 
X 
 
X 
 
X 
X 
Anti-omalizumab antibody 
 
X 
 
 
 
 
 
 
X 
Drug administration 
 
 
 
 
 
 
 
 
 
Two-weekly 
 
X 
X 
X 
X 
X 
X 
 
 
Four-weekly 
 
X 
 
X 
 
X 
 
 
 
Concomitant medication/ therapy 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event 
X 
X 
X 
X 
X 
X 
X 
X 
 
Epoch disposition 
X 
 
 
 
 
 
 
X 
X 
TD = Study treatment discontinuation 
X = assessment to be recorded on clinical data base 
S = assessment to be recorded on source documentation only 
NOTE: PROs must be completed prior to other assessments. 
NOTE: Unless otherwise indicated, all assessments should be performed pre-administration. 
NOTE: Visit 101 should be performed in approximately 3 weeks between mid-January and mid-February in 2018, which will be will be determined by the sponsor.  
NOTE: Visit 104 should be targeted between 1st March and 16th March and Visit 105 should be targeted between 17th March and 31st March, respectively. Visit 199 
should be targeted on or after “FPFT (first patient first treatment) plus 12 weeks” except patients with TD. 
NOTE: Allowable range of study drug administration recommended is the designated day ± 7 days. In addition, at least one-week interval will be kept between 
administrations. 
a: Visit 102 and Visit 106 should be performed for patients with two-weekly study drug administration. 
b: For patients with TD, Visit 299 should be performed 24 weeks after last administration of study drug. 
c: IC obtained prior to all study specific screening procedures during or as close to the start of the screening period as possible 
d: e-Diary Includes nasal symptoms (sneezing, rhinorrhea and nasal congestion), ocular symptoms (itchy and watery eye), medication use (fluticasone propionate, 
fexofenadine hydrochloride, tramazoline hydrochloride and levocabastine hydrochloride) and impairment of daily activities. The e-Diary will be given to patients at 
Visit 1, and the patients will be trained by the site staff how to use the e-Diary. The e-Diary will be completed daily (once a day) by the patients from Visit 1 to Visit 199 
or TD. 
e: If urine pregnancy test results at the sites are positive, dosing should be held and a serum pregnancy test will be performed by the central laboratory. 
f: Pre-dose sampling at Visit 101, 103 and 105. 


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6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next 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, source of patient referral, relevant medical history/current 
medical condition present before signing informed consent where possible, diagnoses and not 
symptoms will be recorded. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
Information about characteristics of symptoms of Japanese cedar pollinosis in Japanese cedar 
pollen season in 2017 and treatments received in Japanese cedar pollen season in 2016 and 2017 
will be collected. 
Total IgE and specific IgE to Japanese cedar, Japanese cypress, house dusts, dermatophagoides 
pteronyssinus, dermatophagoides farinae, and aspergillus will be measured at the screening 
epoch. Lab manuals will be provided with detailed information on sample collection, handling, 
and shipment. 
6.3 
Treatment exposure and compliance 
6.3.1 
Omalizumab/Placebo 
All doses of study treatment (omalizumab/placebo) 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 counts and information provided by the 
unblinded pharmacist or unblinded authorized site staff responsible for treatment dispensation 
and preparation. 
6.3.2 
Concomitant medications for Japanese cedar pollinosis 
Patients are required to record in the e-diary their use of fexofenadine hydrochloride, fluticasone 
propionate, (tramazoline hydrochloride and levocabastine hydrochloride) on a daily 
basis.Compliance will be assessed by the investigator and/or study personnel at each visit using 
e-diary. 
6.4 
Efficacy 
A number of efficacy variables will be assessed during the study. At each visit, the assessment 
will be started with patient reported outcomes (PROs) and then move to other assessments and 


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laboratory assessments. All PROs should be completed by patients before they see the study 
investigator for any clinical assessment or evaluation. 
All patients will complete the PRO questions in the language most familiar to the respondent 
via an electronic tablet. Patients should be given sufficient instruction, space, time, and privacy 
to complete all study PROs. If patients experience any difficulties with submission after they 
complete the PROs, the study staff should assist them with submitting their PRO responses. 
Attempts should be made to collect responses to all PROs for all patients, including from those 
who prematurely discontinue prior to the study evaluation completion visit, however, if patients 
refuse to complete PROs, this should be documented in study source records. Patient’s refusal 
to complete study PROs are not protocol deviations. 
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). The investigator should review not only the responses to the questions in the 
questionnaires but also for any unsolicited comments written by the patient. If AEs or SAEs are 
confirmed, then the physician must record the events as per instructions given in Section 7.1 
and Section 7.2 of the protocol. 
6.4.1 
e-Diary assessment 
The patient e-diary will be provided at the screening visit and will be returned at the end of the 
treatment epoch. Patients should carefully record their nasal symptoms, ocular symptoms, usage 
of rescue medications and impairments of daily activities on their e-diaries everyday during the 
screening and treatment epoch (Appendix 3). The patient e-diary will be checked by a 
designated study staff member at each visit; in case of incomplete patient diaries, the study site 
staff will counsel the patient on the correct use and frequency of the patient diary. 
6.4.1.1 
Nasal symptoms 
Nasal symptoms (sneezing, rhinorrhea and nasal congestion) will be recorded by the patient 
everyday in their e-Diary, on a following scale of 0 (none) to 4 (intense/severe) (Table 6-2, 
Practical guideline for the management of allergic rhinitis in Japan 2016). 
Nasal symptom score (0-12 point) consisted of score for severity of sneezing (0-4 point), 
rhinorrhea (0-4 point) and nasal congestion (0-4 point). 
Table 6-2 
Severity of nasal symptoms 
Score (/day) 
4 
3 
2 
1 
0 
Paroxysmal sneezing  
(number of episodes of 
paroxysmal sneezing in 
a day) 
≥ 21 times 
20-11 times 
10-6 times 
5-1 times 
0 
Rhinorrhea 
(number of episodes of 
nose blowing a day) 
≥ 21 times 
20-11 times 
10-6 times 
5-1 times 
0 
Nasal congestion 
Completely 
obstructed all 
day 
Severe nasal 
congestion causing 
prolonged oral 
breathing in a day 
Severe nasal 
congestion causing 
occasional oral 
breathing in a day 
Nasal 
congestion 
without oral 
breathing 
Less severe 
degree than 
score of 1 


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6.4.1.2 
Ocular symptoms 
Ocular symptoms (itchy and watery eye) will be recorded by the patient everyday in their e-
Diary, on a following scale of 0 (none) to 4 (intense/severe) (Table 6-3). 
Ocular symptom score (0-8 point) consisted of score for severity of itchy eye (0-4 point), watery 
eye (0-4 point). 
Table 6-3 
Severity of ocular symptoms 
Score (/day) 
4 
3 
2 
1 
0 
Itchy eye 
More severe 
degree than 
score of 3 
Frequently 
rubbing one's 
eyes 
Occasionally 
rubbing one's 
eyes 
not to the extent 
of rubbing one's 
eyes 
None 
Watery eye 
More severe 
degree than 
score of 3 
Frequently 
wiping one's 
tears 
Occasionally 
wiping one's 
tears 
not to the extent 
of wiping one's 
tears 
None 
6.4.1.3 
Medication use 
Medication use for Japanese cedar pollinosis (fluticasone propionate, fexofenadine 
hydrochloride, tramazoline hydrochloride and levocabastine hydrochloride) will be recorded by 
the patient everyday in their e-Diary.  
Medication score for nasal and ocular symptoms will be calculated based on a following scale 
(Table 6-4, Practical guideline for the management of allergic rhinitis in Japan 2016). 
Table 6-4 
Score for medication use 
Treatments 
Score (/day) 
Fluticasone propionate (nasal) 
2 
Fexofenadine hydrochloride (oral) 
1 
Tramazoline hydrochloride (nasal) 
1 
Levocabastine hydrochloride (ocular) 
1 
6.4.1.4 
Impairment of daily activities 
Impairment of daily activities will be recorded by the patient everyday in their e-Diary, on a 
following scale of 0 (none) to 4 (intense/severe) (Table 6-5, Practical guideline for the 
management of allergic rhinitis in Japan 2016). 
Table 6-5 
Severity of impairment of daily activities 
Score (/day) 
4 
3 
2 
1 
0 
Impairment of 
daily activities* 
Impossible 
Painful and 
complicating 
daily life 
Intermediate in 
degree 
between score 
of 3 and score 
of 1 
Few troubles 
Less severe 
degree than 
score of 1 
* Work, study, household work, sleep, going outside, etc. 


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6.4.2 
Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ) 
The Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ, No.1) is a standard 
Quality of Life Questionnaire for Japanese allergic rhinitis developed in 2002 (Practical 
guideline for the management of allergic rhinitis in Japan 2016). Patients rate their nasal and 
eye symptoms in the previous 1 - 2 weeks, as well as their impact on various aspects of their 
lives using a 0 to 4-point scale. The questionnaire will be completed by the patients before they 
see the study physician where applicable (Appendix 4). 
6.4.3 
Appropriateness of efficacy assessments 
The measures described above are standard outcome measures in trials with Japanese cedar 
pollinosis (allergic rhinitis). 
The primary assessment is nasal symptom score, which is a validated classical mean of 
assessing nasal symptoms of Japanese cedar pollinosis. It is a composite score that measures 
symptoms of sneezing, rhinorrhea and nasal congestion based on the patient reported data 
collected via the e-diary. Because most Japanese cedar pollinosis patients develop eye 
symptoms complicated, these are assessed by using ocular symptom score based on the patient 
reported e-diary data, as well. 
Impair quality of life (QoL) caused by symptoms of Japanese cedar pollinosis will be evaluated 
by using JRQLQ No.1, which is validated well-known tools in this disease area in Japan. 
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 examination will include the examination of general appearance and vital signs 
(Systolic blood pressure, diastolic blood pressure and pulse). 
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 blood pressure, body temperature 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. 


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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, unless otherwise 
specified. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential counts, and platelet count will be measured. 
6.5.4.2 
Clinical chemistry 
Blood urea nitrogen, creatinine, total bilirubin, Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), alkaline phosphatase, sodium, potassium, chloride, calcium, 
phosphorous, total protein, total cholesterol, albumin, uric acid, c-reactive protein, C3, C4, and 
CH50 will be measured. 
6.5.4.3 
Urinalysis 
Dipstick measurements for specific gravity, PH, protein, glucose, bilirubin, ketones, and blood 
will be performed. Microscopy including WBC and RBC sediments will be assessed in case of 
an abnormal dipstick test. 
6.5.4.4 
Anti-omalizumab antibody 
Serum samples for the determination of anti-omalizumab antibodies will be collected At 
Visit 101, i.e. prior to first dosing, and Visit 299, i.e. 24 weeks after the last administration. The 
24-week waiting period is required to ensure the elimination of omalizumab as presence of 
omalizumab may affect the detection of anti-omalizumab antibodies. Refer to the blood log in 
Appendix 6, Table 18-2 for sample collection. 
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 


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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 of fertility 
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. 
A positive urine pregnancy test during the treatment epoch of the study requires immediate 
interruption of study treatment until serum Beta Human Chorionic Gonadotropin (β-hCG) is 
performed and found to be negative. If the serum β-hCG test is positive, study treatment must 
be discontinued. 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected in this study are appropriate and standard for patients with 
Japanese cedar pollinosis and known safety profile of omalizumab. 
6.6 
Other assessments 


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6.6.3 
Resource utilization 
Not applicable. 
6.6.4 
Pharmacokinetics and pharmacodynamics 
At Visits 101 (baseline), 103 (trough), 105 (trough), 199 (trough, i.e. 2 weeks after the last two-
weekly dose or 4 weeks after the last four-weekly dose) and 299 (follow-up investigation) or at 
discontinuation, serum samples will be collected for evaluation of serum total omalizumab, free 
and total IgE concentration. 
Further details on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manual. Also refer to the blood log in Appendix 6, Table 18-1 for sample collection. 
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 the treatment epoch. 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. 


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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. 
• 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 or 


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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: 
• 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). 


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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 following the end of the treatment epoch must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 30 day period following the end of the treatment epoch 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 to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information. 
 
7.3 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 


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The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE): 
• 
Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• 
Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2. 
For the liver laboratory trigger: 
• 
Repeating the liver function test (LFT) within the next week to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are associated 
with this event must be reported on the Liver CRF pages. 
• 
If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver event 
overview CRF pages. 
7.4 
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 


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uses outside of what is foreseen in the protocol will be collected in the DAR (dosage 
administration record) eCRF irrespective of whether or not associated with an AE/SAE and 
reported to Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE. 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error 
type 
Document in Dosage 
Administration record 
(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 
7.5 
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 3 months after the birth 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 data capture requirements (ie eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis Clinical Teams to assist with trial oversight.The investigator must 
maintain source documents for each patient in the study, consisting of case and visit notes 


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(hospital or clinic medical records) containing demographic and medical information, 
laboratory data, electrocardiograms, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the patient's file. The 
investigator must also keep the original informed consent form signed by the patient (a signed 
copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the EDC system. 
Designated investigator site staff will not be given access to the system until they have been 
trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3 
Database management and quality control 
Novartis staff (or Contract Research Organization (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 PRO data will be entered into an electronic device by the patient. The system will 
be supplied by a vendor(s), who will also manage the database. The database will be sent 
electronically to Novartis personnel (or designated CRO). 


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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 
Not required. 
9 
Data analysis 
The primary analysis will be conducted on all subject data at the time the treatment epoch ends. 
The PK analysis for the follow-up epoch will be conducted on all subject data at the time the 
post-treatment follow-up epoch ends. Any data analysis carried out independently by the 
investigator should be submitted to Novartis before publication or presentation. 
9.1 
Analysis sets  
The following analysis sets will be used in this study; 
Randomized set (RAN): The RAN will include all randomized patients, regardless of whether 
they received any study medication. Patients in the RAN will be analyzed according to the 
treatment assigned at randomization. Patients who are randomized in error will be excluded 
from the RAN. 
Full analysis set (FAS): The FAS will consist of all patients in the RAN who received at least 
one dose of study medication. Following the intent-to-treat principle, patients in the FAS will 
be analyzed according to the treatment they are assigned to at randomization. 
Safety set (SAF): The SAF will consist of all patients who received at least one dose of study 
medication. Patients in the SAF will be analyzed according to treatment actually received. 
Pharmacokinetic set (PK): The PK will consist of all randomized patients who received at 
least one dose of study medication and have evaluable PK/PD data. Patients in the PK will be 
analyzed according to the treatment they actually received. 
Note that the set of patients included in the FAS and SAF are the same except that the SAF 
allows the inclusion of non-randomized patients who received study medication in error. 


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The analysis of the primary objective will be performed on the FAS. The FAS will also be used 
for the analysis of all other efficacy endpoints. The SAF will be used for the analysis of all 
safety endpoints. The PK will be used for PK analysis. 
9.2 
Patient demographics and other baseline characteristics 
Demographic, background data and key efficacy variables at baseline will be summarized for 
the RAN by treatment group that patients are assigned to at randomization using descriptive 
statistics (number of non-missing data, mean, standard deviation, median, first and third 
quartiles, minimum, and maximum) for continuous variables and number and percentage of 
patients in each category including a category for missing data if any for categorical variables. 
Summaries will be provided for age, gender, race, ethnicity, baseline height, weight, body mass 
index (BMI), and relevant medical history. More detail of variables will be defined in statistical 
analysis plan (SAP). No imputation will be done for missing data. 
Baseline will be defined as the last measurement before or at the randomization visit. 
No statistical analysis will be provided for baseline comparability between the treatment groups. 
9.3 
Treatments 
A listing of study drug administration will be presented. The total number of doses of study 
drug administered will be summarized by dosing schedule and treatment group for the SAF. 
The dose and regimen of study drug and the duration of exposure will also be summarized for 
the SAF. Duration of exposure to study treatment will be calculated as last visit (Day 85 date 
or early discontinuation) of the treatment epoch – first dose date + 1 (days). 
Concomitant medications and non-drug therapies used will be coded, listed, and summarized 
for the SAF 
9.4 
Analysis of the primary variable(s) 
Analyses will be based on the patients in the FAS, unless otherwise specified. 
9.4.1 
Primary Variable(s) 
The primary efficacy variable is mean nasal symptom score during the severe symptom period. 
The severe symptom period will be defined as: the three weeks where the cumulative value of 
the mean daily nasal symptom score will be the maximum, if it meets one of the following 
criteria; 
• ≥ 70% of the period with concomitant use of fluticasone propionate (nasal) is included in 
this three weeks.  
• ≥ 70% of this three weeks includes the period with concomitant use of fluticasone 
propionate (nasal). 
If not, severe symptom period will be extended at a minimum to meets one of the criteria above. 
To specify the three week severe symptom period, the mean daily nasal symptom score will be 
derived as: the total nasal symptom score of all patients will be divided by the non-missing 
number of patients per day. The severe symptom period will be the same for all patients. 


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The severe symptom period will be specified during blinded review. The detail rule of definition 
for the severe symptom period will be described in statistical analysis plan (SAP). 
As the primary efficacy variable, the mean nasal symptom score during the severe symptom 
period for each patient will be calculated for patient who has the data of the nasal symptom 
score for at least 50% of days during the severe symptom period. 
The analysis of the primary efficacy variable using the FAS will be the primary basis of 
conclusion. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The mean nasal symptom score during the severe symptom period will be compared between 
treatments using an analysis of variance model with treatment group, dosing schedule 
(two-weekly or four-weekly) and randomization strata based on hypotheses below. The test will 
be conducted at the two-sided significance level of 5%. Least-square mean difference between 
treatment groups and corresponding 95% confidence interval will be calculated based on the 
model. 
H0: Omalizumab is not different to placebo with respect to mean nasal symptom score over the 
severe symptom period. 
H1: Omalizumab is different to placebo with respect to mean nasal symptom score over the 
severe symptom period. 
9.4.3 
Handling of missing values/censoring/discontinuations 
The mean nasal symptom score as the primary variable will be calculated for the patients who 
have the data of the nasal symptom score for at least 50% of days during the severe symptom 
period (extended if applicable). No imputation will be done for the patients who don’t have the 
data of the nasal symptom score more than 50% of days during the severe symptom period and 
they will not be included in the primary analysis. It might be that the number of patients 
providing data to an analysis is smaller than the number of subjects in the FAS. Handling of 
missing variable for secondary 
 analysis will be done in the same way except 
for analysis of JRQLQ score and 
 at evaluation visit. 
9.4.4 
Sensitivity analyses 
As a sensitivity analysis to the handling of missing values for the primary analysis, if we have 
more number of patients who don’t have the data of the nasal symptom score more than 50% 
of days during the severe symptom period than expected as drop-out rate in the protocol (10%), 
imputation will be performed for the missing data, e.g., using multiple imputation method under 
Missing at Random (MAR) assumption. The analysis will be conducted using the same model 
as the primary variable for the FAS and detail of imputation method will be described in 
statistical analysis plan (SAP). 
9.5 
Analysis of secondary variables 
Analyses will be based on the patients in the FAS. No imputation for missing data will be done 
for secondary variables. 


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No adjustment of multiplicity will be considered for secondary endpoints. 
9.5.1 
Efficacy variables 
The following variables during the severe symptom period will be analyzed using the same 
model as the primary variable. Least-square mean difference between treatment groups and 
corresponding 95% confidence interval will be calculated based on the model. 
- 
Mean ocular symptom score and nasal ocular symptom score 
- 
Mean nasal symptom medication score, ocular symptom medication score, and nasal 
ocular symptom medication score 
- 
Mean score for severity of sneezing, rhinorrhea and nasal congestion 
- 
Mean score for severity of itchy and watery eye 
- 
Mean score for impairment of daily activities 
- 
Mean rescue medication (tramazoline hydrochloride, levocabastine hydrochloride) score 
The following variables during the severe symptom period will be analyzed by stratified 
Wilcoxon rank sum (van Elteren) test with dosing schedule (two-weekly or four-weekly) and 
randomization strata. 
- 
Number of symptom free days (days with all nasal symptoms are not more than mild in 
severity)  
- 
Number of days with no rescue medication (tramazoline hydrochloride, levocabastine 
hydrochloride) 
- 
Amount number of rescue medication (tramazoline hydrochloride, levocabastine 
hydrochloride) used 
The following variable at evaluation visit will be analyzed using the same model as the primary 
variable. Basically the evaluation visit will be the visit during the severe symptom period and 
detail rule for definition of the evaluation visit will described in statistical analysis plan (SAP). 
- 
Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ, No1) score 
9.5.2 
Safety variables 
All safety evaluations will be performed on the SAF. 
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 
summarized for randomized-treatment epoch. Non-treatment emergent AEs (occurring in 
screening epoch) 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 


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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, SAE, and AEs 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. 
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 patients with both baseline and post baseline values. 
Anti-omalizumab antibody 
A summary of anti-omalizumab antibody data 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 patients 
with both baseline and post-baseline values. 
9.5.3 
Resource utilization 
Not applicable. 
9.5.4 
Pharmacokinetics 
Refer to PK/PD Section 9.5.7. 
9.5.5 
DNA 
Not applicable. 
9.5.6 
Biomarkers 
Not applicable. 


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9.5.7 
PK/PD 
Serum omalizumab concentration, free IgE concentration and total IgE concentration at each 
evaluation visits will be summarized with descriptive statistics for the PK. No imputation for 
missing data will be done. 
9.7 
Interim analyses 
There will be no interim analysis in this study. A primary analysis will be performed on all the 
data during the screening epoch and the treatment epoch after all patients complete the treatment 
epoch to support the registration. The database lock for this analysis will be done after 30 days 
safety evaluation following the end of the treatment epoch will be completed for all patients. 
After completion of post-treatment follow-up visit for all patients, PK analysis for the follow-
up epoch will be performed separately. 
9.8 
Sample size calculation 
For primary efficacy variable, with sample size of 155 subjects per group the study will provide 
90% power to detect difference for omalizumab versus placebo. This power estimate is based 
on a two-sided type-I-error of 5%, a treatment difference in mean daily nasal symptom score of 
0.87 and a common standard deviation of 2.35. A 0.87 treatment difference (0.29/each nasal 
symptom of sneezing, rhinorrhea and nasal congestion) is considered clinically relevant (Higaki 
et al 2013). A standard deviation of approximately 2.35 has been observed in the analysis for 
severe subjects in the previous study (CIGE025A1305). Assuming an early discontinuation rate 
of approximately 10%, a total of 346 subjects will be randomized. 
Sensitivity of power to change in assumptions is summarized in Table 9-1. 


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Table 9-1 
Sensitivity of power to change in assumptions for N=346 
True treatment difference 
for omalizumab vs placebo 
(units) 
SD (units) 
Power for primary endpoint (2-sided alpha =5%) 
With 10% drop-out rate 
0.80 
2.35 
2.00 
2.50 
84% 
93% 
80% 
0.70 
2.35 
2.00 
2.50 
74% 
86% 
69% 
0.60 
2.35 
2.00 
2.50 
61% 
74% 
55% 
0.50 
2.35 
2.00 
2.50 
46% 
59% 
41% 
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 (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable 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 
should indicate assent by personally signing and dating the written informed consent document 
or a separate assent form. Informed consent must be obtained before conducting any study-
specific procedures (e.g. all of the procedures described in the protocol). The process of 
obtaining informed consent must be documented in the patient source documents.Novartis will 
provide to investigators in a separate document a proposed informed consent form that complies 
with the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be agreed 
to by Novartis before submission to the IRB/IEC, and a copy of the approved version must be 
provided to the Novartis monitor after IRB/IEC approval. 
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 


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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, 
informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients/subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
10.5 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess Good Clinical Practice (GCP) compliance with global and local 
regulatory requirements, protocols and internal Standard Operating Procedures, and are 
performed according to written Novartis processes. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients/subjects should 
be administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 


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not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
11.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 


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12 
References 
Beck LA, Marcotte GV, MacGlashan D, et al (2004) Omalizumab-induced reductions in mast 
cell Fce psilon RI expression and function. J Allergy Clin Immunol; 114(3):527-30. 
Committee for practical guideline for the management of allergic rhinitis (2015): Practical 
guideline for the management of allergic rhinitis in Japan 2016. 8th edition; Tokyo: Life 
Science (written in Japanese). 
Hayashi N, Tsukamoto Y, Sallas WM, et al (2007) A mechanism-based binding model for the 
population pharmacokinetics and pharmacodynamics of omalizumab. Br J Clin Pharmacol; 
63(5):548-61. 
Higaki T, Okano M, Kariya S, et al (2013) Determining minimal clinically important 
differences in Japanese cedar/cypress pollinosis patients. Allergol Int; 62(4):487-93. 
Lin H, Boesel KM, Griffith DT, et al (2004) Omalizumab rapidly decreases nasal allergic 
response and FcepsilonRI on basophils. J Allergy Clin Immunol; 113(2):297-302. 
Nagakura T, Ogino S, Okubo K, et al (2008) Omalizumab is more effective than suplatast 
tosilate in the treatment of Japanese cedar pollen-induced seasonal allergic rhinitis. Clin Exp 
Allergy; 38(2):329-37. 
Ogino S, Nagakura T, Okubo K, et al (2009) Re-treatment with omalizumab at one year 
interval for Japanese cedar pollen-induced seasonal allergic rhinitis is effective and well 
tolerated. Int Arch Allergy Immunol; 149(3):239-45. 
Okubo K, Kurono Y, Ichimura K, et al (2017) Japanese guidelines for allergic rhinitis 2017. 
Allergol Int; 66(2):205-19. 
Okubo K, Ogino S, Nagakura T, et al (2006) Omalizumab is effective and safe in the 
treatment of Japanese cedar pollen-induced seasonal allergic rhinitis. Allergol Int; 55(4):379-
86. 
Okubo K and Okuda M (2012) Allergology & Immunology; 19(1):113-124 (written in 
Japanese). 
Presta LG, Lahr SJ, Shields RL, et al (1993) Humanization of an antibody directed against 
IgE. J Immunol; 151(5):2623-32. 
Reilly MC, Tanner A, Meltzer EO (1996) Work, classroom, and activity impairment 
instruments. Validation studies in allergic rhinitis. Clin Drug Investig; 11(5):278–88. 
Shields RL, Werther WR, Zioncheck K, et al (1995) Inhibition of allergic reactions with 
antibodies to IgE. Int Arch Allergy Immunol; 107(1-3):308-12. 
References are available upon request. 


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13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
Refer to Appendix 2 for clinically notable laboratory values for hepatotoxicity. 
The following other specific criteria have been identified for this study: 
• Platelets < 75 000/µL 
The following actions must be taken if the specific value in platelet counts are observed: 
• In case of a platelet count < 75 000/µL (75 × 109/L) is detected, further dosing must be 
suspended and a second ‘retest’ blood-sample must be taken immediately (recommended 
within 1 - 2 days). 
• If the second (‘re-test’) blood sample confirms a platelet count < 75 000/µL (75 × 109/L), 
the patient should discontinue the study treatment and will be followed as clinically 
appropriate. 
• If the second sample does not confirm the low platelet count, the patient will continue to 
receive study medication as scheduled, following discussion with Clinical Trial Leader at 
Novartis. 
The Central Laboratory will flag laboratory values falling outside of the normal ranges on the 
Central Laboratory Report. Investigators are responsible for reviewing these abnormal values 
for clinical significance, signing the laboratory reports to indicate their review, and reporting 
values considered clinically significant in the appropriate eCRF. 
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined. 


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14 
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements 
Table 14-1 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
• 
3 × ULN < ALT / AST ≤ 5 × ULN 
• 
1.5 × ULN < TBL ≤ 2 × ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
 
• 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
• 
ALT or AST > 3 × ULN and INR > 1.5 
 
• 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN (mainly conjugated fraction) without notable 
increase in ALP to > 2 × ULN) 
 
• 
Any clinical event of jaundice (or equivalent term) 
 
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia 
 
• 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms 
TBL: total bilirubin; ULN: upper limit of normal  
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 3 × ULN and 
INR > 1.5 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, continue follow-up 
monitoring 
• 
If elevation persists for more than 2 
weeks, discontinue the study drug 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN 
accompanied by 
symptomsb 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish causality 
• 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, discontinue the study 
drug immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated (indirect) 
bilirubin) 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient  
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
Jaundice 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study treatment interruption or 
discontinuation  
• 
Hospitalization if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
Investigator discretion 
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 


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15 
Appendix 3: Patient e-Diary (sample) 
 
Please complete the following questions about Japanese cedar pollinosis once each day during 
the screening and treatment epoch (preferably at the same time each day). 
 
• Today’s Date: 
 
1. Please rate each of your nasal symptoms of Japanese cedar pollinosis today (please select 
only one response). 
Paroxysmal 
sneezing 
(Number of episodes of 
paroxysmal sneezing in a 
day) 
Score 4: ≥ 21 times 
Score 3: 20-11 times 
Score 2: 10-6 times 
Score 1: 5-1 times 
Score 0: 0 
Rhinorrhea 
(Number of episodes of 
nose blowing a day) 
Score 4: ≥ 21 times 
Score 3: 20-11 times 
Score 2: 10-6 times 
Score 1: 5-1 times 
Score 0: 0 
Nasal congestion 
Score 4: Completely obstructed all day 
Score 3: Severe nasal congestion causing prolonged oral breathing 
in a day 
Score 2: Severe nasal congestion causing occasional oral 
breathing in a day 
Score 1: Nasal congestion without oral breathing 
Score 0: Less severe degree than score of 1 
 


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2. Please rate each of your ocular symptoms of Japanese cedar pollinosis today (please select 
only one response). 
Itchy eye 
Score 4: More severe degree than score of 3 
Score 3: Frequently rubbing eye(s) 
Score 2: Occasionally rubbing eye(s) 
Score 1: Not to the extent of rubbing eye(s) 
Score 0: None 
Watery eye 
Score 4: More severe degree than score of 3 
Score 3: Frequently wiping tears 
Score 2: Occasionally wiping tears 
Score 1: Not to the extent of wiping tears 
Score 0: None 
 
3. Please rate the impairments of your daily activities caused by Japanese cedar pollinosis 
today (please select only one response). 
Impairment 
of 
daily 
activities 
Score 4: Impossible 
Score 3: Painful and complicating daily life 
Score 2: Intermediate in degree between score of 3 and score of 1 
Score 1: Few troubles 
Score 0: Less severe degree than score of 1 
 
4. Please record the usage of the following medications for Japanese cedar pollinosis today. 
Fexofenadine hydrochloride (oral) 
Number of tablets taken in the morning 
Number of tablets taken in the evening 
Fluticasone propionate (nasal) 
Number of rhinenchysis in the morning 
Number of rhinenchysis in the evening 
Tramazoline hydrochloride (nasal) 
Number of rhinenchysis in a day 
Levocabastine hydrochloride (ocular) Number of ocular instillation in a day 
 


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16 
Appendix 4: Japanese Rhino-conjunctivitis Quality of Life 
Questionnaire (JRQLQ) 
 
Japanese Rhino-conjunctivitis Quality of Life Questionnaire  
(JRQLQ No1) 
 
To patients with allergic rhinitis (including pollinosis) 
These days, the aim of medical treatment is not just to cure disease but also to give patients a 
better quality of life. The purpose of this survey is to determine to what extent your rhinitis 
interferes with your life and whether it would be improved by treatment. As with all medical 
treatment, the information you provide in this survey will remain strictly confidential. 
 
You may find some of the following questions difficult to answer, but just answer to the best of 
your ability. 
 
I. 
Tick the box that best describes the severity of the worst nasal and eye symptoms you 
have experienced in the past 1 - 2 weeks. 
 
Nasal and eye 
symptoms 
0, No  
symptoms 
1,  
Mild 
2,  
Moderate 
3,  
Severe 
4,  
Very severe 
Runny nose 
□ 
□ 
□ 
□ 
□ 
Sneezing 
□ 
□ 
□ 
□ 
□ 
Blocked 
nose 
(nasal congestion) 
□ 
□ 
□ 
□ 
□ 
Itchy nose 
□ 
□ 
□ 
□ 
□ 
Itchy eyes 
□ 
□ 
□ 
□ 
□ 
Watery eyes 
□ 
□ 
□ 
□ 
□ 
 
II. Tick the box that best describes the worst extent to which the symptoms in I above 
have interfered with your quality of life in the past 1 - 2 weeks. If any of the items 
listed under Quality of life below definitely do not relate to the symptoms in I (nose, 
eye). then there is no need to tick a box for that particular item. 
 


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Protocol No. CIGE025F1301 
 
 
Quality of life 
0,  
No 
1, Yes, 
slightly 
2, Yes, 
moderately 
3, Yes, 
greatly 
4, Yes, 
very 
greatly 
1. Reduced 
productivity 
at 
work/home 
□ 
□ 
□ 
□ 
□ 
2. Poor mental concentration 
□ 
□ 
□ 
□ 
□ 
3. Reduced thinking power 
□ 
□ 
□ 
□ 
□ 
4. Impaired reading book / 
newspaper 
□ 
□ 
□ 
□ 
□ 
5. Reduced memory 
□ 
□ 
□ 
□ 
□ 
6. Limitation of outdoor life 
(e.g. sport, picnics) 
□ 
□ 
□ 
□ 
□ 
7. Limitation of going out 
□ 
□ 
□ 
□ 
□ 
8. Hesitation visiting friend or 
relatives 
□ 
□ 
□ 
□ 
□ 
9. Reduced contact with friends 
or others by telephone or 
conversation 
□ 
□ 
□ 
□ 
□ 
10. Not an easy person to be 
around 
□ 
□ 
□ 
□ 
□ 
11. Impaired sleeping 
□ 
□ 
□ 
□ 
□ 
12. Tiredness 
□ 
□ 
□ 
□ 
□ 
13. Fatigue 
□ 
□ 
□ 
□ 
□ 
14. Frustration 
□ 
□ 
□ 
□ 
□ 
15. Imitability 
□ 
□ 
□ 
□ 
□ 
16. Depression 
□ 
□ 
□ 
□ 
□ 
17. Depression 
□ 
□ 
□ 
□ 
□ 
 
III. Please circle the number of the face that best describes your general state (including 
your symptoms, life and emotion) in the past 1 - 2 weeks. 
 
 
Okubo K, Kurono Y, Ichimura K, et al (2017) Japanese guidelines for allergic rhinitis 2017. 
Allergol Int; 66(2):205-19. 


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Protocol No. CIGE025F1301 
 
 
 


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Protocol No. CIGE025F1301 
 
 


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Protocol No. CIGE025F1301 
 
 
18 
Appendix 6: Blood log 
 
Table 18-1 
Blood log for PK and PD Samples 
 
Omalizumab 
Total IgE 
Free IgE 
Matrix 
Serum 
Serum 
Serum 
Name and type of analysis 
PK 
PD 
PD 
Visit 
Dose 
Reference 
ID 
Sample 
Number 
Dose 
Reference 
ID 
Sample 
Number 
Dose 
Reference 
ID 
Sample 
Number 
Visit 101 pre-dose 
1 
101 
1 
201 
1 
301 
Visit 103 pre-dose 
3 
102 
3 
202 
3 
302 
Visit 105 pre-dose 
5 
103 
5 
203 
5 
303 
Visit 199 14 days or 28 
days post dose 
6 
104 
6 
204 
6 
304 
Visit 299 168 days post 
treatment 
6 
105 
6 
205 
6 
305 
 
Table 18-2 
Blood log for immunogenicity 
 
Immunogenicity 
Matrix 
Serum 
Visit 
Dose 
Reference ID 
Sample Number 
Visit 101 (pre-dose) 
1 
401 
Visit 299 168 days post 
treatment 
6 
402 
 

SAP_000.pdf: 
Clinical Development 
CIGE025/Omalizumab 
CIGE025F1301 / NCT03369704 
A 12 week, multi-center, randomized, double-blind, 
placebo-controlled phase III study to evaluate the efficacy 
and safety of omalizumab in adult and adolescent patients 
with inadequately controlled severe Japanese cedar 
pollinosis despite the current recommended therapies 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
  
Document type: 
SAP Documentation 
Document status: 
Final 2.0 - Amendment 1 
Release date: 
19-Jul-2018
Number of pages: 
37 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
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Page 2 
SAP 
 
CIGE025F1301 
 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and title 
impacted 
(Current) 
11-
Dec-
2017 
Prior to 
FPFV 
 
Final 2.0 
 
19-
Jul-
2018 
Prior to 
DB lock 
Creation of 
Amendmen
t 1 
- Modified the member of Author. (Author 
members are changed.) 
Cover 
 
 
 
- Objectives and related endpoints Study 
objectives and endpoints 
Added the footnote about the definition of 
symptom free days. 
1.2 
 
 
 
- Severe symptom period 
Clalified that the severe symptom period will be 
set as a period not exceeding April 13. 
- Baseline 
Added handle of unscheduled visits. 
- 
Handling 
of 
data 
from 
premature 
discontinuation or unscheduled visit 
Added the details of data handling. 
- Handling of duplicatedata in patient-reported 
outcomes (PRO) 
New addition. 
- Definition of evaluation visit 
Added the details of data handling. 
2.1.1 
 
 
 
- Subgroup of interest 
Deleted the following subgroups; Age (<15 
years/ >=15 years, and Having cedar pollinosis 
symptoms at the initial drug administration (Yes/ 
No ). 
Modified the subgroup categoty of Total IgE 
concentration at baseline and Severity of cedar 
pollinosis in 2017. 
2.2.1 
 
 
 
- Demographic characteristics 
Deleted the following items; Age category; <15 
years/ >=15 years. 
- Disease characteristics 
2.3 


Novartis 
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SAP 
 
CIGE025F1301 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and title 
impacted 
(Current) 
Deleted the following items; Coexistence of 
perennial allergic rhinitis; Nasal eosinophil 
count; Not done. 
Modified the following item; Japanese cedar 
pollinosis related medical history; Severity of 
nasal symptom in the previous season (2017) . 
Deleted the category label of “Randomization 
strata”.  
- Medical history 
Deleted the medical history from summarized 
items. 
 
 
 
- The disposition table 
Clarified the analysis set of each summary. 
2.3.1 
 
 
 
- Prior and concomitant therapies 
Modified the description regarding coding 
procedure and analysis procedure for Medication, 
therapies, and surgical and medical procedures. 
2.4.2 
 
 
 
- Statistical hypothesis, model, and method of 
analysis 
Added the considering a weight of the strata for 
least-square mean. 
Clalified the data source of stratifications for the 
randomization. 
2.5.2 
 
 
 
- Subgroup analyses 
Added details of handling of subgroup variale. 
- Supportive analysis using the adjusted nasal 
congestion score (AdNCS) 
Modified the description regarding definition of 
AdNCS, added the reference information. 
2.5.4 
 
 
 
- The variables regarding each mean score of the 
symptoms and/or rescue medication 
Added the considering a weight of the strata for 
least-square mean. 
Added the description of Mean score for 
severity of sneezing, rhinorrhea and nasal 
2.7.2 


Novartis 
For business use only 
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SAP 
 
CIGE025F1301 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and title 
impacted 
(Current) 
congestion, and Mean score for severity of itchy 
and watery eye.  
- The variables regarding symptom free days 
and/or rescue medication 
Modified the description about eatimate of 
stratified Hodges-Lehmann estimates. 
- A proportion of patients 
Modified the description regarding a proportion 
of patients with categorical mean scores. 
Modified the items presented as histogram. 
- The JRQLQ, No1 score at evaluation visit 
Modified the details of figures box-plot to bar 
graph. 
 
 
 
- Adverse events (AEs) 
Added the summary by presenting SMQ. 
Modified the threashold of AEs 3% to 2%. 
Deleted the some of safety analyses; 
*Number (%) of patients reporting AEs 
suspected to be related to study drug by SOC, PT 
and maximum severity. 
*Number (%) of patients reporting SAEs by 
SOC, PT and maximum severity. 
*Number (%) of patients reporting SAEs 
suspected to be related to study drug by SOC and 
PT. 
*Number (%) of patients reporting AEs leading 
to discontinuation regardless of study drug 
relationship by SOC, PT and maximum severity . 
*Number (%) of patients reporting AEs leading 
to discontinuation related to study drug by SOC 
and PT. 
Added the some of safety analyses; 
*Number (%) of patients reporting AEs by 
SMQ. 
*Number (%) of patients reporting AEs by SMQ 
and PT. 
2.8.1 


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SAP 
 
CIGE025F1301 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and title 
impacted 
(Current) 
 
 
 
- Adverse events of special interest / grouping of 
AEs 
Deleted the following analyses; Laboratory 
triggers. 
Clalified the summary for the AEs of special 
interest. 
2.8.1.1 
 
 
 
- Laboratory data 
Deleted the following analyses for laboratory 
data; Frequency table by visit. (Urinalysis), 
Boxplot by visit. (Hematology, Biochemistry). 
Added the following analysis for laboratory 
data; Descriptive summary statistics for post-
baseline maximum values and their changes from 
baseline in liver parameters. 
Modified 
the 
criterion 
for 
the 
notable 
abnormalities of platelets. 
2.8.3 
 
 
 
- PK/PD analyses 
Modified the description about %changes from 
baseline to each visit. 
Added description; Both of Serum total IgE 
[IU/mL] and free IgE [ng/mL] will be presented 
in the same unit [ng/mL]. 
2.10 
 
 
 
- e-Diary assessment (Nasal symptoms, Ocular 
symptoms, Medication use, and Impairment of 
daily activities) 
Added the explanation about e-Diary data 
collection and added handling of collection date. 
2.11.1 
 
 
 
 
- Computation rule for Variables 
Modified the description "rescue drug use" to 
"comcomitant/ rescue drug use". 
2.11.1.5 
 
 
 
- Japanese Rhino-conjunctivitis Quality of Life 
Questionnaire (JRQLQ) 
Added the analysis of total scores of JRQLQ II. 
2.11.2 
 
 
 


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SAP 
 
CIGE025F1301 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and title 
impacted 
(Current) 
 
 
 
 
 
 
- Change to protocol specified analyses 
Added changes described in the following 
sections; 
Section 2.5.2, 2.7.2, 2.8.1 
4 
 
 
 
- Rule of exclusion criteria of analysis sets 
Modified the No. of reference tables Table 1 to 
Table 5-1, and Table 2 to Table 5-2. 
5.4 
 
 
 
- Reference 
Added the reference regaring AdNCS. 
6 
 
 
 
Minor update for grammatical error and typo. 
- Subgroup of interest (2.2.1) 
- Patient disposition, demographics and other 
baseline characteristics (2.3) 
- Statistical hypothesis, model, and method of -
analysis (2.7.2) 
- Adverse events of special interest / grouping of 
AEs (2.8.1.1) 
- Laboratory data (2.8.3) 
 
2.2.1 
2.3 
2.7.2 
2.8.1.1 
2.8.3 
2.13 


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SAP 
 
CIGE025F1301 
 
Table of contents 
Table of contents ................................................................................................................. 7 
List of abbreviations ............................................................................................................ 9 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design........................................................................................................... 10 
1.2 
Study objectives and endpoints ............................................................................. 11 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 13 
2.2 
Analysis sets .......................................................................................................... 15 
2.2.1 
Subgroup of interest .............................................................................. 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.3.1 
Patient disposition ................................................................................. 18 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 20 
2.4.2 
Prior and concomitant therapies ............................................................ 21 
2.5 
Analysis of the primary objective .......................................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 22 
2.5.4 
Supportive analyses ............................................................................... 22 
2.6 
Analysis of the key secondary objective ............................................................... 23 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 23 
2.7.1 
Secondary endpoint ............................................................................... 23 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 25 
2.8 
Safety analyses ....................................................................................................... 25 
2.8.1 
Adverse events (AEs) ............................................................................ 25 
2.8.2 
Deaths .................................................................................................... 26 
2.8.3 
Laboratory data ..................................................................................... 27 
2.8.4 
Other safety data ................................................................................... 28 
2.9 
Pharmacokinetic endpoints .................................................................................... 29 
2.10 
PK/PD analyses ..................................................................................................... 29 
2.11 
Patient-reported outcomes ..................................................................................... 29 
2.11.1 
e-Diary assessment (Nasal symptoms, Ocular symptoms, 
Medication use, and Impairment of daily activities) ............................. 29 


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CIGE025F1301 
 
2.11.2 
Japanese Rhino-conjunctivitis Quality of Life Questionnaire 
(JRQLQ) ................................................................................................ 31 
 
 
 32 
2.12 
Biomarkers ............................................................................................................. 33 
 
 33 
2.14 
Interim analysis ...................................................................................................... 34 
3 
Sample size calculation ..................................................................................................... 34 
4 
Change to protocol specified analyses .............................................................................. 35 
5 
Appendix ........................................................................................................................... 36 
5.1 
Imputation rules ..................................................................................................... 36 
5.2 
AEs coding/grading ............................................................................................... 36 
5.3 
Statistical models ................................................................................................... 36 
5.3.1 
Primary analysis .................................................................................... 36 
5.3.2 
Key secondary analysis ......................................................................... 36 
5.4 
Rule of exclusion criteria of analysis sets.............................................................. 36 
6 
Reference ........................................................................................................................... 37 


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CIGE025F1301 
 
List of abbreviations 
AdNCS 
Adjusted Nasal Congestion Score 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Classification 
BMI 
Body Mass Index 
CSR 
Clinical Study Report 
DBL 
Database Lock 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
IgE 
Immunoglobulin E 
IRT 
Interactive Response Technology 
JRQLQ 
Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ No.1) 
LPLV 
Last Patient Last Visit 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCS 
Nasal Congestion Score 
PD 
Pharmacodynamics 
PD 
Protocol Deviation 
PK 
Pharmacokinetics, Pharmacokinetic set 
PRO 
Patient-Reported Outcomes 
PT 
Preferred Term 
QOL 
Quality of Life 
RAN 
Randomized set 
SAE 
Serious Adverse Event 
SAF 
Safety set 
SAP 
Statistical Analysis Plan 
SI 
International System of Units 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TFL 
Tables, Figures, Listings 
ULN 
Greater than Upper Limit of Normal range 
 
 
 


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CIGE025F1301 
 
1 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical methods for CIGE025F 
1301 study. It is planned as 
- 
A draft of Section 9.7 (Statistical methods planned in the protocol and determination of 
sample size) of the clinical study report (CSR) 
- 
A draft of Appendix 16.1.9 (Documentation of statistical methods) of the CSR 
Appendix 16.1.9 text will contain details of statistical methods and issues that are too long to 
be included in the CSR text (Appendix 16.1.9 is not mandatory for abbreviated and synoptic 
reports.).  
The statistical methods planned in this document will also be used for Benefit & Risk 
assessment of the study drug. 
It is written in future tense. It will be reviewed and updated (including conversion to past tense) 
for entry into the CSR after the analysis has taken place. 
1.1 
Study design 
CIGE025F1301 is a Phase III multi-center, randomized, double-blind, placebo-controlled study 
in patients with severe Japanese cedar pollinosis, whose symptoms were inadequately 
controlled despite the current recommended therapies (nasal corticosteroid plus one or more 
medications out of anti-histamine (second generation), leukotriene receptor antagonist, or 
prostaglandin D2/thromboxane A2 receptor antagonist) in the previous 2 Japanese cedar pollen 
seasons. The purpose of this study is to demonstrate the efficacy and safety of omalizumab 
compared with placebo, on top of SoC (anti-histamine and nasal corticosteroid). 
Approximately 346 patients will be enrolled in the Kanto-area of Japan. 
Eligible patients will be randomly assigned in a 1:1 ratio to receive omalizumab or placebo by 
subcutaneous injection. Patients will be stratified using Interactive Response Technology (IRT), 
based on the age group (≥ 12 to < 15 years and ≥ 15 to < 75 years), coexistence of perennial 
allergic rhinitis (Yes / No), dose frequency (every 2 weeks and 4 weeks) and having cedar 
pollinosis symptoms at the time of initial drug administration (Yes / No). 
The study consists of 3 distinct study epochs: 
• Screening epoch: Day -35 to Day -1 (1 - 5 weeks) 
• Treatment epoch: Day 1 to Day 85 (12 weeks) 
• Post-treatment follow-up: Day 225/239 (24 weeks after the last dosing) 
• 
 


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CIGE025F1301 
 
 
*Start date of fluticasone propionate use and duration of fluticasone propionate use (2 - 4 weeks) will 
be determined by the sponsor based on the forecast of cedar pollen scattering. 
There will be no interim analysis in this study. A primary analysis will be performed on all the 
data during the screening epoch and the treatment epoch after all patients complete the treatment 
epoch to support the registration. The database lock (DBL) for this analysis will occur when all 
the patients complete 30 days safety evaluation following the end of the treatment epoch or 
prematurely discontinue the study. After completion of post-treatment follow-up visit for all 
patients, PK analysis and anti-omalizumab antibody analysis for the follow-up epoch will be 
performed separately. 
1.2 
Study objectives and endpoints 
Table 1-1 Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• To demonstrate the efficacy of 
omalizumab compared with placebo 
Endpoint(s) for primary objective(s) 
• Mean nasal symptom score during the 
severe symptom period 
Secondary Objective(s) 
• To evaluate the efficacy (symptoms, 
quality of life impairment) of 
omalizumab compared with placebo 
Endpoint(s) for secondary objective(s) 
• Mean score of the following endpoints 
during the severe symptom period 
- Ocular symptom score and nasal 
ocular symptom score 
- Nasal symptom medication score, 
ocular symptom medication score, and 
nasal ocular symptom medication 
score 


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CIGE025F1301 
 
Objective(s) 
Endpoint(s) 
- Score for severity of sneezing, 
rhinorrhea and nasal congestion 
- Score for severity of itchy and watery 
eye 
- Score for impairment of daily 
activities 
• Symptom free days (days with all nasal 
symptoms are not more than milda in 
severity) during the severe symptom 
period 
• Use of rescue medication (tramazoline 
hydrochloride, levocabastine 
hydrochloride) during the severe 
symptom period 
- Rescue medication score 
- Number of days with no rescue 
medication 
- Amount of rescue medication used 
• Japanese Rhinoconjunctivitis Quality of 
Life Questionnaire (JRQLQ, No1) score 
at evaluation visit 
• To evaluate the safety of omalizumab 
compared with placebo 
• Adverse events, serious adverse events, 
adverse events of special interest, 
physical examinations, laboratory 
assessments, vital signs and anti-
omalizumab antibodies 
• To evaluate the PK/PD of omalizumab 
• Serum omalizumab concentration, free 
IgE concentration and total IgE 
concentration at evaluation visit 


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CIGE025F1301 
 
Objective(s) 
Endpoint(s) 
 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Data will be analyzed by Novartis and 
 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. 
All data analyses will be performed using SAS® statistical software (Version 9.4) unless 
otherwise noted. 
The primary analysis will be conducted on all subject data at the time the treatment epoch ends 
or premature discontinuation. The PK analysis and anti-omalizmab antibody analysis for the 
follow-up epoch will be conducted on all subject data at the time the post-treatment follow-up 
epoch ends. Any data analysis carried out independently by the investigator should be submitted 
to Novartis before publication or presentation. 
2.1.1 
General definitions  
Severe symptom period: The three weeks where the cumulative value of the mean daily nasal 
symptom score is the maximum. The severe symptom period will be set as a period not 
exceeding April 13. It will be specified during blinded review before DBL and will be the same 
for all patients. 
To specify the three week severe symptom period, the mean daily nasal symptom score will be 
derived as: the total nasal symptom score of all patients divided by the non-missing number of 
patients per day. 
The three weeks must also meet one of the following criteria; 
• ≥ 70% of the period with concomitant use of fluticasone propionate (nasal) is included 
in this three weeks. 
• ≥ 70% of this three weeks includes the period with concomitant use of fluticasone 
propionate (nasal). 


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CIGE025F1301 
 
If not, severe symptom period will be extended at a minimum to meet one of the criteria above. 
Severe pollen period: The period between the first and last days when ≥ 50 grains/cm2 of 
Japanese cedar pollen are counted. It will be announced before DBL by the sponsor based on 
the data of Japanese cedar pollen count. 
Pollen period: The start day of the pollen period is defined as the first of 2 consecutive days 
when ≥ 1 grain/cm2 of Japanese cedar pollen is counted; the end day of the pollen period is the 
first of 3 consecutive days when no grain is counted. It will be announced before DBL by the 
sponsor based on the data of Japanese cedar pollen count. 
Japanese cedar pollen count: The data at Chiyoda-Ku, Tokyo, which will be provided from 
, will be used in the study. 
 
General descriptive statistical rules to summarize quantitative or qualitative parameters: 
Continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, median, standard deviation, first and third quartiles, minimum, and maximum) and 
categorical variables will be summarized in terms of the number and percentage of patients in 
each category including a category for missing data if any. 
Study day: Study day is defined as the number of days since the date of first dose of study 
medication. The date of first dose of study medication is defined as Day 1 and the day before 
the first dose of study medication is defined as Day -1. 
Therefore, for a particular date, study day will be calculated as follows: 
• For dates on or after the first dose of study medication, 
Study day = Assessment date – Date of first dose of study medication + 1; 
• For dates prior to the first dose of study medication, 
Study day = Assessment date – Date of first dose of study medication. 
Baseline: In general, the last measurement (including unscheduled visits) before or at the 
randomization visit. For diary data, baseline is defined as an average during 7 days prior to Visit 
101 (randomization). 
Change from baseline: When change from baseline is of interest, the following formula will 
be used for each scheduled visit where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value. 
Handling of data from premature discontinuation or unscheduled visit: 
For patients who do not complete the study, the treatment/study discontinuation visit will be 
remapped to the next scheduled visit with reference to the planned duration between the two 
visits, or mapped as an unscheduled visit. If the discontinuation visit is greater or equal to half 
of the visit interval from the preceding scheduled visit but not exceeding the target date +7 days 
(the time window as allowed in the study protocol) then the discontinuation visit number will 
be assigned to the next scheduled visit; else it will be mapped as unscheduled visit. The data 
from the unmapped treatment/study discontinuation or unscheduled visit will not be used for 
the efficacy or by-visit safety analyses except for baseline but will be used for the summary of 
notable abnormalities for laboratory tests and shift tables. Data from unscheduled visits or the 
unmapped premature treatment/study discontinuation visits will be included in listings. 


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Handling of duplicatedata in patient-reported outcomes (PRO): 
PRO records are entered by subjects and there is case when more than one values are entered 
by subject for one entry due to technical reasons. In such a case, value of the available first 
entry will be used. 
Definition of evaluation visit: 
For JRQLQ, 
, evaluation visit 
will be defined as the visit during the severe symptom period if there is a single visit during the 
period, and will be defined as Visit 105 or, in case Visit 105 is outside the period, the visit 
during the period which is the closest to Visit 105 if there is more than one visit during the 
period for each patient. The evaluation visit will be derived independently for each evaluation 
item described above. If there will be no visit during the period, the evaluation visit will be set 
as missing.  
Classification of symptom severity and disease types of Japanese cedar pollinosis: 
Symptom severity and disease types will be determined according to Table 2-1 which is based 
on the Nasal symptom score shown in Section 2.11.1.1. 
Table 2-1 Symptom severity and disease types 
 
Paroxysmal sneezing or Rhinorrhea * 
4 
3 
2 
1 
0 
Nasal 
congestion 
4 
Most severe 
Most severe 
Most severe 
Most severe 
Most severe 
3 
Most severe 
Severe 
Severe 
Severe 
Severe 
2 
Most severe 
Severe 
Moderate 
Moderate 
Moderate 
1 
Most severe 
Severe 
Moderate 
Mild 
Mild 
0 
Most severe 
Severe 
Moderate 
Mild 
No symptom 
*Select more severe one, sneezing or rhinorrhea 
Disease type: Sneezing and rhinorrhea type; white cells, Nasal blockage type; light gray cells, 
Combined type; dark cells  
2.2 
Analysis sets 
Randomized set (RAN): The RAN will include all randomized patients, regardless of whether 
they received any study medication. Patients in the RAN will be analyzed according to the 
treatment assigned at randomization. Patients who are randomized in error will be excluded 
from the RAN. 
Full analysis set (FAS): The FAS will consist of all patients in the RAN who received at least 
one dose of study medication. Following the intent-to-treat principle, patients in the FAS will 
be analyzed according to the treatment they are assigned to at randomization. 
Safety set (SAF): The SAF will consist of all patients who received at least one dose of study 
medication. Patients in the SAF will be analyzed according to treatment actually received. 


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Pharmacokinetic set (PK): The PK will consist of all randomized patients who received at 
least one dose of study medication and have at least one evaluable PK measurement. Patients 
in the PK will be analyzed according to the treatment they actually received. 
Note that the set of patients included in the FAS and SAF are the same except that the SAF 
allows the inclusion of non-randomized patients who received study medication in error. The 
analysis of the primary objective will be performed on the FAS. The FAS will also be used for 
the analysis of all other efficacy endpoints. The SAF will be used for the analysis of all safety 
endpoints. The PK will be used for PK analysis. 
2.2.1 
Subgroup of interest 
For safety analysis;  
• Age (<15 years/ 15<=, <65 years/ >=65 years) 
• Age (<18 years/ >=18 years) 
• Sex 
• Dose frequency (2 weeks/ 4weeks)  
For efficacy analysis;  
• Age (<15 years/ 15<=, <65 years/ >=65 years) 
• Age (<18 years/ >=18 years) 
• Sex 
• Dose frequency (2 weeks/ 4weeks).  
• Coexistence of perennial allergic rhinitis (Yes/ No) 
• Score of serum cedar pollen-specific IgE level at baseline (score=3/4/5,6) 
• Total IgE concentration at baseline (in quartile) 
• Severity of cedar pollinosis in 2017 (Most severe/ Severe/ Moderate) 
• Type of cedar pollinosis in 2017 (Sneezing and rhinorrhea type/ Nasal blockage type/ 
Combined type) 
Refer to Section 2.5 and 2.8 in this document for subgroup analyses. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographics, disease characteristics, key efficacy variables and medical history at baseline 
will be summarized for the RAN unless otherwise specified, by treatment group that patients 
are assigned to at randomization using descriptive statistics (number of non-missing data, mean, 
standard deviation, median, first and third quartiles, minimum, and maximum) for continuous 
variables and number and percentage of patients in each category including a category for 
missing data if any for categorical variables. Unless otherwise stated, listings will be on all 
subjects included in the population under consideration. 
No imputation will be done for missing data. No statistical analysis will be provided for baseline 
comparability between the treatment groups. 
The summaries include 
Demographic characteristics: 
Variables 
Category 
Age (years) 
(descriptive statistics) 


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Height (cm) 
Weight (kg) 
Body mass index (BMI) (kg/m2) 
Age (years) 
< 18 year/ >= 18 years 
<15 years/ 15<=, <65 years/ 
>= 65 years 
Sex 
Male/ Female 
Race 
(if applicable) 
Ethnicity 
(if applicable) 
 
Disease characteristics: 
Variables 
Category 
Japanese cedar pollinosis related medical history 
(ongoing at screening visit); 
 
Japanese cypress pollinosis 
Seasonal allergic rhinitis  
caused by other than Japanese cedar/cypress 
Perennial allergic rhinitis 
Chronic rhinosinusitis 
Allergic conjunctivitis 
Asthma 
Atopic dermatitis 
Urticaria 
Food allergy 
Oral allergy syndrome 
Yes/ No 
Japanese cedar pollinosis disease background; 
 
Duration of Japanese cedar pollinosis (years) 
Symptom score in the previous season (2017) 
- 
Nasal symptoms 
- 
Ocular symptoms 
(descriptive statistics) 
Symptom score in the previous season (2017) 
- 
Nasal 
symptoms 
(Paroxysmal 
sneezing, 
Rhinorrhea, Nasal congestion) 
- 
Ocular symptoms (Itchy eye, Watery eye) 
0/ 1/ 2/ 3/ 4 
Medication use for Japanese cedar pollinosis in the 
past 2 seasons 
- 
Each drug in 2016 
- 
Each drug in 2017 
Yes/ No 
Severity of nasal symptom in the previous season 
(2017) 
Most 
severe/ 
Severe/ 
Moderate 
Type of disease in the previous season (2017) 
Sneezing 
and 
rhinorrhea 
type/ Nasal blockage type/ 
Combined type 
Having cedar pollinosis symptoms at the initial drug 
administration 
Yes/ No 


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Symptom score at baseline; 
 
Mean scores of each symptom during 7 days prior to 
the randomization 
- 
Nasal symptoms 
- 
Ocular symptoms 
(descriptive statistics) 
Medication use at baseline; 
 
Medication use during 7 days prior to the 
randomization 
Yes/ No 
Symptom related assessment at baseline; 
 
JRQLQ for three part and six domains 
 
Total IgE concentration 
Cedar pollen-specific IgE concentration 
 
(descriptive statistics) 
 
 
Score of cedar pollen-specific IgE level 
3/ 4/ 5/ 6 
 
Medical history: 
Medical history and current medical conditions not related to Japanese cedar pollinosis, entered 
on the Medical history eCRF page, will be coded using the Medical Dictionary for Drug 
Regulatory Affairs (MedDRA) dictionary (the latest version). Japanese cedar pollinosis non-
related current medical conditions will be summarized by primary system organ class (SOC), 
preferred term (PT), and treatment. 
Randomized allocation to treatment: 
Randomized allocation will be summarized by dosing schedule, treatment group, and dose 
prescribed. 
2.3.1 
Patient disposition 
Subject disposition at the end of each study epoch will be presented in table and listing. The 
number and percentage of subjects in each disposition category will be presented by treatment 
group. No statistical analysis will be presented. 
The disposition table includes: 
•  Number of subjects screened (Screened patients) 
•  Number of subjects who completed the screening epoch (Screened patients) 
•  Number of subjects who discontinued the screening epoch (Screened patients) 
•  Number of subjects per each primary reason for discontinuation during the screening 
epoch (Screened patients) 
• Number of subjects who randomized (RAN) 
•  Number of subjects who completed the treatment epoch (RAN) 
•  Number of subjects who discontinued the treatment epoch (RAN) 
•  Number of subjects per each primary reason for discontinuation during the treatment 
epoch (RAN) 
• Number of subjects who entered the follow-up (RAN) 


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• Number of subjects who completed the follow-up (RAN) 
• Number of subjects who discontinued the follow-up (RAN) 
•  Number of subjects per each primary reason for discontinuation during the follow-up 
(RAN) 
 
Subject discontinuation might occur for the following reasons: 
•  AEs 
•  Death 
• Lack of efficacy 
• No longer requires treatment 
• New therapy for study indication 
• Non-compliance with study treatment 
•  Pregnancy 
• Protocol deviation 
• Screen failure 
•  Study terminated by sponsor 
•  Technical problems 
•  Lost to follow-up 
•  Physician’s decision 
•  Subject/guardian decision 
Protocol deviations by deviation category will be presented in table and listing separately. 
A summary table will be generated to present the number and percentage of subjects included 
in each of the analysis sets. Subjects excluded from each of the analysis sets will also be 
presented in listing. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
In this study, patients will be assigned to omalizumab arm (IGE025) or placebo (PLACEBO) 
arm. Furthermore dose (75 to 600 mg) and dosing frequency (every 2 or 4 weeks) of the study 
drug will be determined by serum total IgE level (IU/mL) and body weight (kg) measured at 
the screening epoch according the dosing table (Table 2-2). 


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Table 2-2 Dosing table (mg/dose) 
 
During the treatment epoch, fexofenadine hydrochloride should be used as a concomitant 
medication irrespective of patient’s symptoms. 
• Fexofenadine hydrochloride (oral, 60 mg/time, twice per day) 
In addition, in approximately 2 - 4 weeks around in March (Start date and duration will be 
determined by the sponsor), fluticasone propionate should be used as a concomitant medications 
irrespective of patient’s symptoms, as well. 
For patients aged ≥ 15 to < 75 years: 
• Fluticasone propionate (nasal, 1 spray (50 μg)/nostril, twice per day) 
For patients aged ≥ 12 to < 15 years: 
• Fluticasone propionate (nasal, 1 spray (25 μg)/nostril, twice per day) 
The following rescue medications are allowed to use for symptoms: 
• Fexofenadine hydrochloride (only during the screening period) 
• Tramazoline hydrochloride 
• Levocabastine hydrochloride 
2.4.1 
Study treatment / compliance 
A listing of study drug administration will be presented. 
The listing includes; Dose prescribed, Treatment visit/ Date time/ Day of dose, Dose 
administered (mg), Reason, Pack number of drug dispensed in error. 
The dose and regimen of study drug and the duration of exposure will be summarized for the 
SAF. The total number, total exposure, and duration of exposure of doses of study drug 
administered will be summarized by dosing schedule and treatment group. Duration of exposure 
to study treatment will be calculated as last visit (Day 85 date or early discontinuation) of the 
treatment epoch - first dose date + 1 (days). 


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2.4.2 
Prior and concomitant therapies 
Prior medication, therapy, and surgical and medical procedures for Japanese cedar pollinosis in 
2016/2017 seasons will be presented in table and listing for the SAF. Furthermore, concomitant 
medications, and surgical and medical procedures will also be presented in table for treatment 
epoch only and listing for both screening and treatment epochs for the SAF. 
Medications and therapies will be coded based on Anatomical Therapeutic Classification (ATC) 
class and PT. The number and percentage of patients having any therapy in each PT within ATC 
class will be presented by treatment group. Furthermore, surgical and medical procedures will 
be coded using the MedDRA dictionary (the latest version). The number and percentage of 
patients having any procedures will be summarized by SOC, PT and treatment group. 
 
The listing includes; Medication/non-drug therapy name, Type of therapy, Reason for use, 
Start/End date, Dose, Unit, Frequency, Route. 
2.5 
Analysis of the primary objective 
Primary objective of this study is to demonstrate the efficacy of omalizumab compared with 
placebo with respect to mean nasal symptom score during the severe symptom period. 
Analyses will be based on the patients in the FAS, unless otherwise specified. 
The details of each variable are described in Section 2.11. 
2.5.1 
Primary endpoint 
The primary efficacy variable is mean nasal symptom score during the severe symptom period. 
The definition of the severe symptom period was described in Section 2.1.1. 
As the primary efficacy variable, the mean nasal symptom score during the severe symptom 
period for each patient will be calculated for patients who have data for nasal symptom score 
for at least 50% of days during the severe symptom period. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The mean nasal symptom score during the severe symptom period will be compared between 
treatments using an analysis of variance model with treatment group, dosing schedule (two-
weekly or four-weekly) and randomization strata based on hypotheses below. The test will be 
conducted at the two-sided significance level of 5%. Least-square mean difference between 
treatment groups and corresponding 95% confidence interval as well as p-value will be 
calculated based on the model with considering a weight of the strata.  
In addition, the mean nasal symptom score during the severe symptom period by treatment 
group will be summarized. 
H0: Omalizumab is not different to placebo with respect to mean nasal symptom score over the 
severe symptom period. 
H1: Omalizumab is different to placebo with respect to mean nasal symptom score over the 
severe symptom period. 


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Stratifications for the randomization are shown; 
These variables are derived from eCRF and e-Diary data. 
• Age group (< 15 years, >= 15 years) 
• Coexistence of perennial allergic rhinitis (Yes/No) 
• Dose frequency (every 2 weeks and 4 weeks) 
• Having cedar pollinosis symptoms at the initial drug administration (Yes/No) 
A proportion of patients with categorical mean nasal symptom score during the severe symptom 
period for each treatment group will be summarized and presented as histogram. 
2.5.3 
Handling of missing values/censoring/discontinuations 
The mean nasal symptom score as the primary variable will be calculated for the patients who 
have the data of the nasal symptom score for at least 50% of days during the severe symptom 
period (extended if applicable). No imputation will be done for the patients who don’t have the 
data of the nasal symptom score more than 50% of days during the severe symptom period and 
they will not be included in the primary analysis. It might be that the number of patients 
providing data to an analysis is smaller than the number of subjects in the FAS. 
Handling of missing variable for secondary 
 analysis will be done in the same 
way except for analysis of JRQLQ score, 
 
 at evaluation visit. 
2.5.4 
Supportive analyses 
Subgroup analyses 
The primary analysis for the mean nasal symptom score will be repeated for the subgroups 
shown in Section 2.2.1. If the subgroup variable is included in the covariates of the model, it 
must be excluded from the model. 
Supportive analysis using the adjusted nasal congestion score (AdNCS) 
The primary analysis for the mean nasal symptom score will be repeated by using the AdNCS 
instead of symptom score for nasal congestion. The daily AdNCS is based on the study of 
Grouin et al. (2012) (Refer to Section 6.), and is arranged for this study associated with the 
characteristics of concomitant/rescue medications. The daily AdNCS is defined by the 
following algorithm: 


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Sensitivity analysis for missing data 
As a sensitivity analysis for the handling of missing values for the primary analysis, if there is 
a greater percentage of patients without data for nasal symptom score more than 50% of days 
during the severe symptom period than expected as drop-out rate in the protocol (10%), 
imputation will be performed for the daily missing data, using multiple imputation method 
under Missing at Random (MAR) assumption. The analysis will be conducted using the same 
model as the primary variable for the patients who have at least one record of nasal symptom 
score during the severe symptom period in the FAS. 
This approach involves three distinct steps. As the first step, multiple imputation is used to 
create a number of complete datasets. In Step 2, each of these datasets is analyzed by the 
standard procedure (here it is ANCOVA model) and in Step 3, the results of the multiple 
analyses are combined into a single analysis. 
Since an arbitrary data missing pattern is applied, Markov chain Monte Carlo (MCMC) method 
assuming multivariate normality will be therefore used for imputation. The imputations will be 
done separately for each treatment group. Here the number of imputations will be specified to 
500 and the seed to start the pseudo-random number generator will be set to 251301 for this 
study. 
2.6 
Analysis of the key secondary objective 
Not applicable. 
2.7 
Analysis of secondary efficacy objective(s) 
Analyses will be based on the patients in the FAS, unless otherwise specified. 
No adjustment of multiplicity will be considered for secondary endpoints. 
2.7.1 
Secondary endpoint 
The following variables regarding each mean score of the symptoms and/or rescue medication 
during the severe symptom period will be analyzed; 
• Mean ocular symptom score and nasal ocular symptom score 
• Mean nasal symptom medication score, ocular symptom medication score, and nasal 
ocular symptom medication score 
• Mean score for severity of sneezing, rhinorrhea and nasal congestion 
• Mean score for severity of itchy and watery eye 
• Mean score for impairment of daily activities 
• Mean rescue medication (tramazoline hydrochloride, levocabastine hydrochloride) 
score 
The following variables regarding symptom free days and/or rescue medication used during the 
severe symptom period will be analyzed; 


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• Number of nasal symptom free days (days with all nasal symptoms are not more than 
mild in severity) 
• Number of ocular symptom free days (days with all ocular symptoms are not more than 
mild in severity) 
• Number of days with no rescue medication (tramazoline hydrochloride, levocabastine 
hydrochloride) 
• Number of nasal symptom free days with no rescue medication use (days with all nasal 
symptoms are not more than mild in severity and with no rescue medication: tramazoline 
hydrochloride) 
• Amount number of rescue medication (tramazoline hydrochloride, levocabastine 
hydrochloride) used 
The following variables at evaluation visit will be analyzed; 
• Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ, No1) score 
2.7.2 
Statistical hypothesis, model, and method of analysis 
The variables regarding each mean score of the symptoms and/or rescue medication during the 
severe symptom period will be analyzed using the same model as the primary variable. Least-
square mean difference between treatment groups and corresponding 95% confidence interval 
will be calculated based on the model with considering a weight of the strata. In addition, each 
of these mean scores will be summarized by treatment group. Mean score for severity of 
sneezing, rhinorrhea, nasal congestion, itchy and watery eye will also be presented as bar graph 
by treatment groups. 
The variables regarding symptom free days and/or rescue medication used during the severe 
symptom period will be analyzed by stratified Wilcoxon rank sum (van Elteren) test with dosing 
schedule (two-weekly or four-weekly) and randomization strata. In addition, stratified Hodges-
Lehmann estimates for the median will be derived and summarized for each treatment group as 
well as confidence intervals for comparison between treatment groups with p-value from van 
Elteren test. In case only one treatment group is assigned to a stratum category, this stratum will 
not be considered in the analysis. Descriptive statistics for these variables will be summarized 
by treatment group. 
A proportion of patients with categorical mean ocular and nasal ocular symptom score, a 
proportion of patients with categorical number of nasal or ocular symptom free days, anda 
proportion of patients with categorical rescue medication (tramazoline hydrochloride, 
levocabastine hydrochloride) free days during the severe symptom period for each treatment 
group will be summarized,  and presented as histogram except for the proportion of patients 
with categorical rescue medication free days. 
In addition, proportion of patients who are completely nasal symptom free during the severe 
symptom period defined as below will be compared between treatments using logistic 
regression model with treatment group, dosing schedule (two-weekly or four-weekly) and 
randomization strata. Odds ratio estimate and 95% confidence interval will be presented. If a 
parameter is not estimated due to separated or nearly separated data, Firth method based on 
penalized maximum likelihood will be applied for parameter estimation. 


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The proportion of patients who are completely nasal symptom free during the severe symptom 
period will be defined as: number of patients who are symptom free (all nasal symptoms are 
not more than mild in severity) on all non-missing days and have data for nasal symptom score 
for at least 18 days (i.e., up to 3 days of missing of the data will be allowed) during the 21 days 
of severe symptom period (if the severe symptom period is extended to more than 21 days, up 
to 4 days of missing of the data will be allowed to define the completely nasal symptom free 
patients) divided by number of patients who have data for nasal symptom score for at least 50% 
of days during the severe symptom period. 
The analyses for the variables regarding symptom free days and/or rescue medication used 
during the severe symptom period above will be implemented for the patients who have data 
for nasal symptom score for at least 50% of days during the severe symptom period in the FAS. 
The JRQLQ, No1 score at evaluation visit will be analyzed using the same model as the primary 
variable, and will be summarized and presented as bar graph by treatment groups.  
JRQLQ, No1 score will be summarized for 3 parts: Nasal and eye symptoms (JRQLQ I), QOL-
related questionnaire (JRQLQ II) mean score and 6 domain scores, and Overall face scale 
(JRQLQ III). 
2.7.3 
Handling of missing values/censoring/discontinuations 
Same as the handling of missing value for the primary analysis described in Section 2.5.3 except 
for the analysis of JRQLQ, No1 score at evaluation visit. No imputation for missing data will 
be done for the secondary variables. 
For counting of number of symptom free days and/or rescue medication used during the severe 
symptom period, the daily missing score will be treated as that there is symptom and/or rescue 
medication use on the day. 
2.8 
Safety analyses 
All safety evaluations will be performed on the SAF. No imputation will be done for missing 
data. 
2.8.1 
Adverse events (AEs) 
All the AEs occurring after providing written informed consent will be recorded on the Adverse 
Event eCRF page. For AE summaries, SOC and PT as listed by MedDRA will be used. 
AEs starting during the treatment period or events present prior to the first dose of study 
treatment but increased in severity during the treatment period based on preferred term will be 
classified as treatment emergent AEs. The treatment period will be taken from the date of first 
drug administration to the last Visit date of treatment period (Visit 199). Overall AEs, SAEs, 
AEs by severity will be summarized for randomized-treatment epoch. Non-treatment emergent 
AEs (occurring in screening epoch) 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 SOC, having each 
individual AE (PT) and having each standardized MedDRA Query (SMQ). Summaries will be 
also presented for treatment emergent AEs by severity and for study treatment related AEs.  


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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 SAE and AEs leading to discontinuation. 
The FPFV and LPLV dates, the number of patients who had informed consent, treated, 
discontinued and had AEs related to study drug treatment will be provided by center. 
The following summaries will be produced: 
• Number (%) of patients reporting AEs by SOC and PT. 
• Number (%) of patients reporting AEs (threshold 2%) by SOC and PT. 
• Number (%) of patients reporting AEs by SOC, PT and maximum severity. 
• Number (%) of patients reporting AEs suspected to be related to study drug by SOC and 
PT.  
• Number (%) of patients reporting SAEs by SOC and PT. 
• Number (%) of patients reporting AEs leading to discontinuation regardless of study 
drug relationship by SOC and PT. 
• Number (%) of patients reporting AEs by SMQ. 
• Number (%) of patients reporting AEs by SMQ and PT. 
Subgroup analyses 
The following summaries for the treatment emergent AEs will be repeated for the subgroups 
shown in Section 2.2.1. 
• Number (%) of patients reporting AEs by SOC and PT. 
• Number (%) of patients reporting AEs by SOC, PT and maximum severity. 
• Number (%) of patients reporting AEs suspected to be related to study drug by SOC and 
PT.  
2.8.1.1 
Adverse events of special interest / grouping of AEs 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events will be done. Treatment emergent AEs of special interest and liver events for 
omalizumab treatment will be summarized. AEs of special interest of this study will be defined 
in an external file according to the latest version of eCRS and J-RMP at the DBL. 
Summary tables that present numbers and percentages of patients with the AEs of special 
interest will be presented by risk name, seach term, preferred term and treatment. 
2.8.2 
Deaths 
The number and percentage of patients who died will be summarized by treatment group and 
the principal cause in primary SOC and PT. 


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2.8.3 
Laboratory data 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). 
The following summaries will be presented: 
• Descriptive summary statistics for absolute values and changes from baseline to each 
study visit. (Hematology, Biochemistry) 
• A shift table of change from baseline to final value based on normal range. (Hematology, 
Biochemistry, Urinalysis) 
• A shift table of change from baseline to most extreme post-baseline value based on 
normal range. (Hematology, Biochemistry, Urinalysis) 
• Descriptive summary statistics for post-baseline maximum values and their changes 
from baseline in liver parameters. 
• Listing of all laboratory data with the flag relative to the laboratory normal ranges. 
These summaries will be presented by test group, laboratory test and treatment group. 
Definition of baseline and change from baseline are described in Section 2.1.1. Change from 
baseline will only be summarized for patients with both baseline and post baseline values. 
The incidence of newly occurring notable abnormalities will be summarized for the following 
key parameters. 


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Table 2-3 Newly occurring notable laboratory test abnormalities  
 
 
Notable abnormalities 
Category 
Item 
Low 
High 
Hematology 
Platelets 
< 7.5×10^10/ L 
- 
Table 2-4 Newly occurring liver enzyme abnormalities  
 
Liver enzyme abnormalities 
Item 
Low 
High 
ALT 
- 
> 3x ULN 
> 5x ULN 
> 10x ULN 
> 20x ULN 
ALT or AST 
- 
> 3x ULN 
> 5x ULN 
> 8x ULN 
> 10x ULN 
> 20x ULN 
ALT or AST, and TBL 
- 
ALT or AST > 3x ULN & TBL > 1.5x ULN  
ALT or AST > 3x ULN & TBL > 2x ULN 
ALP 
- 
> 1.5x ULN  
> 2x ULN  
> 5x ULN 
TBL 
- 
> 1x ULN  
> 1.5x ULN  
> 2x ULN 
 
- 
ALP > 3x ULN & TBL > 2x ULN 
ALP > 5x ULN & TBL > 2x ULN 
ALT or AST, TBL, and ALP 
- 
ALT or AST > 3x ULN & TBL > 2x ULN & ALP <= 2x ULN 
ALT or AST, and symptoms 
- 
ALT or AST > 3x ULN & (nausea or vomiting or fatigue or general 
malaise or abdominal pain or rash with eosinophilia) 
TBL: total bilirubin; ULN: upper limit of normal 
2.8.4 
Other safety data 
2.8.4.1 
Anti-omalizumab antibody 
Anti-omalizumab antibody data will be listed for the SAF. 


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2.8.4.2 
Vital signs 
Analysis of the vital sign measurements using summary statistics will be performed. 
The following summaries will be presented: 
• Descriptive summary statistics for absolute values and changes from baseline to each 
study visit. 
• Listing of all individual data including unscheduled visits. 
These descriptive summaries will be presented by vital sign and treatment group. Changes from 
baseline will only be summarized for patients with both baseline and post-baseline values. 
The following summaries will be produced: 
• Systolic/ Diastolic blood pressure 
• Pulse 
2.9 
Pharmacokinetic endpoints 
Refer to PK/PD Section 2.10. 
2.10 
PK/PD analyses 
All subjects with evaluable PK and PD parameters will be included in the data analysis. 
Serum omalizumab concentration, free IgE concentration and total IgE concentration at each 
evaluation visits will be summarized with descriptive statistics for the PK: serum omalizmab, 
PD: serum free and total IgE concentration.  
The following values will be calculated, and will be summarized with descriptive statistics for 
absolute values and %changes from baseline to each visit. 
• Free IgE: 100 * (free IgE at each visit - total IgE at baseline) / total IgE at baseline 
• Total IgE: 100 * (total IgE at each visit - total IgE at baseline) / total IgE at baseline 
Serum total IgE concentration is delivered in SI unit [IU/mL], while free IgE 
concentration is shown in [ng/mL]. All summaries will be presented in the same unit 
[ng/mL]. The conversion factor; 1 IU/mL = 2.42 ng/mL will be used. 
No imputation for missing data will be done. 
2.11 
Patient-reported outcomes 
In this study, The Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ, No.1), 
, 
and e-Diary are used as the patient-reported outcomes (PRO). 
Refer to Section 2.7.1 and 2.13 for the details of analyses. 
2.11.1 
e-Diary assessment (Nasal symptoms, Ocular symptoms, Medication 
use, and Impairment of daily activities) 
e-Diary assessment consists of nasal symptoms, ocular symptoms, medication use, and 
impairment of daily activities. It will be recorded by the patients everyday. If e-Diay data will 
be collected from 0:00 AM to 2:00 AM, they will be assigned to the previous day. 


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2.11.1.1 Nasal symptoms (sneezing, rhinorrhea and nasal congestion) 
Nasal symptoms will be recorded by the patient everyday in their e-Diary, on a following scale 
of 0 (none) to 4 (intense/severe) (Table 2-5). Nasal symptom score (0-12 point) will consist of 
score for severity of sneezing (0-4 point), rhinorrhea (0-4 point) and nasal congestion (0-4 point). 
Table 2-5 Severity of nasal symptoms 
Score (/day) 
4 
3 
2 
1 
0 
Paroxysmal sneezing 
(number of episodes 
of paroxysmal 
sneezing in a day) 
≥ 21 times 
20-11 times 
10-6 times 
5-1 times 
0 
Rhinorrhea 
(number of episodes 
of nose blowing a day) 
≥ 21 times 
20-11 times 
10-6 times 
5-1 times 
0 
Nasal congestion 
Completely 
obstructed all 
day 
Severe nasal 
congestion 
causing 
prolonged 
oral breathing 
in a day 
Severe nasal 
congestion 
causing 
occasional 
oral breathing 
in a day 
Nasal 
congestion 
without 
oral 
breathing 
Less 
severe 
degree 
than 
score of 1 
2.11.1.2 Ocular symptoms (itchy and watery eye) 
Ocular symptoms will be recorded by the patient everyday in their e-Diary, on a following scale 
of 0 (none) to 4 (intense/severe) (Table 2-6). Ocular symptom score (0-8 point) will consist of 
score for severity of itchy eye (0-4 point) and watery eye (0-4 point). 
Table 2-6 Severity of ocular symptoms 
Score (/day)  
4 
3 
2 
1 
0 
Itchy eye 
More severe 
degree than 
score of 3 
Frequently 
rubbing one's 
eyes 
Occasionally 
rubbing one's 
eyes 
not to the 
extent of 
rubbing one's 
eyes 
None 
Watery eye 
More severe 
degree than 
score of 3 
Frequently 
wiping one's 
tears 
Occasionally 
wiping one's 
tears  
not to the 
extent of 
wiping one's 
None 
2.11.1.3 Medication use 
Medication use for Japanese cedar pollinosis (fluticasone propionate, fexofenadine 
hydrochloride, tramazoline hydrochloride and levocabastine hydrochloride) will be recorded by 
the patient everyday in their e-Diary. Medication score for nasal and ocular symptoms will be 
calculated as the sum of scores of medications used based on a following scale. Fexofenadine 
hydrochloride, an oral medication, will be counted as nasal and/or ocular medication. 


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Table 2-7 Score for medication use 
Treatments  
Score (/day) 
Fluticasone propionate (nasal) 
2 
Fexofenadine hydrochloride (oral) 
1 
Tramazoline hydrochloride (nasal) 
1 
Levocabastine hydrochloride (ocular) 
1 
2.11.1.4 Impairment of daily activities 
Impairment of daily activities will be recorded  by the patient everyday in their e-Diary, on a 
following scale of 0 (none) to 4 (intense/severe) (Table 2-8). 
Table 2-8 Severity of impairment of daily activities 
Score (/day)  
4 
3 
2 
1 
0 
Impairment of daily 
activities* 
Impossible 
Painful and 
complicating 
daily life 
Intermediate 
in degree 
between 
score of 3 and 
score of 1 
Few troubles 
Less severe 
degree than 
score of 1 
* Work, study, household work, sleep, going outside, etc. 
2.11.1.5 Computation rule for Variables  
For the secondary endpoint (Section 2.7.1), further scores regarding each symptoms and 
concomitant/ rescue drug use during the severe symptom period will be calculated as below; 
• Nasal ocular symptom score = Nasal symptom score + Ocular symptom score 
• Nasal symptom medication score = Nasal symptom score + Medication score 
(Fexofenadine hydrochloride, Fluticasone propionate, Tramazoline hydrochloride) 
• Ocular symptom medication score = Ocular symptom score + Medication score 
(Fexofenadine hydrochloride, Levocabastine hydrochloride) 
• Nasal ocular symptom medication score = Nasal symptom score + Ocular symptom 
score + Medication score (Fexofenadine hydrochloride, Fluticasone propionate, 
Tramazoline hydrochloride, Levocabastine hydrochloride) 
2.11.2 
Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ) 
The Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ, No.1) is a standard 
Quality of Life (QOL) Questionnaire for Japanese allergic rhinitis developed in 2002 (Practical 
guideline for the management of allergic rhinitis in Japan 2016). Patients rate their nasal and 
eye symptoms in the previous 1 - 2 weeks, as well as their impact on various aspects of their 
lives using a 0 to 4-point scale. The questionnaire will be completed by the patients before they 
see the study physician where applicable. 
The JRQLQ is composed of three parts: 


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Nasal and eye symptoms (JRQLQ I) include six categories: Runny nose, Sneezing, Nasal 
congestion, Itchy nose, itchy eyes and watery eyes, on a five-point scale as 0 (no symptoms) to 
4 (very severe symptoms). 
Mean scores for these six categories will be determined as the nasal and eye symptom (JRQLQ 
I) score for each patient. 
QOL-related questionnaire (JRQLQ II) include 17 items: i) Reduced productivity at 
work/home/school; ii) Poor mental concentration; iii) Reduced thinking power; iv) Impaired 
reading book/paper; v) Reduced memory loss; vi) Limitation of outdoor life (e.g. sports, picnic); 
vii) Limitation of going out; viii) Hesitation visiting friend or relatives; ix) Reduced contact 
with friends or others by telephone or conversation; x) Not an easy person to be around; xi) 
Impaired sleeping; xii) Tiredness; xiii) Fatigue; xiv) Frustration; xv) Irritability; xvi) 
Depression; and xvii) Unhappiness, on a five-point scale as 0 (no significant problem) to 4 (very 
greatly). 
Total and mean scores for these 17 items will be determined as the QOL-related questionnaire 
(JRQLQ II) mean score for each patient. 
In addition, these 17 items are divided into six domains including; Usual daily activities (for 
items i to v); Outdoor activities (for items vi and vii); Social functioning (for items viii to x); 
Sleep problem (for item xi); General physical problems (for items xii and xiii); and Emotional 
function (for items xiv to xvii). 
Mean scores of items classified into each of these 6 domains will be determined as QOL-related 
questionnaire (JRQLQ II) domain scores for each patient. 
Overall face scale (JRQLQ III) evaluates overall symptoms, condition and feelings for the 
past 1–2 weeks on a five-point scale from 0 (fine) to 4 (crying). 


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2.12 
Biomarkers 
Not applicable. 


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2.14 
Interim analysis 
There will be no interim analysis in this study. 
A primary analysis will be performed on all the data during the screening epoch and the 
treatment epoch after all patients complete the treatment epoch to support the registration. The 
DBL for this analysis will be done after 30 days safety evaluation following the end of the 
treatment epoch will be completed for all patients. 
After completion of post-treatment follow-up visit for all patients, anti-omalizumab antibody, 
PK and PD analyses for the follow-up epoch will be performed separately. 
3 
Sample size calculation 
For the primary efficacy variable, with sample size of 155 subjects per group the study will 
provide 90% power to detect difference for omalizumab versus placebo. This power estimate is 
based on a two-sided type-I-error of 5%, a treatment difference in mean daily nasal symptom 
score of 0.87 and a common standard deviation of 2.35. A 0.87 treatment difference (0.29/each 
nasal symptom of sneezing, rhinorrhea and nasal congestion) is considered clinically relevant 
(Higaki et al 2013). A standard deviation of approximately 2.35 has been observed in the 
analysis for severe subjects in the previous study (CIGE025A1305). Assuming an early 
discontinuation rate of approximately 10%, a total of 346 subjects will be randomized. 
Sensitivity of power to change in assumptions is summarized in Table 3-1. 


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Table 3-1 Sensitivity of power to change in assumptions for N=346 
True treatment difference 
for omalizumab vs placebo 
(units) 
SD (units) 
Power 
for 
primary 
endpoint 
(2-sided 
alpha 
=5%) 
With 10% drop-out rate 
0.80 
2.35 
2.00 
2.50 
84% 
93% 
80% 
0.70 
2.35 
2.00 
2.50 
74% 
86% 
69% 
0.60 
 
2.35 
2.00 
2.50 
61% 
74% 
55% 
0.50 
 
2.35 
2.00 
2.50 
46% 
59% 
41% 
4 
Change to protocol specified analyses 
We added followings. 
Section 2.5.2 & 2.7.2 
Considering a weight of the strata for least-square mean 
Section 2.5.4 
Supportive analysis by using the adjusted mean nasal congestion symptom score 
Section 2.7.1 
The variables regarding symptom free days and/or rescue medication used during the severe 
symptom period. 
• Number of ocular symptom free days (days with all ocular symptoms are not more than 
mild in severity) 
• Number of nasal symptom free days with no rescue medication use (days with all nasal 
symptoms are not more than mild in severity and with no rescue medication: tramazoline 
hydrochloride) 
Section 2.8.1 
Summary by presenting SMQ for treatment emergent AEs 
Section 2.13 


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The variable regarding symptom severity during the severe symptom period 
• Number of days with each symptom severity (most severe/ severe/ moderate/ mild/ no 
symptoms) 
5 
Appendix 
5.1 
Imputation rules 
Refer to Section 2.5.4. 
5.2 
AEs coding/grading 
Refer to Section 2.8.  
5.3 
Statistical models 
The following SAS procedure will be used in this study. 
PROC MIXED for the primary analysis shown in Section 2.5.2 
PROC MI for the multiple imputation shown in Section 2.5.4 
PROC MIANALYZE for combining of the multiple analysis results shown in Section 2.5.4 
PROC NPAR1WAY for Wilcoxon rank sum (van Elteren) test shown in Section 2.7.2 
PROC LOGISTIC for logistic regression analysis shown in Section 2.7.2 
5.3.1 
Primary analysis 
Refer to Section 2.5.2. 
5.3.2 
Key secondary analysis 
Not applicable. 
5.4 
Rule of exclusion criteria of analysis sets  
Protocol deviation specifications (Table 5-1) and non-protocol deviation classification criteria 
(Table 5-2) that exclude subjects from the analysis sets are given below. 
Table 5-1 
Protocol deviations that cause subjects to be excluded 
Deviation ID Description of Deviation 
Exclusion in Analyses 
TRT01 
Patient is randomized in error 
RAN, FAS, PK 
TRT02 
Patient is randomized but no study 
drug is taken 
FAS, SAF, PK 
TRT03 
Patient receives study drug but is 
not randomized into study 
RAN, FAS, PK 
 


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Table 5-2 
Subject Classification 
Analysis Set 
PD ID that  
cause subjects to be excluded 
Non-PD criteria that cause 
subjects to be excluded 
RAN 
TRT01, TRT03 
- 
FAS 
TRT02 
Not in RAN 
SAF 
TRT02 
- 
PK 
TRT02 
Not in RAN 
Missing of all data for PK/PD assessment 
6 
Reference 
1. Grouin JM et all (2012), The average Adjusted Symptom Score, a new primary efficacy 
end-point for specific allergen immunotherapy trials. Clin Exp Allergy; 41(9):1282-8.