Clinical trial NCT04195958
Conditions: Moderate-to-severe Allergic Asthma
Sponsor: Genentech, Inc.
Start date: 2020-11-30; Completion date: 2021-10-18
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will assess the effect of omalizumab on exercise capacity, physical activity, and sleep quality after 24 weeks of treatment in participants with moderate to severe allergic asthma. Exercise capacity will be assessed using cardiopulmonary exercise testing (CPET). Physical activity and sleep quality will be assessed with a wearable physical activity and sleep monitor. The study will consist of a 4-week screening period, a 24-week treatment period, and a 4-week safety follow-up. Approximately 60 participants will be enrolled, and omalizumab will be dosed according to the approved United States Package Insert (USPI) dosing table.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Omalizumab
Intervention descriptions: intervention 1: Omalizumab will be administered by subcutaneous (SC) injection at a dose of 150 milligrams (mg) to 375 mg every 2 or 4 weeks. The dose and frequency will be determined by body weight (kg) and the level of total IgE (IU/mL) measured during screening.

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable 
Ethics Committee or Institutional Review Board.  It is understood that this information will not be 
disclosed to others without written authorization from Genentech except to the extent necessary to 
obtain informed consent from persons to whom the drug may be administered.
Xolair (omalizumab)—Genentech, Inc.
Protocol ML41615, Version 3
PROTOCOL
TITLE:
A MULTICENTER, OPEN-LABEL, SINGLE-ARM
STUDY TO ASSESS THE IMPACT OF 
OMALIZUMAB ON EXERCISE CAPACITY, 
PHYSICAL ACTIVITY, AND SLEEP QUALITY IN 
PATIENTS WITH MODERATE TO SEVERE 
ALLERGIC ASTHMA
PROTOCOL NUMBER:
ML41615
VERSION NUMBER:
3
EUDRACT NUMBER:
N/A
IND NUMBER:
N/A
NCT NUMBER:
NCT04195958
TEST PRODUCT:
Omalizumab (RO5489789)
MEDICAL MONITOR:
 Ph.D.
SPONSOR:
Genentech, Inc.
APPROVAL DATE:
See electronic date stamp below
 
11-Dec-2020 00:09:55
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Xolair (omalizumab)—Genentech, Inc.
2/Protocol ML41615, Version 3
PROTOCOL HISTORY
Protocol
Version
Date Final
1
6 September 2019
2
30 January 2020




Xolair (omalizumab)—Genentech, Inc.
4/Protocol ML41615, Version 3

The description of the efficacy analyses was revised to align with the revised study 
design (e.g., mixed-effect model repeated measurement (MMRM) model was 
changed to descriptive summary statistics) (Section 6.4).

An interim analysis was added (Section 6.5.1).

The number of sites was revised from 30-150 to 20-25 to accommodate the revised
study design (Section 9.5).

Appendix 1 has updated to reflect the updated screening period, the additional study
treatment visits for patients on a 2-week dosing schedule, and the removal of ECGs 
and laboratory tests listed above.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in Book Antiqua italics. This amendment 
represents cumulative changes to the original protocol.


Xolair (omalizumab)—Genentech, Inc.
5/Protocol ML41615, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1. 
BACKGROUND .......................................................................................... 20
1.1 
Background on Asthma ......................................................... 20 
1.2 
Background on Omalizumab ................................................. 21 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 21
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 22
2.1 
Efficacy Objectives ................................................................ 23
2.1.1 
Primary Efficacy Objective..................................................... 23
2.1.2 
Secondary Efficacy Objectives .............................................. 23
2.1.3 
Exploratory Efficacy Objectives ............................................. 23
2.2 
Safety Objectives................................................................... 24
3. 
STUDY DESIGN ......................................................................................... 24
3.1 
Description of the Study......................................................... 24
3.2 
End of Study and Length of Study......................................... 25
3.3 
Rationale for Study Design.................................................... 25
3.3.1 
Rationale for Xolair Dose and Schedule................................ 25
3.3.2 
Rationale for Patient Population ............................................ 25
4. 
MATERIALS AND METHODS .................................................................... 26
4.1 
Patients.................................................................................. 26
4.1.1 
Inclusion Criteria.................................................................... 26
4.1.2 
Exclusion Criteria................................................................... 28
4.2 
Method of Treatment Assignment ......................................... 30
4.2.1 
Patient ID Assignment ........................................................... 30
4.2.2 
Patients Enrolled Under the Double-Blind,
Placebo-Controlled Protocol.................................................. 30 
4.3 
Study Treatment and Other Treatments Relevant
to the Study Design ............................................................... 30 
4.3.1 
Study Treatment Formulation, Packaging, and
Handling ................................................................................ 30 
4.3.1.1 
Omalizumab .......................................................................... 30


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4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 31
4.3.2.1
Omalizumab .......................................................................... 31
4.3.3
Investigational Medicinal Product Accountability ................... 32
4.3.4
Continued Access to Omalizumab......................................... 32
4.4
Concomitant Therapy ............................................................ 32
4.4.1
Required Asthma Controller Therapy .................................... 32
4.4.2
Short-Acting Rescue Therapy................................................ 33
4.4.3
Systemic Corticosteroid Use.................................................. 33
4.4.4
Medication Use Prior to Spirometry 
Measurements and CPET ..................................................... 33
4.4.5
Permitted Therapy................................................................. 33
4.4.6
Prohibited Therapy ................................................................ 34
4.5
Study Assessments ............................................................... 35
4.5.1
Informed Consent Forms and Screening Log........................ 35
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 35
4.5.3
Physical Examinations........................................................... 36
4.5.4
Vital Signs.............................................................................. 36
4.5.5
Height and Weight................................................................. 36
4.5.6
Spirometry ............................................................................. 36
4.5.6.1
Pre-Bronchodilator Spirometry .............................................. 36
4.5.7
Asthma Exacerbations........................................................... 37
4.5.8
Cardiopulmonary Exercise Testing........................................ 37
4.5.9
Wrist-Worn Physical Activity and Sleep Monitor.................... 39
4.5.10
Laboratory Assessments ....................................................... 39
4.5.11
Clinical Outcome Assessments ............................................. 40
4.5.11.1
Assessments Completed by the Patient at Home.................. 40
4.5.11.2
Clinical Outcome Assessments Completed 
During Site Visits ................................................................... 41
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 42
4.6.1
Study Treatment Discontinuation........................................... 42
4.6.2
Patient Discontinuation from the Study.................................. 43


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4.6.3
Study Discontinuation............................................................ 43
4.6.4
Site Discontinuation............................................................... 43
5.
ASSESSMENT OF SAFETY....................................................................... 44
5.1
Safety Plan ............................................................................ 44
5.1.1
Safety and Data Monitoring ................................................... 44
5.1.2
Anaphylaxis Adjudication Committee .................................... 44
5.1.3
Risks Associated with Omalizumab....................................... 45
5.1.3.1
Anaphylaxis ........................................................................... 45
5.1.3.2
Serum Sickness..................................................................... 45
5.1.3.3
Churg-Strauss Syndrome and Hypereosinophilic 
Syndrome .............................................................................. 46
5.1.3.4
Thrombocytopenia................................................................. 46
5.1.3.5
Malignancies.......................................................................... 46
5.1.3.6
Arterial Thrombotic Events .................................................... 47
5.1.3.7
Antibody Formation to Omalizumab ...................................... 47
5.1.3.8
Parasitic Infections ................................................................ 47
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 48
5.1.4.1
Dose Modifications and Treatment Interruption..................... 48
5.1.4.2
Management of Drug Induced Liver Injuries.......................... 48
5.2
Safety Parameters and Definitions ........................................ 48
5.2.1
Adverse Events ..................................................................... 48
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 49
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 49
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 50
5.3.1
Adverse Event Reporting Period ........................................... 50
5.3.2
Eliciting Adverse Event Information....................................... 51
5.3.3
Assessment of Severity of Adverse Events ........................... 51
5.3.4
Assessment of Causality of Adverse Events ......................... 51
5.3.5
Procedures for Recording Adverse Events............................ 52
5.3.5.1
Injection-Site Reactions......................................................... 52


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5.3.5.2
Anaphylactic Reactions ......................................................... 53
5.3.5.3
Diagnosis versus Signs and Symptoms................................. 53
5.3.5.4
Adverse Events That Are Secondary to Other 
Events.................................................................................... 53
5.3.5.5
Persistent or Recurrent Adverse Events................................ 54
5.3.5.6
Abnormal Laboratory Values ................................................. 54
5.3.5.7
Abnormal Vital Sign Values ................................................... 55
5.3.5.8
Abnormal Liver Function Tests.............................................. 55
5.3.5.9
Deaths ................................................................................... 56
5.3.5.10
Preexisting Medical Conditions.............................................. 56
5.3.5.11
Lack of Efficacy or Worsening of Asthma .............................. 56
5.3.5.12
Hospitalization or Prolonged Hospitalization.......................... 56
5.3.5.13
Cases of Accidental Overdose or Medication 
Error....................................................................................... 57
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 58
5.4.1
Emergency Medical Contacts................................................ 59
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 59
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 59
5.4.2.2
Events That Occur after Study Drug Initiation........................ 59
5.4.3
Reporting Requirements for Pregnancies.............................. 60
5.4.3.1
Pregnancies in Female Patients............................................ 60
5.4.3.2
Abortions ............................................................................... 60
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 61
5.4.4
Reporting Requirements for Medical Device 
Complaints............................................................................. 61
5.5
Follow-Up of Patients after Adverse Events .......................... 61
5.5.1
Investigator Follow-Up........................................................... 61
5.5.2
Sponsor Follow-Up ................................................................ 61
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 62
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 62


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 62
6.1
Determination of Sample Size ............................................... 62
6.2
Summaries of Conduct of Study............................................ 63
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 63
6.4
Efficacy Analyses .................................................................. 63
6.4.1
Primary Efficacy Endpoint...................................................... 64
6.4.2
Secondary Efficacy Endpoints............................................... 64
6.4.3
Exploratory Efficacy Endpoints.............................................. 64
6.5
Safety Analyses..................................................................... 64
6.5.1
Planned Interim Analyses...................................................... 65
7.
DATA COLLECTION AND MANAGEMENT ............................................... 65
7.1
Data Quality Assurance......................................................... 65
7.2
Electronic Case Report Forms............................................... 65
7.3
Electronic Patient Reported Outcome Data........................... 66
7.4
Source Data Documentation.................................................. 66
7.5
Use of Computerized Systems .............................................. 67
7.6
Retention of Records............................................................. 67
8.
ETHICAL CONSIDERATIONS.................................................................... 67
8.1
Compliance with Laws and Regulations ................................ 67
8.2
Informed Consent.................................................................. 68
8.3
Institutional Review Board ..................................................... 69
8.4
Confidentiality........................................................................ 69
8.5
Financial Disclosure .............................................................. 70
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 70
9.1
Study Documentation ............................................................ 70
9.2
Protocol Deviations................................................................ 70
9.3
Management of Study Quality ............................................... 70
9.4
Site Inspections ..................................................................... 71
9.5
Administrative Structure......................................................... 71
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 71




Xolair (omalizumab)—Genentech, Inc.
11/Protocol ML41615, Version 3
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, OPEN-LABEL, SINGLE-ARM
STUDY TO ASSESS THE IMPACT OF 
OMALIZUMAB ON EXERCISE CAPACITY, 
PHYSICAL ACTIVITY, AND SLEEP QUALITY IN 
PATIENTS WITH MODERATE TO SEVERE 
ALLERGIC ASTHMA
PROTOCOL NUMBER:
ML41615
VERSION NUMBER:
3
EUDRACT NUMBER:
N/A
NCT NUMBER:
NCT04195958
IND NUMBER:
N/A
TEST PRODUCT:
Omalizumab (RO5489789)
MEDICAL MONITOR:
 Ph.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to the Sponsor or their designee. Contact details will be provided to the 
investigator prior to the study start.  Please retain the original copy for your study files.


Xolair (omalizumab)—Genentech, Inc.
12/Protocol ML41615, Version 3
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO 
ASSESS THE IMPACT OF OMALIZUMAB ON EXERCISE 
CAPACITY, PHYSICAL ACTIVITY, AND SLEEP QUALITY IN 
PATIENTS WITH MODERATE TO SEVERE ALLERGIC ASTHMA
PROTOCOL NUMBER:
ML41615
VERSION NUMBER:
3
EUDRACT NUMBER:
N/A
IND NUMBER:
N/A
NCT NUMBER:
NCT04195958
TEST PRODUCT:
Omalizumab (RO5489789)
PHASE:
IV
INDICATION:
Allergic Asthma
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will assess the effect of omalizumab on exercise capacity, physical activity, and sleep 
quality after 24 weeks of treatment in patients with moderate to severe allergic asthma.
Specific objectives and corresponding endpoints for the study are outlined below.
Primary Efficacy Objective
The primary efficacy objective is to assess the effect of omalizumab on the basis of the following 
endpoint:

Change from baseline at Week 24 in endurance time (minutes) during cardiopulmonary
exercise testing (CPET) at a constant work rate (CWR)
Secondary Efficacy Objectives
The secondary efficacy objective is to assess the effect of omalizumab on the basis of the 
following endpoints:

Change from baseline at Week 24 in physical activity (min/day), as assessed by the
physical activity and sleep monitor

Change from baseline to Week 24 in dynamic hyperinflation at isotime, as measured by
inspiratory capacity during CPET at a CWR

Change from baseline at Week 24 in sleep efficiency, as assessed by the physical activity
and sleep monitor 
Exploratory Efficacy Objectives
The exploratory efficacy objective is to assess the effect of omalizumab on the basis of the      
following endpoints:

Change from baseline at Week 24 in pre-bronchodilator FEV1 (liters)

Percent change from baseline at Week 24 in endurance time (minutes) during a CPET at a
CWR

Change from baseline at Week 24 in percent bronchoconstriction


Xolair (omalizumab)—Genentech, Inc.
13/Protocol ML41615, Version 3

Change from baseline at Week 24 in min/day spent in sedentary, light, moderate or 
vigorous activity as assessed by the physical activity and sleep monitor

Percent change from baseline to Week 24 of time/day spent in sedentary, light, moderate or 
vigorous activity as assessed by the physical activity and sleep monitor

Change from baseline at Week 24 in energy expenditure (kcal/day) as assessed by the 
physical activity and sleep monitor

Change from baseline at Week 24 in number of night-time awakenings as assessed by the 
physical activity and sleep monitor

Change from baseline at Week 24 in wake after sleep onset (WASO) as assessed by the 
physical activity and sleep monitor

Change from baseline at Week 24 in Asthma Daytime Symptom Diary (ADSD) score

Change from baseline at Week 24 in Asthma Nighttime Symptom Diary (ANSD) score 

Clinician Global Impression of Change (CGIC) at Week 24
Safety Objectives
The safety objective for this study is to assess the safety of omalizumab on the basis of the      
following endpoints:

Incidence of adverse events

Incidence of serious adverse events

Incidence of adverse events leading to discontinuation of omalizumab
Study Design
Description of Study
This study is a Phase IV, open-label, single-arm, multicenter study to assess the effect of 
omalizumab on exercise capacity, physical activity, and sleep quality in patients with moderate
to severe allergic asthma.
The study will consist of a 4-week screening period, a 24-week treatment period, and a 4-week 
safety follow-up. Approximately 60 patients will be enrolled, and omalizumab will be dosed 
according to the approved United States Package Insert (USPI) dosing table.
Before performing any study specific tests or evaluations, written informed consent will be 
obtained for all patients.
During the screening period, patients will be evaluated to determine if they meet all eligibility 
criteria.  Patients will be evaluated for their ability to perform required assessments that will take 
place during the study, including CPET using a cycle ergometer. Patients will then be assessed 
for adherence with their current asthma controller therapy, the degree of asthma control
provided by their standard-of-care asthma medications and compliance with an eDiary, as well 
as a wrist-worn physical activity and sleep monitor.  Patients will also be provided with 
information about the importance of regular physical activity to improve asthma control.
During the treatment period, at scheduled visits, exercise capacity will be assessed by CPET 
using a cycle ergometer.  Additional measurements will include spirometry, questionnaires, 
adverse events, blood draws, rescue medication, and health care utilization.  Physical activity 
and sleep will be assessed throughout the study using a wrist worn physical activity and sleep 
monitor.
Number of Patients
Approximately 60 patients with moderate-to-severe allergic asthma will be enrolled in this study. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 1865 years at time of signing Informed Consent Form

Body mass index (BMI) of 1835 kg/m2


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
Physician-diagnosed asthma for at least 12 months prior to screening

Documented history of positive skin test or in vitro reactivity to a perennial aeroallergen
If no historical documentation is available, the skin test or in vitro reactivity to a 
perennial aeroallergen will need to be performed during screening.

Eligibility per the study drugdosing table (serum IgE level 30 to 700 IU/mL and body 
weight 30 to 150 kg) and ability to be dosed per the USPI dosing table

Able to comply with asthma control medication adherence, physical activity and sleep 
monitoring data collection, and eDiary requirements during screening period.  Compliance
will be assessed during the last 2 weeks prior to study enrollment and non-compliance is 
defined as:
- 
Asthma control medication use 70% of the time during the 2 week period before study
enrollment
- 
Wearing the physical activity and sleep monitor less than approximately 80% of the time
(approximately 90 hours during the day and approximately 44 hours at night) for each 
week during the 2 week period before study enrollment
- 
Using the eDiary 5 out of 7 days for each week during the 2 week period before study 
enrollment

Able to safely complete incremental exercise tolerance test at screening

Able to comply with the study protocol for the duration of the study, in the investigator's
judgment, including but not limited to:
- 
Able and willing to use a wrist-worn activity and sleep monitor every day and night for
the duration of the study
- 
Able and willing to use eDiary device throughout the duration of the study

Pre-bronchodilator FEV1 of 40%80% of predicted at screening

Documented history of variable airflow obstruction or hyper-responsiveness within
12 months of study entry via at least one of the following criteria:
- 
FEV1 bronchodilator response 12% and 200 mL with up to 400 g albuterol
- 
Concentration of methacholine needed to produce a 20% decrease in FEV1 from
baseline (PC20 8 mg/mL or PD20 200 g)
- 
In patients with a forced expiratory volume in 1 second (FEV1)/forced vital capacity
(FVC) 70%, FEV1 variability should be 12% spontaneously (e.g., between clinic 
visits) or in response to oral corticosteroids
If no documented history is available, an assessment will need to be performed during 
screening.

On inhaled corticosteroids (ICS) therapy at a total daily dose 500 g of fluticasone 
propionate or equivalent and at least one second controller (long-acting beta agonist
[LABA], long-acting muscarinic antagonist [LAMA], leukotriene receptor antagonist [LTRA]) 
for 3 months prior to screening, with no changes within 4 weeks prior to screening or 
during the screening period and no anticipated changes in controller dosing regimens 
throughout the study

Uncontrolled asthma during the screening period, defined as an Asthma Control 
Questionnaire 5 (ACQ5) 0.75 score and both of the following symptoms that are not
controlled according to EPR (2007) and GINA (2019)
- 
Night time awakening due to asthma in the past 4 weeks 
- 
Activity limitations due to asthma in the past 4 weeks

Sleep disturbance due to asthma (e.g. cough, wheezing etc.) in the opinion of the 
investigator

Medical Research Council Dyspnoea scale 2 at screening


 
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 
Impaired exercise capacity defined as VO2max % of predicted 80% of healthy volunteers 
(Koch et al. 2009) during the incremental exercise test at screening 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or to use adequate contraception during the treatment period and 
for 60 days after the final dose of study drug. 
- 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations. 
- 
The following are examples of adequate contraceptive methods:  bilateral tubal ligation; 
male sterilization; hormonal contraceptives; hormone-releasing intrauterine devices; 
copper intrauterine devices; male or female condom with or without spermicide; and 
cap, diaphragm, or sponge with spermicide. 
- 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.  If required per local guidelines or regulations, 
locally recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Known history of anaphylaxis/hypersensitivity to omalizumab 
 
Treatment with investigational drugs within 12 weeks or 5 half-lives (whichever is longer) 
prior to screening  
 
Treatment with monoclonal antibodies (e.g., omalizumab, mepolizumab, dupilumab) for 
6 months prior to screening  
 
Treatment with non-steroid immunosuppressants (e.g., cyclosporine, methotrexate, 
azathioprine, mycophenolate, sirolimus, tacrolimus) within 2 months or 5 half-lives, 
whichever is longer, prior to screening  
 
Asthma exacerbation, defined as new or increased asthma symptoms that require use of 
systemic corticosteroids for 3 days and/or hospitalization or emergency visit with systemic 
corticosteroid administration within 4 weeks prior to screening 
 
Intubation for respiratory failure due to asthma within 12 months prior to screening 
 
Maintenance oral corticosteroid therapy, defined as daily or alternate-day oral corticosteroid 
within 3 months prior to screening or during the screening period 
 
Treatment with systemic (oral, IV, or IM) corticosteroids within 4 weeks prior to screening or 
during the screening period for any reason, including an acute exacerbation event 
 
Inability to withhold short acting bronchodilators for a period up to 6 hours 
 
Isolated diagnosis of exercise induced asthma without chronic symptoms 
 
History of interstitial lung disease, COPD, or other clinically significant lung disease other 
than asthma 
 
Current participation or participation in the last 6 months in pulmonary rehabilitation prior to 
screening 
 
Current malignancy or history of malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix or non-melanoma skin carcinoma that 
has been treated or excised and is considered resolved 
 
Any serious medical condition (including but not limited to significant arrhythmia, 
uncontrolled hypertension) or abnormality in clinical laboratory tests that precludes the 
patient’s safe participation in and completion of the study in the opinion of the investigator 


 
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 
Elevated IgE due to hyperimmunoglobulin E syndrome or allergic bronchopulmonary 
aspergillosis 
 
Unable to complete cardiopulmonary exercise testing and/or perform physical activity due to 
underlying cardiac, neurologic or orthopedic conditions 
 
Ongoing physician-treated sleep disorder that is unrelated to asthma within 6 months 
prior to screening 
 
Use of any prescription or over-the-counter sedative sleep medication for the duration of the 
study (e.g., zolpidem) 
 
Physician determination of patient lifestyle that can interfere with study endpoints, (e.g., 
rotating shifts, any prescription or over the counter medical cannabis, use of recreational 
drugs, etc.) 
 
Planned major surgery during the course of the study 
 
Current smoker or past smoker with 10 pack years 
 
Known HIV infection at screening 
 
Known acute or chronic infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) 
at screening 
 
Infection that meets any of the following criteria: 
- 
Resulted in hospital admission within 4 weeks prior to screening 
- 
Required treatment with intravenous or intramuscular antibiotics within 4 weeks prior to 
screening 
- 
Any active infection that required treatment with oral antibiotics within 2 weeks prior to 
screening 
- 
Note:  Antibiotics are considered to include any antimicrobial therapy used to treat 
bacterial, fungal, parasitic, viral, or other infections.  
 
Active parasitic infection, including nematodes (e.g., Ascaris, Ancylostoma), platyhelminths 
(e.g., Schistosoma), or Listeria monocytogenes infection within 6 months prior to screening 
 
Active tuberculosis requiring treatment within 12 months prior to screening  
- 
Patients who have completed treatment for tuberculosis at least 12 months prior to 
screening and have no evidence of recurrent disease are permitted. 
 
Initiation of or change in allergen immunotherapy within 3 months prior to screening.  
 
Initiation of or change in aspirin desensitization within 4 months prior to screening. 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
60 days after the last dose of omalizumab 
- 
Women of childbearing potential must have a negative serum pregnancy test result 
during the screening period. 
 
History of alcohol, drug, or chemical abuse within 6 months of screening 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or 
safety follow-up is received from the last patient, whichever occurs later.  The end of the study 
is expected to occur approximately 28 weeks after the last patient is enrolled. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 1.5 years. 
Investigational Medicinal Product 
The investigational medicinal product (IMP) for this study is omalizumab.  Omalizumab will be 
supplied by Genentech. 
Test Product (Investigational Drug) 
Omalizumab will be administered subcutaneously to patients by qualified personnel who are not 
involved with conducting safety or efficacy evaluations using a prefilled syringe.  The 


 
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recommended injection sites are the upper arm and the front and middle of the thighs.  Do not 
inject into moles, scars, bruises, or areas where the skin is tender, red, or hard, or if there are 
breaks in the skin.  Choose a different injection site for each new injection at least 1 inch from 
the area used for the last injection.  The injection may take 510 seconds to administer. 
The dose (mg) and dosing frequency will be determined by serum total IgE level (IU/mL) 
(measured before the start of treatment) and body weight (kg) and study drug may be 
administered every 2 or 4 weeks.  Assignment of the omalizumab dose will be determined by 
using the study drugdosing table.  Based on the dosing required, some patients may need 
more than one injection.  Do not administer more than one injection per injection site.  The 
prefilled syringe is to be used for single use administration only. 
Omalizumab kits must be stored at 2C8C (36F46F) in refrigerated conditions in a limited 
access area and/or a locked refrigerator.  Study drug should not be frozen or shaken.  Study 
drug should be stored immediately upon receipt.  Before administration, set aside the study 
drug PFS carton unopened for at least 1530 minutes so the syringe can warm up on its own to 
room temperature.  For further details on drug handling, see the pharmacy manual.  
After administration of omalizumab, patients should be observed for signs and symptoms of 
anaphylaxis.  More details are provided in Section 5.1.3.1.  In addition, the study staff should be 
prepared to manage anaphylaxis.  Patients should also be informed of the signs and symptoms 
of anaphylaxis and be instructed to seek immediate care should symptoms occur (see 
Appendix 2). 
For additional details, see the pharmacy manual. 
Statistical Methods 
Primary Analysis 
The primary analysis will assess the effect of omalizumab in the primary endpoint, change from 
baseline at Week 24 in endurance time (minutes). 
Determination of Sample Size   
The target sample size of 54 is based on feasibility. 
The sample size was calculated based on data from Bonini 2019, which suggested that an 
improvement in the endurance time of at least 1 minute 40 seconds from baseline or 33% is 
clinically important.  When the sample size is 54, a two-sided 95% confidence interval for the 
mean change from baseline will extend 1 minute 4 seconds from the observed mean change, 
assuming that the standard deviation is known to be 4 minutes and the confidence interval is 
based on the z-distribution (see table below).  Assuming a 10% withdrawal rate, a sample size 
of 60 will be enrolled. 
Confidence Intervals for Different Standard Deviations with Sample Size of 54 
 Standard Deviation 
95% Confidence Interval 
4 minutes 
(0 min 36 sec, 2 min 44 sec) 
5 minutes 
(0 min 20 sec, 3 min 0 sec) 
6 minutes 
(0 min 4 sec,   3 min 16 sec) 
 
Interim Analyses 
The Sponsor may conduct interim analyses of efficacy/safety and no formal multiplicity 
adjustment will be performed.  If performed, these interim analyses will not affect conduct of 
the study unless safety signals were identified.  The decision to conduct such an interim 
analysis and its timing will be documented in the Sponsor’s study master file prior to the 
conduct of the interim analysis.  
The Clinical Study Report will also document that such an interim analysis occurred.  The 
interim analysis, should it occur, will be performed by the Sponsor study team. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACQ5
Asthma Control Questionnaire 5
ADA
anti-drug antibody
ADSD
Asthma Daytime Symptom Diary
AE
adverse event
ANSD
Asthma Nighttime Symptom Diary
ATE
arterial thrombotic event
ATS/ERS
American Thoracic Society/European Respiratory Society
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval 
CGIC
Clinician Global Impression of Change
ClinRO
Clinician-Reported Outcome 
COPD
chronic obstructive pulmonary disease
CPET
cardiopulmonary exercise testing
CSU/CIU
chronic spontaneous urticaria/chronic idiopathic urticaria
CRO
contract research organization
CWR
constant work rate
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
eDiary
electronic Diary
FDA
Food and Drug Administration
FEF25-75
forced expiratory flow during the middle half of the forced vital capacity
FVC
forced vital capacity
FEV1
forced expiratory volume in 1 second 
GCP
Good Clinical Practice
GETE
Global Evaluation of Treatment Effectiveness
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IC
inspiratory capacity
ICH
International Conference on Harmonisation
ICS 
inhaled corticosteroids 
iDMC
independent Data Monitoring Committee
IET
incremental exercise test 
IgE
immunoglobulin E


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Abbreviation
Definition
IM
Intramuscular
IMP
investigational medicinal product
IND
Investigational New drug
IRB
Institutional Review Board
IV
Intravenous
IWRS
interactive voice or web-based response system
LABA
long-acting beta agonist 
LAMA
long-acting muscarinic antagonist
LDH
lactate dehydrogenase
LTRA
leukotriene receptor antagonist
LPLV
last patient, last visit
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NHLBI
National Heart, Lung, and Blood Institute of the National Institutes of Health 
PRO
patient-reported outcome
RBC
red blood cell
SABA
short-acting -agonist
SAMA
short-acting muscarinic antagonist
SAP
Statistical Analysis Plan
SD
standard deviation
SWFI
Sterile Water for Injection
ULN
upper limit of normal
USP
United States Pharmacopeia
USPI 
U. S. Package Insert 
WASO
wake after sleep onset
WBC
White Blood Cell


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1.
BACKGROUND
Omalizumab is an anti-IgE recombinant DNA-derived humanized monoclonal antibody 
designed to treat IgE-mediated inflammation by reducing the concentration of free IgE in 
blood by selectively binding to human IgE.  Atopic patients respond immunologically to 
common, naturally occurring allergens by producing IgE antibodies.  The IgE molecules 
circulate in the blood and bind tightly to the high affinity IgE binding receptor (FcRI) on 
the surface of basophils and mast cells in the circulation and various tissues.  
Omalizumab selectively binds to human IgE at the same site as does the FcεRI 
(Schulman 2001).
The approved indications for omalizumab (Xolair) are allergic asthma and chronic 
spontaneous urticaria/chronic idiopathic urticaria (CSU/CIU).
1.1
BACKGROUND ON ASTHMA
Asthma is a multifactorial chronic disease of the airways that involves a complex 
interaction of airflow obstruction, bronchial airway hyper-responsiveness and an 
underlying inflammation (NHLBI 2007).  This interaction can be highly variable among 
patients and within patients over time, with distinct but overlapping patterns that reflect 
different aspects of the disease, such as intermittent versus persistent or acute versus 
chronic manifestations.
The causal role of IgE in allergic disease is well established (Johansson et al. 1967; 
Ishizaka et al. 1970).  The allergic cascade is initiated when IgE, bound to high-affinity 
FcRI receptors on the surface of basophils and mast cells, are cross-linked by allergen, 
resulting in the degranulation of these effector cells and the release of inflammatory 
mediators, such as histamine and leukotrienes.  Epidemiologic studies have consistently 
shown that patients with asthma have elevated levels of IgE compared with 
nonasthmatic populations (Burrows 1989; Criqui 1990; Borish 2005).  IgE antibodies 
have a relationship with asthma severity and the airway’s early response to allergens 
through binding and signaling via high affinity IgE receptors (NHLBI 2003; Borish 2005).
It is estimated that the population-based proportion of asthma cases attributable to atopy 
is between 50%60% (Pearce 1999; Arbes 2007).  Studies have confirmed that 
sensitization among susceptible populations to certain indoor allergens, such as 
house-dust mites, animal dander, and cockroaches, or, to a lesser extent, outdoor 
allergens, such as the fungus Alternaria or certain pollens (e.g., grass, ragweed), is a 
risk factor for developing asthma (NHLBI 2007).  Data from longitudinal studies and 
prospective clinical trials indicate that between 60%82% of children with asthma and
48% of adults with asthma have at least 1 positive skin test (Ostergaard 1985; Lin 1995; 
Remes 1996). 
It is estimated that approximately 55%60% of asthma patients have uncontrolled 
disease (Peters 2007; Stanford 2010).  Analysis of data from the TENOR study 


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demonstrate that asthma exacerbations are frequent in patients with severe or 
difficult-to-treat asthma, notwithstanding treatment with multiple long-term asthma 
controllers, management by asthma specialists, and lung function of greater than 80% of 
predicted values (Zeiger 2009; Zeiger 2012).  
1.2
BACKGROUND ON OMALIZUMAB
Omalizumab is a recombinant DNA-derived humanized IgG1 monoclonal antibody with a 
molecular mass of approximately 149 kilodaltons that selectively binds to human IgE.
Omalizumab has demonstrated consistent effectiveness in patients previously 
inadequately controlled with standard asthma treatments. In two identical pivotal studies 
in severe allergic asthma patients receiving inhaled corticosteroids, omalizumab was 
superior to placebo in reducing asthma exacerbations and in inducing a clinically 
important improvement in daily symptom score and rescue medications (Busse et al. 
2001; Solèr et al. 2001). In another study in severe allergic asthma patients receiving
maintenance inhaled corticosteroids and a long acting beta2-agonist, omalizumab 
treatment resulted in the ability to reduce the dose of inhaled steroids compared to 
placebo and a greater proportion of patients on omalizumab were able to reduce their 
inhaled steroid use (Holgate et al. 2004). Subsequent additional studies confirmed the 
beneficial effects on asthma outcomes of omalizumab compared to placebo (Hanania et 
al. 2011; Humbert et al. 2005). Safety of omalizumab treatment has been evaluated in 
approximately 14,500 patients included in clinical studies (Phase IIII) for asthma and 
CSU/CIU.  The most studied population, patients with moderate to severe allergic 
asthma, includes approximately 3500 patients from the double-blind, placebo-controlled 
studies.  
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The current standard of care for the management of moderate to severe asthma is the 
use of inhaled corticosteroids and a second controller medication. Despite these 
medications, a proportion of patients remains uncontrolled and will need additional 
medications, including biologics, to reduce the risk of asthma exacerbations and to 
control symptoms. 
Patients with asthma are less physically active and are more sedentary than healthy 
controls (Lang, 2019; Cordova-Revera, 2018).  Frequent routine exercise has been 
shown to improve quality of life, symptom control, and decrease in systemic 
inflammation in patients with asthma (Lang, 2019; Cordova-Revera, 2018). In addition, it 
has been shown that the average sleep duration per night is less in patients with asthma 
compared to controls (Yang et al. 2019). Sleep disturbance due to nocturnal asthma
symptoms, including chest tightness, shortness of breath, cough, and/or wheezing may 
impact the ability to perform daily activities and quality of life.  Increasing the capacity to 
perform physical activities and improving sleep duration and quality may improve overall 
health status (Agusti et al. 2016).  Therefore, it is important for patients with asthma to 


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improve sleep to enable them to be more physically active and consequently have better
asthma symptom control.
Currently, methods of assessing sleep quality and impairment of daily activities are often 
limited to patient reported outcomes (PRO).  Omalizumab has shown improvement in 
asthma symptoms obtained by PROs, which include questions on sleep and limitations 
in daily activity (Busse, 2001, Solèr 2001). The limitation of these PROs is that they 
usually rely on the patient’s recollection over a previous time period, which are based on 
patient’s recall and can be limited to days or week in duration.  
There is limited data available that objectively measures exercise capacity, the level of 
physical activity, and sleep quantity and quality upon treatment of asthma patients with 
any asthma treatment. A small study using omalizumab showed promising preliminary 
data using cardiopulmonary exercise testing (CPET) (Schaper 2011). Omalizumab 
improved the initially impaired exercise capacity and these improvements were 
associated with clinical response, as measured by Global Evaluation of Treatment 
Effectiveness (GETE).
The aim of this study is to extend these findings and objectively assess whether 
omalizumab can improve the patient’s exercise capacity, physical activity and improve 
sleep quality. The ability to improve exercise capacity will be assessed by performing 
CPET at a constant work rate (CWR) on a cycle ergometer. CPET at a CWR is 
relatively independent from motivation and will provide information on whether 
omalizumab can improve the ability to perform exercise. Although limited information is 
available in patients with asthma, CPET at a CWR is a well-accepted method in patients 
with chronic obstructive pulmonary disease (COPD) in monitoring response to 
therapeutic interventions. CPET will be performed under close monitoring by trained 
and qualified personnel.
In addition to assessing exercise capacity, patients will be provided with a wrist-worn 
Physical activity and sleep monitor, which will capture physical activity levels and sleep 
data continuously over the duration of the study.  The physical activity data will provide 
information on whether improved exercise capacity is translated into patients being more 
physically active. The sleep data will allow assessments of changes in sleep quality in 
the patient’s natural environment and usual asthma triggers.
2.
OBJECTIVES AND ENDPOINTS
This study will assess the effect of omalizumab on exercise capacity, physical activity,
and sleep quality after 24 weeks of treatment in patients with moderate to severe allergic 
asthma. Specific objectives and corresponding endpoints for the study are outlined 
below.


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2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective is to assess the effect of omalizumab on the basis of the 
following endpoint:

Change from baseline at Week 24 in endurance time (minutes) during a CPET at a 
CWR
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objective is to assess the effect of omalizumab on the basis of the 
following endpoints:

Change from baseline at Week 24 in physical activity (min/day), as assessed by the 
physical activity and sleep monitor

Change from baseline to Week 24 in dynamic hyperinflation at isotime, as measured 
by inspiratory capacity during CPET at a CWR

Change from baseline at Week 24 in sleep efficiency, as assessed by the physical 
activity and sleep monitor
2.1.3
Exploratory Efficacy Objectives
The exploratory efficacy objective is to assess the effect of omalizumab on the basis of 
the following endpoints:

Change from baseline at Week 24 in pre-bronchodilator FEV1 (liters)

Percent change from baseline at Week 24 in endurance time (minutes) during a 
CPET at a CWR

Change from baseline at Week 24 in percent bronchoconstriction 

Change from baseline at Week 24 in min/day spent in sedentary, light, moderate or 
vigorous activity as assessed by the physical activity and sleep monitor

Percent change from baseline to Week 24 of time/day spent in sedentary, light, 
moderate or vigorous activity as assessed by the physical activity and sleep monitor

Change from baseline at Week 24 in energy expenditure (kcal/day) as assessed by 
the physical activity and sleep monitor

Change from baseline at Week 24 in number of night-time awakenings as assessed
by the physical activity and sleep monitor

Change from baseline at Week 24 in wake after sleep onset (WASO) as assessed 
by the physical activity and sleep monitor

Change from baseline at Week 24 in Asthma Daytime Symptom Diary (ADSD)
score

Change from baseline at Week 24 in Asthma Nighttime Symptom Diary (ANSD) 
score

Clinician Global Impression of Change (CGIC) at Week 24


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2.2 
SAFETY OBJECTIVES
The safety objective for this study is to assess the safety of omalizumab on the basis of 
the following endpoints:

Incidence of adverse events

Incidence of serious adverse events

Incidence of adverse events leading to discontinuation of omalizumab
3. 
STUDY DESIGN
3.1 
DESCRIPTION OF THE STUDY
This study is a Phase IV, open-label, single-arm, multicenter study to assess the effect of 
omalizumab on exercise capacity, physical activity, and sleep quality in patients with 
moderate to severe allergic asthma.
The study will consist of a 4-week screening period, a 24-week treatment period, and a 
4-week safety follow-up. Approximately 60 patients will be enrolled, and omalizumab will 
be dosed according to the approved United States Package Insert (USPI) dosing table.
Before performing any study specific tests or evaluations, written informed consent will 
be obtained for all patients.
During the screening period, patients will be evaluated to determine if they meet all 
eligibility criteria. Patients will be evaluated for their ability to perform required 
assessments that will take place during the study, including CPET using a cycle 
ergometer. Patients will then be assessed for adherence with their current asthma 
controller therapy, the degree of asthma control provided by their standard-of-care 
asthma medications and compliance with an eDiary, as well as a wrist-worn physical 
activity and sleep monitor. Patients will also be provided with information about the 
importance of regular physical activity to improve asthma control.
During the treatment period, at scheduled visits, exercise capacity will be assessed by 
CPET using a cycle ergometer. Additional measurements will include spirometry, 
questionnaires, adverse events, blood draws, rescue medication, and health care 
utilization. Physical activity and sleep will be assessed throughout the study using a 
wrist worn physical activity and sleep monitor.
Figure 1 presents an overview of the study design. A schedule of activities is provided in 
Appendix 1.


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Figure 1
Study Schema
Note:  Visit 3 is the enrollment visit. Patients will enroll in the study, perform all baseline 
assessments, and receive omalizumab. A patient may screen fail at Visit 3 due to non-
compliance with the physical activity and sleep monitor and/or eDiary.
a Visits 2 and 2b are flexible visits and can be performed any time after Visit 1 and before 
Week -2.
b Patients will need to use the eDiary and wear the physical activity and sleep monitor to assess 
compliance with the devices.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or safety follow-up is received from the last patient, whichever occurs later.  The end of 
the study is expected to occur approximately 28 weeks after the last patient is enrolled.
Each patient will be followed approximately 32 weeks (4-week screening period, 
24-week treatment period, 4-week safety follow-up period).
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 1.5 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Xolair Dose and Schedule
Dosing of omalizumab will be according to the approved USPI. Omalizumab will be 
administered from 150 mg to 375 mg by subcutaneous injection every 2 or 4 weeks. 
The dose (mg) and dosing frequency will be determined by serum total IgE level (IU/mL), 
measured before the start of study treatment, and by body weight (kg).
3.3.2
Rationale for Patient Population
The study population includes patients with moderate to severe asthma who have a 
positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms 
are inadequately controlled despite daily use of inhaled corticosteroids and a second 
controller. As the study aims to assess changes in exercise capacity, physical activity,
and sleep, patients must demonstrate evidence of impaired exercise capacity, sleep 
disturbance due to asthma, and interference with daily activities. The patient population 
will include patients who are willing and able to perform physical activity. Therefore, 
patients with cardiac, neurologic, or orthopedic conditions and patients who are unable 
to safely complete CPET or who are not able or willing to wear a physical activity and 
sleep monitor for the duration of the study will be excluded from the study.  Patients with 


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ongoing physician treated sleep disorders that are unrelated to asthma, will also not be 
eligible to participate in the study.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 60 patients with moderate-to-severe allergic asthma will be enrolled in 
this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 1865 years at time of signing Informed Consent Form

Body mass index (BMI) of 1835 kg/m2

Physician-diagnosed asthma for at least 12 months prior to screening

Documented history of positive skin test or in vitro reactivity to a perennial 
aeroallergen
If no historical documentation is available, the skin test or in vitro reactivity to 
a perennial aeroallergen will need to be performed during screening.

Eligibility per the study drugdosing table (serum IgE level 30 to 700 IU/mL and 
body weight 30 to 150 kg) and ability to be dosed per the USPI dosing table 

Able to comply with asthma control medication adherence, physical activity and 
sleep monitoring data collection, and eDiary requirements during screening period.  
Compliance will be assessed during the last 2 weeks prior to study enrollment and 
non-compliance is defined as: 
–
Asthma control medication use 70% of the time during the 2 week period
before study enrollment
–
Wearing the physical activity and sleep monitor less than approximately 80% of 
the time (approximately 90 hours during the day and approximately 44 hours at 
night) for each week during the 2 week period before study enrollment)
–
Using the eDiary 5 out of 7 days for each week during the 2 week period
before study enrollment

Able to safely complete incremental exercise tolerance at screening

Able to comply with the study protocol for the duration of the study, in the 
investigator's judgment, including but not limited to:
–
Able and willing to use a wrist-worn physical activity and sleep monitor every 
day and night for the duration of the study
–
Able and willing to use eDiary device throughout the duration of the study

Pre-bronchodilator FEV1 of 40%80% of predicted at screening


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
Documented history of variable airflow obstruction or hyper-responsiveness within 
12 months of study entry via at least one of the following criteria:
–
FEV1 bronchodilator response 12% and 200 mL with up to 400 g albuterol
–
Concentration of methacholine needed to produce a 20% decrease in FEV1
from baseline (PC20 8 mg/mL or PD20 200 g)
–
In patients with a forced expiratory volume in 1 second (FEV1)/forced vital 
capacity (FVC) 70%, FEV1 variability should be 12% spontaneously 
(e.g., between clinic visits) or in response to oral corticosteroids 
If no documented history is available, an assessment will need to be performed 
during screening.

On inhaled corticosteroid (ICS) therapy at a total daily dose 500 g of fluticasone 
propionate or equivalent and at least one second controller (long-acting beta agonist 
[LABA], long-acting muscarinic antagonist [LAMA], leukotriene receptor antagonist 
[LTRA]) for 3 months prior to screening, with no changes within 4 weeks prior to 
screening or during the screening period and no anticipated changes in controller 
dosing regimens throughout the study

Uncontrolled asthma during the screening period, defined as an Asthma Control 
Questionnaire 5 (ACQ5) 0.75 score and both of the following symptoms that are 
not controlled according to EPR (2007) and GINA (2019)
–
Night time awakening due to asthma in the past 4 weeks
–
Activity limitations due to asthma in the past 4 weeks

Sleep disturbance due to asthma (e.g., cough, wheezing, etc.) in the opinion of the 
investigator

Medical Research Council Dyspnoea scale 2 at screening

Impaired exercise capacity defined as VO2max % of predicted 80% of healthy 
volunteers (Koch et al. 2009) during the incremental exercise test at screening

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or to use adequate contraception during the treatment 
period and for 60 days after the final dose of study drug.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
The following are examples of adequate contraceptive methods:  bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing 
intrauterine devices; copper intrauterine devices; male or female condom with 
spermicide; and cap, diaphragm, or sponge with spermicide.


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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known history of anaphylaxis/hypersensitivity to omalizumab

Treatment with investigational drugs within 12 weeks or 5 half-lives (whichever is 
longer) prior to screening 

Treatment with monoclonal antibodies (e.g., omalizumab, mepolizumab, dupilumab)
for 6 months prior to screening 

Treatment with non-steroid immunosuppressants (e.g., cyclosporine, methotrexate, 
azathioprine, mycophenolate, sirolimus, tacrolimus) within 2 months or 5 half-lives, 
whichever is longer, prior to screening 

Asthma exacerbation, defined as new or increased asthma symptoms that require 
use of systemic corticosteroids for 3 days and/or hospitalization or emergency visit 
with systemic corticosteroid administration within 4 weeks prior to screening

Intubation for respiratory failure due to asthma within 12 months prior to screening

Maintenance oral corticosteroid therapy, defined as daily or alternate-day oral 
corticosteroid within 3 months prior to screening or during the screening period

Treatment with systemic (oral, IV, or IM) corticosteroids within 4 weeks prior to 
screening or during the screening period for any reason, including an acute 
exacerbation event

Inability to withhold short acting bronchodilators for a period up to 6 hours

Isolated diagnosis of exercise induced asthma without chronic symptoms

History of interstitial lung disease, COPD, or other clinically significant lung disease 
other than asthma

Current participation or participation in the last 6 months in pulmonary rehabilitation
prior to screening

Current malignancy or history of malignancy within 5 years prior to screening, 
except for appropriately treated carcinoma in situ of the cervix or non-melanoma 
skin carcinoma that has been treated or excised and is considered resolved


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
Any serious medical condition (including but not limited to significant arrhythmia, 
uncontrolled hypertension) or abnormality in clinical laboratory tests that precludes 
the patient’s safe participation in and completion of the study in the opinion of the 
investigator

Elevated IgE due to hyperimmunoglobulin E syndrome or allergic bronchopulmonary 
aspergillosis

Unable to complete cardiopulmonary exercise testing and/or perform physical 
activity due to underlying cardiac, neurologic or orthopedic conditions

Ongoing physician-treated sleep disorder that is unrelated to asthma within 
6 months prior to screening

Use of any prescription or over-the-counter sedative sleep medication for the 
duration of the study (e.g., zolpidem)

Physician determination of patient lifestyle that can interfere with study endpoints, 
(e.g., rotating shifts, any prescription or over the counter medical cannabis, use of 
recreational drugs, etc.)

Planned major surgery during the course of the study

Current smoker or past smoker with 10 pack years

Known HIV infection at screening

Known acute or chronic infections with hepatitis C virus (HCV) and hepatitis B virus 
(HBV) at screening

Infection that meets any of the following criteria:
–
Resulted in hospital admission within 4 weeks prior to screening
–
Required treatment with intravenous or intramuscular antibiotics within 4 weeks 
prior to screening
–
Any active infection that required treatment with oral antibiotics within 2 weeks 
prior to screening
–
Note:  Antibiotics are considered to include any antimicrobial therapy used to 
treat bacterial, fungal, parasitic, viral, or other infections. 

Active parasitic infection, including nematodes (e.g., Ascaris, Ancylostoma), 
platyhelminths (e.g., Schistosoma), or Listeria monocytogenes infection within 
6 months prior to screening

Active tuberculosis requiring treatment within 12 months prior to screening 
Patients who have completed treatment for tuberculosis at least 12 months prior 
to screening and have no evidence of recurrent disease are permitted.

Initiation of or change in allergen immunotherapy within 3 months prior to screening.

Initiation of or change in aspirin desensitization within 4 months prior to screening.

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 60 days after the last dose of omalizumab


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Women of childbearing potential must have a negative serum pregnancy test 
result during the screening period.

History of alcohol, drug, or chemical abuse within 6 months of screening
4.2 
METHOD OF TREATMENT ASSIGNMENT
This is an open-label, single-arm study.
4.2.1 
Patient ID Assignment
After initial written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established for a patient, the 
study site will obtain the patient’s identification number from an interactive voice or 
web-based response system (IWRS) at Visit 3.
4.2.2 
Patients Enrolled Under the Double-Blind, Placebo-
Controlled Protocol
Patients who have been enrolled under the double-blind, placebo-controlled protocol
(i.e., Version 1 or Version 2) can continue in the open-label study if they choose. Study 
drug assignments will be unblinded, and patients who were assigned to the omalizumab 
arm will continue per schedule. Patients who were assigned to the placebo arm will
need to restart at Visit 3/baseline. Before enrolling patients previously receiving 
placebo, please contact the medical monitor. After enrollment follow the study schedule 
through the treatment and safety period.
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is omalizumab.
4.3.1 
Study Treatment Formulation, Packaging, and Handling
4.3.1.1 
Omalizumab
Omalizumab will be supplied by the sponsor. Omalizumab is a sterile, preservative-free, 
clear to slightly opalescent and colorless to pale brownish-yellow solution for 
subcutaneous injection.  Omalizumab is provided as prefilled single use syringe and is 
available in two doses. The prefilled syringes are for single use and should not be 
re-used or tampered with.
Each 75 mg prefilled syringe delivers 75 mg omalizumab in 0.5 mL and contains 
L-arginine hydrochloride (21.05 mg), L-histidine (0.68 mg), L-histidine hydrochloride 
monohydrate (1.17 mg), and polysorbate 20 (0.2 mg) in Sterile Water for Injection 
(SWFI), United States Pharmacopeia (USP).
Each 150 mg prefilled syringe delivers 150 mg omalizumab in 1 mL and contains 
L-arginine hydrochloride (42.1 mg), L-histidine (1.37 mg), L-histidine hydrochloride 
monohydrate (2.34 mg), and polysorbate 20 (0.4 mg) in SWFI, USP.


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The removable needle cap of Xolair solution for injection in pre-filled syringe contains a 
derivative of natural rubber latex. Although no natural rubber latex is detected in the 
removable needle cap, the safe use of Xolair solution for injection in pre-filled syringe in 
latex-sensitive individuals has not been studied.
For additional details, see the pharmacy manual and the Omalizumab Investigator’s
Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.3.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Dose modifications or interruptions are not permitted during the study.  Cases of 
omalizumab accidental overdose or medication error, along with any associated adverse 
events, should be reported as described in Section 5.3.5.13.
4.3.2.1
Omalizumab 
Study drug will be administered subcutaneously to patients by qualified personnel who 
are not involved with conducting safety or efficacy evaluations using a prefilled syringe.  
The recommended injection sites are the upper arm and the front and middle of the 
thighs. Do not inject into moles, scars, bruises, or areas where the skin is tender, red, or 
hard, or if there are breaks in the skin. Choose a different injection site for each new 
injection at least 1 inch from the area used for the last injection. The injection may take 
510 seconds to administer.
The dose (mg) and dosing frequency will be determined by serum total IgE level (IU/mL) 
(measured before the start of treatment) and body weight (kg) and study drug may be 
administered every 2 or 4 weeks.  Assignment of the study drug dose will be determined 
by using the study drugdosing table (see Appendix 8).  Based on the dosing required, 
some patients may need more than one injection. Do not administer more than one 
injection per injection site. The prefilled syringe is to be used for single use 
administration only.
Study drug kits must be stored at 2C8C (36F46F) in refrigerated conditions in a 
limited access area and/or a locked refrigerator.  Study drug should not be frozen or 
shaken.  Study drug should be stored immediately upon receipt. Before administration, 
set aside the study drug PFS carton unopened for at least 1530 minutes so the syringe 
can warm up on its own to room temperature. For further details on drug handling, see 
the pharmacy manual.
After administration of omalizumab, patients should be observed for signs and 
symptoms of anaphylaxis.  More details are provided in Section 5.1.3.1.  In addition, the 


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study staff should be prepared to manage anaphylaxis.  Patients should also be 
informed of the signs and symptoms of anaphylaxis and be instructed to seek immediate 
care should symptoms occur (see Appendix 2).
For additional details, see the pharmacy manual
4.3.3
Investigational Medicinal Product Accountability
The IMP (omalizumab) required for completion of this study will be provided by the 
Sponsor.  The study site will acknowledge receipt of IMPs supplied by the Sponsor using 
the IWRS to confirm the shipment condition and content.  Any damaged shipments will 
be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site’s method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Omalizumab
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide omalizumab to patients who have completed the study.  The Sponsor 
may evaluate whether to continue providing omalizumab in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
All medications used for the treatment of asthma should be recorded on the appropriate 
electronic Case Report Form (eCRF). Other medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from Week -4
(first screening visit) should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Required Asthma Controller Therapy
All patients will continue their asthma controller therapy as recommended in asthma 
guidelines (EPR3 2007; GINA 2019).  Required asthma controller therapy for this study 
includes daily ICS therapy (500–2000 g/day of fluticasone propionate DPI or 
equivalent; refer to Appendix 9) and at least one of the following second controller 


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medications: LABA, LTRA, or LAMA. Refer to Section 4.4.4 for additional details 
regarding ICS and second controller therapy.
4.4.2 
Short-Acting Rescue Therapy
It is expected that the majority of patients will be using short-acting B-agonist (SABA) or 
short-acting muscarinic antagonist (SAMA) therapy for symptoms of uncontrolled asthma 
per existing treatment guidelines. Combination SABA or SAMA inhalers (e.g., 
albuterol/ipratropium) are also permitted. Short-acting rescue therapy must be 
administered via the patient’s prescribed inhaler or nebulizer. Any short-acting therapy 
that is prescribed as asthma rescue medication over the course of the study or 
administered during hospitalization or an emergency department, urgent care visit, or 
urgent unscheduled office visit should be documented on the appropriate eCRF. 
Restrictions on the timing of administration of SABA or SAMA therapy relative to 
spirometry measurements and CPET are described in Section 4.4.4.
4.4.3 
Systemic Corticosteroid Use
Patients who require any systemic corticosteroids (oral, IV, or IM) within 4 weeks prior to 
screening or during the screening period will not be eligible for the study (see
Section 4.1.2). The use of systemic corticosteroids is permitted for acute patient 
management after enrollment. Corticosteroids used for treatment of asthma should be 
documented on the appropriate eCRF. Whereas systemic corticosteroids should not be 
used other than for asthma exacerbation, in the event that they are used to treat other 
medical conditions, this should be documented on the Concomitant Medications eCRF.
4.4.4 
Medication Use Prior to Spirometry Measurements and CPET 
At specified timepoints during the study, patients will undergo pre-bronchodilator 
spirometry and CPET measurements in the clinic. Bronchodilator use is prohibited 
within a specified window prior to these measurements as follows:

Twice-daily LABA and LAMA: prohibited within 12 hours prior to spirometry and
CPET

Once-daily LABA and LAMA: prohibited within 24 hours prior to spirometry and CPET

SABA or SAMA: prohibited within 6 hours prior to spirometry and CPET
4.4.5 
Permitted Therapy
The following asthma medications are permitted with the following instructions in Table 1.


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Table 1
Permitted Asthma Medications
Medication
Restrictions a
ICS therapy
No changes in ICS therapy within 4 weeks prior to 
Visit 1/screening and throughout the study
LABAs
LTRAs
LAMAs
No changes in dose or initiation of therapy within 4 weeks prior to 
Visit 1/screening and throughout the study
Allergen immunotherapy
No changes in allergen immunotherapy or initiation of new 
allergen immunotherapy within 3 months prior to Visit 1/screening 
and throughout the study
ICSinhaled corticosteroid; LABAlong-acting β-agonist; LAMAlong-acting muscarinic 
antagonist; LTRAleukotriene receptor antagonist.
a The Medical Monitor should be consulted in cases of uncertainty.
4.4.6
Prohibited Therapy
The following medications are prohibited with the instructions in Table 2.
Table 2
Prohibited Asthma Medications
Medication
Restrictions a
Maintenance corticosteroids (e.g., daily
or every other day oral therapy)
Prohibited within 3 months prior to Visit 1/screening
and throughout the study
Zileuton
Prohibited within 4 weeks prior to Visit 1/screening and 
throughout the study
Immunomodulatory or 
immunosuppressive therapy (other than 
monoclonal antibodies or 
corticosteroids [see separate 
exclusion])
Prohibited within 3 months or 5 drug half-lives prior to 
Visit 1/screening (whichever is longer) and throughout 
the study
Licensed or investigational b
monoclonal antibodies for asthma or 
any other indication
Prohibited within 6 months or 5 drug half-lives prior to 
Visit 1/screening (whichever is longer) and throughout 
the study
Any other investigational drug not 
described above (including 
investigational use of a formulation of 
an approved drug) b
Prohibited within 4 weeks or 5 drug half-lives prior to 
Visit 1/screening (whichever is longer) and throughout 
the study
Pulmonary rehabilitation
Prohibited for 6 months prior to Visit 1/screening and 
throughout the study
Any prescription or over-the-counter 
sedative sleep medication 
(e.g., zolpidem).
Prohibited from Visit 1/screening throughout the study
a The Medical Monitor should be consulted in cases of uncertainty.
b Patients participating in a clinical trial that has not been unblinded should be assumed to have 
received the active drug.


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4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly.
If a patient is having an acute asthma exacerbation event or has a respiratory infection 
at the time of a scheduled study visit, the CPET and spirometry visit should be 
scheduled at the next 4-week visit (e.g., if an exacerbation happens at Visit 6, the patient 
should be scheduled for CPET and spirometry at Visit 7). 
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for all patients (enrolled patients and for patients who are not 
subsequently enrolled) will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Patients who fail screening are allowed to be rescreened once, at the discretion of the 
investigator.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including, but not limited to, clinically significant diseases, surgeries, 
cancer history, reproductive status, and smoking history will be recorded at screening.  
In addition, all asthma and other medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient prior to Visit 1 (first screening visit) will be recorded.  At the time of each 
follow-up physical examination, an interval medical history will be obtained and any 
changes in medications and allergies will be recorded.
In particular, any history of anaphylaxis, cardiovascular disease, neurological disease, 
orthopedic conditions, inflammatory or autoimmune disease, and parasitic disease will
be recorded on the eCRF.


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Demographic data to be collected will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A physical examination, performed at the first screening visit should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits, as outlined in the schedule of assessments in Appendix 1 (or as 
clinically indicated), physical examinations should be performed as clinically indicated.  
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and body temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Height and Weight
Height and weight will be measured at visits according to the schedule of assessments.  
Weight will be determined to the nearest 0.1 kg.  For body weight measurements, the 
patient should wear street clothes, without shoes, outerwear, or accessories.
4.5.6
Spirometry
Spirometry, including the procedure for bronchodilator testing if needed, will be 
conducted as per the study pulmonary function testing manual, which is based on the 
American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus 
Statement “Standardisation of Spirometry” (Graham et al. 2019).  The manual will 
include information on equipment, procedures, patient instructions, and precautions.  
Existing spirometry equipment and capabilities will be assessed at all sites. Training on
equipment use, system calibration, and data storage and transfer will be provided.
4.5.6.1
Pre-Bronchodilator Spirometry
Pre-bronchodilator spirometry evaluations should ideally be performed in the morning, 
before use of bronchodilators.  Every attempt should be made to perform spirometry 
approximately at the same time of the day throughout the study for each patient. 
Asthma therapies that may affect spirometry must be withheld until pre-bronchodilator 
spirometry measurements are completed.  Patients must be made aware that 


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bronchodilator use is prohibited within a specified window prior to each clinic visit at
which spirometry will be performed as follows:

Twice-daily LABA and twice-daily LAMA: prohibited within 12 hours prior to 
spirometry

Once-daily LABA and once-daily LAMA: prohibited within 24 hours prior to 
spirometry

SABA or SAMA: prohibited within 6 hours prior to spirometry
If a patient arrives for a study visit having used a bronchodilator within the time window 
defined above for each medication, spirometry should be rescheduled to the next 
4-week visit. All assessments that do not require bronchodilator withholding should be 
performed as scheduled.
Spirometric assessments will include FEV1, FVC, percentage of predicted values for 
FEV1 and FVC, FEV1 to FVC ratio, and average expiratory flow during the middle portion 
of the expiration (FEF25-75).  The percentage of predicted values for FEV1 FVC and 
FEF25-75 will be derived from the Global Lung Function Initiative (Quanjer et al. 2012). 
Each test procedure requires that three valid spirometry maneuvers be performed within 
1 hour.  An acceptable session must also meet ATS/ERS repeatability criteria for FEV1
and FVC (Graham et al. 2019). The highest FEV1 and FVC values from the set of three 
accepted maneuvers will be recorded.  Other parameters will be taken from the 
accepted maneuver with the highest sum of FEV1 and FVC.  A hard-copy report of the 
spirometry results will be maintained in the patient’s medical record.
4.5.7
Asthma Exacerbations
At each study visit, the investigator will ask directed questions to assess whether the 
patient experienced any protocol-defined asthma exacerbations since the last study visit.  
An asthma exacerbation is defined as new or increased asthma symptoms (including 
wheeze, cough, dyspnea, chest tightness, and/or night-time awakening due to these 
symptoms) that lead to treatment with systemic corticosteroids or to hospitalization. 
Treatment with systemic corticosteroids is defined as treatment with oral, IV, or IM 
corticosteroids for at least 3 days or an emergency department visit with at least one 
dose of IV or IM corticosteroids.  An asthma exacerbation must be reported as an 
adverse event (or serious adverse event as applicable) as per Section 5.2.  Sites should 
update the appropriate eCRF with all medications used for treatment of the asthma 
exacerbation.
4.5.8
Cardiopulmonary Exercise Testing
CPET will be performed on an electromagnetically braked cycle ergometer.  Patients will 
perform the exercise while breathing through a mouthpiece with nose clip in place.  
Ventilation and gas exchange will be measured breath-by-breath by a metabolic cart.  
Heart rate will be assessed via the ECG.  Arterial oxygen saturation will be estimated by 


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pulse oximetry. CPET will be performed under close monitoring of trained and qualified 
personnel.
At the second screening visit (Visit 2a), patients will perform an incremental exercise 
test (IET) to the limit of tolerance.  Recordings will be made for 3 minutes at rest, 
3 minutes during unloaded pedaling and then at continuously increasing work rate (on a 
ramp-like fashion) until unable to maintain pedaling rate or intolerable shortness of 
breath despite standardized encouragement.
At screening Visit 2b, a CWR testing at 80% of the peak work rate (determined by the 
IET) will be performed to tolerance. This will identify an individualized work rate that the 
patient can tolerate for 38 minutes.  The procedure will be as follows: After 3 minutes of 
rest, the work rate will be increased abruptly to 80% of the work rate tolerated in the 
incremental test.  Patients will continue to exercise at this work rate until unable to 
maintain pedaling rate or intolerable shortness of breath despite standardized 
encouragement.  If the tolerated time falls outside the 38 minute window, a repeat of 
the CWR testing will need to be performed, after work rate adjustment. Visit 2b is a 
flexible visit and may be a series of visits depending on the preference of the patient and 
study site.  A maximum of three CWR tests (one initial and two adjusted) may need to be 
performed during screening. The window may be extended by +10 days accumulatively 
to complete the CWR. Patients who fail to achieve a CWR with an endurance time 
between 38 minutes within three attempts will not qualify for the study.  At the 
discretion of the investigator, the patient may rescreen once. If two tests are performed 
on the same day, the time between the tests needs to be at least 90 minutes to allow for 
recovery. If a SABA or SAMA rescue medication is used during or after CWR testing, 
the patient will need to perform the adjusted work-rate test on a separate day.
At the baseline visit (enrollment visit/Visit 3), testing of the individualized CWR that is 
established during screening will be performed to tolerance and will be the baseline 
endurance time.  The CWR testing will be repeated at Week 12 and Week 24 to assess 
change in endurance time. During the CWR test, dynamic hyperinflation will be 
measured by serial inspiratory capacity (IC) maneuvers.  After the CWR test, serial 
spirometry will be performed to assess bronchoconstriction and recovery from 
bronchoconstriction.
All CPET evaluations should be performed after resting ECG and spirometry. Every 
attempt should be made to perform CPET approximately at the same time of day 
throughout the study for each patient.
Asthma therapies that may affect CPET must be withheld until CPET measurements are 
completed as follows:

Twice-daily LABA and twice-daily LAMA: prohibited within 12 hours prior to CPET

Once-daily LABA and once-daily LAMA: prohibited within 24 hours prior to CPET

SABA or SAMA: prohibited within 6 hours prior to CPET


 
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If a patient arrives for a study visit having used a bronchodilator within the time window 
defined above for each medication, CPET should be rescheduled to the next 4-week 
visit.  All assessments that do not require bronchodilator withholding should be 
performed as scheduled. 
Details for IET and CWR testing are provided in a separate CPET laboratory manual. 
4.5.9 
Wrist-Worn Physical Activity and Sleep Monitor 
At the second screening visit (Visit 2b), a wrist-worn physical activity and sleep monitor 
will be provided to patients who meet inclusion and exclusion criteria requirements.  
Physical activity and sleep data will be collected from patients continuously via a 
wrist-worn accelerometer (physical activity and sleep monitor).  The physical activity and 
sleep monitor will be worn day and night, from the moment the patient receives the 
monitor, on the patient’s non-dominant wrist for the entire duration of the study.  The 
study will utilize the CentrePoint Insight Watch (Actigraph Corp, USA) as the activity and 
sleep monitor, which was selected due to its high accuracy, long battery life, excellent 
form-factor (e.g., ease and comfort of use) and clinically validated algorithms for 
measuring the relevant physical-activity and sleep-based endpoints.  The watch collects 
raw accelerometry data in m/s2 in 3-dimensions and transmits wirelessly via 3G cellular 
network to Actigraph’s cloud-based servers.  The raw physical activity and sleep data is 
processed for analyses using Actigraph’s ActiLife software to determine the endpoints as 
described in this protocol using algorithms such as those detailed in Staudenmayer et al. 
(2015).  All data collected by the watch will be uploaded passively to a hub at the 
patient’s home.  The data is anonymous and patients will not be able to view their 
individual data during the course of the study. 
All patients will also be provided with information about the importance of regular 
physical activity to improve asthma control, and provided with a tip sheet ‘Being Active 
When You Have Asthma (exercise is medicine) from the American College of Sports 
Medicine. 
4.5.10 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 
 
Serum and urine pregnancy test 
All women of childbearing potential must have a negative serum pregnancy test 
during the screening period, prior to initiation of study drug.  Additionally, women 
should have a urine pregnancy test, performed at the site, prior to the initiation of 
study drug, every 4 weeks during study treatment period, as indicated in 
Appendix 1.  Urine pregnancy test results must be reviewed and confirmed to be 
negative before study drug administration.  If a urine pregnancy test is positive or 
borderline, it must be confirmed by a serum pregnancy test before giving study 
drug. 


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
Total IgE for study eligibility and dosing determination

Standard hematology panel, may include but is not limited to: WBC count, RBC 
count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells)

Standard chemistry panel (serum or plasma), may include but is not limited to: 
sodium, potassium, chloride, bicarbonate, glucose, BUN/urea, creatinine, 
total protein, albumin, phosphorus, calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, uric acid, LDH
4.5.11
Clinical Outcome Assessments 
4.5.11.1
Assessments Completed by the Patient at Home
At the screening Visit 2b patients who meet inclusion and exclusion criteria requirements
will receive an eDiary device that will be used for documenting asthma controller 
medication use, answering questions related to asthma symptoms, nighttime 
awakenings due to asthma, activity limitations and use of short-acting rescue therapy. 
Patients will be given instructions on how to use the eDiary device and how to complete
the eDiary assessments:

Patients should complete their diaries in a quiet area with minimal distractions and 
disruptions.

Patients should answer questions to the best of their ability; there are no right or 
wrong answers.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.
Details of each home assessment are detailed below.
Morning and Evening Asthma Diaries
The daily diary comprises morning items (Asthma Nighttime Symptom Score [ANSD], 
rescue medication since going to bed and nighttime awakenings due to asthma 
symptoms, to be completed when patients wake up) and evening items (Asthma 
Daytime Symptom Score [ADSD], rescue medication use since getting up in the morning 
and activity limitations during the day to be completed before bedtime).  Patients will 
complete daily diary questions on the eDiary twice a day for 2 weeks before the baseline 
visit (enrollment visit), for 2 weeks before the Week 12, and for 2 weeks before the 
Week 24. Rescue medication use will need to be entered throughout the study every 
day that the patient uses rescue medication. The eDiary will remind patients when it is 
time to complete their diary through text and sound alerts.  
Sites must report to sponsor within 10 business days after experiencing or receiving any 
reported issues with the use of the eDiary.
A copy of morning and evening diaries are provided in Appendix 4 and Appendix 5.


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4.5.11.2
Clinical Outcome Assessments Completed During Site Visits
Patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) instruments 
will be completed to support understanding of treatment benefit of omalizumab as 
measured by physical activity and sleep quality assessments. 
PRO data will be collected through use of Asthma Control Questionnaire 5 (ACQ5) and 
ClinRO data will be collected through assessment of the patient’s Urgent 
Asthma-Related Health Care Utilization and Clinician Global Impression of Change 
(CGIC).
The ACQ5 will be completed in its entirety by the patient. The urgent asthma-related 
health care utilization assessment and CGIC will be completed by the investigator as 
described below. All instruments will be administered at specified timepoints during the 
study, as outlined in Appendix 1. 
Site-completed instruments should be administered as outlined below:

ACQ5 will be administered before the patient receives any information on disease 
status, prior to the performance of non-PRO assessments, and prior to the 
administration of study treatment, unless otherwise specified

Patients' health status should not be discussed prior to administration of the 
instruments.

Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 5 minutes at each administration time.

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions.

Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers.

Site staff should not interpret or explain questions, but may read questions verbatim 
upon request.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.
Site staff should review the completed ACQ5 and should ask the patient to rectify any 
response that is not clearly marked in the appropriate location.  If a response is missing, 
site staff should ask the patient to complete the item or confirm that the item was 
intentionally left blank
The ACQ5, Urgent Asthma-Related Healthcare Resource Utilization assessment, and 
CGIC will be recorded on the official, dedicated eCRF.
Details of assessments to be completed at the sites are detailed below.


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Asthma Control Questionnaire 5
Asthma control, as measured by the ACQ5 (Juniper et al. 1999) will be assessed by 
asking patients to recall their experience with asthma during the previous week. The 
ACQ5 consists of five questions related to symptoms (i.e., nighttime awakening, asthma 
symptoms upon awakening in the morning, activity limitation, shortness of breath, and 
wheezing frequency).  The items are scored on a scale ranging from 0 (totally controlled) 
to 6 (extremely poorly controlled).  The items are equally weighted.  The ACQ5 is scored 
as the mean of the five symptom-related items. The ACQ5 has strong measurement 
properties for use in both clinical practice and clinical trials. The ACQ5 is part of the 
eligibility criteria and will be administered at the screening, baseline (enrollment), Week 
12 and Week 24 Visits.  
A copy of the ACQ5 is provided in Appendix 6.
Clinician Global Impression of Change
The CGIC is a single-item assessment of the clinician’s impression of a patient’s change 
in asthma symptoms since beginning the 24-week treatment period (Visit 3). Change in 
asthma symptoms is rated on a 7-point scale ranging from “very much worse” to “very 
much improved.” The CGIC is completed by the investigator and takes less than 
1 minute to complete. The CGIC will be completed at Weeks 12 and 24. 
A copy of the CGIC is provided in Appendix 7.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
Patients who discontinue study treatment should continue with the remaining study 
assessments.
Patients who do not wish to continue with study assessments will be asked to return to 
the clinic for a dosing termination visit within 4 weeks after the last dose of study 
treatment. The patient will bring the eDiary and physical activity and sleep monitor.
The dosing termination visit may be performed virtual if needed in which case the 
eDiary and physical activity and sleep monitor will need to be shipped to the site. The 
patient will subsequently receive a phone call as safety follow-up 4 weeks after their 
dosing termination visit.


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4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 

Investigator or Sponsor determines it is in the best interest of the patient 

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Patients 
who withdraw from the study will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies with omalizumab 
indicates a potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice (GCP)

No study activity (i.e., all patients have completed the study and all obligations have 
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5. 
ASSESSMENT OF SAFETY
5.1 
SAFETY PLAN
The clinical safety of omalizumab has been well documented in a number of clinical trials 
that involve adults and children with moderate to severe allergic asthma.  The adverse 
event profile of omalizumab observed during the clinical development program of allergic 
asthma was similar to placebo, with the most commonly reported adverse events being 
headaches and injection site reactions, including injection site pain, swelling, erythema, 
pruritus.  Anaphylactic reactions were observed but were rare and typically occurred 
within 2 hours of the first or subsequent injection although some occurred beyond
2 hours. Omalizumab has also been investigated in patients with chronic idiopathic 
urticaria, seasonal allergic rhinitis, perennial allergic rhinitis, atopic dermatitis, nasal 
polyps, and peanut allergy. The safety profile of omalizumab in non-asthma trials has
not differed from the safety profile of omalizumab in asthma trials.
The anticipated important safety risks for omalizumab are outlined below.  Please refer
to the omalizumab Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events or discontinuation are provided appropriately 
(see Section 4.6).
5.1.1 
Safety and Data Monitoring
All safety events will be closely monitored by the study team. The sponsor followed the 
U.S. Food and Drug Administration (FDA) guidance (FDA 2006; 
https://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm) to evaluate the 
need for an independent data monitoring committee (iDMC) and decided not to have an 
iDMC for this study based on the criteria mentioned in the guidance, the established 
safety record of omalizumab, and the outcomes being examined.
5.1.2 
Anaphylaxis Adjudication Committee
All potential anaphylaxis cases reported by investigators to the Sponsor will be 
subsequently submitted for adjudication to a 3-member anaphylaxis adjudication        
committee composed of external experts in allergic diseases. The committee will assess 
whether the reported event is a true anaphylaxis event (based on Sampson's criteria,  
Appendix 3) and whether the reported anaphylaxis event is causally related to 
omalizumab. Further details will be provided in the Anaphylaxis Adjudication Charter.


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5.1.3
Risks Associated with Omalizumab
5.1.3.1
Anaphylaxis
Anaphylaxis has been reported to occur after administration of omalizumab in clinical 
trials and in post-marketing spontaneous reports.  Anaphylactic reactions were rare in 
clinical trials (0.1%) and estimated as 0.2% from post-marketing reporting.  The reported 
signs and symptoms included but were not limited to bronchospasm, hypotension, 
syncope, urticaria, and/or angioedema of the throat or tongue.  Some of these events 
have been reported as life threatening.
The majority of anaphylactic-type reactions have been reported to occur after the 
first dose, with numbers decreasing with subsequent doses, but such reactions were 
also reported beyond 1 year after starting scheduled treatment.  The events were 
reported to occur predominantly within the first 2 hours post-dose, with few reports 
occurring as far as 36 hours post-dose. 
Details regarding management of these events are provided below:

Administer omalizumab only in a healthcare setting by healthcare providers 
prepared to manage anaphylaxis that can be life-threatening; medications for the 
treatment of anaphylactic reactions should be available for immediate use following 
administration of omalizumab. 

Patients should be observed for at least 2 hours after the first 3 study drug doses 
and at least 30 minutes after subsequent doses.  However, some patients may 
require longer observation periods, depending on investigator judgment taking into 
account the time to onset of anaphylaxis seen in clinical trials and post-marketing 
spontaneous reports.  The American College of Allergy, Asthma, and Immunology 
guideline on the observation period after omalizumab administration (Kim et al. 
2010) recommends 2 hours of monitoring in the clinic after the first 3 injections and 
30 minutes or an appropriate time agreed upon by the individual patient and 
healthcare professional for subsequent injections.  However, a delayed onset of 
symptoms and protracted progression of anaphylaxis should be taken into account 
when administering omalizumab (Limb et al. 2007).  

Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek 
immediate medical care should signs or symptoms occur.

Discontinue omalizumab in patients who experience a severe hypersensitivity 
(anaphylactic) reaction. 
5.1.3.2
Serum Sickness
Serum sickness and serum sicknesslike reactions, which are delayed allergic type III 
reactions, have rarely been seen in patients treated with humanized monoclonal 
antibodies including omalizumab in the post-approval use.  The onset has typically been 
15 days after administration of the first or subsequent injections, also after long 
duration of treatment.  Symptoms suggestive of serum sickness include 


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arthritis/arthralgia, rash (urticaria or other forms), fever, and lymphadenopathy.  
Antihistamines and corticosteroids may be useful for preventing or treating this disorder.

Patients should be informed and advised to report any suspected symptoms of 
serum sicknesslike reactions.

Physicians should stop omalizumab if a patient develops this constellation of signs 
and symptoms.
5.1.3.3
Churg-Strauss Syndrome and Hypereosinophilic Syndrome
Patients with severe asthma may rarely present systemic hypereosinophilic syndrome or 
allergic eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), both of 
which are usually treated with systemic corticosteroids.  In rare cases, patients on 
therapy with anti-asthma medicinal products, including omalizumab, may present or 
develop systemic eosinophilia and vasculitis.  These events are commonly associated 
with the reduction of oral corticosteroid therapy and manifested by the development of 
marked eosinophilia, vasculitic rash, worsening pulmonary symptoms, paranasal sinus 
abnormalities, cardiac complications, and/or neuropathy. 
Abrupt discontinuation of systemic or inhaled corticosteroids after initiation of 
omalizumab therapy is not recommended.  Decreases in corticosteroids should be 
performed under the direct supervision of a physician and may need to be performed 
gradually.  Patients with known or suspected Churg-Strauss syndrome should be 
excluded from the study.
5.1.3.4
Thrombocytopenia
In nonclinical studies, a dose-dependent and reversible circulating platelet reduction was 
observed.  In clinical studies, few patients experienced platelet counts below the lower 
limit of the normal laboratory range.  None of these changes was associated with 
bleeding episodes or a decrease in hemoglobin.  
5.1.3.5
Malignancies
During initial clinical trials in adults and adolescents 12 years of age and older with 
allergic asthma, there was a numerical imbalance in cancers arising in the active 
treatment group, compared with the control group.  The number of observed cases was 
uncommon (1/100) in both the active and the control group.  In a subsequent 
observational study (EXCELS) comparing 5007 omalizumab-treated patients and 
2829 non-omalizumab-treated patients followed for up to 5 years, the incidence rates of 
primary malignancies per 1000 patient years were 16.01 (295/18,426 patient years) and 
19.07 (190/9963 patients years), respectively, which does not indicate an increased 
malignancy risk (rate ratio 0.84, 95% CI: 0.621.13).  In a further analysis of randomized 
double-blind placebo-controlled clinical trials, including 4254 patients on omalizumab 
and 3178 patients on placebo, omalizumab treatment was not associated with an 
increased malignancy risk based on incidence rates per 1000 patient years of 4.14 
(14/3382 patient years) for omalizumab-treated patients and 4.45 (11/2474 patient 


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years) for placebo patients (rate ratio 0.93, 95% CI: 0.392.27).  The overall observed 
incidence rate of malignancy in the omalizumab clinical trial program was comparable to 
that reported in the general population.  There were no cases of malignancy in clinical 
trials in allergic asthma in the 6 to 12 years-of-age group with omalizumab; there were 
2 cases of malignancy in the control group (medulloblastoma and nephroblastoma).
In the Phase III CIU/CSU program (733 patients enrolled and receiving at least 1 dose of 
omalizumab, including 684 patients exposed for 12 weeks and 427 exposed for 
24 weeks), there was 1 case of malignancy in the placebo group (242 patients) and 
1 case in the omalizumab 300-mg group (412 patients) in a patient with a pre-existing 
history.
5.1.3.6
Arterial Thrombotic Events
In controlled clinical trials in allergic asthma and during interim analyses of EXCELS (an 
observational study), a numerical imbalance of arterial thrombotic events (ATEs) was 
observed.  ATEs included stroke, transient ischemic attack, myocardial infarction, 
unstable angina, and cardiovascular death (including death from unknown cause).  
Final results from the EXCELS study revealed an increased ATE rate in the omalizumab
cohort as compared to the non-omalizumab cohort, with a hazard ratio of 1.32 (95% CI: 
0.91, 1.91) when adjusted for confounders and risks factors.  The results from the 
EXCELS study revealed the rate of ATEs per 1000 patient years was 7.52 (115/15286 
patient years) for omalizumab-treated patients and 5.12 (51/9963 patient years) for 
control patients.  Although there was no consistent evidence of an association between 
omalizumab use and risk of ATEs, the 95% CIs were wide and could not definitively 
exclude an elevated risk.  In a new analysis of pooled clinical trials of 8 weeks duration,
the rate of ATE per 1000 patient years was 2.69 (5/1856 patient years) for 
omalizumab-treated patients and 2.38 (4/1680 patient years) for placebo patients.
5.1.3.7
Antibody Formation to Omalizumab
Omalizumab is a humanized monoclonal anti-IgE antibody.  The formation of 
anti-omalizumab antibodies (also called anti-drug antibodies [ADAs]) after omalizumab 
administration is a rare event.  In the clinical trials for asthma and CSU/CIU, out of the 
23,498 samples tested, only 5 samples were confirmed to be ADA positive in the 
confirmatory assay.  However, 2 of the 4 samples tested positive had been collected 
prior to omalizumab administration. In both cases, the post-dose samples of these 
subjects were negative. Importantly, the 3 ADA-positive cases following omalizumab 
administration were not associated with any serious adverse events.
5.1.3.8
Parasitic Infections
IgE may be involved in the immunological response to some infections.  In patients at 
chronic high risk of helminth infection, a placebo-controlled trial in allergic patients 
showed a slight increase in infection rate with omalizumab, although the course, 
severity, and response to treatment of infection were unaltered.  The helminth infection 


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rate in the overall clinical program, which was not designed to detect such infections, 
was less than 1 in 1,000 patients.  However, caution may be warranted in patients at 
high risk of helminth infection, in particular when traveling to areas where helminthic 
infections are endemic.  If patients do not respond to recommended anti-helminth 
treatment, discontinuation of omalizumab should be considered.
5.1.4
Management of Patients Who Experience Specific Adverse 
Events
5.1.4.1
Dose Modifications and Treatment Interruption
Dose modification and/or treatment interruption is not allowed during the conduct of the 
study.  Omalizumab should be discontinued in patients who experience a severe 
hypersensitivity reaction.
5.1.4.2
Management of Drug Induced Liver Injuries
Liver injury has not been described as a risk associated with omalizumab.  However, 
1) if the patient's AST or ALT is 8ULN, or 2) if the patient's ALT or AST 3ULN and 
total bilirubin 2ULN or clinical jaundice occurs, study drug should be discontinued,
liver test should be repeated, and an evaluation for causes for the liver test abnormality 
should be initiated.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.10 and 
5.3.5.11 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline


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
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 


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Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Suspected anaphylaxis/anaphylactoid reactions identified based on Sampson's 
criteria (see Appendix 3)

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.8)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.  The 
investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4).
For each adverse event recorded on the Adverse Event eCRF, the investigator will make
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until the end of the safety 
follow-up period (Week 28).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"


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accordingly.  The following guidance should be taken into consideration (see also 
Table 4.

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection-Site Reactions
Local adverse events that occur during (or within 24 hours) after study drug 
administration and are judged to be related to study drug injection should be captured as 
a diagnosis (e.g., "injection-site reaction" on the Adverse Event eCRF).  Associated 


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signs and symptoms should be recorded on the dedicated Injection-Site Reaction eCRF.  
If a patient experiences both a local and systemic reaction to the same dose of study 
drug, each reaction should be recorded separately on the Adverse Event eCRF, with 
signs and symptoms also recorded separately on the dedicated Injection-Site 
Reaction eCRF.
5.3.5.2
Anaphylactic Reactions
The investigator should use Sampson's criteria (see Appendix 3) to identify the potential 
cases of anaphylaxis and report as a diagnosis on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Any case of known or suspected 
anaphylaxis will require the completion of a dedicated eCRF to record the specific signs 
and symptoms associated with this event.  
5.3.5.3
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.4
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.3.5.5
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.6
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for
details on recording persistent adverse events).
5.3.5.7
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for
details on recording persistent adverse events).
5.3.5.8
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).


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5.3.5.9
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.10
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.11
Lack of Efficacy or Worsening of Asthma
Medical occurrences or symptoms of deterioration that are anticipated as part of asthma
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of asthma on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of asthma).
5.3.5.12
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  


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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.13
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For
omalizumab, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with omalizumab, regardless of whether they 
result in an adverse event, should be recorded on the eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.


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
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Medical device complaints (see Section 5.4.4 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and the Institutional Review Board/ Ethics Committee 
(IRB/EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Genentech Medical Monitor contact information:
Medical Monitor:
, M.D.
Telephone No.:
Alternate Genentech Medical Monitor contact information:
Medical Monitor:
, Ph.D.
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk 
(1-888-835-2555) will access the Roche Medical Emergency List, escalate emergency 
medical calls, provide medical translation service (if necessary), connect the investigator 
with a Roche Medical Responsible (listed above and/or on the Roche Medical 
Emergency List), and track all calls.  The Emergency Medical Call Center Help Desk will 
be available 24 hours per day, 7 days per week.  
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until completion of the safety follow-up period (Week 28).  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper form Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 


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investigators should be completed and submitted to the Sponsor or its designee
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.  Once the EDC system is available, all information will need to be entered 
and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur post-study are provided in 
Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 60 days after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 


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5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.4.4
Reporting Requirements for Medical Device Complaints
In this study, the prefilled syringe and the physical activity and sleep monitor 
(CentrePoint Insight Watch) are considered medical devices.  
For the prefilled syringe, the investigator must report all complaints to the Sponsor.  The 
investigator should document as much information as possible on the IMP Deviation 
Form, including the product batch number, and forward the form to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event) (refer to the 
pharmacy manual for further details).  If the medical device results in an adverse event 
to the study patient, the event must be reported on the Adverse Event eCRF and 
submitted through the EDC system.  If the event is serious, the Adverse Event eCRF 
must be completed immediately (i.e., no more than 24 hours after learning of the event), 
as outlined in Section 5.4.2.
For complaints and adverse events associated with the CentrePoint Insight Watch, the 
investigator must report all complaints to the sponsor who will forward the complaint to 
the manufacturer. The manufacturer will report all AEs according to the regulatory 
requirements for reporting of medical device-related adverse events (21 CFR 803).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 


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summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (see
Section 4.3.1) if the event is believed to be related to prior study drug treatment.  These 
events should be reported through use of the Adverse Event eCRF.  However, if the 
EDC system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the paper Clinical 
Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the 
fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Omalizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The analysis of complete data from the 24-week treatment period and 4 week safety 
follow-up period will be performed when all patients have either completed the study or 
discontinued the study early, all data from the study are in the database, and the 
database is cleaned and locked.
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP).
6.1
DETERMINATION OF SAMPLE SIZE
The target sample size of 54 is based on feasibility.


 
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The sample size was calculated based on data from Bonini 2019, which suggested that 
an improvement in the endurance time of at least 1 minute 40 seconds from baseline or 
33% is clinically important.  When the sample size is 54, a two-sided 95% confidence 
interval for the mean change from baseline will extend 1 minute 4 seconds from the 
observed mean change, assuming that the standard deviation is known to be 4 minutes 
and the confidence interval is based on the z-distribution (see Table 5).  Assuming a 
10% withdrawal rate, a sample size of 60 will be enrolled. 
Table 5 
Confidence Intervals for Different Standard Deviations with 
Sample Size of 54 
Standard Deviation 
95% Confidence Interval 
4 minutes 
(0 min 36 sec, 2 min 44 sec) 
5 minutes 
(0 min 20 sec, 3 min 0 sec) 
6 minutes 
(0 min 4 sec,   3 min 16 sec) 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Descriptive statistics will be used to evaluate the conduct of the study.  The number of 
patients enrolled will be tabulated by study site in all patients with data.  Patient 
disposition (the number of patients enrolled, treated, and completed) will be tabulated in 
all patients with data.  Premature study drug discontinuation and study discontinuation, 
as well as reasons for discontinuations, will be summarized. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, baseline 
endurance time and other baseline variables used for efficacy endpoints will be 
summarized with descriptive statistics in all patients with data.  Baseline disease 
characteristics will be defined as the last measurement prior to enrollment.  Exposure to 
omalizumab (number of omalizumab treatments and duration of treatment) will be 
summarized in all patients with data. 
6.4 
EFFICACY ANALYSES 
The primary efficacy analysis population will consist of all omalizumab treated patients, 
who have both baseline and at least one post-baseline assessment at Week 12 or Week 
24 and received any dose of omalizumab. 
Change from baseline at Week 24 in the primary endpoint will be summarized 
descriptively. 
Details of the efficacy analyses will be provided in the SAP. 


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6.4.1
Primary Efficacy Endpoint
The primary analysis will assess the effect of omalizumab in the primary endpoint, change 
from baseline at Week 24 in endurance time (minutes).
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Change from baseline at Week 24 in physical activity (min/day)

Change from baseline to Week 24 in dynamic hyperinflation at isotime, as measured 
by inspiratory capacity during CPET at a CWR

Change from baseline at Week 24 in sleep efficiency
For each patient, physical activity and sleep efficiency at baseline, Week 12 and Week 
24 will be calculated as the average of the daily moving time and average of daily sleep 
efficiency during 14 days prior to the baseline visit (enrollment visit), Week 12 visit and 
Week 24 visit.
Each secondary efficacy endpoint will be summarized descriptively.
6.4.3
Exploratory Efficacy Endpoints
Details on analysis of exploratory efficacy endpoints will be provided in the SAP.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all enrolled patients who received any dose 
of study drug. Safety summaries will be presented for all treated patients. 
Safety will be assessed through the summary of adverse events, laboratory test results, 
and vital signs. 
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be coded, and their 
incidence will be summarized. A treatment-emergent adverse event is defined as any 
new adverse event reported or any worsening of an existing condition on or after the first 
dose of study drug. In addition, separate summaries will be generated for serious 
adverse events, deaths, adverse event of special interest, and adverse events leading to 
discontinuation of study drug. 
Vital Signs
Vital signs (pulse rate, systolic and diastolic blood pressure while the patient is in a 
seated position) will be summarized by descriptive statistics by timepoint.


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6.5.1
Planned Interim Analyses
The Sponsor may conduct interim analyses of efficacy/safety. The decision to conduct 
such an interim analysis and its timing will be documented in the Sponsor’s study 
master file prior to the conduct of the interim analysis. 
The Clinical Study Report will also document that such an interim analysis occurred. 
The interim analysis, should it occur, will be performed by the Sponsor study team.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality
checking of the data. Data entered manually will be collected via EDC through use of 
eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 
discrepant data, the Sponsor or contract research organization (CRO) will request data 
clarification from the sites, which the sites will resolve electronically in the EDC system. 
Local laboratory data will be sent to sites and results will be entered into the EDC 
system.
The Sponsor will produce an EDC Study Specification document that describes the
quality checking to be performed on the data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Spirometry and CPET data will be securely transmitted from sites to a central 
spirometry/CPET core lab. Quality control will be conducted to ensure data integrity of 
each record and all data points are acceptable and correct. Data will be securely 
maintained and subsequently securely transferred to the Sponsor. 
Physical activity and sleep monitor data will be automatically captured and securely 
transmitted from each device to a cloud-based server maintained by the digital device 
vendor.  The digital device data will be sent directly to the Sponsor, using the Sponsor’s 
standard procedures to handle and process the electronic transfer of these data.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT REPORTED OUTCOME DATA
eDiary data will be collected through the use of an electronic device provided by a 
vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with U.S. FDA regulations for electronic records (21 CFR 
Part 11).  The data from devices will be transmitted to a secured centralized database 
maintained by the electronic device vendor.
The electronic data will be available for view access only via a secure web portal.  Only 
identified and trained site users may view the data, and their actions will become part of 
the audit trail.  The Sponsor will manage data quality and discrepant data through the 
secured web portal and all actions will become part of the audit trail. System backups 
for data stored by the Sponsor and records retention for the study data will be consistent 
with the Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Genentech will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the applicable laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to 
the individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  


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Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
Application will comply with U.S. FDA regulations and applicable local, state, and federal 
laws.  Studies conducted in the European Union or European Economic Area will comply 
with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, and 
national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of language that may be used by 
some of the participating patients as their primary way of communication.  The Sponsor 
or its designee must review and approve any proposed deviations from the Sponsor's 
sample Informed Consent Forms or any alternate consent forms proposed by the site 
(collectively, the "Consent Forms") before IRB submission.  The final IRBapproved 
Consent Forms must be provided to the Sponsor for health authority submission 
purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 


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each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB by the Principal 
Investigator and reviewed and approved by the IRB before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB.  Investigators are also responsible for 
promptly informing the IRB of any protocol amendments (see Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB.  Investigators may receive written IND safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB, and 
archived in the site's study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB and governmental 
approval.  In addition, at the end of the study, the investigator will receive the patient 
data, including an audit trail containing a complete record of all changes to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 


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processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will be 
responsible for clinical operations management, data management, and medical 
monitoring.
Approximately 20-25 sites in the US will participate in this study and are expected to 
enroll approximately 60 patients.  Enrollment will occur through an IWRS.  
An anaphylaxis adjudication committee will be employed to assess whether a reported 
anaphylaxis event is a true anaphylaxis event (based on Sampson's criteria) and 
whether the reported anaphylaxis event is causally related to omalizumab.  Further 
details will be provided in the Anaphylaxis Adjudication Charter.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 


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an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB and to regulatory authorities in accordance with local regulatory 
requirements.
Approval must be obtained from the IRB and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects 
only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1  
Schedule of Activities 
 
Screening 
Treatment 
Safety  
Follow-Up 
Dosing/ 
Early 
Term. 
Visit 
Day (5 days) 
-28 to -14 
0 
14 28 
42 
56 
70 
84 
98 
112 126 
140 
154 
168 
 
 
Week 
-4 to -2 
0  
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
28 
NA 
Visit 
1 
2 a  
2b b 
3 c 
3.5 
4 
4.5 
5 
5.5 
6 
6.5 
7 
7.5 
8 
8.5 
9 
telephone 
call 
NA 
Informed consent d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Omalizumab administration e 
 
 
 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and asthma history f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Weight g 
x 
x g 
x g 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination h 
x 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
ACQ5 
x 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
CGIC 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
Pre-bronchodilator spirometry i 
 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
CPET (IET) j, k 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1: Schedule of Activities
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Screening
Treatment
Safety 
Follow-Up
Dosing/ 
Early 
Term.
Visit
Day (5 days)
-28 to -14
0
14
28
42
56
70
84
98
112
126
140
154
168
Week
-4 to -2
0
2
4
6
8
10
12
14
16
18
20
22
24
28
NA
Visit
1
2 a
2b b
3 c
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
9
telephone 
call
NA
CPET (CWR) k
x l
x
x m
x m
x n
Distribution of eDiary, physical 
activity/sleep monitor o
x
Collection of eDiary, physical 
activity/sleep monitor
x p
x
x
Morning and Evening Asthma 
Diaries q
x
x
x
Physical activity/sleep monitoring r
x
x
x
x
x
x
x
x
x
x
x
x
x
Total IgE s
x
Hematology
x
x
x
x
x
Chemistry
x
x
x
x
Pregnancy test t
x u
x
x
x
x
x
x
Adverse events v
x v
x v
x v
x v
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Care Utilization
x
x
x
x
x
x
x
x
x
x
x
x
Rescue medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ACQ5Asthma Control Questionnaire 5; ADSDAsthma Daytime Symptom Diary; ANSDAsthma Nighttime Symptom Diary; CGICclinician 
global impression of change; CPETcardiopulmonary exercise testing; IETincremental exercise testing; CWRConstant Work Rate; 
eCRFelectronic Case Report Form; LABAlong-acting beta agonist; LAMAlong-acting muscarinic antagonist; NAnot applicable; 
SABAshort-acting beta agonist; SAMAshort-acting muscarinic antagonist; Term.Termination; USPIUnited States Package Insert.


Appendix 1: Schedule of Activities
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79/Protocol ML41615, Version 3
Notes:  All assessments should be performed within 5 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments 
should be performed prior to dosing, unless otherwise specified.
a The second screening visit will be completed for patients who meet all screening criteria from Visit 1.  
b The purpose of the visit is to establish the CWR that will be used during the study.  Visit 2b is a flexible visit and may be a series of visits 
depending on the preference of the patient and study site.  Up to three visits may be scheduled within the -4 to -2 week. If more than 1 visit is 
needed for Visit 2b, the window may be extended up to 10 days accumulatively.
c Visit 3 should be scheduled at least 14 (5 days) days after Visit 2b to ensure sufficient time to assess compliance with medication, eDiary use,
and wearing of the physical activity and sleep monitor.
d Written informed consent for participation in the study must be obtained before performing any study-specific tests or evaluations.
e Omalizumab administration will be per approved USPI dosing schedule and may be every 2 or 4 weeks.  The last dose for patients who receive 
omalizumab every 4 weeks will be at Week 20 and patients who receive omalizumab every 2 weeks will be at Week 22.
f
Medical history will include clinically significant diseases and surgeries, smoking history, and medication allergies.  In particular, sites should 
record whether the patient has any history of anaphylaxis, cancer, cardiovascular disease, eosinophilic disease, inflammatory or autoimmune 
disease, and parasitic disease.
g If the clinical site and CPET site are separate sites, weight (without shoes) will be captured at the clinical site and provided to the CPET site, 
except at Visits 2 and 2b where the weight can be captured by the CPET site.
h A physical examination, performed at the first screening visit should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.  At subsequent visits (or as clinically indicated), physical 
examinations should be performed as clinically indicated.  
i Pre-bronchodilator spirometry needs to be performed before taking any bronchodilators for specific time periods:

Twice-daily LABA and twice-daily LAMA:  prohibited within 12 hours prior to spirometry 

Once-daily LABA and once-daily LAMA:  prohibited within 24 hours prior to spirometry 

SABA or SAMA:  prohibited within 6 hours prior to spirometry 
j
If an upper respiratory infection or exacerbation occurred, the visit needs to be postponed until the resolution of the event and the patient is 
stable.
k CPET needs to be performed after spirometry.  Bronchodilators will need to be withheld for specific time periods:

Twice-daily LABA and twice-daily LAMA:  prohibited within 12 hours prior to CPET 

Once-daily LABA and once-daily LAMA:  prohibited within 24 hours prior to CPET

SABA or SAMA:  prohibited within 6 hours prior to CPET 
l
A CWR test, determined as 80% of the peak rate during the IET, will be performed to identify an individualized work rate that can be tolerated for 
38 minutes.  If the CWR tolerated time falls outside the 38 minute window, a repeat of the constant work rate testing will need to be performed 
after work rate adjustment.  Up to three CWR tests (one initial and two adjusted) may be performed during screening.  Patients who fail to 


Appendix 1: Schedule of Activities
Xolair (omalizumab)—Genentech, Inc.
80/Protocol ML41615, Version 3
achieve a CWR with an endurance time between 38 minutes will not qualify for the study.  At the discretion of the investigator, the patient may 
rescreen once.  
If two tests are performed on the same day, the time between the tests needs to be at least 90 minutes to allow for recovery. If a SABA or 
SAMA rescue medication is used during or after CWR testing, the patient will need to perform the adjusted work rate test on a separate day. 
m If CPET CWR cannot be performed (e.g., due to patient not withholding bronchodilators, upper respiratory infection, exacerbation), the 
assessment should be done at the next monthly visit.  The event has to be resolved and the patient needs to be stable. 
n A patient who discontinues the study early may be asked to perform a final CPET CWR test.  This is voluntary and can only be performed if there 
are no safety risks. 
o The eDiary and the physical activity and sleep monitor will be distributed at the screening visit at which the CWR is successfully completed 
(CWR that results in endurance time between 38 minutes).  Compliance with the eDiary and the physical activity and sleep monitor will be 
assessed during the 2 weeks prior to enrollment (Day -14-0).
p If a patient screen fails, the eDiary device and the physical activity and sleep monitor will be collected at the baseline visit (enrollment visit).
q The morning asthma and evening asthma diaries are to be completed on an eDiary daily in the morning and evening during the 2 weeks before 
the baseline/enrollment visit and 2 weeks before the Week 12 and Week 24 visits only.  The three measures completed in the morning are: 
ANSD, overnight rescue medication use, and nighttime awakening.  The three measures completed in the evening are: ADSD, daytime rescue 
medication use, and impact on daytime activities. Rescue medication will also need to be reported through the duration of the study.  The 
question on use of daily medication will need to be answered daily only in the 2 weeks before the baseline/enrollment visit.
r
Patients should wear the physical activity and sleep monitor continuously (day and night) on their non-dominant wrist continuously from the time 
it is distributed until it is returned to the study site, as per instructions provided.  Physical activity and sleep data will be collected continuously 
throughout the trial.
s If the Total IgE level is outside the dosing range per USPI dosing table, retesting is allowed once at the physician’s discretion.
t
All women of childbearing potential must have a negative serum pregnancy test during the screening period, prior to initiation of study drug.
u Pregnancy test is performed at the site for all female patients of childbearing potential.  If the urine pregnancy test result is positive, dosing 
should be held and a serum pregnancy test should be performed.  Once the pregnancy is confirmed, the patient must be discontinued from study 
drug.
v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  Adverse events include exacerbations. 


Xolair (omalizumab)—Genentech, Inc.
81/Protocol ML41615, Version 3
Appendix 2
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.
7.
Collect serum samples for immunogenicity testing if clinically indicated.
8.
Ask the patient to return for immunogenicity sample collection at the time of washout 
(approximately 16 weeks after last dose), if appropriate.


Xolair (omalizumab)—Genentech, Inc.
82/Protocol ML41615, Version 3
Appendix 3
Sampson’s Criteria for Diagnosing Potential Cases of 
Anaphylaxis
Anaphylaxis is highly likely when any one of the following three criteria are fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia, syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours):

Infants and children:  low systolic blood pressure (age specific) or greater than 
30% decrease in systolic blood pressure

Adults:  systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline
Source: Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of 
anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006;117:39111.






Appendix 4: Morning Asthma Diary
Xolair (omalizumab)—Genentech, Inc.
85/Protocol ML41615, Version 3
No, I did not take any rescue medication
Yes, I used a rescue inhaler 
How many puffs of a rescue inhaler did you take?  ______ puffs
Yes, I used a nebulizer (breathing machine)
How many times did you use a nebulizer (breathing machine)?  ________ times






Appendix 5: Evening Asthma Diary
Xolair (omalizumab)—Genentech, Inc.
88/Protocol ML41615, Version 3
Rescue Medication Use 
[INSTRUCTION] We would like you to complete this diary every evening before you go to bed for the entire 
duration of the study.
Since you got up this morning, did you take any rescue medication for your asthma symptoms 
(shortness of breath, cough, wheeze, or chest tightness)? 
No, I did not take any rescue medication
Yes, I used a rescue inhaler 
How many puffs of a rescue inhaler did you take?  ______  puffs
Yes, I used a nebulizer (breathing machine)
How many times did you use a nebulizer (breathing machine)?  ________ times
Compliance with Asthma Controller Medication 
[INSTRUCTION] We would like you to complete this diary every night before you go to bed up during the 
two weeks prior to visit 3 (week 0/baseline/randomization)
Did you take your preventive inhaler (medications) today?
Yes
No


Xolair (omalizumab)—Genentech, Inc.
89/Protocol ML41615, Version 3
Appendix 6
Asthma Control Questionnaire 5 (ACQ5)


ACQ-5 - Canada/English - Mapi. 
ACQ-5_AU1.0_eng-CAori.doc 
ASTHMA CONTROL 
QUESTIONNAIRE (ACQ) 
(SYMPTOMS ONLY) 
© 2002 
QOL TECHNOLOGIES LTD. 
For further information: 
Elizabeth Juniper, MCSP, MSc 
Professor 
20 Marcuse Fields 
Bosham, West Sussex 
PO18 8NA, England 
Telephone: +44 1243 572124 
Fax: +44 1243 573680 
E-mail: juniper@qoltech.co.uk
Web: http://www.qoltech.co.uk
©
The Asthma Control Questionnaire (ACQ) is copyrighted and all rights are 
reserved. No part of this questionnaire may be sold, modified or 
reproduced in any form without the express permission of Elizabeth 
Juniper on behalf of QOL Technologies Limited 
DECEMBER 2002 
™
This translation has been made possible through 
a grant from 
Translated by Mapi 
Senior Translator: 
Xolair (omalizumab)—Genentech, Inc. 
90/Protocol ML41615, Version 3


ASTHMA CONTROL QUESTIONNAIRE© 
PATIENT ID: 
(LANGUAGE VERSION FOR COUNTRY) 
DATE: 
Page 1 of 1 
ACQ-5 - Canada/English - Mapi. 
ACQ-5_AU1.0_eng-CAori.doc 
Please answer questions 1 - 5. 
Circle the number of the response that best describes how you have been during the past week. 
1.
On average, during the past week,
how often were you woken by your
asthma during the night?
0 
Never 
1 
Hardly ever 
2 
A few times 
3 
Several times 
4 
Many times 
5 
A great many times 
6 
Unable to sleep because of asthma 
2.
On average, during the past week,
how bad were your asthma symptoms
when you woke up in the morning?
0 
No symptoms 
1 
Very mild symptoms 
2 
Mild symptoms 
3 
Moderate symptoms 
4 
Quite severe symptoms 
5 
Severe symptoms 
6 
Very severe symptoms 
3.
In general, during the past week, how
limited were you in your activities
because of your asthma?
0 
Not limited at all 
1 
Very slightly limited 
2 
Slightly limited 
3 
Moderately limited 
4 
Very limited 
5 
Extremely limited 
6 
Totally limited 
4.
In general, during the past week, how
much shortness of breath did you
experience because of your asthma?
0 
None 
1 
A very little 
2 
A little 
3 
A moderate amount 
4 
Quite a lot 
5 
A great deal 
6 
A very great deal 
5.
In general, during the past week, how
much of the time did you wheeze?
0 
Not at all 
1 
Hardly any of the time 
2 
A little of the time 
3 
A moderate amount of the time 
4 
A lot of the time 
5 
Most of the time 
6 
All the time 
Xolair (omalizumab)—Genentech, Inc. 
91/Protocol ML41615, Version 3


Xolair (omalizumab)—Genentech, Inc. 
92/Protocol ML41615, Version 3
Appendix 7
Clinician Global Impression of Change (CGIC)
How would you rate the change in the subject’s asthma symptoms since starting 
taking the study drug?
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse




Omalizumab—Genentech, Inc. 
94/Protocol ML41615, Version 3
Appendix 9
Examples of Estimated Equipotent Daily Doses of Inhaled Corticosteroids in the United States
The following table lists inhaled corticosteroids commonly used in the United States at the time of protocol publication, to serve as 
examples of eligible corticosteroid doses.  
Generic ICS/combination Name
Formulation
Brand Name
ICS Dose 
(g)
Dose (g) equivalent 
to 500 g/d FP a
Dose (g) equivalent 
to 1000 g/d FP
Beclomethasone dipropionate
HFA-MDI
Qvar
40,80
480b
960
Budesonide
DPI
Pulmicort Flexhaler
90, 180
720
1440
Budesonide
DPI
Pulmicort Turbuhaler
200
800
1600
Budesonide/formoterol
HFA-MDI
Symbicort
80, 160
640
1280
Ciclesonide
HFA-MDI
Alvesco
80, 160
320
640
Fluticasone propionate/ salmeterol
HFA-MDI
AdvairHFA
45, 115, 230
460
920
Fluticasone propionate
HFA-MDI
FloventHFA
44, 110, 220
440
880
Fluticasone propionate/ salmeterol
DPI
Advair Diskus
100, 250, 500
500
1000
Fluticasone propionate
DPI
Flovent Diskus
50, 100, 250
500
1000
Fluticasone furoate
DPI
Breo Ellipta
100, 200
100
200c
Fluticasone furoate
DPI
Arnuity Ellipta
100, 200
100
200c
Mometasone furoate/ formoterol
HFA-MDI
Dulera
100, 200
400
800
Mometasone furoate
DPI
Asmanex Twisthaler
110, 220
440
880
DPIdry powder inhaler; FPfluticasone propionate; HFAhydrofluoroalkane; MDImetered dose inhaler.
Note:  Dose information is intended as a guide when determining eligibility for the studies and is not intended as a prescribing guide. 
a GINA 2015.
b EPR3 2007.
c Busse et al. 2012.