XTEND-CIU (Xolair Treatment Efficacy of Longer Duration in Chronic Idiopathic Urticaria): A Phase IV, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Omalizumab Through 48 Weeks in Patients With Chronic Idiopathic Urticaria
Phase: PHASE4
Conditions: Urticaria
Sponsor: Genentech, Inc.

 
Official Title: 
XTEND-CIU (Xolair Treatment Efficacy of Longer Duration in Chronic 
Idiopathic Urticaria): A Phase IV, Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety 
of Omalizumab through 48 Weeks in Patients With Chronic Idiopathic 
Urticaria 
NCT Number: 
NCT02392624 
Document Dates: 
Protocol Version 2: 09-May-16 
Protocol Version 1: 17-Dec-14 
 
 

 
Title
09-May-2016 18:24:04
Date and Time (UTC)
Clinical Science Leader
Approver's Name
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The information contained in this document, especially any unpublished data, is the property of 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. 
 
Omalizumab—Genentech, Inc. 
Protocol ML29510, Version 2 
PROTOCOL 
TITLE: 
XTEND-CIU (XOLAIR TREATMENT EFFICACY OF 
LONGER DURATION IN CHRONIC IDIOPATHIC 
URTICARIA):  A PHASE IV, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF OMALIZUMAB 
THROUGH 48 WEEKS IN PATIENTS WITH 
CHRONIC IDIOPATHIC URTICARIA 
PROTOCOL NUMBER: ML29510 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
101,612 
TEST PRODUCT: 
Omalizumab (RO5489789) 
MEDICAL MONITOR: 
 M.D., M.S. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  17 December 2014 
DATE AMENDED: 
Version 2:  See electronic date stamp below 

Omalizumab—Genentech, Inc. 
2/Protocol ML29510, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized below: 
• 
The Medical Monitor has been changed to 
, M.D., M.S., and contact 
information has been updated (cover pages and Section 5.4.3). 
• 
Text has been added to clarify that, in order to be eligible for treatment during the 
open-label period, patients cannot have any missing electronic diary (eDiary) entries 
in the 7 days prior to baseline.  It was also clarified that if a patient fails screening 
due to missed eDiary entries during this period, the patient will be permitted to 
rescreen once (Section 3.1). 
• 
In order to be eligible for randomization, the patient must achieve an Urticaria 
Activity Score over 7 days (UAS7) ≤ 6 in the final 2 weeks of the open-label 
treatment period, which has been clarified to be the 2 consecutive weeks 
immediately prior to randomization (instead of Weeks 23 and 24 specifically).  
These 2 weeks are still scheduled to occur during Weeks 23 and 24, but slight 
variation has been allowed to accommodate for patient scheduling.  Furthermore, it 
has been clarified that randomization is not permitted after Day 190 from baseline 
(Sections 3.1 and 4.2; Appendices 1 and 2).  
• 
All pharmacokinetic and pharmacodynamic (PD) assessments have been removed, 
with the exception of the PD assessment of total serum immunoglobulin E (IgE) 
level measured at screening (pre-dose), as all other assessments are no longer 
considered necessary for the study based on further review of the data (Sections 
3.1, 3.4.4, 4.2, 4.5.4, and 6.6; Appendices 1, 2, and 3). 
• 
It has been clarified that H1 antihistamine treatment permitted in this study must be 
non-sedating (Section 4.1.1).  In addition, text has been added to state that, if more 
than one H1 antihistamine is used during the study, the combined total dose cannot 
exceed four times the approved dose of H1 antihistamines.  Furthermore, the 
dosages of H1 antihistamines, H2 blockers, and leukotriene receptor antagonists 
should remain stable throughout the study (Section 4.4.1).   
• 
The independent Data Monitoring Committee and the independent Data 
Coordinating Center have been removed, as an independent panel to adjudicate 
anaphylaxis events is no longer being used for the study.  Instead, a single external 
adjudicator will be used.  In addition, text has been added to clarify that, in order to 
minimize bias, study site personnel responsible for reconstituting and/or 
administering study drugs will not be permitted to conduct any safety or efficacy 
evaluations during or after the randomization period (Week 24 to Week 60), even if 
the patient has been transitioned back to open-label treatment (Sections 4.2, 4.6.3, 
and 5.1). 
• 
The stipulation that patients who receive any excluded therapy after randomization 
will be discontinued from study treatment has been removed.  This deletion has 
been made in order to minimize potential biases that could occur from removing 
patients from the study after randomization (Section 4.4.2). 

Omalizumab—Genentech, Inc. 
3/Protocol ML29510, Version 2 
• 
The window for the screening period has been extended from 14 to 20 days long 
instead of 12 to 18 days long.  Additionally, it has been clarified that the Day −14 
visit should be conducted 20 to 14 days prior to baseline (instead of 18 to 12 days 
prior to baseline) (Appendix 1). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

Omalizumab—Genentech, Inc. 
4/Protocol ML29510, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.1:  DESCRIPTION OF STUDY 
Patients will have the 2-week screening period to establish their eligibility for the study 
and baseline symptom scores.  For the duration of the screening period, patients must 
maintain stable doses of their pre-screening H1 antihistamine treatment.  To be eligible 
for treatment during the open-label treatment period, patients must have: 
• 
No missing eDiary entries during the 7 days prior to baseline (Note:  If a patient 
fails screening due to missed eDiary entries during this 7-day period, the patient is 
permitted to rescreen once.);  
• 
A UAS7 symptom score of ≥ 16 during the 7 days prior to baseline (equivalent to 
moderate to severe CIU symptoms for at least 4 out of 7 days in a week); and  
• 
A weekly itch score (a component of the UAS7) of ≥ 8 during the 7 days prior to 
baseline. 
 
… Patients will be eligible for randomization if they meet both of the following criteria: 
• 
Achieve UAS7 ≤ 6 in the final 2 weeks of the open-label treatment period, which are 
the 2 consecutive weeks immediately prior to randomization.  (These final 2 weeks 
are scheduled to occur during Week 23 and Week 24 but may vary somewhat 
depending on patient scheduling.) 
AND 
• 
Comply with omalizumab dosing for at least 5 out of the 6 planned doses, including 
a dosage at Week 20, during the initial 24-week open-label treatment period 
(i.e., patients may only be randomized if they have missed at most one dosage of 
omalizumab during the initial open-label treatment period AND did not miss their 
Week 20 dosage) 
 
Patients who meet the criteria for randomization will be randomized at a ratio of 3:2 
(omalizumab:placebo).  Randomization to treatment groups will be stratified by UAS7 at 
the point of randomization (UAS 7 = 0 vs. UAS7 > 0) and study site.  Efficacy, and safety, 
pharmacokinetic (PK), and pharmacodynamic (PD) data will be collected.  Subsequent 
to randomization, patients will continue to be evaluated twice daily using the eDiary for 
weekly calculation of UAS7, which includes a weekly itch score. 
Patients who do not meet the criteria for randomization (e.g., because of non-response 
to omalizumab during the open-label treatment period) should return for a final follow-up 
visit 12 weeks after Visit 9 (the Week 24 visit), which will include a blood draw for 

Omalizumab—Genentech, Inc. 
5/Protocol ML29510, Version 2 
PK/PD measurement, and assessments for adverse events and PROs (see Appendix 1).  
Patients will not be required to complete the eDiary during this 12-week period. 
After completion of the randomization period (end of Week 48), all patients will enter a 
12-week follow-up period to allow for further characterization of the pharmacokinetics 
and pharmacodynamics of omalizumab and collection of additional efficacy and safety 
data.  Patients will continue to visit the study site at 4-week intervals. ... 
FIGURE 2:  Study Schema 
Figure 2 has been revised to reflect changes to the protocol. 
SECTION 3.4.4:  Pharmacokinetic/Pharmacodynamic Outcome Measures 
Serum total omalizumab, and totalTotal and free serum IgE concentrationslevel will be 
measured at screening (pre-dose).: 
• 
Baseline (pre dose), Week 24 (pre dose), Week 48, and Week 60 or early 
termination 
• 
The time of discontinuation from blinded treatment (i.e., start of open label treatment 
post randomization [pre dose]), among patients who make the post randomization 
transition to open label omalizumab 
• 
The end of follow up (i.e., 12 weeks after stopping the initial 24 week course of 
open label omalizumab), among patients not responding to the initial 24 week 
course of open label omalizumab  
 
SECTION 4.1.1:  Inclusion Criteria 
• 
Diagnosis of CIU refractory to H1 antihistamines at baseline, as defined by all of the 
following: 
− 
Patients must have been on a non-sedating H1 antihistamine treatment 
specified in Section 4.4.1 (up to four times the approved dose) for CIU for at 
least the 3 consecutive days immediately prior to the Day −14 screening visit 
and must document current use on the day of the initial screening visit. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use two adequate methods of contraception, including at least 
one method with a failure rate of <1% per year, during the treatment period and for 
at least 4 months after the last dose of study drug 
– 
Abstinence is only acceptable if it is in line with 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. 
– 
Barrier methods must always be supplemented with the use of a spermicide. 
 
SECTION 4.1.2:  Exclusion Criteria 
• 
Pregnant or lactating, or intending to become pregnant during the study 

Omalizumab—Genentech, Inc. 
6/Protocol ML29510, Version 2 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result within 3 days prior to initiation of study drug. 
• 
Nursing women or women of childbearing potential, defined as all women 
physiologically capable of becoming pregnant, including women whose career, 
lifestyle, or sexual orientation precludes intercourse with a male partner and women 
whose partners have been sterilized by vasectomy or other means, UNLESS they 
meet the following definition of post menopausal:  12 months of natural 
(spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum 
follicle stimulating hormone (FSH) levels > 40 mIU/mL or 6 weeks post surgical 
bilateral oophorectomy (with or without hysterectomy) or hysterectomy OR are using 
one or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, 
oral), and double barrier methods (any double combination of:  intrauterine device, 
male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap)  
 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
At the Week 24 visit, patients who completed the 24-week open-label treatment period 
and have met the criteria for response (UAS7 ≤ 6 for both Weeks 23 and 24 in the 
2 consecutive weeks immediately prior to randomization) and also met the omalizumab 
compliance criteria (5 out of 6 planned doses, including a dosage at Week 20) will be 
randomized to 300 mg omalizumab or placebo at an approximately 3:2 ratio using an 
interactive voice and web response system (IxRS).  Patients, all study personnel, the 
designated evaluating physician(s), and the Sponsor and its agents (with the exception 
of the IxRS service provider, the remote unblinded monitoring staff, the unblinding 
statistician, and the unblinded pharmacists at the sites, the independent Data Monitoring 
Committee [iDMC] members, and the independent Data Coordinating Center [iDCC] 
personnel) will be blinded to treatment assignment.  Only the IxRS provider, and the 
Sponsor’s unblinding statistician, and the iDCC statistician will have access to the 
unblinding code during the study.    
… To minimize the risk of potential bias, study site personnel who are responsible for 
reconstituting and/or administering study drugs will not be permitted to conduct any 
safety or efficacy evaluations during or after the randomization period (Week 24 to 
Week 60), even if the patient has been transitioned back to open-label omalizumab.  
Additionally, personnel administering study drug should apply bandages over injections 
sites to help maintain blinding.  To minimize risk of potential bias arising from access 
to laboratory results that could potentially unblind treatment assignments (e.g., free IgE 
levels and serum omalizumab concentrations), the Sponsor and sites will be restricted 
from accessing such laboratory results.  
SECTION 4.4.1:  Permitted Therapy 
The long-acting H1 antihistamines, H2 blockers, and LTRAs allowed during the study 
are as follows.  Note that the H1 antihistamines may be used at up to four times the 
approved dose listed below; however, if more than one H1 antihistamine is used, the 

Omalizumab—Genentech, Inc. 
7/Protocol ML29510, Version 2 
combined total dose cannot exceed four times an approved dose of H1 antihistamines.  
For example, a patient receiving loratadine 20 mg QD would be permitted to also 
receive cetirizine at up to 20 mg QD.  The dosages of H1 antihistamines, H2 blockers, 
and LTRAs should remain stable throughout the duration of the study.   
All patients will be allowed to take study-defined H1 antihistamine medications at 
up to four times the approved dose, H2 blockers, and/or LTRAs during the screening, 
treatment, and follow-up periods.  Patients should remain on a stable H1 antihistamine, 
H2 blocker, and/or LTRA treatment regimen throughout the randomization periodstudy 
(Day −14 to Week 60Week 24 to Week 48).  Diphenhydramine (25 mg) may also be 
used on an as-needed basis (maximum three times/day) during the screening, treatment, 
and follow-up periods. 
SECTION 4.4.2:  Prohibited Therapy 
Patients who receive any excluded therapy during screening should be considered a 
screen failure.  Patients who receive any excluded therapy after randomization will be 
discontinued from study treatment; if a patient has received at least one dose of 
omalizumab following enrollment, the patient should enter the 12 week follow up period 
(see Appendix 2).   
SECTION 4.5.5:  Laboratory Assessments 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  Please refer to the laboratory manual for additional details on central 
laboratory assessments and sample handling.  The assessments listed below will be 
performed at a central laboratory or at Genentech: 
• 
PK assessments:  serum total omalizumab 
• 
PD assessments:  total serum IgE and free serum IgE levels at screening (pre-dose) 
 
SECTION 4.6.3:  Study and Site 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: 
• 
In addition, the Sponsor may decide to discontinue the study based on the iDMC 
recommendation. 
 
SECTION 5.1:  SAFETY PLAN 
An iDMC will review blinded and unblinded safety data provided by an iDCC every 
6 months for the duration of the study. 
SECTION 5.4.3:  Medical Contact 
Genentech Medical Monitor:  
, M.D., M.S. 
Genentech, Inc. 
Telephone No.: 
 
 

Omalizumab—Genentech, Inc. 
8/Protocol ML29510, Version 2 
SECTION 6.6:  PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSIES 
Serum total omalizumab, and tTotal and free serum IgE concentration level at screening 
(pre-dose) versus time data will be tabulated by treatment group and summarized using 
descriptive statistics (e.g., mean, standard deviation, minimum, and maximum).  
Additional PK and PD analyses may be conducted as appropriate. 
SECTION 7.1:  DATA QUALITY ASSURANCE 
Paper PRO questionnaires will be faxed, scanned, or couriered from the site to the data 
entry center.  Scanned paper PROs will be transferred via a secure email system. 
APPENDIX 1:  Schedule of Assessments 
Appendix 1 has been revised to reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Assessments for Double-Blind Randomization 
Period and Follow-Up Period 
Appendix 2 has been revised to reflect the changes to the protocol. 
APPENDIX 3:  Schedule of Assessments for Patients Who Transition to 
Open-Label Omalizumab After Randomization 
Appendix 3 has been revised to reflect the changes to the protocol. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 
 

Omalizumab—Genentech, Inc. 
9/Protocol ML29510, Version 2 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15 
PROTOCOL SYNOPSIS .................................................................................... 16 
1. 
BACKGROUND .......................................................................................... 26 
1.1 
Chronic Idiopathic Urticaria.................................................... 26 
1.2 
Omalizumab .......................................................................... 26 
1.2.1 
Clinical Experience with Omalizumab in Patients 
with CIU................................................................................. 27 
1.2.2 
Summary of Omalizumab Clinical Efficacy in 
Patients with CIU................................................................... 28 
1.2.3 
Summary of Omalizumab Clinical Safety in 
Patients with CIU................................................................... 30 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 30 
2. 
OBJECTIVES.............................................................................................. 31 
2.1 
Primary Objective .................................................................. 31 
2.2 
Secondary Objectives............................................................ 31 
2.3 
Exploratory Objectives........................................................... 31 
3. 
STUDY DESIGN ......................................................................................... 32 
3.1 
Description of Study .............................................................. 32 
3.2 
End of Study.......................................................................... 37 
3.3 
Rationale for Study Design.................................................... 37 
3.3.1 
Omalizumab Dose and Schedule .......................................... 38 
3.4 
Outcome Measures ............................................................... 38 
3.4.1 
Primary Efficacy Outcome Measure ...................................... 38 
3.4.2 
Secondary Efficacy Outcome Measures................................ 38 
3.4.3 
Safety Outcome Measures .................................................... 39 
3.4.4 
Pharmacodynamic Outcome Measure .................................. 39 
3.4.5 
Exploratory Outcome Measures ............................................ 39 
4. 
MATERIALS AND METHODS .................................................................... 40 
4.1 
Patients.................................................................................. 40 
4.1.1 
Inclusion Criteria.................................................................... 40 
4.1.2 
Exclusion Criteria................................................................... 41 

Omalizumab—Genentech, Inc. 
10/Protocol ML29510, Version 2 
4.2 
Method of Treatment Assignment and Blinding..................... 42 
4.3 
Study Treatment.................................................................... 43 
4.3.1 
Formulation............................................................................ 43 
4.3.2 
Dosage, Administration, and Storage .................................... 43 
4.3.3 
Investigational Medicinal Product Accountability ................... 44 
4.3.4 
Post-Trial Access to Omalizumab.......................................... 45 
4.4 
Concomitant Therapy ............................................................ 45 
4.4.1 
Permitted Therapy ................................................................. 45 
4.4.2 
Prohibited Therapy ................................................................ 46 
4.5 
Study Assessments ............................................................... 46 
4.5.1 
Informed Consent Forms and Screening Log........................ 46 
4.5.2 
Medical History and Demographic Data ................................ 47 
4.5.3 
Vital Signs.............................................................................. 47 
4.5.4 
Physical Examinations........................................................... 47 
4.5.5 
Laboratory Assessments ....................................................... 47 
4.5.6 
Exploratory Blood RNA and Blood Biomarker 
Samples................................................................................. 48 
4.5.7 
Patient eDiary........................................................................ 48 
4.5.8 
Patient-Reported Outcomes .................................................. 49 
4.5.9 
Clinician-Reported Outcomes................................................ 51 
4.5.10 
Samples for Roche Clinical Repository.................................. 51 
4.5.10.1 
Overview of the Roche Clinical Repository............................ 51 
4.5.10.2 
Sample Collection.................................................................. 52 
4.5.10.3 
Confidentiality........................................................................ 52 
4.5.10.4 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 53 
4.5.10.5 
Withdrawal from the Roche Clinical Repository..................... 53 
4.5.10.6 
Monitoring and Oversight....................................................... 54 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 54 
4.6.1 
Patient Discontinuation.......................................................... 54 
4.6.2 
Study Treatment Discontinuation........................................... 54 
4.6.3 
Study and Site Discontinuation.............................................. 54 
5. 
ASSESSMENT OF SAFETY....................................................................... 55 

Omalizumab—Genentech, Inc. 
11/Protocol ML29510, Version 2 
5.1 
Safety Plan ............................................................................ 55 
5.1.1 
Anaphylaxis ........................................................................... 56 
5.1.2 
Clinical Trial Experience with Omalizumab in 
Patients with CIU................................................................... 57 
5.1.3 
Management of Specific Adverse Events .............................. 61 
5.2 
Safety Parameters and Definitions ........................................ 62 
5.2.1 
Adverse Events ..................................................................... 62 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 62 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 63 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 64 
5.3.1 
Adverse Event Reporting Period ........................................... 64 
5.3.2 
Eliciting Adverse Event Information ....................................... 64 
5.3.3 
Assessment of Severity of Adverse Events ........................... 65 
5.3.4 
Assessment of Causality of Adverse Events ......................... 65 
5.3.5 
Procedures for Recording Adverse Events............................ 66 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 66 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 67 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 67 
5.3.5.4 
Abnormal Laboratory Values ................................................. 67 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 68 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 69 
5.3.5.7 
Deaths ................................................................................... 69 
5.3.5.8 
Preexisting Medical Conditions.............................................. 70 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic 
Idiopathic Urticaria................................................................. 70 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 70 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 71 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 71 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 71 

Omalizumab—Genentech, Inc. 
12/Protocol ML29510, Version 2 
5.4.1 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 72 
5.4.1.1 
Events That Occur prior to Study Drug Initiation.................... 72 
5.4.1.2 
Events That Occur after Study Drug Initiation........................ 72 
5.4.2 
Reporting Requirements for Pregnancies.............................. 72 
5.4.2.1 
Pregnancies in Female Patients............................................ 72 
5.4.2.2 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 73 
5.4.3 
Medical Contact..................................................................... 73 
5.5 
Follow-Up of Patients after Adverse Events .......................... 73 
5.5.1 
Investigator Follow-Up........................................................... 73 
5.5.2 
Sponsor Follow-Up ................................................................ 74 
5.6 
Post-Study Adverse Events................................................... 74 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 74 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 74 
6.1 
Determination of Sample Size ............................................... 74 
6.2 
Summaries of Conduct of Study............................................ 75 
6.3 
Summaries of Treatment Group Comparability ..................... 75 
6.4 
Efficacy Analyses .................................................................. 75 
6.4.1 
Missing Data for Efficacy Analyses........................................ 76 
6.4.2 
Primary Efficacy Endpoint...................................................... 76 
6.4.3 
Secondary Efficacy Endpoints............................................... 76 
6.5 
Safety Analyses..................................................................... 77 
6.6 
Pharmacodynamic AnalysIs .................................................. 77 
6.7 
Exploratory Analyses............................................................. 77 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 77 
7.1 
Data Quality Assurance......................................................... 77 
7.2 
Electronic Case Report Forms............................................... 78 
7.3 
Electronic Patient-Reported Outcome Data........................... 78 
7.4 
Source Data Documentation.................................................. 78 
7.5 
Use of Computerized Systems .............................................. 79 

Omalizumab—Genentech, Inc. 
13/Protocol ML29510, Version 2 
7.6 
Retention of Records............................................................. 79 
8. 
ETHICAL CONSIDERATIONS.................................................................... 80 
8.1 
Compliance with Laws and Regulations ................................ 80 
8.2 
Informed Consent .................................................................. 80 
8.3 
Institutional Review Board or Ethics Committee.................... 81 
8.4 
Confidentiality........................................................................ 82 
8.5 
Financial Disclosure .............................................................. 82 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 82 
9.1 
Study Documentation ............................................................ 82 
9.2 
Protocol Deviations................................................................ 83 
9.3 
Site Inspections ..................................................................... 83 
9.4 
Administrative Structure......................................................... 83 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 83 
9.6 
Protocol Amendments ........................................................... 84 
10. REFERENCES ........................................................................................... 85 
 
 
LIST OF TABLES 
Table 1 
Twice Daily Assessment of Disease Activity in Patients with 
Chronic Idiopathic Urticaria (Urticaria Activity Score).................. 49 
Table 2 
Adverse Reactions Occurring in ≥ 2% in Omalizumab-
Treated Patients and More Frequently than in Patients 
Treated with Placebo (Day 1 to Week 12) in CIU Trials.............. 58 
Table 3 
Guidelines for Management of Specific Adverse Events ............ 61 
Table 4 
Adverse Event Severity Grading Scale ....................................... 65 
Table 5 
Causal Attribution Guidance ....................................................... 66 
 
 
LIST OF FIGURES 
Figure 1 
Change from Baseline in Mean UAS7:  Study Q4881g 
(ASTERIA I; Placebo versus 24 Weeks Omalizumab)................ 29 
Figure 2 
Study Schema............................................................................. 35 
 

Omalizumab—Genentech, Inc. 
14/Protocol ML29510, Version 2 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments for Screening and Open-Label 
Treatment Period ........................................................................ 87 
Appendix 2 
Schedule of Assessments for Double-Blind Randomization 
Period and Follow-Up Period ...................................................... 91 
Appendix 3 
Schedule of Assessments for Patients Who Transition to 
Open-Label Omalizumab after Randomization ........................... 94 
Appendix 4 
Study Drug Preparation and Administration................................ 97 
Appendix 5 
Study Drug Dosing and Scheduling Table .................................. 99 
Appendix 6 
Patient Electronic Diary (eDiary)............................................... 100 
Appendix 7 
Dermatology Life Quality Index (DLQI) ..................................... 105 
Appendix 8 
Urticaria Control Test (UCT) ..................................................... 106 
Appendix 9 
Urticaria Activity and Impact Measure (U-AIM) ......................... 107 
Appendix 10 Insomnia Severity Index (ISI).................................................... 110 
Appendix 11 Generalized Anxiety Disorder 7 Item (GAD-7) Scale ................ 112 
Appendix 12 Work Productivity and Activity Impairment Questionnaire:  
Chronic Urticaria V2.0 (WPAI:CU) ............................................ 113 
Appendix 13 Patient Global Impression of Change (P-GIC) Scale ................ 115 
Appendix 14 In-Clinic Urticaria Activity Score (IC-UAS) (Max 6) ................... 116 
Appendix 15 Clinician Global Impression of Change (C-GIC) Scale.............. 117 
Appendix 16 Sampson’s Criteria of Anaphylaxis ........................................... 118 

Omalizumab—Genentech, Inc. 
15/Protocol ML29510, Version 2 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
XTEND-CIU (XOLAIR TREATMENT EFFICACY OF 
LONGER DURATION IN CHRONIC IDIOPATHIC 
URTICARIA):  A PHASE IV, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF OMALIZUMAB 
THROUGH 48 WEEKS IN PATIENTS WITH 
CHRONIC IDIOPATHIC URTICARIA 
PROTOCOL NUMBER: ML29510 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
101,612 
TEST PRODUCT: 
Omalizumab (RO5489789) 
MEDICAL MONITOR: 
 M.D., M.S. 
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 as 
instructed by the CRO. 
 

 
Omalizumab—Genentech, Inc. 
16/Protocol ML29510, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
XTEND-CIU (XOLAIR TREATMENT EFFICACY OF LONGER 
DURATION IN CHRONIC IDIOPATHIC URTICARIA):  A PHASE IV, 
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF OMALIZUMAB THROUGH 48 WEEKS IN PATIENTS 
WITH CHRONIC IDIOPATHIC URTICARIA 
PROTOCOL NUMBER: 
ML29510 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
101,612 
TEST PRODUCT: 
Omalizumab (RO5489789) 
PHASE: 
IV 
INDICATION: 
Chronic idiopathic urticaria 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Primary Objective 
The primary objective for this study is to evaluate the level of control of chronic idiopathic 
urticaria (CIU) symptoms through 48 weeks, among patients continuing omalizumab as 
compared to those receiving placebo after an initial 24 weeks of omalizumab treatment. 
Secondary Objectives 
The secondary objectives for this study are as follows: 
• 
To evaluate the response to retreatment with omalizumab in patients with CIU who have 
responded to omalizumab, but experienced recurrence or clinical worsening of disease after 
withdrawal of therapy  
• 
To evaluate whether patients who have achieved response to omalizumab after 24 weeks 
of therapy demonstrate similar levels of response after 48 weeks of therapy 
• 
To evaluate the safety of omalizumab therapy through 48 weeks in patients with CIU 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To compare the level of control of CIU symptoms, over 12 weeks after withdrawal of 
omalizumab, subsequent to completing 48 weeks versus 24 weeks of omalizumab therapy, 
among patients with CIU who have responded to omalizumab therapy 
• 
To obtain additional data on patient-reported outcome (PRO) response to omalizumab 
 
Study Design 
Description of Study 
This is a Phase IV, multicenter, randomized, double-blind, placebo controlled study to evaluate 
the efficacy and safety of subcutaneous (SC) omalizumab through 48 weeks as an add-on 
therapy for the treatment of refractory CIU in adolescent and adult patients (12−75 years of age) 

 
Omalizumab—Genentech, Inc. 
17/Protocol ML29510, Version 2 
who remain symptomatic despite standard H1 antihistamine treatment (including doses up to 
four times above the approved dose), H2 blockers, and/or leukotriene receptor antagonists 
(LTRAs).  The study will enroll approximately 207 patients at approximately 40 study sites in 
the U.S. 
The study will consist of the following study periods with a total duration of 62 weeks 
(see Figure 2): 
• 
Screening Period:  Day  −14 to Baseline (Week −2 to Baseline) 
• 
Open-Label Treatment Period:  Day 1 to Day 168 (Baseline to Week 24) 
• 
Double-Blind Randomization Period:  Day 169 to Day 336 (Week 24 to Week 48) 
• 
Follow-Up Period:  Day 337 to Day 420 (Week 48 to end of Week 60) 
 
The screening period will consist of visits at Day −14 and Day −7.  Day 1 (baseline) will mark 
the commencement of the 24-week open-label treatment period.  Patients must meet all of the 
following criteria prior to receiving treatment in the open-label treatment period: 
• 
Non-electronic diary-based Urticaria Activity Score (UAS) ≥ 4 established in the clinic 
(i.e., in-clinic UAS [IC-UAS]) based on the patient’s condition over 12 hours prior to either 
Day −14, Day −7, or Day 1 despite being on H1 antihistamine therapy 
• 
Use of H1 antihistamine treatment (up to four times the approved dose) for CIU at Day −14 
and for at least the 3 consecutive days immediately prior to Day −14 (see Section 4.4.1 for 
a list of H1 antihistamines available for use in this study) 
• 
Willing and able to complete a symptom electronic diary (eDiary), also referred to as the 
Urticaria Patient Daily Diary (UPDD), twice daily throughout the screening period to 
establish the patient’s UAS7  
 
Patients will have the 2-week screening period to establish their eligibility for the study and 
baseline symptom scores.  For the duration of the screening period, patients must maintain 
stable doses of their pre-screening H1 antihistamine treatment.  To be eligible for treatment 
during the open-label treatment period, patients must have:  
• 
No missing eDiary entries during the 7 days prior to baseline (Note:  If a patient fails 
screening due to missed eDiary entries during this 7-day period, the patient is permitted 
to rescreen once.); 
• 
A UAS7 symptom score of ≥ 16 during the 7 days prior to baseline (equivalent to moderate 
to severe CIU symptoms for at least 4 out of 7 days in a week); and  
• 
A weekly itch score (a component of the UAS7) of ≥ 8 during the 7 days prior to baseline. 
 
Only in exceptional circumstances, when information concerning eligibility is outstanding 
(e.g., pending laboratory data), will a screening period longer than 2 weeks be permitted.  
Patients may be re-screened upon approval from the Medical Monitor.  Circumstances that may 
permit re-screening include, but are not limited to, an IC-UAS or laboratory test results that do 
not meet eligibility requirements.  
On Day 1, eligible patients will begin open-label omalizumab 300 mg SC every 4 weeks (Q4W) 
and will continue on treatment during the 24-week open-label treatment period.  During this 
period, patients will continue reporting twice daily their UAS-related symptoms through the 
eDiary, necessary for the weekly calculation of UAS7 (which is based on the last 7 days of 
symptoms).  At the end of the open-label treatment period, patients who have responded to 
omalizumab will be randomized in a double-blinded fashion to either continue omalizumab or to 
transition to placebo for a further 24 weeks.  Patients will be eligible for randomization if they 
meet both of the following criteria: 
• 
Achieve UAS7 ≤ 6 in the final 2 weeks of the open-label treatment period, which are the 
2 consecutive weeks immediately prior to randomization.  (These final 2 weeks are 
scheduled to occur during Week 23 and Week 24 but may vary somewhat depending on 
patient scheduling.) 
 
AND 

 
Omalizumab—Genentech, Inc. 
18/Protocol ML29510, Version 2 
• 
Comply with omalizumab dosing for at least 5 out of the 6 planned doses, including a 
dosage at Week 20, during the initial 24-week open-label treatment period (i.e., patients 
may only be randomized if they have missed at most one dosage of omalizumab during the 
initial open-label treatment period AND did not miss their Week 20 dosage) 
 
Patients who meet the criteria for randomization will be randomized at a ratio of 3:2 
(omalizumab:placebo).  Randomization to treatment groups will be stratified by UAS7 at the 
point of randomization (UAS 7 = 0 vs. UAS7 > 0) and study site.  Efficacy and safety data will be 
collected.  Subsequent to randomization, patients will continue to be evaluated twice daily using 
the eDiary for weekly calculation of UAS7, which includes a weekly itch score. 
Throughout the study (Day −14 to Week 60), patients must maintain stable doses of their 
pre-randomization combination therapy with H1 antihistamine treatment, H2 blockers, and/or 
LTRAs.  Patients will be prohibited from using non-study-drug omalizumab during the study 
(Day −14 to Week 60) (e.g., commercially available omalizumab is not permitted during the 
study).  Patients receiving non-study-drug omalizumab during the study, for any indication, will 
be discontinued from the study. 
Patients who do not meet the criteria for randomization (e.g., because of non-response to 
omalizumab during the open-label treatment period) should return for a final follow-up visit 
12 weeks after Visit 9 (Week 24 visit), which will include assessments for adverse events and 
PROs (see Appendix 1).  Patients will not be required to complete the eDiary during this 12-
week period. 
Subsequent to randomization, patients may, at the discretion of the investigator, be transitioned 
from blinded study drug to open-label omalizumab at 300 mg SC Q4W if they experience 
clinically significant worsening in their CIU (as judged by the investigator); clinical worsening 
must also be accompanied by UAS7 ≥ 12 for at least 2 consecutive weeks.  That is, patients 
may potentially be transitioned to open-label omalizumab if this is deemed by the investigator to 
be clinically indicated based on clinical worsening CIU and if, after the investigator has made 
this assessment, patients are confirmed to have experienced UAS7 ≥ 12 for at least 
2 consecutive weeks as determined by eDiary entries.  Patients who are transitioned to 
open-label omalizumab will not be unblinded with respect to the treatment they had received 
between randomization and transition to open-label omalizumab.  Patients who are transitioned 
to open-label omalizumab will continue to receive open-label omalizumab as study drug until 
Week 48, after which omalizumab will be discontinued. 
The primary endpoint for this study is the percentage of patients who experience clinical 
worsening in CIU defined as UAS7 ≥ 12 for at least 2 consecutive weeks.   
After completion of the randomization period (end of Week 48), all patients will enter a 12-week 
follow-up period to allow for collection of additional efficacy and safety data.  Patients will 
continue to visit the study site at 4-week intervals.  The Week 48 and Week 60 visits will take 
place at the study site.  The Week 52 and Week 56 visits will take place by telephone by the 
study site personnel to include collection of adverse events and concomitant medication 
information.  Patients will continue to be assessed via eDiary during this period.  No study 
treatment will be given during the follow-up period. 
The double blindness of randomization to treatment groups should be maintained for the full 
post-randomization period of the study (until the end of the study).   
Schedule of assessments are provided in Appendix 1, Appendix 2, and Appendix 3. 
Number of Patients 
Approximately 207 patients are planned to be enrolled in this study at approximately 40 study 
sites in the U.S.  Approximately 117 patients will be randomized in this study after accounting 
for dropout, non-adherence, and non-response during the open-label treatment period.  
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 12−75 years 
• 
Diagnosis of CIU refractory to H1 antihistamines at baseline, as defined by all of 
the following: 

 
Omalizumab—Genentech, Inc. 
19/Protocol ML29510, Version 2 
− 
The presence of itch and hives for ≥ 8 consecutive weeks at any time prior to 
enrollment despite current use of H1 antihistamine treatment (up to four times the 
approved dose) during this time period 
− 
UAS7 score (range 0−42) ≥ 16 and itch component of UAS7 (range 0−21) ≥ 8 during 
7 days prior to baseline 
− 
IC-UAS ≥ 4 on at least one of the screening visit days (Day −14, Day  −7, or Day 1) 
(see Section 4.5.9 for details on IC-UAS) 
− 
Patients must have been on a non-sedating H1 antihistamine treatment specified in 
Section 4.4 (up to four times the approved dose) for CIU for at least the 3 consecutive 
days immediately prior to the Day −14 screening visit and must document current use 
on the day of the initial screening visit. 
− 
CIU diagnosis for ≥ 6 months.  The methods used to confirm duration of CIU diagnosis 
may include patient report of onset of CIU symptoms, and the duration of CIU diagnosis 
may be made based on the initial date of these symptoms even if the diagnosis of CIU 
was made at a later date. 
• 
Willing to give written informed consent, adhere to the visit schedules, and meet study 
requirements 
− 
For patients below the legal age of consent, the child must be willing to give written 
informed assent and the parent(s)/guardian(s) must be willing to give written informed 
consent. 
− 
For patients below the legal age of consent, both child and parent must be able to 
adhere to dose and visit schedules and meet study requirements. 
• 
Willing and able to complete a daily symptom eDiary for the duration of the study 
• 
Patients must not have any missing eDiary entries in the 7 days prior to baseline. 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use two adequate methods of contraception, including at least one method with a failure 
rate of <1% per year, during the treatment period and for at least 4 months after the last 
dose of study drug 
− 
Abstinence is only acceptable if it is in line with 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. 
− 
Barrier methods must always be supplemented with the use of a spermicide. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Treatment with an investigational agent within 30 days of Day −14 
• 
Weight less than 20 kg (44 lbs) 
• 
Clearly defined underlying etiology for chronic urticarias other than CIU (main manifestation 
being physical urticaria).  This includes the following urticarias: 
− 
Acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure, or contact 
Any of the following diseases, which may have symptoms of urticaria or angioedema:  
urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary 
or acquired angioedema, lymphoma, leukemia, or generalized cancer 
• 
Evidence of parasitic infection defined as having the following three items:  
− 
Risk factors for parasitic disease (chronic gastrointestinal [GI] symptoms, travel within 
the last 6 months to an endemic area, and/or chronic immunosuppression)  
AND 
− 
An absolute eosinophil count more than twice the upper limit of normal (ULN)  
AND 

 
Omalizumab—Genentech, Inc. 
20/Protocol ML29510, Version 2 
− 
Evidence of parasitic colonization or infection on stool evaluation for ova and parasites.  
Stool ova and parasite evaluation will only be conducted in patients with both risk 
factors and an eosinophil count more than twice the ULN. 
• 
Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or other skin 
disease associated with itch 
• 
Previous treatment with omalizumab within 1 year prior to Day −14 
• 
Routine (daily/every other day during 5 or more consecutive days) doses of the following 
medications within 30 days prior to Day −14:  systemic corticosteroids, hydroxychloroquine, 
methotrexate, mycophenolate, cyclosporine, or cyclophosphamide 
• 
Intravenous immunoglobulin G (IVIG) or plasmapheresis within 30 days prior to Day −14 
• 
Regular (daily/every other day) doxepin (oral) use within 14 days prior to Day −14 
• 
Patients with current malignancy, history of malignancy, or currently under work-up for 
suspected malignancy except non-melanoma skin cancer that has been treated or excised 
and is considered resolved 
• 
Hypersensitivity to omalizumab or any component of the formulation 
• 
History of anaphylactic shock 
• 
Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, or 
other pathological conditions that could interfere with the interpretation of the study results 
and or compromise the safety of the patients 
• 
Medical examination or laboratory findings that suggest the possibility of decompensation of 
co-existing conditions for the duration of the study.  Any items that are cause for uncertainty 
must be reviewed with the Medical Monitor.  
• 
Inability to comply with study and follow-up procedures 
• 
Evidence of current drug or alcohol abuse 
• 
Contraindications to diphenhydramine 
• 
Pregnant or lactating, or intending to become pregnant during the study 
− 
Women of childbearing potential must have a negative serum pregnancy test result 
within 3 days prior to initiation of study drug. 
 
Length of Study 
The total duration of the study is anticipated to be 62 weeks consisting of a 2-week screening 
period, a 24-week open-label treatment period, a 24-week double-blind randomization period, 
and a 12-week follow-up period. 
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.  LPLV is expected to 
occur 60 weeks after the last patient is enrolled. 
Outcome Measures 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the percentage of patients who experience clinical 
worsening in CIU as assessed by UAS7.  The specific threshold for clinical worsening in CIU 
symptoms will be UAS7 ≥ 12, maintained for at least 2 consecutive weeks, from randomization 
(Week 24) to Week 48. 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Time to clinical worsening in CIU, defined based on the same criteria as the primary 
endpoint (maintaining UAS7 ≥ 12 for at least 2 consecutive weeks), from randomization 
(Week 24) to Week 48 

 
Omalizumab—Genentech, Inc. 
21/Protocol ML29510, Version 2 
• 
Percentage of patients who experience clinical worsening in CIU assessed by UAS7, where 
the threshold for clinical worsening is UAS7 > 6 for at least 2 consecutive weeks, from 
randomization (Week 24) to Week 48 
• 
UAS7 (24- vs. 48-week value) among patients who have responded to omalizumab 
treatment at 24 weeks and completed a further 24 weeks of omalizumab (48 weeks total), 
which will be assessed by the change from randomization (Week 24) to Week 48 in UAS7 
• 
Retreatment efficacy, defined by change in UAS7 from time of retreatment to 12 weeks 
after retreatment, among patients randomized to the placebo arm who are retreated with 
open-label omalizumab after randomization and receive at least 12 weeks of omalizumab 
therapy as retreatment 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in vital signs 
• 
Clinical laboratory evaluations 
 
Pharmacodynamic Outcome Measure 
Total serum immunoglobulin E (IgE) level will be measured at screening (pre-dose). 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
The proportion of patients experiencing clinical worsening in CIU (defined as maintaining 
UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 48 and 60 among patients 
randomized to continue omalizumab (i.e., during the 12 weeks after discontinuing a 
48-week course of omalizumab)  
• 
The proportion of patients experiencing clinical worsening in CIU (defined as maintaining 
UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 24 and 36 among patients 
randomized to placebo 
• 
Change from randomization (Week 24) to Week 48 in weekly itch score 
• 
Change from randomization (Week 24) to Week 48 in UAS7 
• 
Change from randomization (Week 24) to Week 48 in health-related quality-of-life as 
measured by the Dermatology Life Quality Index (DLQI) total score  
• 
Insomnia Severity Index (ISI); General Anxiety Disorder 7-Item (GAD-7) scale; and Work 
Productivity and Activity Index (WPAI) will be assessed as: 
− 
Change from baseline to Week 24 
− 
Change from randomization to Week 48  
− 
Change from the end of the randomization period (Week 48) to the end of the study 
(end of Week 60) 
• 
Proportion of angioedema days, evaluated through patient self-reports via eDiary, from 
Week 24 to Week 48 
• 
Urticaria Control Test (UCT) response and correlation with UAS7 
− 
Change in UCT from baseline to Week 24 
− 
Change in UCT from randomization to Week 48 
− 
Correlation between UCT and UAS7 from baseline to Week 24 
• 
Urticaria Activity and Impact Measure (U-AIM) response and correlation with UAS7 
− 
Change in U-AIM from baseline to Week 24 
− 
Change in U-AIM from randomization to Week 48 
− 
Correlation between U-AIM and UAS7 from baseline to Week 24 

 
Omalizumab—Genentech, Inc. 
22/Protocol ML29510, Version 2 
• 
Patient Global Impression of Change (P-GIC) scale and Clinician Global Impression of 
Change (C-GIC) scale assessed at Week 24 and Week 48 
 
Investigational Medicinal Products 
Study Drug 
Omalizumab will be supplied by the Sponsor.  Omalizumab is a sterile, white, preservative-free, 
lyophilized powder, contained in a single-use, 5-mL vial that will be reconstituted with Sterile 
Water for Injection (SWFI), USP, and administered as a SC injection.  Each omalizumab vial 
contains 202.5 mg of omalizumab, 145.5 mg sucrose, 2.8 mg L-histidine hydrochloride 
monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20.  Each vial is designed to deliver 
150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP. 
For additional details, see the pharmacy manual and the Omalizumab Investigator's Brochure. 
Patients will receive omalizumab 300 mg or placebo administered SC Q4W at the study site.  
Missed doses will not be replaced.  Each patient will receive two injections of study medication 
at every treatment visit.  
Placebo 
The placebo contains the same ingredients as the omalizumab formulation listed above, 
excluding omalizumab. 
Non-Investigational Medicinal Products 
See Section 4.4.1 for the long-acting H1 antihistamines, H2 blockers, and LTRAs allowed 
during the study. 
All patients will be allowed to take study-defined H1 antihistamine medications at up to four 
times the approved dose, H2 blockers, and/or LTRAs during the screening, treatment, and 
follow-up periods.  Patients should remain on a stable H1 antihistamine, H2 blocker, and/or 
LTRA treatment regimen throughout the randomization period (Week 24 to Week 48).  
Diphenhydramine (25 mg) may also be used on an as-needed basis (maximum three times/day) 
during the screening, treatment, and follow-up periods.  
Statistical Methods 
Efficacy Analyses 
Efficacy analyses will be based on the modified intent-to-treat (mITT) principle.  All patients 
meeting criteria for randomization, who are also randomized and receive at least one dosage of 
blinded study drug, will be included in analyses.  Analyses groups will be defined according to 
the patients’ assigned treatments regardless of the actual treatment received.   
Analyses comparing rates of clinical worsening CIU after randomization, including the primary 
analysis, will include the counts and proportions of the response among all patients as well as in 
the treatment groups being compared.  The 95% confidence intervals will be presented for each 
within-group proportion and for the difference in proportions between treatment groups.  The 
2-sided chi-square p-value will be presented to compare the treatment group proportions.   
Analyses comparing changes in UAS7 or any other continuous outcome measure will include 
the means, standard deviations, and 95% confidence intervals for all patients, for each 
treatment group, and for the difference between groups accompanied by p-values whenever 
applicable. 
For all efficacy analyses, statistical significance will be declared if the p-value for the 
comparison is less than 0.05. 
Missing Data for Efficacy Analyses 
For the purposes of comparing clinical worsening CIU rates, any patient who discontinues from 
the study before the end of the applicable observation period will be considered to have 
experienced clinical worsening, as defined by the primary endpoint.  For analyses related to 
continuous endpoints, any patient who discontinues from the study may have their endpoints 
imputed whenever appropriate.  Further details related to imputations for missing data will be 
outlined in the Statistical Analysis Plan (SAP) before the database is locked. 

 
Omalizumab—Genentech, Inc. 
23/Protocol ML29510, Version 2 
Safety Analyses 
Safety analyses will be performed for all patients treated with study drug.  Safety will be 
assessed by adverse events, vital signs, and clinical laboratory evaluations.  
Adverse events will be collected from the time of the first study-specific procedure through the 
last observation visit.  Verbatim descriptions of adverse events will be coded and analyzed 
using appropriate thesaurus terms.  A treatment-emergent adverse event is defined as any 
adverse event reported, or worsening of an existing condition on or after the first dose of study 
drug.  Treatment-emergent adverse events will be summarized by treatment group.  Clinical 
laboratory data (e.g., serum chemistry and hematology evaluations) and vital signs will be 
summarized by descriptive statistics for each treatment group. 
Pharmacodynamic Analysis 
Total serum IgE level at screening (pre-dose) versus time data will be tabulated by treatment 
group and summarized using descriptive statistics (e.g., mean, standard deviation, minimum, 
and maximum).   
Exploratory Analyses 
For details on how each exploratory analysis will be conducted, see the SAP. 
Determination of Sample Size 
Assuming a 60% rate of clinical worsening in CIU assessed by UAS7 in the placebo group 
(including 10% dropout imputed as worsening CIU) and a rate of 30% in the omalizumab 
continuation group (including 10% dropout imputed as clinical worsening CIU) in the period up 
to 24 weeks post-randomization, a total of 117 patients will need to be randomized at a 3:2 ratio 
(3 omalizumab continuation group patients for every 2 placebo patients) to ensure 90% power 
to detect a difference in clinical worsening CIU rates as a primary analysis comparison at the 
0.05 alpha level (2-sided test).  In addition, as it is estimated that 15% of patients will either drop 
out during the open-label treatment period or not meet the adherence criteria, and that 66.5% of 
those who do not drop out or fail adherence criteria will be responders, this study will need to 
enroll at least 207 (117 / [0.665 • 0.85]) patients to ensure adequate randomization numbers for 
the primary analysis.  This sample size will also ensure at least 80% power for each of the 
secondary analyses.   
  

 
Omalizumab—Genentech, Inc. 
24/Protocol ML29510, Version 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartase transaminase 
BID 
twice per day 
BUN 
blood urea nitrogen 
C-GIC 
Clinician Global Impression of Change (scale) 
CIU 
chronic idiopathic urticaria 
CRO 
contract research organization 
CSU 
chronic spontaneous urticaria 
DLQI 
Dermatology Life Quality Index 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eDiary 
electronic diary (also referred to as the UPDD) 
FcεRI 
high-affinity IgE receptor 
FDA 
U.S. Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GAD-7 
General Anxiety Disorder 7-Item (scale) 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
IC-UAS 
in-clinic Urticaria Activity Score 
ICH 
International Conference on Harmonisation 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
IVIG 
intravenous immunoglobulin G 
IxRS 
interactive voice and web response system 
LDH 
lactate dehydrogenase 
LPLV 
last patient, last visit 
LTRA 
leukotriene receptor antagonist 
MID 
minimally important difference 
mITT 
modified intent-to-treat (principle) 
P-GIC 
Patient Global Impression of Change (scale) 

 
Omalizumab—Genentech, Inc. 
25/Protocol ML29510, Version 2 
Abbreviation 
Definition 
PD 
pharmacodynamic 
PRO 
patient-reported outcome 
Q4W 
every 4 weeks 
QD 
once per day 
QID 
four times per day 
RBC 
red blood cell 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SWFI 
Sterile Water for Injection 
U-AIM 
Urticaria Activity and Impact Measure 
UAS 
Urticaria Activity Score 
UAS7 
Urticaria Activity Score over 7 days 
UCT 
Urticaria Control Test 
ULN 
upper limit of normal 
UPDD 
Urticaria Patient Daily Diary 
USPI 
U.S. Package Insert 
WBC 
white blood cell 
WPAI 
Work Productivity and Activity Index 

 
Omalizumab—Genentech, Inc. 
26/Protocol ML29510, Version 2 
1. 
BACKGROUND 
1.1 
CHRONIC IDIOPATHIC URTICARIA 
Chronic idiopathic urticaria (CIU; also referred to as chronic spontaneous urticaria [CSU]) 
is defined as the spontaneous occurrence of daily, or almost daily, hives and itching for 
at least 6 weeks without an obvious cause (Greaves 2003).  The majority of patients with 
CIU achieve symptomatic control with conventional H1 antihistamine therapy.  In some 
patients, CIU can be a debilitating condition because of a lack of clinical response as 
well as the unpredictable course of the disease, both of which can have a profound 
negative influence on the patient’s quality of life (Tilles 2005). 
Some patients may remain symptomatic despite ongoing H1 antihistamine treatment, 
and for this group of patients, therapies such as immunosuppressants 
(including cyclosporine, corticosteroids, intravenous immunoglobulin G [IVIG], 
and methotrexate) and plasmapheresis have been used (Kozel and Sabroe 2004).  
These agents have variable success and may be associated with severe adverse effects. 
The etiology of CIU is not clear.  There are several theories, including one proposing an 
infectious origin and another related to an autoimmune origin.  Some studies have found 
that approximately 30−60% of patients with CIU have an autoimmune component 
(Fiebiger et al. 1995; Tong et al. 1997; Zweiman et al. 1998).  In patients suspected of 
having an autoimmune etiology for their CIU, symptoms result from mediator release 
following the cross-linking of high-affinity immunoglobulin E (IgE) receptors on mast cells 
and basophils.  Anti-IgE antibodies and functional antibodies against the alpha chain of 
the high-affinity IgE receptor found on mast cells, basophils, and antigen-presenting cells 
have been isolated from the serum of patients with CIU (Grattan et al. 1991; 
Hide et al. 1993; Niimi et al. 1996).  Given the association of high-affinity receptor 
activation, mediator release, and CIU, several studies have been conducted to 
determine if omalizumab could be a useful therapy for this disease. 
1.2 
OMALIZUMAB 
Omalizumab (Xolair®) is a humanized anti-IgE recombinant monoclonal antibody 
approved to treat allergic asthma by inhibiting the binding of IgE to the high-affinity IgE 
receptor (FcεRI) on the surface of mast cells and basophils.  Reduction in surface-bound 
IgE on the FcεRI-expressing cells limits the degree of release of mediators in the allergic 
response.  Omalizumab has been studied for safety and efficacy in over 5000 adult and 
adolescent (≥ 12 years of age) patients with moderate to severe asthma, and more 
recently, in patients with CIU.  Omalizumab was approved by the U.S. Food and Drug 
Administration (FDA) for CIU in March 2014.  More than 60,000 patients have been 
treated with omalizumab worldwide.  
There are two hypotheses for the mechanism of action of omalizumab in patients with 
CIU.  One hypothesis is that the density of IgE receptors at the surface of mast cells and 
basophils is proportional to the plasma IgE level.  Lowering free IgE to near undetectable 

 
Omalizumab—Genentech, Inc. 
27/Protocol ML29510, Version 2 
levels should therefore down regulate the IgE receptors so that the immunoglobulin G 
(IgG) autoantibody cannot cross-link FcεRI.  Cell activation would be suppressed, and all 
the subsequent inflammatory processes (complement activation, cellular infiltration) 
would be suppressed as well.  As a consequence, the frequency and severity of 
symptoms of chronic urticaria should be markedly diminished.  It has also been 
hypothesized that the down regulation of FcεRI may be accompanied by an increase in 
the threshold above which degranulation of mast cells is triggered.  This may be an 
independent mechanism of action, unrelated to prevention of cross-linkage of surface 
receptors, or the two mechanisms might be complementary.  The exact mechanism for 
how omalizumab may work for patients with CIU is, however, unknown. 
Omalizumab is indicated for the treatment of adults and adolescents (12 years of age 
and above) with CIU who remain symptomatic despite H1 antihistamine treatment.  The 
FDA-approved dose for patients with CIU is 150 or 300 mg administered by 
subcutaneous (SC) injection every 4 weeks (Q4W). 
1.2.1 
Clinical Experience with Omalizumab in Patients with CIU 
The Phase III clinical program for omalizumab consisted of three studies: 
• 
Study Q4881g (ASTERIA I; Saini et al. 2014) and Study Q4882g (ASTERIA II; 
Maurer et al. 2013) evaluated patients with CIU who were refractory to 
H1 antihistamines at approved doses. 
• 
Study Q4883g (GLACIAL; Kaplan et al. 2013) evaluated patients with CIU who 
were refractory to H1 antihistamines at up to four times approved doses, 
H2 blockers, and/or leukotriene receptor antagonists (LTRAs). 
 
Studies Q4881g and Q4882g were both global, Phase III, multicenter, randomized, 
double-blind, placebo-controlled, parallel-group studies to evaluate the efficacy and 
safety of omalizumab, administered SC Q4W as add-on therapy for the treatment of 
adolescent and adult patients (12−75 years of age) with CIU refractory to conventional 
H1 antihistamines, as demonstrated by:  the presence of itch and hives for 
≥ 8 consecutive weeks at any time prior to enrollment, Urticaria Activity Score (UAS) over 
7 days (UAS7) confirming uncontrolled symptoms prior to randomization, and a CIU 
diagnosis for ≥ 6 months.  The studies evaluated the comparative efficacy between three 
doses of omalizumab (75 mg, 150 mg, and 300 mg) and placebo as well as the time to 
onset of clinical effect for patients with CIU who remained symptomatic despite 
treatment with approved doses of H1 antihistamine therapy.  The 150-mg dose, which 
was not studied in the Phase II study (Q4577g; Saini et al. 2011), was included as an 
intermediate between the 75- and 300-mg dose in order to better define the dose 
response.  The inclusion of the 75-mg dose served to characterize the lower end of the 
dose response after multiple doses, since only a single dose was tested in 
Study Q4577g. 

 
Omalizumab—Genentech, Inc. 
28/Protocol ML29510, Version 2 
Studies Q4481g and Q4882g differed in duration of treatment (24 weeks compared to 
12 weeks for Studies Q4881g and Q4882g, respectively).  The primary efficacy outcome 
measure was change from baseline in weekly itch score (a component of the UAS7) at 
Week 12.  In total, 319 patients were randomized from 53 centers globally, and 
323 patients were randomized from 55 centers globally in Studies Q4881g and Q4882g, 
respectively. 
Study Q4883g was a global Phase III, multicenter, randomized, double-blind, placebo-
controlled, parallel-group study to evaluate the safety and efficacy of omalizumab 
300 mg administered SC Q4W as an add-on therapy for the treatment of adolescent and 
adult patients (12−75 years of age) who have been diagnosed with CIU who remain 
symptomatic despite H1 antihistamine treatment doses up to four times above the 
approved dose, H2 blockers, and/or LTRAs.  The duration of treatment for 
Study Q4883g was 24 weeks.  The primary safety outcome measure was the incidence 
and severity of adverse events and serious adverse events.  Efficacy, a secondary 
objective, was measured in a similar manner as Studies Q4881g and Q4882g.  In total, 
336 patients were randomized from 65 centers globally. 
1.2.2 
Summary of Omalizumab Clinical Efficacy in Patients with CIU  
Consistent treatment effects were observed in all omalizumab-treated groups across all 
three pivotal studies (Q4881g, Q4882g, and Q4883g), similar to that noted in the 
Phase II dose-ranging study (Q4577g) (Saini et al. 2011; Kaplan et al. 2013; 
Maurer et al. 2013; Saini et al. 2014). 
Both the 150-mg and 300-mg groups met the primary efficacy endpoint of change from 
baseline to Week 12 in weekly itch score in all three pivotal studies (in Study Q4883g, 
only the 300-mg dose was studied), supporting the use of omalizumab for the treatment 
of adults and adolescents (12 years of age and above) with CIU who remain 
symptomatic despite H1 antihistamine treatment.  For the 300-mg group, the mean 
change from baseline in weekly itch score at Week 12 showed statistically significant 
improvements compared with placebo (−9.4 vs. −3.6, −9.8 vs. −5.1, and −8.6 vs. −4.0 for 
Studies Q4881g, Q4882g, and Q4883g, respectively).  The 75-mg group met the primary 
endpoint in Study Q4881g only. 
Studies Q4881g and Q4882g showed consistent evidence of a dose response with the 
300-mg dose demonstrating greater therapeutic benefit relative to 150 mg for the 
primary endpoint (formal statistical comparisons were not performed between 
omalizumab groups). 
At the 300-mg dose, the proportion of patients achieving a therapeutic response at 
Week 12 (secondary efficacy endpoint) was as follows:  52%, 66%, and 52% with 
UAS7 ≤ 6; and 36%, 44%, and 24% with UAS7 = 0 for Studies Q4881g, Q4882g, and 
Q4883g, respectively.  In addition, the proportion of patients at the 300-mg dose 

 
Omalizumab—Genentech, Inc. 
29/Protocol ML29510, Version 2 
achieving UAS7 ≤ 6 at both Weeks 23 and 24 was 67.6% and 65.5% for Studies Q4881g 
and Q4883g, respectively. 
As noted in Studies Q4881g and Q4883g, the decreases in mean weekly itch score and 
UAS7 with omalizumab treatment at Week 12 were maintained for up to 24 weeks of 
treatment suggesting there was no tolerance or tachyphylaxis to prolonged omalizumab 
dosing.   
After cessation of treatment, mean weekly itch score and UAS7 increased to reach 
values similar to the placebo group mean values, but did not return to baseline values for 
the duration of the 16-week follow-up period in any of the omalizumab treatment groups 
in all three pivotal studies.  The mean weekly itch score and UAS7 in the 300-mg group 
appeared to take longer to reach a similar level to that in the placebo group than was the 
case for lower omalizumab doses.  This suggests a longer lasting effect of the 300-mg 
dose. 
Figure 1 shows UAS7 scores over time in Study Q4881g (ASTERIA I), where the 
duration of potential omalizumab therapy was 24 weeks (Saini et al. 2014; Genentech 
data on file).  Study Q4883g (GLACIAL) showed a similar pattern of return to placebo 
group mean after the 24-week omalizumab treatment period (Kaplan et al. 2013). 
Figure 1 Change from Baseline in Mean UAS7:  Study Q4881g (ASTERIA I; 
Placebo versus 24 Weeks Omalizumab) 
 
UAS7 = Urticaria Activity Score over 7 days. 
 

 
Omalizumab—Genentech, Inc. 
30/Protocol ML29510, Version 2 
1.2.3 
Summary of Omalizumab Clinical Safety in Patients with CIU  
The overall safety profile of omalizumab in patients with CIU, across all four studies 
comprising the clinical development program (Q4577g, Q4881g, Q4882g, and Q4883g), 
revealed no unexpected safety signals or concerns different than the known safety 
profile of omalizumab in patients with allergic asthma (Saini et al. 2011; 
Kaplan et al. 2013; Maurer et al. 2013; Saini et al. 2014). 
Few serious adverse events were reported (< 2% of patients reported serious adverse 
events during the 12-week treatment period and < 4% during the 24-week treatment 
period) and no deaths were observed in any of the studies.  The most frequent adverse 
events demonstrating imbalances were common conditions such as nasopharyngitis, 
headache, and sinusitis.  The safety profile was similar between 12 weeks and 24 weeks.  
In general, the majority of adverse events were mild or moderate in intensity.  Overall, 
omalizumab was well tolerated with few adverse events leading to study discontinuation 
(< 2%) or withdrawal of treatment (< 4%) during the study period.  A treatment 
comparison of the main safety endpoints over the entire study period for all three 
Phase III studies pooled showed no major differences in the safety profile between the 
150- and 300-mg groups.  Treatment differences indicating greater risk in omalizumab-
treated patients were small and associated with a higher level of uncertainty.  Those 
differences that were observed were expected given the known safety profile of 
omalizumab in allergic asthma.  Specifically, a dose-dependent increase in suspected 
adverse events was observed for injection site reactions, which has been previously 
described (Xolair U.S. Package Insert 2014).  Such reactions were infrequent, occurring 
in < 3% of patients among those treated at the higher 300-mg dose, and none were 
considered severe.  Although an imbalance in hypersensitivity events for the 300-mg 
dose group was observed over the entire study, this imbalance was not observed during 
either the 12- or 24-week treatment period.  For the majority of patients suffering from 
moderate to severe CIU, the benefit of treatment with omalizumab would likely outweigh 
these risks. 
See the Omalizumab Investigator's Brochure for additional details on clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The three pivotal studies (Q4881g, Q4882g, and Q4883g) examined the safety and 
efficacy of omalizumab administered over 12 to 24 weeks.  Currently, there is limited 
clinical trial experience on the long-term treatment beyond 24 weeks (or approximately 
6 months) in patients with CIU.  The U.S. Package Insert (USPI) for omalizumab notes 
that the appropriate duration of therapy for CIU has not been evaluated and advises 
health practitioners to periodically reassess the need for continued therapy.     
This study will assess the safety and potential benefits of continuing omalizumab beyond 
24 weeks of dosing (through 48 weeks of dosing, or approximately 1 year).  Through the 
primary outcome, as well as the secondary and exploratory outcomes, this study should 

 
Omalizumab—Genentech, Inc. 
31/Protocol ML29510, Version 2 
assist healthcare providers in weighing the relative benefits of omalizumab continuation 
beyond 24 weeks by elucidating the extent to which omalizumab might be expected to 
maintain control of CIU and related symptoms.      
In Studies Q4881g (ASTERIA I) and Q4883g (GLACIAL), all patients discontinued 
omalizumab after 24 weeks and, in Study Q4882g (ASTERIA II), all patients 
discontinued omalizumab after 12 weeks.  Moreover, patients were unblinded at 
discontinuation (i.e., patients knew they were discontinuing omalizumab).  In 
Studies Q4881g and Q4883g, the mean weekly itch score and UAS7 after omalizumab 
discontinuation increased to reach values similar to that of the placebo arms 
(Kaplan et al. 2013; Maurer et al. 2013; Saini et al. 2014).  This study will evaluate 
whether continuation of omalizumab beyond 24 weeks might be expected to maintain 
control of CIU and related symptoms in the context of being blinded to omalizumab 
continuation versus discontinuation.   
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective for this study is to evaluate the level of control of CIU symptoms 
through 48 weeks, among patients continuing omalizumab as compared to those 
receiving placebo after an initial 24 weeks of omalizumab treatment. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives for this study are as follows: 
• 
To evaluate the response to retreatment with omalizumab in patients with CIU who 
have responded to omalizumab, but experienced recurrence or clinical worsening of 
disease after withdrawal of therapy 
• 
To evaluate whether patients who have achieved response to omalizumab after 
24 weeks of therapy demonstrate similar levels of response after 48 weeks of 
therapy 
• 
To evaluate the safety of omalizumab therapy through 48 weeks in patients with CIU 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To compare the level of control of CIU symptoms, over 12 weeks after withdrawal of 
omalizumab, subsequent to completing 48 weeks versus 24 weeks of omalizumab 
therapy, among patients with CIU who have responded to omalizumab therapy 
• 
To obtain additional data on patient-reported outcome (PRO) response to 
omalizumab 
 

 
Omalizumab—Genentech, Inc. 
32/Protocol ML29510, Version 2 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a Phase IV, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of SC omalizumab through 48 weeks as an add-on 
therapy for the treatment of refractory CIU in adolescent and adult patients (12−75 years 
of age) who remain symptomatic despite standard H1 antihistamine treatment (including 
doses up to four times above the approved dose), H2 blockers, and/or LTRAs.  The 
study will enroll approximately 207 patients at approximately 40 study sites in the U.S. 
The study will consist of the following study periods with a total duration of 62 weeks 
(see Figure 2): 
• 
Screening Period:  Day −14 to Baseline (Week −2 to Baseline) 
• 
Open-Label Treatment Period:  Day 1 to Day 168 (Baseline to Week 24) 
• 
Double-Blind Randomization Period:  Day 169 to Day 336 (Week 24 to Week 48) 
• 
Follow-Up Period:  Day 337 to Day 420 (Week 48 to end of Week 60) 
 
The screening period will consist of visits at Day −14 and Day −7.  Day 1 (baseline) will 
mark the commencement of the 24-week open-label treatment period.  Patients must 
meet all of the following criteria prior to receiving treatment in the open-label treatment 
period: 
• 
Non-electronic diary-based UAS ≥ 4 established in the clinic (i.e., in-clinic UAS 
[IC-UAS]) based on the patient’s condition over 12 hours prior to either Day −14, 
Day −7, or Day 1 despite being on H1 antihistamine therapy 
• 
Use of H1 antihistamine treatment (up to four times the approved dose) for CIU at 
Day −14 and for at least the 3 consecutive days immediately prior to Day −14 
(see Section 4.4.1 for a list of H1 antihistamines available for use in this study) 
• 
Willing and able to complete a symptom electronic diary (eDiary), also referred to as 
the Urticaria Patient Daily Diary (UPDD), twice daily throughout the screening period 
to establish the patient’s UAS7  
 
Patients will have the 2-week screening period to establish their eligibility for the study 
and baseline symptom scores.  For the duration of the screening period, patients must 
maintain stable doses of their pre-screening H1 antihistamine treatment.  To be eligible 
for treatment during the open-label treatment period, patients must have: 
• 
No missing eDiary entries during the 7 days prior to baseline (Note:  If a patient 
fails screening due to missed eDiary entries during this 7-day period, the patient is 
permitted to rescreen once.);  
• 
A UAS7 symptom score of ≥ 16 during the 7 days prior to baseline (equivalent to 
moderate to severe CIU symptoms for at least 4 out of 7 days in a week); and  
• 
A weekly itch score (a component of the UAS7) of ≥ 8 during the 7 days prior to 
baseline. 

 
Omalizumab—Genentech, Inc. 
33/Protocol ML29510, Version 2 
 
Only in exceptional circumstances, when information concerning eligibility is outstanding 
(e.g., pending laboratory data), will a screening period longer than 2 weeks be permitted.  
Patients may be re-screened upon approval from the Medical Monitor.  
Circumstances that may permit re-screening include, but are not limited to, an IC-UAS or 
laboratory test results that do not meet eligibility requirements.  
On Day 1, eligible patients will begin open-label omalizumab 300 mg SC Q4W and will 
continue on treatment during the 24-week open-label treatment period.  During this 
period, patients will continue reporting twice daily their UAS-related symptoms through 
the eDiary, necessary for the weekly calculation of UAS7 (which is based on the last 
7 days of symptoms).  At the end of the open-label treatment period, patients who have 
responded to omalizumab will be randomized in a double-blinded fashion to either 
continue omalizumab or to transition to placebo for a further 24 weeks.  Patients will be 
eligible for randomization if they meet both of the following criteria: 
• 
Achieve UAS7 ≤ 6 in the final 2 weeks of the open-label treatment period, which are 
the 2 consecutive weeks immediately prior to randomization.  (These final 2 weeks 
are scheduled to occur during Week 23 and Week 24 but may vary somewhat 
depending on patient scheduling.) 
AND 
• 
Comply with omalizumab dosing for at least 5 out of the 6 planned doses, including 
a dosage at Week 20, during the initial 24-week open-label treatment period 
(i.e., patients may only be randomized if they have missed at most one dosage of 
omalizumab during the initial open-label treatment period AND did not miss their 
Week 20 dosage) 
 
Patients who meet the criteria for randomization will be randomized at a ratio of 3:2 
(omalizumab:placebo).  Randomization to treatment groups will be stratified by UAS7 at 
the point of randomization (UAS 7 = 0 vs. UAS7 > 0) and study site.  Efficacy and safety 
data will be collected.  Subsequent to randomization, patients will continue to be 
evaluated twice daily using the eDiary for weekly calculation of UAS7, which includes a 
weekly itch score. 
Throughout the study (Day −14 to Week 60), patients must maintain stable doses of their 
pre-randomization combination therapy with H1 antihistamine treatment, H2 blockers, 
and/or LTRAs.  Patients will be prohibited from using non-study-drug omalizumab during 
the study (Day −14 to Week 60) (e.g., commercially available omalizumab is not 
permitted during the study).  Patients receiving non-study-drug omalizumab during the 
study, for any indication, will be discontinued from the study. 
Patients who do not meet the criteria for randomization (e.g., because of non-response 
to omalizumab during the open-label treatment period) should return for a final follow-up 
visit 12 weeks after Visit 9 (Week 24 visit), which will include assessments for adverse 

 
Omalizumab—Genentech, Inc. 
34/Protocol ML29510, Version 2 
events and PROs (see Appendix 1).  Patients will not be required to complete the eDiary 
during this 12-week period. 
Subsequent to randomization, patients may, at the discretion of the investigator, be 
transitioned from blinded study drug to open-label omalizumab at 300 mg SC Q4W if 
they experience clinically significant worsening in their CIU (as judged by the 
investigator); clinical worsening must also be accompanied by UAS7 ≥ 12 for at least 
2 consecutive weeks.  That is, patients may potentially be transitioned to open-label 
omalizumab if this is deemed by the investigator to be clinically indicated based on 
clinical worsening CIU and if, after the investigator has made this assessment, patients 
are confirmed to have experienced UAS7 ≥ 12 for at least 2 consecutive weeks as 
determined by eDiary entries.  Patients who are transitioned to open-label omalizumab 
will not be unblinded with respect to the treatment they had received between 
randomization and transition to open-label omalizumab.  Patients who are transitioned to 
open-label omalizumab will continue to receive open-label omalizumab as study drug 
until Week 48, after which omalizumab will be discontinued. 
The primary endpoint for this study is the percentage of patients who experience clinical 
worsening in CIU defined as UAS7 ≥ 12 for at least 2 consecutive weeks.   
After completion of the randomization period (end of Week 48), all patients will enter a 
12-week follow-up period to allow for collection of additional efficacy and safety data.  
Patients will continue to visit the study site at 4-week intervals.  The Week 48 and Week 
60 visits will take place at the study site.  The Week 52 and Week 56 visits will take 
place by telephone by the study site personnel to include collection of adverse events 
and concomitant medication information.  Patients will continue to be assessed via 
eDiary during this period.  No study treatment will be given during the follow-up period. 
The double blindness of randomization to treatment groups should be maintained for the 
full post-randomization period of the study (until the end of the study).   
Schedule of assessments are provided in Appendix 1, Appendix 2, and Appendix 3. 

 
Omalizumab—Genentech, Inc. 
35/Protocol ML29510, Version 2 
Figure 2 Study Schema 
 
Q4W = every 4 weeks; UAS7 = Urticaria Activity Score over 7 days. 
a Patients who do not meet the criteria for randomization (e.g., because of non-response to omalizumab during the open-label treatment period) 
should return for a final follow-up visit 12 weeks after the Week 24 visit, which will include assessments for adverse events and PROs (see 
Appendix 1).  Patients will not be required to complete the eDiary during this 12-week period. 
b At Week 24, patients will be randomized 3:2 (omalizumab:placebo).  
c The final two weeks of the open-label treatment period are scheduled to occur during Weeks 23 and 24 but may vary somewhat depending on 
patient scheduling.  Randomization will not be permitted after Day 190 from baseline. 

 
Omalizumab—Genentech, Inc. 
36/Protocol ML29510, Version 2 
Figure 2 Study Schema (cont.) 
 
d Patients will be eligible to transition to open-label omalizumab, at the discretion of the investigator, if they experience clinically significant 
worsening in their CIU (as judged by the investigator) that is also accompanied by UAS7 ≥ 12 for at least 2 consecutive weeks.  Patients who 
begin open-label omalizumab subsequent to randomization will receive omalizumab as study drug until Week 48. 

 
Omalizumab—Genentech, Inc. 
37/Protocol ML29510, Version 2 
3.2 
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.  LPLV is 
expected to occur 60 weeks after the last patient is enrolled. 
3.3 
RATIONALE FOR STUDY DESIGN 
The pivotal studies demonstrated efficacy and safety of omalizumab through 24 weeks 
of treatment.  Efficacy and safety beyond 24 weeks of treatment was not examined, as 
will be addressed in this study.   Because of the previously demonstrated efficacy 
through 24 weeks, this study will begin with an initial 24-week open-label treatment 
period before any possibility of randomization to placebo.   
The primary outcome of this study is clinical worsening in CIU as assessed by UAS7.  
The specific threshold for clinical worsening in CIU symptoms is UAS7 ≥ 12, maintained 
for at least 2 consecutive weeks.  The threshold of UAS7 ≥ 12 (lower than the inclusion 
criteria of UAS7 ≥ 16) was chosen to allow patients to restart omalizumab at a lower 
threshold than that required to initiate omalizumab for the first time.  Based on advisor 
input, this is believed to mirror general clinical practice for reinitiating therapies after 
withdrawal.  Moreover, a requirement for patients to return to their baseline prior to 
reinitiating therapy is believed to be unreasonable, especially in the context of prior 
control established by omalizumab.  The specific threshold of UAS7 ≥ 12 was chosen 
because of the precedent established in the CIU Phase II study in which this was used 
as an inclusion criterion (Saini et al. 2011).  Additionally, all patients who are randomized 
will have a UAS7 ≤ 6 at time of randomization; therefore, a UAS7 ≥ 12 would confirm that 
the UAS7 score has at least doubled since randomization, representing an intuitive 
clinical threshold for reinitiating omalizumab.  The secondary outcome of this study will 
also assess time to clinical worsening as well as the level of control of CIU symptoms 
assessed by whether or not patients maintain UAS7 ≤ 6 during the randomization period 
(Week 24 to Week 48).  Separately, patients who have demonstrated a UAS7 ≥ 12 
(maintained for at least 2 consecutive weeks), who are also clinically assessed as 
having worsening CIU warranting a transition to open-label omalizumab, will be offered 
such a transition to ensure that patients do not remain symptomatic for an undue period 
of time. 
The inclusion and exclusion criteria for this study allow for up to four times the approved 
doses of H1 antihistamines, as well as H2 blockers and/or LTRAs.  These 
inclusion/exclusion criteria reflect the reality that such medications are often used at 
these doses before advancing therapy to omalizumab, as discussed in practice 
parameters and guidelines (Bernstein et al. 2014; Zuberbier et al. 2014). 
This study examines several secondary and exploratory endpoints, including PRO 
measures.  The PRO instruments used in this study include those used in the pivotal trial 
data (e.g., Dermatology Life Quality Index [DLQI]) as well as new PROs, such as anxiety 

 
Omalizumab—Genentech, Inc. 
38/Protocol ML29510, Version 2 
symptoms and work productivity that may be related to CIU and response to therapy.  In 
addition, this study will examine the validity of intermittently assessed PROs, such as the 
Urticaria Control Test (UCT) and Urticaria Activity and Impact Measure (U-AIM), 
compared with the twice daily eDiary device, in providing a clinical evaluation of patients 
with CIU.   
3.3.1 
Omalizumab Dose and Schedule 
The FDA-approved dose for patients with CIU is 150 or 300 mg SC Q4W.  In this CIU 
Phase IV study, only the 300-mg dose will be examined.  The 300-mg dose was the only 
dosage to meet both the primary outcome as well as all secondary outcomes in both 
pivotal efficacy studies (Q4881g and Q4882g).  Additionally, as shown in Figure 1, the 
average efficacy observed was numerically better with the 300-mg dose than for other 
doses.  Also, relapse to mean placebo values after cessation of the 300-mg dose of 
omalizumab took longer, on average, than after other doses of omalizumab.  
3.4 
OUTCOME MEASURES  
3.4.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the percentage of patients who experience 
clinical worsening in CIU as assessed by UAS7.  The specific threshold for clinical 
worsening in CIU symptoms will be UAS7 ≥ 12, maintained for at least 2 consecutive 
weeks, from randomization (Week 24) to Week 48. 
3.4.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Time to clinical worsening in CIU, defined based on the same criteria as the primary 
endpoint (maintaining UAS7 ≥ 12 for at least 2 consecutive weeks), from 
randomization (Week 24) to Week 48 
• 
Percentage of patients who experience clinical worsening in CIU assessed by UAS7, 
where the threshold for clinical worsening is UAS7 > 6 for at least 2 consecutive 
weeks, from randomization (Week 24) to Week 48 
• 
UAS7 (24- vs. 48-week value) among patients who have responded to omalizumab 
treatment at 24 weeks and completed a further 24 weeks of omalizumab (48 weeks 
total), which will be assessed by the change from randomization (Week 24) to 
Week 48 in UAS7 
• 
Retreatment efficacy, defined by change in UAS7 from time of retreatment to 
12 weeks after retreatment, among patients randomized to the placebo arm who are 
retreated with open-label omalizumab after randomization and receive at least 
12 weeks of omalizumab therapy as retreatment 
 

 
Omalizumab—Genentech, Inc. 
39/Protocol ML29510, Version 2 
3.4.3 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in vital signs 
• 
Clinical laboratory evaluations 
 
3.4.4 
Pharmacodynamic Outcome Measure 
Total serum IgE level will be measured at screening (pre-dose). 
3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
The proportion of patients experiencing clinical worsening in CIU (defined as 
maintaining UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 48 and 60 
among patients randomized to continue omalizumab (i.e., during the 12 weeks after 
discontinuing a 48-week course of omalizumab)  
• 
The proportion of patients experiencing clinical worsening in CIU (defined as 
maintaining UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 24 and 36 
among patients randomized to placebo 
• 
Change from randomization (Week 24) to Week 48 in weekly itch score 
• 
Change from randomization (Week 24) to Week 48 in UAS7 
• 
Change from randomization (Week 24) to Week 48 in health-related quality-of-life as 
measured by the DLQI total score  
• 
Insomnia Severity Index (ISI); General Anxiety Disorder 7-Item (GAD-7) scale; and 
Work Productivity and Activity Index (WPAI) will be assessed as: 
− 
Change from baseline to Week 24 
− 
Change from randomization to Week 48  
− 
Change from the end of the randomization period (Week 48) to the end of the 
study (end of Week 60) 
• 
Proportion of angioedema days, evaluated through patient self-reports via eDiary, 
from Week 24 to Week 48 
• 
UCT response and correlation with UAS7 
− 
Change in UCT from baseline to Week 24 
− 
Change in UCT from randomization to Week 48 
− 
Correlation between UCT and UAS7 from baseline to Week 24 
• 
U-AIM response and correlation with UAS7 
− 
Change in U-AIM from baseline to Week 24 
− 
Change in U-AIM from randomization to Week 48 
− 
Correlation between U-AIM and UAS7 from baseline to Week 24 

 
Omalizumab—Genentech, Inc. 
40/Protocol ML29510, Version 2 
• 
Patient Global Impression of Change (P-GIC) scale and Clinician Global Impression 
of Change (C-GIC) scale assessed at Week 24 and Week 48 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 207 patients are planned to be enrolled in this study at approximately 
40 study sites in the U.S.  Approximately 117 patients will be randomized in this study 
after accounting for dropout, non-adherence, and non-response during the open-label 
treatment period.  
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 12−75 years 
• 
Diagnosis of CIU refractory to H1 antihistamines at baseline, as defined by all of the 
following: 
− 
The presence of itch and hives for ≥ 8 consecutive weeks at any time prior to 
enrollment despite current use of H1 antihistamine treatment (up to four times 
the approved dose) during this time period 
− 
UAS7 score (range 0−42) ≥ 16 and itch component of UAS7 (range 0−21) ≥ 8 
during 7 days prior to baseline 
− 
IC-UAS ≥ 4 on at least one of the screening visit days (Day −14, Day  −7, or 
Day 1) (see Section 4.5.9 for details on IC-UAS) 
− 
Patients must have been on a non-sedating H1 antihistamine treatment 
specified in Section 4.4.1 (up to four times the approved dose) for CIU for at 
least the 3 consecutive days immediately prior to the Day −14 screening visit 
and must document current use on the day of the initial screening visit. 
− 
CIU diagnosis for ≥ 6 months.  The methods used to confirm duration of CIU 
diagnosis may include patient report of onset of CIU symptoms, and the duration 
of CIU diagnosis may be made based on the initial date of these symptoms 
even if the diagnosis of CIU was made at a later date. 
• 
Willing to give written informed consent, adhere to the visit schedules, and meet 
study requirements 
− 
For patients below the legal age of consent, the child must be willing to give 
written informed assent and the parent(s)/guardian(s) must be willing to give 
written informed consent. 
− 
For patients below the legal age of consent, both child and parent must be able 
to adhere to dose and visit schedules and meet study requirements. 
• 
Willing and able to complete a daily symptom eDiary for the duration of the study 
• 
Patients must not have any missing eDiary entries in the 7 days prior to baseline. 

 
Omalizumab—Genentech, Inc. 
41/Protocol ML29510, Version 2 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use two adequate methods of contraception, including at least 
one method with a failure rate of <1% per year, during the treatment period and for 
at least 4 months after the last dose of study drug 
– 
Abstinence is only acceptable if it is in line with 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. 
– 
Barrier methods must always be supplemented with the use of a spermicide. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Treatment with an investigational agent within 30 days of Day −14 
• 
Weight less than 20 kg (44 lbs) 
• 
Clearly defined underlying etiology for chronic urticarias other than CIU (main 
manifestation being physical urticaria).  This includes the following urticarias: 
− 
Acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure, or contact 
Any of the following diseases, which may have symptoms of urticaria or 
angioedema:  urticarial vasculitis, urticaria pigmentosa, erythema multiforme, 
mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or 
generalized cancer 
• 
Evidence of parasitic infection defined as having the following three items:  
− 
Risk factors for parasitic disease (chronic gastrointestinal [GI] symptoms, travel 
within the last 6 months to an endemic area, and/or chronic immunosuppression)  
AND 
− 
An absolute eosinophil count more than twice the upper limit of normal (ULN)  
AND 
− 
Evidence of parasitic colonization or infection on stool evaluation for ova and 
parasites.  Stool ova and parasite evaluation will only be conducted in patients 
with both risk factors and an eosinophil count more than twice the ULN. 
• 
Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or 
other skin disease associated with itch 
• 
Previous treatment with omalizumab within 1 year prior to Day −14 
• 
Routine (daily/every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to Day −14:  systemic corticosteroids, 
hydroxychloroquine, methotrexate, mycophenolate, cyclosporine, or 
cyclophosphamide 
• 
IVIG or plasmapheresis within 30 days prior to Day −14 
• 
Regular (daily/every other day) doxepin (oral) use within 14 days prior to Day −14 

 
Omalizumab—Genentech, Inc. 
42/Protocol ML29510, Version 2 
• 
Patients with current malignancy, history of malignancy, or currently under work-up 
for suspected malignancy except non-melanoma skin cancer that has been treated 
or excised and is considered resolved 
• 
Hypersensitivity to omalizumab or any component of the formulation 
• 
History of anaphylactic shock 
• 
Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, 
or other pathological conditions that could interfere with the interpretation of the 
study results and or compromise the safety of the patients 
• 
Medical examination or laboratory findings that suggest the possibility of 
decompensation of co-existing conditions for the duration of the study.  Any items 
that are cause for uncertainty must be reviewed with the Medical Monitor.  
• 
Inability to comply with study and follow-up procedures 
• 
Evidence of current drug or alcohol abuse  
• 
Contraindications to diphenhydramine 
• 
Pregnant or lactating, or intending to become pregnant during the study 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result within 3 days prior to initiation of study drug. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
At the Week 24 visit, patients who completed the 24-week open-label treatment period 
and have met the criteria for response (UAS7 ≤ 6 in the 2 consecutive weeks 
immediately prior to randomization) and also met the omalizumab compliance criteria 
(5 out of 6 planned doses, including a dosage at Week 20) will be randomized to 300 mg 
omalizumab or placebo at an approximately 3:2 ratio using an interactive voice and web 
response system (IxRS).  Patients, all study personnel, the designated evaluating 
physician(s), and the Sponsor and its agents (with the exception of the IxRS service 
provider, the remote unblinded monitoring staff, the unblinding statistician, and the 
unblinded pharmacists at the sites) will be blinded to treatment assignment.  Only the 
IxRS provider and the Sponsor’s unblinding statistician will have access to the 
unblinding code during the study.    
A pharmacist or other qualified individual designated by the study site will prepare and 
administer the study drug as outlined in Section 4.3.2 and Appendix 4.  While blinded 
treatment kits will be used during the randomization phase of the study (Week 24 to 
Week 48), and because of potential differences in the viscosity of the omalizumab and 
placebo preparations, unblinding of the study site personnel responsible for 
reconstituting and/or administering study drug is possible.  To minimize the risk of 
potential bias, study site personnel who are responsible for reconstituting and/or 
administering study drugs will not be permitted to conduct any safety or efficacy 
evaluations during or after the randomization period (Week 24 to Week 60), even if the 
patient has been transitioned back to open-label omalizumab.  Additionally, personnel 

 
Omalizumab—Genentech, Inc. 
43/Protocol ML29510, Version 2 
administering study drug should apply bandages over injections sites to help maintain 
blinding.  
4.3 
STUDY TREATMENT 
4.3.1 
Formulation 
Study Drug 
Omalizumab will be supplied by the Sponsor.  Omalizumab is a sterile, white, 
preservative-free, lyophilized powder, contained in a single-use, 5-mL vial that will be 
reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a SC 
injection.  Each omalizumab vial contains 202.5 mg of omalizumab, 145.5 mg sucrose, 
2.8 mg L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg 
polysorbate 20.  Each vial is designed to deliver 150 mg of omalizumab in 1.2 mL after 
reconstitution with 1.4 mL SWFI, USP. 
For additional details, see the pharmacy manual and the Omalizumab Investigator's 
Brochure. 
Placebo 
The placebo contains the same ingredients as the omalizumab formulation listed above, 
excluding omalizumab.   
4.3.2 
Dosage, Administration, and Storage 
Patients will receive omalizumab 300 mg or placebo administered SC Q4W at the study 
site.  Missed doses will not be replaced. 
Each patient will receive two injections of study medication at every treatment visit.  For 
details regarding study drug preparation and administration, and the study drug dosing 
schedule, please refer to Appendix 4 and Appendix 5, respectively. 
Doses will be divided among more than one injection site to limit injections to not more 
than 150 mg per site.  
The reconstituted vial is to be used for single-dose administration only.  Study drug will 
be administered SC to patients in the deltoid region of the right or left arm.  Alternatively, 
the injections can be administered in the thigh if medically significant reasons preclude 
administration in the deltoid region.   
Prior to randomization, during the initial open-label treatment period, study drug will be 
administered open-label as known omalizumab.  After randomization, subjects will be 
assigned to either active or placebo medication.  As described in Section 3.1, certain 
patients meeting prespecified criteria may, at the discretion of the investigator, be 
transitioned to open-label omalizumab. 

 
Omalizumab—Genentech, Inc. 
44/Protocol ML29510, Version 2 
Study drug must be stored in refrigerated conditions (2°C−8°C; 36°F−46°F) in a limited 
access area and/or a locked refrigerator.  Study drug should be stored according to the 
storage instructions on the box immediately upon receipt but no later than 24 hours after 
receipt.  
Study drug should not be frozen or shaken.  Study drug is for single use only 
and contains no preservatives.  The solution should be used for SC injection within 
8 hours following reconstitution if stored in the vial at 2°C−8°C (36°F−46°F), or within 
4 hours of reconstitution if stored at room temperature.  Reconstituted vials should be 
protected from direct sunlight. 
Patients should be closely observed after administration of open-label omalizumab and 
blinded study drug for signs and symptoms of anaphylaxis.  This observation should be 
for a period of time that is judged to be appropriate by the investigator.  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. 
Guidelines for treatment interruption or discontinuation are provided in Section 5.1.3.   
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  See Section 5.3.5.11 for guidance on adverse 
events associated with an overdose. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(omalizumab) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs, using the IxRS 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 returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any 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. 

 
Omalizumab—Genentech, Inc. 
45/Protocol ML29510, Version 2 
4.3.4 
Post-Trial Access to Omalizumab 
The Sponsor (Genentech) may offer continued access to the study drug after study 
completion, in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  All concomitant medications should be 
reported to the investigator and recorded on the appropriate eCRF.  Patients will be 
encouraged to use the minimal dose required to control their symptoms. 
The long-acting H1 antihistamines, H2 blockers, and LTRAs allowed during the study 
are as follows.  H1 antihistamines may be used at up to four times the approved dose 
listed below; however, if more than one H1 antihistamine is used, the combined total 
dose cannot exceed four times an approved dose of H1 antihistamines.  For example, a 
patient receiving loratadine 20 mg QD would be permitted to also receive cetirizine at 
up to 20 mg QD.  The dosages of H1 antihistamines, H2 blockers, and LTRAs should 
remain stable throughout the duration of the study.   
• 
H1 antihistamines 
− 
Cetirizine 5 or 10 mg once per day (QD) 
− 
Levocetirizine dihydrochloride 2.5 or 5 mg QD 
− 
Fexofenadine 60 mg twice per day (BID), or 180 mg QD 
− 
Loratadine 10 mg QD 
− 
Desloratadine 5 mg QD  
• 
H2 blockers  
− 
Cimetidine 800 mg BID, or 400 mg four times per day (QID) 
− 
Famotidine 40 mg QD, or 20 mg QD or BID 
− 
Nizatidine 150 mg QD 
− 
Ranitadine 150 mg BID 
• 
LTRAs  
− 
Montelukast 10 mg QD 

 
Omalizumab—Genentech, Inc. 
46/Protocol ML29510, Version 2 
− 
Zafirlukast 20 mg BID 
 
All patients will be allowed to take study-defined H1 antihistamine medications at 
up to four times the approved dose, H2 blockers, and/or LTRAs during the screening, 
treatment, and follow-up periods.  Patients should remain on a stable H1 antihistamine, 
H2 blocker, and/or LTRA treatment regimen throughout the study (Day −14 to Week 60).  
Diphenhydramine (25 mg) may also be used on an as-needed basis 
(maximum three times/day) during the screening, treatment, and follow-up periods.  
4.4.2 
Prohibited Therapy 
The following medications and treatments will be restricted as specified below: 
• 
Routine (daily or every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to Day −14 and during the study period 
(baseline to Week 60):  systemic corticosteroids, hydroxychloroquine, methotrexate, 
mycophenolate, cyclosporine, or cyclophosphamide.  Additionally, during the study 
period (baseline to Week 60), prohibited routine usage also includes usage for 
greater than 10 total days during any 30-day period. 
− 
Note:  inhaled asthma controllers, including inhaled corticosteroids, are 
permitted during the study. 
• 
Routine (daily or every other day during 5 or more consecutive days) doses of 
doxepin within 14 days prior to Day −14 and during the study period (baseline to 
Week 60) 
• 
Omalizumab within 1 year prior to screening and during the study period (baseline 
to Week 60), except as provided by this study   
• 
Either IVIG or plasmapheresis within 30 days prior to Day −14 and during the study 
period (baseline to Week 60) 
 
Patients who receive any excluded therapy during screening should be considered a 
screen failure.   
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1, Appendix 2, and Appendix 3 for the schedule of assessments 
performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent from the patient or a legally authorized representative, and 
patient assent, if applicable, for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for 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 randomization.  The investigator will maintain a screening log 

 
Omalizumab—Genentech, Inc. 
47/Protocol ML29510, Version 2 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases (including onset of CIU symptoms, 
date of diagnosis, and therapies received for CIU), surgeries, reproductive status, 
smoking history, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to the screening visit.  In addition, the following specific medications used by 
the patient within 1 year prior to the screening visit will be collected:  systemic 
corticosteroids, cutaneous (topical) corticosteroids, hydroxychloroquine, methotrexate, 
cyclosporine, and cyclophosphamide. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Vital Signs 
Vital signs include measurements of pulse, and systolic and diastolic blood pressure 
while the patient is in a seated position.   
4.5.4 
Physical Examinations 
A complete physical examination performed at screening 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. 
During the study, 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. 
4.5.5 
Laboratory Assessments 
All blood draws should be performed prior to study drug administration. 
The following laboratory tests will be performed at the study site’s local laboratory: 
• 
Stool ova and parasite evaluation:  This test should be conducted in patients who 
have risk factors for parasitic disease (e.g., living in an endemic area, travel to an 
endemic area within the last 6 months, chronic GI symptoms, or chronic 
immunosuppression) AND an eosinophil count > 2 times the ULN.  This test should 
be conducted anytime during the screening period after the Day −14 results are 
available for applicable patients. 
• 
Urine pregnancy test:  All women of childbearing potential (including those who 
have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal 
women and women who have had a hysterectomy will not be required to have 
pregnancy testing.  If a local urine pregnancy test shows a positive result, then study 

 
Omalizumab—Genentech, Inc. 
48/Protocol ML29510, Version 2 
drug and/or open-label omalizumab will not be administered that day.  Other study 
procedures should also be postponed and the result must be confirmed by a serum 
pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  Please refer to the laboratory manual for additional details on central 
laboratory assessments and sample handling.  The assessments listed below will be 
performed at a central laboratory or at Genentech: 
• 
Hematology:  hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, 
white blood cell (WBC) count, percent and absolute differential count (neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells) 
• 
Serum chemistries:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN), creatinine, calcium, phosphorus, magnesium, total and direct 
bilirubin, total protein, albumin, alanine transaminase (ALT), aspartase 
transaminase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), 
creatine phosphokinase, and uric acid 
• 
Serum pregnancy test:  If a local urine pregnancy test shows a positive result, then 
the result must be confirmed by a serum pregnancy test (performed by central 
laboratory). 
• 
Urinalysis:  dipstick (pH, specific gravity, glucose, protein, ketones, blood) and 
microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria) 
• 
PD assessment:  total serum IgE level at screening (pre-dose) 
• 
Blood RNA for exploratory research (see Section 4.5.6) 
• 
Blood samples for biomarker and biochemical analyses for exploratory research 
(see Section 4.5.6) 
 
4.5.6 
Exploratory Blood RNA and Blood Biomarker Samples 
Blood samples for biomarkers and biochemical analyses will be collected from all 
patients at selected visits and stored for exploratory research and markers of drug 
response. 
Optional blood RNA samples will be collected from those patients who specifically 
consent to this optional collection.  These samples will be stored for future exploratory 
research. 
4.5.7 
Patient eDiary 
The patient eDiary (see Appendix 6), also referred to as the Urticaria Patient Daily Diary 
(UPDD), consists of questions (with specific recall periods) about the following:  itch 
severity (12 hours, twice daily), number of hives (12 hours, twice daily), largest hive size 
(12 hours, twice daily), sleep interference (24 hours), daily activity interference 
(24 hours), diphenhydramine use (24 hours), and the occurrence of angioedema 
(24 hours).  In addition, management of angioedema occurrences (24 hours) and calls to 

 
Omalizumab—Genentech, Inc. 
49/Protocol ML29510, Version 2 
a doctor, nurse, or nurse practitioner because of CIU (24 hours) will be recorded.  The 
eDiary will be given to each patient at the Day −14 visit. 
Patients will be instructed to complete the eDiary twice a day for the entire duration of 
the study, beginning at Day −14.  Patients should be encouraged to make every effort to 
stay current with their eDiary entries, even when travelling or in a location where data 
reception connectivity will not allow daily transfer of eDiary entries to the central server.  
When data reception connectivity is not available, data entries will be stored locally on 
the eDiary device and transferred at the time that such connectivity becomes available. 
The UAS is a composite score (recorded via eDiary) that reflects daily itch severity and 
daily number of hives.  The daily itch score (range 0−3) comprises the average of the 
two scores of itch severity (12-hour recall each morning and evening; see Table 1).  The 
daily number of hives score (range 0−3) comprises the average of the two scores 
(12-hour recall each morning and evening; see Table 1) associated with number of hives.  
The daily UAS (range 0−6) is the sum of the daily itch score and the daily number of 
hives score.  The UAS7 is the sum of the daily UAS during the last 7 days. 
Table 1 
Twice Daily Assessment of Disease Activity in Patients with 
Chronic Idiopathic Urticaria (Urticaria Activity Score) 
Score 
Wheals (Hives) 
Pruritus (Itch) 
0 
None 
None 
1 
Mild (1−6 hives/12 hour) 
Mild 
2 
Moderate (7−12 hives/12 hour) 
Moderate 
3 
Intense (> 12 hives/12 hour) 
Severe 
 
4.5.8 
Patient-Reported Outcomes 
The following PRO instruments will be administered as specified in Appendix 1, 
Appendix 2, and Appendix 3: 
• 
Dermatology Life Quality Index (DLQI) 
The DLQI (see Appendix 7) is a 10-item dermatology-specific health-related quality 
of life measure (Finlay and Khan 1994).  Patients rate their dermatology symptoms 
and the impact of their skin condition on various aspects of their health-related 
quality of life.  An overall score will be calculated as well as separate scores for the 
following domains:  symptoms and feelings, daily activities, leisure, work and 
school, personal relationships, and treatment.  The minimally important difference 
(MID) of overall DLQI score for patients with CIU is estimated at 2.24−3.10 
(Shikiar et al. 2005).   
• 
Urticaria Control Test (UCT) 
The UCT (see Appendix 8) is 4-item instrument, designed as a brief and 
easy-to-use tool; it may be utilized to assess urticarial control and to screen urticaria 

 
Omalizumab—Genentech, Inc. 
50/Protocol ML29510, Version 2 
patients with poorly controlled disease (Weller et al. 2014).  The UCT questionnaire 
has a 4-week recall period.  Low scores indicate poorly controlled urticaria.  The 
developers recommended a value of 12 for controlled disease (i.e., all patients 
exhibiting UCT values of  ≤ 11 are considered to have poorly controlled disease).  
• 
Urticaria Activity and Impact Measure (U-AIM) 
The U-AIM (see Appendix 9) is a 9-item instrument designed to assess the patient’s 
urticaria activity and impact during the past 7 days (Genentech data on file).  The 
questionnaire asks about the severity of the CIU symptoms (itch, hives, and 
angioedema) and how much these symptoms bothered the patient.  It also inquires 
about how much CIU symptoms interfered with the patient’s daily activities and 
sleep.  It concludes by asking the patient to rate the extent to which their urticaria 
was under control.  
• 
Insomnia Severity Index (ISI)  
The ISI (see Appendix 10) is a 7-item questionnaire measuring self-perceptions of 
insomnia symptoms and the impact of these symptoms on patient health and daily 
life (Morin 1993).  It encompasses sleep onset, sleep maintenance, awakening, 
sleep pattern satisfaction, interference with daily functioning, noticeability of sleep 
problem to others, and distress caused by sleep problem.  The total score ranges 
from 0−28 points (higher scores indicate greater insomnia severity).  The developers 
provided the following guidance to the score interpretation; however, this guidance 
needs further empirical validation:  0−7 = no clinically significant insomnia, 
8−14 = sub-threshold insomnia, 15−21 = clinical insomnia (moderate severity), and 
22−28 = clinical insomnia (severe).  The recommended MID for ISI score is 6 
(Bastien 2001; Yang et al. 2009).  
• 
Generalized Anxiety Disorder 7-Item (GAD-7) scale 
The GAD-7 scale (see Appendix 11) is a 7-item questionnaire with good reliability as 
well as criterion, construct, factorial, and procedural validity.  The total score ranges 
from 0−21, with higher scores indicating greater anxiety.  Cut points of 5, 10, and 15 
might be interpreted as representing mild, moderate, and severe levels of anxiety, 
respectively (Spitzer et al. 2006). 
• 
Work Productivity and Activity Index (WPAI) 
The WPAI (see Appendix 12) is a 6-item questionnaire that measures four domains 
of health-related quality of life associated with reduced productivity:  absenteeism, 
presenteeism, work productivity loss, and activity impairment.  The absenteeism is 
assessed as a percentage of total work time that a patient missed due to a health 
problem.  The presenteeism is evaluated as the extent to which a health problem 
affected patient’s productivity while working.  The total productivity loss is the 
product of absenteeism and presenteeism combined.  The impact on activities of 
daily living represents to what extent a health problem affected the patient’s 
activities of daily living outside of work.  The scores are generated as percentages 
for each of the abovementioned domains, with higher scores indicating more 
productivity problems associated with the health state (Reilly et al. 1993). 
• 
Patient Global Impression of Change (P-GIC) scale 

 
Omalizumab—Genentech, Inc. 
51/Protocol ML29510, Version 2 
The P-GIC (see Appendix 13) is a one-item scale asking patients to rate the change 
in their CIU they experienced since the beginning of the study (Genentech data on 
file).  The questionnaire is intended to understand how patients subjectively 
perceive the change in their CIU. 
 
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 5.3.5. 
4.5.9 
Clinician-Reported Outcomes 
• 
In-Clinic Measured Urticaria Activity Score (IC-UAS) 
The IC-UAS (see Appendix 14) is a paper-based, in-clinic measured UAS based on 
the patient’s condition during the 12 hours prior to the visit.  This score will be 
recorded every 4 weeks as outlined in the schedule of assessments 
(see Appendix 1, Appendix 2, and Appendix 3).  The IC-UAS should be completed 
by a healthcare professional based on an interview of the patient.  
The IC-UAS is a composite score with numeric severity intensity ratings (0 = none to 
3 = intense/severe) for the number of wheals (hives) and the severity of the itch.  
The maximum IC-UAS value is 6. 
• 
Clinician Global Impression of Change (C-GIC) scale 
The C-GIC (see Appendix 15) is a one-item scale asking clinicians to rate the 
change in the patient’s CIU since the beginning of the study (Genentech data on 
file).  The questionnaire is intended to understand how clinicians subjectively 
perceive the change in the patient’s CIU. 
 
4.5.10 
Samples for Roche Clinical Repository 
Genentech is a member of the Roche group and participates in the collection and/or 
submission of biological samples to the Roche Clinical Repository (RCR).  Collection 
and submission of biological samples to the RCR is contingent upon the review and 
approval of the RCR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site is not granted the necessary approval for RCR sampling, this 
section of the protocol will not be applicable at that site. 
4.5.10.1 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future. 
RCR specimens will be used to achieve the following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 

 
Omalizumab—Genentech, Inc. 
52/Protocol ML29510, Version 2 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Sample Collection 
The following samples will be collected and stored in the RCR for research purposes, 
including but not limited to research on dynamic (non-inherited) biomarkers related to 
omalizumab or CIU: 
• 
Blood for biomarker and biochemical analyses (required for patients consenting to 
participate in this study) 
• 
Blood for RNA extraction (optional) 
• 
Remaining blood samples from study-related procedures (optional) 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.10.3 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is “double-coded” by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A “linking key” between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 

 
Omalizumab—Genentech, Inc. 
53/Protocol ML29510, Version 2 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens 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. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.10.4 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate in the study ML29510.  Patients may also 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to 
provide optional blood RNA samples and remaining blood samples from study-related 
procedures for storage in the RCR.  Patients who decline to participate in the collection 
of these optional samples will not provide a separate signature.  A separate, specific 
signature is not required for submission of blood for biomarker and biochemical analyses 
to the RCR.   
The investigator should document whether or not the patient has given consent to 
participate in optional blood RNA samples and remaining blood samples from study-
related procedures for storage in the RCR by completing the appropriate section of the 
RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.5.10.5 
Withdrawal from the Roche Clinical Repository 
Patients have the right to withdraw their specimens from the RCR at any time for any 
reason.  If a patient wishes to withdraw consent to the testing of his or her specimens, 
the investigator must inform the Medical Monitor in writing of the patient's wishes through 
use of the RCR Subject Withdrawal Form and, if the trial is ongoing, must enter the date 

 
Omalizumab—Genentech, Inc. 
54/Protocol ML29510, Version 2 
of withdrawal on the RCR Research Sample Withdrawal of Informed Consent eCRF.  
The patient will be provided with instructions on how to withdraw consent after the trial is 
closed.  A patient's withdrawal from Study ML29510 does not, by itself, constitute 
withdrawal of specimens from the RCR.  Likewise, a patient's withdrawal from the RCR 
does not constitute withdrawal from Study ML29510. 
4.5.10.6 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
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 withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
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 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site 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 indicates a 
potential health hazard to patients. 

 
Omalizumab—Genentech, Inc. 
55/Protocol ML29510, Version 2 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
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 Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Omalizumab (Xolair) is currently registered in over 90 countries and is indicated for 
adults and children (6 years of age and above in the E.U.) with moderate to severe 
persistent allergic asthma whose symptoms are inadequately controlled with inhaled 
corticosteroids. 
As of 30 June 2014, Xolair is currently registered in over 40 countries, including the U.S., 
for adults and adolescents (12 years of age and above) with chronic spontaneous 
(idiopathic) urticaria refractory to standard of care.  Consult local prescribing information 
for more information. 
The adverse event profile of omalizumab observed during the allergic asthma clinical 
development program was very similar to placebo with the most commonly reported 
adverse reactions were injection site reactions, including injection site pain, swelling, 
erythema, pruritus, and headaches.  
Of the adverse events of special interest, anaphylactic reactions were observed but were 
rare and typically occurring within 2 hours of the first injection.  
Although a numerical imbalance in malignancy was observed in the omalizumab 
treatment group compared with the control group, the short exposure duration is not 
consistent with the biology of solid organ pathogenesis; additionally, the diversity in the 
type of cancers observed and the clinical features of the individual cases render a causal 
relationship unlikely. 

 
Omalizumab—Genentech, Inc. 
56/Protocol ML29510, Version 2 
The overall adverse event profile in the pooled Phase III CSU studies was consistent 
with the known safety profile of omalizumab in patients with allergic asthma, with the 
exception of adverse events that were specifically related to the respective indications.  
The overall incidence of adverse events across the omalizumab treatment groups was 
broadly similar to that seen with placebo.  In general, omalizumab at the proposed doses 
of 150 mg and 300 mg was well tolerated in the treatment of patients with severe, 
refractory CSU/CIU, including in patients with multiple concomitant medications.  Both 
doses appeared to be well tolerated, with no evidence of dose-related adverse events.  
Injection site reactions are a known side effect of omalizumab treatment, and those 
observed in CSU/CIU patients were consistent with those observed in allergic asthma.  
There were no subsets of patients identified who had increased risks of serious adverse 
events or adverse events of special interest. 
During the conduct of the study, a treatment assignment may be unblinded only in the 
event of a life-threatening medical emergency that requires immediate 
unblinding/unmasking.  In such cases, unblinding will be implemented following standard 
procedures, and only following agreement by both the investigator and Medical Monitor 
that unblinding is necessary. 
The Sponsor Safety Reporting Department (independent from the study team) will break 
the treatment code for all unexpected serious adverse events that are considered by the 
investigator to be related to study drug for the purpose of regulatory reporting.  The 
study team will remain blinded to study treatment. 
Safety data, including serious and non-serious adverse events and laboratory test 
results, will be reviewed internally on a periodic basis during the conduct of the study.   
Events described in Section 5.1.1 through Section 5.1.3 will be closely monitored and 
represent selected adverse events for this study. 
Please refer to the Omalizumab Investigator’s Brochure for additional information on 
safety risks.  
5.1.1 
Anaphylaxis 
Anaphylaxis has been reported to occur after administration of omalizumab in 
premarketing clinical trials and in postmarketing spontaneous reports.  Signs and 
symptoms in these reported cases have included bronchospasm, hypotension, syncope, 
urticaria, and/or angioedema of the throat or tongue.  Some of these events have been 
life-threatening.  In premarketing clinical trials in patients with asthma, anaphylaxis was 
reported in 3 of 3507 (0.1%) patients. 
In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to 
omalizumab use was estimated to be at least 0.2% of patients based on an estimated 

 
Omalizumab—Genentech, Inc. 
57/Protocol ML29510, Version 2 
exposure of about 57,300 patients from June 2003 through December 2006.  
Anaphylaxis has occurred as early as after the first dose of omalizumab, but also has 
occurred beyond 1 year after beginning regularly scheduled treatment.  
The analysis of all cases of anaphylaxis submitted to Novartis show that, the majority of 
anaphylactic-type reactions have been reported to occur after the first dose with 
numbers decreasing with subsequent doses.  As expected for an anaphylactic-type 
reaction (Type I), events were reported to occur predominantly within the first 2 hours 
post-dosing with few reports occurring as far as > 36 hours post-dose.  
Warning 
Because of the risk of anaphylaxis, patients should be closely observed for an 
appropriate period of time after omalizumab administration, and healthcare providers 
administering omalizumab should be prepared to manage anaphylaxis that can be 
life-threatening.  Patients should also be informed of the signs and symptoms of 
anaphylaxis and instructed to seek immediate medical care should symptoms occur. 
Please refer to the Omalizumab Investigator’s Brochure for additional information. 
5.1.2 
Clinical Trial Experience with Omalizumab in Patients with CIU 
The safety of omalizumab for the treatment of CIU was assessed in three placebo-
controlled, multiple-dose clinical trials of 12 weeks (CIU Trial 2) and 24 weeks in duration 
(CIU Trials 1 and 3).  The data described in Table 2 below reflect omalizumab 
exposure for 733 patients enrolled and receiving at least one dose of omalizumab in 
the three clinical trials, including 684 patients exposed for 12 weeks and 427 
exposed for 24 weeks. 

 
Omalizumab—Genentech, Inc. 
58/Protocol ML29510, Version 2 
Table 2 
Adverse Reactions Occurring in ≥ 2% in Omalizumab-Treated 
Patients and More Frequently than in Patients Treated with 
Placebo (Day 1 to Week 12) in CIU Trials 
CIU Trials 1, 2, and 3 Pooled 
Adverse Reactions a 
Omalizumab
150 mg 
(n = 175) 
Omalizumab 
300 mg 
(n = 412) 
Placebo 
(n = 242) 
Gastrointestinal disorders 
 
Nausea 
2 (1.1%) 
11 (2.7%) 
6 (2.5%) 
Infections and infestations 
 
Nasopharyngitis 
16 (9.1%) 
27 (6.6%) 
17 (7.0%) 
 
Sinusitis 
2 (1.1%) 
20 (4.9%) 
5 (2.1%) 
 
Upper respiratory tract infection 
2 (1.1%) 
14 (3.4%) 
5 (2.1%) 
 
Viral upper respiratory tract infection 
4 (2.3%) 
2 (0.5%) 
(0.0%) 
Musculoskeletal and connective tissue disorders 
 
Arthralgia 
5 (2.9%) 
12 (2.9%) 
1 (0.4%) 
Nervous system disorders 
 
Headache 
21 (12.0%) 
25 (6.1%) 
7 (2.9%) 
Respiratory, thoracic, and mediastinal disorders 
 
Cough 
2 (1.1%) 
9 (2.2%) 
3 (1.2%) 
CIU = chronic idiopathic urticaria. 
a by MedDRA (15.1) System Organ Class and Preferred Term. 
 
Malignancies 
A small numerical imbalance (0.5% vs. 0.2%) in malignant neoplasms was observed in 
clinical studies of adults and adolescents (≥ 12 years of age) with asthma and other 
allergic disorders.  The observed malignancies in omalizumab-treated patients were a 
variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid 
occurring more than once, and five other types occurring once each.  The majority of 
patients were observed for less than 1 year.  
A subsequent observational study, A Epidemiologic Study of Xolair (Omalizumab): 
Evaluating Clinical Effectiveness and Long-Term Safety in Patients with Moderate to 
Severe Asthma (EXCELS), was done as a post-marketing commitment to the FDA.  This 
study’s pre-specified primary outcomes measures were all malignancy, all malignancies 
excluding non-melanoma skin carcinoma, and overall serious adverse events.  This 
study enrolled 5007 omalizumab-treated and 2829 non-omalizumab-treated 
patients  ≥ 12 years old with moderate to severe persistent asthma and followed them for 
up to 5 years, with mean follow-up of 3.7 years.  Patients were not randomized or 
blinded and were assigned to omalizumab or non-omalizumab cohorts based on clinical 
decisions related to initiation and continuation of omalizumab.  In EXCELS, the 

 
Omalizumab—Genentech, Inc. 
59/Protocol ML29510, Version 2 
incidence rates of primary malignancies (per 1000 patient years) were similar among 
omalizumab-treated (12.3) and non-omalizumab-treated patients (13.0).  However, study 
limitations preclude definitively ruling out a malignancy risk with omalizumab.  Study 
limitations include:  the observational study design, the bias introduced by allowing 
enrollment of patients previously exposed to omalizumab (88%), enrollment of patients 
(56%) while a history of cancer or a premalignant condition were study exclusion criteria, 
and the high study discontinuation rate (44%). 
Cardiovascular and Cerebrovascular Events from Clinical Studies in 
Patients with Asthma 
In the observational EXCELS study, a higher incidence rate of overall cardiovascular 
and cerebrovascular serious adverse events was observed in omalizumab-treated 
patients (13.4) compared to non-omalizumab-treated patients (8.1).  Increases in rates 
were observed for transient ischemic attack (0.7 vs. 0.1), myocardial infarction (2.1 vs. 
0.8), pulmonary hypertension (0.5 vs. 0), pulmonary embolism/venous thrombosis (3.2 
vs. 1.5), and unstable angina (2.2 vs. 1.4), while the rates observed for ischemic stroke 
and cardiovascular death were similar among both study cohorts.  
In the observational EXCELS study, patients were not randomized or blinded and were 
assigned to omalizumab or non-omalizumab cohorts based on clinical decisions related 
to initiation and continuation of omalizumab.  Omalizumab and non-omalizumab cohorts 
were balanced for smoking history and age.  However, baseline cardiovascular risk 
factors were higher in the omalizumab-treated cohort than the non-omalizumab-treated 
cohort (Food and Drug Administration 2014).  More omalizumab-treated patients were 
diagnosed with severe asthma (50%) compared to the non-omalizumab-treated 
patients (23%). 
Interpretation of the EXCELS study results related to cardiovascular and 
cerebrovascular events has been limited by the observational study design, the inclusion 
of patients previously exposed to omalizumab (88%), baseline imbalances in 
cardiovascular risk factors between the treatment groups, an inability to adjust for 
unmeasured risk factors, and the high study discontinuation rate.  
A separate pooled analysis of 25 randomized double-blind, placebo-controlled clinical 
trials of 8 to 52 weeks in duration included 3342 omalizumab-treated patients and 2895 
placebo-treated patients.  The primary outcomes of interest included cardiovascular 
death, myocardial infarction, arrhythmias, heart failure, stroke, transient ischemic attack, 
pulmonary hypertension, pulmonary embolism, and unstable angina.  Across all the 
studies, a total of 8 events occurred in the omalizumab-treated patients compared with 
15 in the placebo patients, and no notable differences were observed in the rates of 
specific cardiovascular events (Food and Drug Administration 2014).  However, the 
results of the pooled analysis were based on a low number of events, slightly younger 
patients, and shorter duration of follow-up than the observational EXCELS study; 

 
Omalizumab—Genentech, Inc. 
60/Protocol ML29510, Version 2 
therefore, the results are insufficient to confirm or reject the findings noted in the 
observational EXCELS study.  

 
Omalizumab—Genentech, Inc. 
61/Protocol ML29510, Version 2 
5.1.3 
Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 3.   
Table 3 
Guidelines for Management of Specific Adverse Events 
Event 
Action to Be Taken 
Anaphylaxis 
• 
Administer omalizumab only in a healthcare setting by 
healthcare providers prepared to manage anaphylaxis that can 
be life-threatening.  
• 
Observe patients closely for an appropriate period of time after 
administration of omalizumab. 
• 
Inform patients of the signs and symptoms of anaphylaxis, and 
instruct them to seek immediate medical care should signs or 
symptoms occur. 
Acute asthma symptoms 
• 
Omalizumab has not been shown to alleviate asthma 
exacerbations acutely. 
• 
Do not use omalizumab to treat acute bronchospasm or status 
asthmaticus. 
Angioedema 
• 
Patients with CIU can have angioedema as part of their 
symptoms. 
− 
When angioedema poses a risk to the airway, the 
emergent use of systemic corticosteroids is indicated. 
− 
Patients who need to be treated with systemic 
corticosteroids will be discontinued from study treatment 
and followed for safety for the remainder of the study. 
− 
Patients will be provided emergency contact information 
and advised to contact a physician during the entire study, 
in case of angioedema. 
Serum sickness 
• 
In post-approval use, some patients have experienced a 
constellation of signs and symptoms including 
arthritis/arthralgia, rash, fever, and lymphadenopathy with an 
onset 1 to 5 days after the first or subsequent injections of 
omalizumab. 
− 
These signs and symptoms have recurred after additional 
doses in some patients. 
− 
Although circulating immune complexes or a skin biopsy 
consistent with a Type III reaction were not seen with 
these cases, these signs and symptoms are similar to 
those seen in patients with serum sickness. 
− 
Physicians should stop omalizumab if a patient develops 
this constellation of signs and symptoms. 
Parasitic infections 
• 
Monitor patients at high risk of geohelminth infection while on 
omalizumab therapy.  Insufficient data are available to 
determine the length of monitoring required for geohelminth 
infections after stopping omalizumab treatment. 
 

 
Omalizumab—Genentech, Inc. 
62/Protocol ML29510, Version 2 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious 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 Good Clinical Practice, 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), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram, 
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 5.3.5.10) 

 
Omalizumab—Genentech, Inc. 
63/Protocol ML29510, Version 2 
• 
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 criteria; 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 5.4.1 for 
reporting instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious 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 Section 5.4.1 for reporting instructions).  Adverse events of special interest 
for this study include the following: 
• 
Suspected anaphylaxis due to omalizumab, as defined by Sampson’s criteria 
(Sampson et al. 2006; see Appendix 16) 
• 
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. 
• 
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 5.3.5.6). 
 

 
Omalizumab—Genentech, Inc. 
64/Protocol ML29510, Version 2 
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 Section 5.4, Section 5.5, and 
Section 5.6. 
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 5.4.1 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 112 days 
(approximately 5 drug half-lives) after the last administration of study drug or study 
discontinuation/termination, whichever is later.  After this period, the investigator should 
report any serious adverse events that are believed to be related to prior study drug 
treatment (see Section 5.6). 
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?”  
 

 
Omalizumab—Genentech, Inc. 
65/Protocol ML29510, Version 2 
5.3.3 
Assessment of Severity of Adverse Events 
Table 4 provides guidance for assessing adverse event severity. 
Table 4 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see 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 or 
not an adverse event is considered to be related to the study drug, indicating “yes” or 
“no” accordingly.  The following guidance should be taken into consideration (see also 
Table 5): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 
 

 
Omalizumab—Genentech, Inc. 
66/Protocol ML29510, Version 2 
Table 5 
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 
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. 

 
Omalizumab—Genentech, Inc. 
67/Protocol ML29510, Version 2 
5.3.5.2 
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. 
5.3.5.3 
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 5.4.1 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. 
5.3.5.4 
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., dosage modification, treatment 
interruption, or treatment discontinuation) 

 
Omalizumab—Genentech, Inc. 
68/Protocol ML29510, Version 2 
• 
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  
– 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
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., ALP 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 if 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.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
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., dosage modification, treatment 
interruption, or 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. 

 
Omalizumab—Genentech, Inc. 
69/Protocol ML29510, Version 2 
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 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
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 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 a non-serious adverse event of special interest 
(see Section 5.4.1). 
5.3.5.7 
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 5.4.1).  This 
includes death attributed to progression of CIU. 
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.  The term “sudden death” should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  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. 
If the death is attributed to progression of CIU, “chronic idiopathic urticaria progression” 
should be recorded on the Adverse Event eCRF.   

 
Omalizumab—Genentech, Inc. 
70/Protocol ML29510, Version 2 
5.3.5.8 
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”). 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic Idiopathic Urticaria 
Medical occurrences or symptoms of deterioration that are anticipated as part of CIU 
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 CIU on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated chronic idiopathic urticaria”). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient 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.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
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 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available 
 

 
Omalizumab—Genentech, Inc. 
71/Protocol ML29510, Version 2 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded 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 5.4.1). 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
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 using the contact information provided in 
Section 5.4.1.1; 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 (see Section 5.4.1 for further details) 
• 
Non-serious adverse events of special interest (see Section 5.4.1 for further details) 
• 
Pregnancies (see Section 5.4.2 for further details) 
 
The investigator must report new significant follow-up information for these events 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 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 

 
Omalizumab—Genentech, Inc. 
72/Protocol ML29510, Version 2 
5.4.1 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.1.1 
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 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 
below. 
Genentech Drug Safety Department 
Fax No.:  
 
 
650-225-4630 
Alternate Fax No: 
650-225-4682 
Email: 
 
 
 
us_drug.safety@gene.com 
 
5.4.1.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 112 days (approximately 5 drug half-lives) after the 
last administration of study drug or study discontinuation/termination, whichever is later.  
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 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 in Section 5.4.1.1.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.2 
Reporting Requirements for Pregnancies 
5.4.2.1 
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 112 days after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 

 
Omalizumab—Genentech, Inc. 
73/Protocol ML29510, Version 2 
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 the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided in Section 5.4.1.1.  Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system. 
5.4.2.2 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male 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 5.4.1).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant). 
5.4.3 
Medical Contact 
Genentech Medical Monitor:  
, M.D., M.S. 
Genentech, Inc. 
Telephone No.: 
 
 
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.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.2.1. 

 
Omalizumab—Genentech, Inc. 
74/Protocol ML29510, Version 2 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
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 (defined as 
112 days [approximately 5 drug half-lives] after the last administration of study drug or 
study discontinuation/termination, whichever is later), if the event is believed to be 
related to prior study drug treatment.   
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided in 
Section 5.4.1.1. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious 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 U.S. prescribing information for 
omalizumab, found in the USPI.   
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 
6.1 
DETERMINATION OF SAMPLE SIZE 
Assuming a 60% rate of clinical worsening in CIU assessed by UAS7 in the placebo 
group (including 10% dropout imputed as worsening CIU) and a rate of 30% in the 
omalizumab continuation group (including 10% dropout imputed as clinical worsening 
CIU) in the period up to 24 weeks post-randomization, a total of 117 patients will need to 

 
Omalizumab—Genentech, Inc. 
75/Protocol ML29510, Version 2 
be randomized at a 3:2 ratio (3 omalizumab continuation group patients for every 
2 placebo patients) to ensure 90% power to detect a difference in clinical worsening CIU 
rates as a primary analysis comparison at the 0.05 alpha level (2-sided test).  In addition, 
as it is estimated that 15% of patients will either drop out during the open-label treatment 
period or not meet the adherence criteria, and that 66.5% of those who do not drop out 
or fail adherence criteria will be responders, this study will need to enroll at least 207 
(117 / [0.665 • 0.85]) patients to ensure adequate randomization numbers for the primary 
analysis.  This sample size will also ensure at least 80% power for each of the 
secondary analyses. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The disposition of patients for each study period will be summarized by treatment group 
with respect to the number of patients randomized, treated, and completing each study 
period.  Patient discontinuation and the reason for discontinuation will be summarized by 
treatment group for each study period.  The number of patients who complete each 
scheduled dose will be summarized by treatment group.  The number of patients who 
violate key eligibility criteria as well as those who have major protocol deviations will be 
summarized by treatment group for each study period. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Treatment groups entering the double-blind randomization period of the study will be 
assessed for comparability with respect to demographic (e.g., age, sex, race/ethnicity) 
and baseline characteristics (e.g., body weight, total IgE levels, UAS7).  
6.4 
EFFICACY ANALYSES 
Efficacy analyses will be based on the modified intent-to-treat (mITT) principle.  All 
patients meeting criteria for randomization, who are also randomized and receive at 
least one dosage of blinded study drug, will be included in analyses.  Analyses groups 
will be defined according to the patients’ assigned treatments regardless of the actual 
treatment received.   
Analyses comparing rates of clinical worsening CIU after randomization, including the 
primary analysis, will include the counts and proportions of the response among all 
patients as well as in the treatment groups being compared.  The 95% confidence 
intervals will be presented for each within-group proportion and for the difference in 
proportions between treatment groups.  The 2-sided chi-square p-value will be 
presented to compare the treatment group proportions.   
Analyses comparing changes in UAS7 or any other continuous outcome measure will 
include the means, standard deviations, and 95% confidence intervals for all patients, for 
each treatment group, and for the difference between groups accompanied by p-values 
whenever applicable. 

 
Omalizumab—Genentech, Inc. 
76/Protocol ML29510, Version 2 
For all efficacy analyses, statistical significance will be declared if the p-value for the 
comparison is less than 0.05. 
6.4.1 
Missing Data for Efficacy Analyses 
For the purposes of comparing clinical worsening CIU rates, any patient who 
discontinues from the study before the end of the applicable observation period will be 
considered to have experienced clinical worsening, as defined by the primary endpoint.  
For analyses related to continuous endpoints, any patient who discontinues from the 
study may have their endpoints imputed whenever appropriate.  Further details related 
to imputations for missing data will be outlined in the Statistical Analysis Plan (SAP) 
before the database is locked. 
6.4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the percentage of patients who experience 
a clinical worsening of CIU as defined by UAS7 ≥ 12 for at least 2 consecutive weeks 
post-randomization between Weeks 24 and 48.  The analysis of the primary endpoint will 
consist of comparisons made using a simple chi-square test which will include the 
p-value for the comparison between treatment groups as well as the 95% confidence 
interval for the difference.  
6.4.3 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Time to clinical worsening in CIU, defined based on the same criteria as the primary 
endpoint (UAS7 ≥ 12 for at least 2 consecutive weeks), from randomization 
(Week 24) to Week 48 will consist of treatment comparisons using the log-rank 
p-value and 95% confidence interval for the difference in the survival estimates from 
a corresponding Kaplan-Meier survival analysis. 
• 
Percentage of patients who experience a clinical worsening of CIU as defined by 
UAS7 > 6 for at least 2 consecutive weeks post-randomization between Weeks 24 
and 48.  The analysis of this secondary endpoint will consist of comparisons made 
using a simple chi-square test which will include the p-value for the comparison 
between treatment groups as well as the 95% confidence interval for the difference. 
• 
UAS7 (24- vs. 48-week value) among patients who have responded to omalizumab 
treatment at 24 weeks and completed a further 24 weeks of omalizumab (48 weeks 
total) will be assessed by the change from randomization (Week 24) to Week 48 in 
UAS7 and analyzed in the context of a non-inferiority hypothesis test with 
non-inferiority margin 5.  The p-value from the non-inferiority test will be used to 
determine the value of continued treatment in this study. 
• 
Retreatment efficacy, defined by change in UAS7 from time of retreatment to 
12 weeks after retreatment, among patients randomized to the placebo arm who are 
retreated with open-label omalizumab after randomization and receive at least 
12 weeks of omalizumab therapy as retreatment, will be analyzed using a 2-sided, 

 
Omalizumab—Genentech, Inc. 
77/Protocol ML29510, Version 2 
one sample t-test.  The p-value from this test will be used to evaluate the superiority 
of retreating after experiencing clinical worsening among these patients. 
 
6.5 
SAFETY ANALYSES 
Safety analyses will be performed for all patients treated with study drug.  Safety will be 
assessed by adverse events, vital signs, and clinical laboratory evaluations.  
Adverse events will be collected from the time of the first study-specific procedure 
through the last observation visit.  Verbatim descriptions of adverse events will be coded 
and analyzed using appropriate thesaurus terms.  A treatment-emergent adverse event 
is defined as any adverse event reported, or worsening of an existing condition on or 
after the first dose of study drug.  Treatment-emergent adverse events will be 
summarized by treatment group.  Clinical laboratory data (e.g., serum chemistry and 
hematology evaluations) and vital signs will be summarized by descriptive statistics for 
each treatment group. 
6.6 
PHARMACODYNAMIC ANALYSIS 
Total serum IgE level at screening (pre-dose) versus time data will be tabulated by 
treatment group and summarized using descriptive statistics (e.g., mean, standard 
deviation, minimum, and maximum).   
6.7 
EXPLORATORY ANALYSES 
For details on how each exploratory analysis will be conducted, see the SAP. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) 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 CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data or other electronic data will be sent 
directly to the CRO, using the CRO's standard procedures to handle and process the 
electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.   

 
Omalizumab—Genentech, Inc. 
78/Protocol ML29510, Version 2 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures.  
Patient eDiary data will be collected through 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 eDiary device data will be available for view access only via 
secure access to a web server.  Only identified and trained users may view the data, and 
their actions become part of the audit trail.  The Sponsor and study sites will have view 
access only to the web server.  System backups for data stored by the Sponsor and 
records retention for the study data will be consistent with the Sponsor’s standard 
procedures. 
Paper PRO questionnaires will be faxed, scanned, or couriered from the site to the data 
entry center.  Scanned paper PROs will be transferred via a secure email system. 
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 CRO and should be handled in accordance 
with instructions from the CRO. 
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. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Once the study is complete, the eDiary 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 on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification 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.  

 
Omalizumab—Genentech, Inc. 
79/Protocol ML29510, Version 2 
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. 
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, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC 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, PRO completed forms, eDiary data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 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.   

 
Omalizumab—Genentech, Inc. 
80/Protocol ML29510, Version 2 
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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the 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).  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 E.U. or European 
Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  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/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
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 

 
Omalizumab—Genentech, Inc. 
81/Protocol ML29510, Version 2 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  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 
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 of 1996 (HIPAA).  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 OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
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/EC.  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/EC, and 
archived in the site’s study file.  

 
Omalizumab—Genentech, Inc. 
82/Protocol ML29510, Version 2 
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. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
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 (i.e., LPLV). 
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/EC 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. 

 
Omalizumab—Genentech, Inc. 
83/Protocol ML29510, Version 2 
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. 
9.3 
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/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and a CRO.  The CRO will provide clinical operations 
management, data management, and medical monitoring.  An IxRS will be used to 
assign patient numbers, monitor enrollment and patient status, and to manage study 
treatment requests and shipments. 
Patient data will be recorded via an EDC system using eCRFs (see Section 7.2).  
A blinded external adjudication committee will review potential events of anaphylaxis. 
9.5 
PUBLICATION 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, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.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 
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 

 
Omalizumab—Genentech, Inc. 
84/Protocol ML29510, Version 2 
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. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC 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). 

 
Omalizumab—Genentech, Inc. 
85/Protocol ML29510, Version 2 
10. 
REFERENCES 
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research. Sleep Med 2001;2:297−307. 
Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and 
chronic urticaria: 2014 update. J Allergy Clin Immunol 2014;133:1270−7. 
Fiebiger E, Maurer D, Holub H, et al. Serum IgG autoantibodies directed against the 
alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a 
distinct subset of chronic urticaria patients? J Clin Invest 1995;96:2606−12. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure 
for routine clinical use. Clin Exp Dermatol 1994;19:210−16. 
Food and Drug Administration. FDA Drug Safety Communication: FDA approves label 
changes for asthma drug Xolair (omalizumab), including describing slightly higher 
risk of heart and brain adverse events. 26 September 2014 [cited 24 October 
2014]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm414911.htm. 
Grattan CE, Francis DM, Hide M, et al. Detection of circulating histamine releasing 
autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp 
Allergy 1991;21:695−704. 
Greaves MW. Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol 2003;3:363−8. 
Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE 
receptor as a cause of histamine release in chronic urticaria. N Engl J Med 
1993;328:1599−604. 
Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic 
idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy 
Clin Immunol 2013;132:101−9. 
Kozel MM, Sabroe RA. Chronic urticaria: aetiology, management and current and future 
treatment options. Drugs 2004;64:2515−36. 
Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic 
or spontaneous urticaria. N Engl J Med. 2013;368:924−35. 
Morin CM. Insomnia: Psychological Assessment and Management. New York, NY: 
Guilford Press; 1993. 
Niimi N, Francis DM, Kermani F, et al. Dermal mast cell activation by autoantibodies 
against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 
1996;106:1001−6. 
Reilly MC, Zbrozek AS, Dukes E. The validity and reproducibility of a work productivity 
and activity impairment measure.  PharmacoEconomics 1993;4:353−65. 

 
Omalizumab—Genentech, Inc. 
86/Protocol ML29510, Version 2 
Saini SS, Bindslev-Jensen C, Maurer M. Efficacy and safety of omalizumab in patients 
with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 
antihistamines: a randomized, placebo-controlled study. J Invest Dermatol 2014 
Jul 21. doi: 10.1038/jid.2014.306. [Epub ahead of print] 
Saini S, Rosen KE, Hsieh HJ. A randomized, placebo-controlled, dose-ranging study of 
single-dose omalizumab in patients with H1-antihistamine-refractory chronic 
idiopathic urticaria. J Allergy Clin Immunol 2011;128:567−73. 
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;117:391−7. 
Shikiar R, Harding G, Leahy M, et al. Minimal Important Difference (MID) of the 
Dermatology Life Quality Index (DLQI): results from patients with chronic idiopathic 
urticaria. Health Qual Life Outcomes 2005;3:36.  
Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized 
anxiety disorder: the GAD-7. Arch Intern Med 2006;166:1092−7. 
Tilles SA. Approach to therapy in chronic urticaria: when benadryl is not enough. Allergy 
Asthma Proc 2005;26:9−12. 
Tong LJ, Balakrishnan G, Kochan JP, et al. Assessment of autoimmunity in patients with 
chronic urticaria. J Allergy Clin Immunol 1997;99:461−5. 
Weller K, Groffik A, Church MK, et al. Development and validation of the Urticaria 
Control Test: a patient-reported outcome instrument for assessing urticaria control. 
J Allergy Clin Immunol. 2014;133:1365−72. 
XOLAIR® (omalizumab) U.S. Package Insert, Genentech USA, Inc. and Novartis 
Pharmaceuticals Corporation. 2014 Mar [cited 2014 Apr 15]. Available from 
http://www.gene.com/download/pdf/xolair_prescribing.pdf. 
Yang M, Morin CM, Schaefer K, et al. Interpreting score differences in the Insomnia 
Severity Index: using health-related outcomes to define the minimally important 
difference. Curr Med Res Opin. 2009;25:2487−94 
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for 
the definition, classification, diagnosis, and management of urticaria: the 2013 
revision and update. Allergy 2014;69:868−87. 
Zweiman B, Valenzano M, Atkins PC. Modulation of serum histamine releasing activity in 
chronic idiopathic urticaria. Immunopharmacology 1998;39:225−34. 
 

APPENDIX 1 (cont’d) 
Schedule of Assessments for Screening and Open-Label Treatment Period 
Omalizumab—Genentech, Inc. 
88/Protocol ML29510, Version 2 
 
Screening a 
Open-Label Treatment Period (Baseline to Week 24)
End of Study Week
 
 
Baseline
4 
8 
12  
16 
20 
24 b 
Follow-Up 
Visit for 
Non-Responders c
ET d 
Day
(Window)
−14 
(−6/ 
+2) 
−7 
(± 3) 
1 
 
29 
(± 3) 
57 
(± 3) 
85 
(± 3) 
113
(± 3) 
141
(± 3) 
169
(± 3) 
Day 253 
(± 7) 
 
Visit #
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
 
U-AIM k 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
ISI k 
 
 
x 
 
 
x 
 
 
x 
x 
x 
GAD-7 k 
 
 
x 
 
 
x 
 
 
x 
x 
x 
WPAI k 
 
 
x 
 
 
x 
 
 
x 
x 
x 
P-GIC scale k 
 
 
 
 
 
 
 
 
x 
 
 
IC-UAS k  
x 
x 
x 
 
 
 
 
 
x 
x 
x 
C-GIC scale k 
 
 
 
 
 
 
 
 
x 
 
 
Laboratory tests l 
Hematology m 
x 
 
 
 
 
 
 
 
x 
 
x 
Stool ova and parasite evaluation n 
 
x 
 
 
 
 
 
 
 
 
 
Chemistry o 
x 
 
 
 
 
 
 
 
 
 
 
Urinalysis p 
x 
 
 
 
 
 
 
 
 
 
 
Thyroperoxidase antibody 
x 
 
 
 
 
 
 
 
 
 
 
CU index 
x 
 
 
 
 
 
 
 
 
 
 
PD sample (total serum IgE) 
x 
 
 
 
 
 
 
 
 
 
 
Blood samples for storage  
x 
 
 
 
 
 
 
 
x 
 
x 
Blood RNA (optional) q 
x 
 
 
 
 
 
 
 
x 
 
x 

APPENDIX 1 (cont’d) 
Schedule of Assessments for Screening and Open-Label Treatment Period 
Omalizumab—Genentech, Inc. 
89/Protocol ML29510, Version 2 
C-GIC = Clinical Global Impression of Change; CU = chronic urticaria; DLQI = Dermatology Life Quality Index; eDiary = electronic diary; ET = early 
termination; GAD-7 = Generalized Anxiety Disorder Assessment 7-Item Scale; IC-UAS = in-clinic Urticaria Activity Score; IgE = immunoglobulin E; 
ISI = Insomnia Severity Index; IxRS = interactive voice and web response systems; P-GIC = Patient Global Impression of Change; 
PD = pharmacodynamic; PRO = patient-reported outcome; U-AIM = Urticaria Activity and Impact Measure; UAS = Urticaria Activity Score; 
UCT = Urticaria Control Test; WPAI = Work Productivity and Activity Index. 
Note:  Unless otherwise indicated, all assessments should be performed prior to study drug administration. 
a The screening period should be 14 to 20 days long.  Day −14 and Day −7 are provided for reference.  The Day −14 visit should be conducted 
20 to 14 days prior to baseline (Day 1).  Complete eDiary information must be collected on 7 consecutive days prior to the Day 1 visit.  The 
Day −7 visit is intended for review of screening labs collected on Day −14, assessment of IC-UAS score, evaluation of patients’ eDiary use, and 
additional eDiary training if necessary.   
b The Week 24 visit is the end of the open-label treatment period and the start of the double-blind randomization period.  This visit should be 
scheduled on Day 169; a 3-day window is allowed.  Patients who meet criteria for randomization will be randomized and receive their first dose 
of blinded study drug at this visit; this is the only assessment (noted by gray shading) being performed as part of the double-blind randomization 
period (see Appendix 2).  The final two weeks of the open-label treatment period are scheduled to occur during Weeks 23 and 24 but may 
vary somewhat depending on patient scheduling.  Randomization will not be permitted after Day 190 from baseline.   
c Patients who do not meet the criteria for randomization (e.g., because of non-response to omalizumab during the open-label treatment period) 
should return for a final follow-up visit 12 weeks after the Week 24 visit, which will include assessments for adverse events and PROs.  Patients 
will not be required to complete the eDiary during this 12-week period. 
d Patients who discontinue study treatment early (after baseline, but before Week 24 [Day 169]) should return for an early termination visit.  
These assessments do NOT apply to non-responders who discontinue study treatment before the Day 253 visit.  Non-responders who 
complete the Week 24 visit but discontinue study treatment before Day 253 should instead complete the assessments listed under the column 
“Follow-Up Visit for Non-Responders.” 
e Medical history includes clinically significant diseases (including onset of CIU symptoms, date of diagnosis, and therapies received for CIU), 
surgeries, reproductive status, smoking history, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to the screening visit. 
f Vital signs include measurements of pulse, and systolic and diastolic blood pressure while the patient is in a seated position.  Record 
abnormalities on the Adverse Event eCRF. 
g A complete physical examination performed at screening 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. 
h All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal women 
and women who have had a hysterectomy will not be required to have pregnancy testing.  If a local urine pregnancy test shows a positive result, 
then study drug and/or open-label omalizumab will not be administered that day.  Other study procedures should also be postponed and the 
result must be confirmed by a serum pregnancy test (test to be conducted by central laboratory) prior to proceeding. 

APPENDIX 1 (cont’d) 
Schedule of Assessments for Screening and Open-Label Treatment Period 
Omalizumab—Genentech, Inc. 
90/Protocol ML29510, Version 2 
i 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.  After initiation of study drug, all adverse events will be reported until 112 days (approximately 5 drug half-lives) 
after the last dose of study drug or study discontinuation/termination, whichever is later.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that are believed to be related to prior study drug treatment (see Section 5.6).  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. 
j Includes UAS7 (itch score, number of hives), largest size of hives, sleep interference score, activity interference question, rescue medication 
(diphenhydramine) use, angioedema episodes, and number of calls to doctor or nurse.  Daily eDiary is to be completed twice a day by the 
patient.  The eDiary will be given to patients on Day −14. 
k All PROs, including the DLQI, UCT, U-AIM, ISI, GAD-7, WPAI, P-GIC scale, IC-UAS (itch score + number of hives score), and C-GIC scale 
must be completed prior to  administration of study drug. 
l Samples for laboratory tests will be taken pre-dose on dosing days. 
m Hematology to include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count (e.g., neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
n Note that stool ova and parasite examination should be performed on Day −7 in patients with an eosinophil count > 2 times the ULN on Day −14 
AND risk factors for parasitic disease. Stool ova and parasite examination will be performed by a local laboratory. 
o Serum chemistries to include sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and 
direct bilirubin, total protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatine phosphokinase, and uric acid. 
p Urinalysis to include dipstick (i.e., pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (e.g., sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria). 
q Blood RNA to be collected only in patients providing a separate, specific signature on the Informed Consent Form to document the patient's 
agreement to participate in this optional procedure. 

APPENDIX 2 (cont’d) 
Schedule of Assessments for Double-Blind Randomization Period and Follow-Up Period 
Omalizumab—Genentech, Inc. 
93/Protocol ML29510, Version 2 
g All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal women 
and women who have had a hysterectomy will not be required to have pregnancy testing.  If a local urine pregnancy test shows a positive result, 
then study drug and/or open-label omalizumab will not be administered that day.  Other study procedures should also be postponed and the 
result must be confirmed by a serum pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
h 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.  After initiation of study drug, all adverse events will be reported until 112 days (approximately 5 drug half-lives) 
after the last dose of study drug or study discontinuation/termination, whichever is later.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that are believed to be related to prior study drug treatment (see Section 5.6).  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. 
i Includes UAS7 (itch score, number of hives), largest size of hives, sleep interference score, activity interference question, rescue medication 
(diphenhydramine) use, angioedema episodes, and number of calls to doctor or nurse.  Daily eDiary is to be completed twice a day by the 
patient.  The eDiary will be given to patients on Day −14. 
j All PROs, including the DLQI, UCT, U-AIM, ISI, GAD-7, WPAI, P-GIC scale, IC-UAS (itch score + number of hives score), and C-GIC scale 
must be completed prior to administration of study drug. 
k Samples for laboratory tests will be taken pre-dose on dosing days. 
l Hematology to include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count 
(e.g., neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
m Blood RNA to be collected only in patients providing a separate, specific signature on the Informed Consent Form to document the patient's 
agreement to participate in this optional procedure. 

 
Omalizumab—Genentech, Inc. 
94/Protocol ML29510, Version 2 
Appendix 3  
Schedule of Assessments for Patients Who Transition to Open-Label Omalizumab 
after Randomization 
Post-Randomization 
Open-Label Treatment Period a 
Follow-Up Period b 
First Day of
Transition 
Every 4 Weeks 
Until 48 Weeks 
of Total Treatment
Week 48 c 
Week 52 c
Week 56 c 
Week 60 c
ET 
Visit Window (days)
 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
Vital signs (blood pressure 
and pulse) d 
x 
x 
x 
 
 
x 
x 
Weight/height 
 
 
 
 
 
x 
x 
Pregnancy test e 
x 
x 
 
 
 
 
 
Concomitant medication usage 
x 
x 
x 
x 
x 
x 
x 
Adverse events f 
x 
x 
x 
x 
x 
x 
x 
Open-label omalizumab 
x 
x 
 
 
 
 
 
Site to contact IxRS 
x 
x 
 
 
 
x 
x 
PROs 
Patient eDiary g 
x 
x 
x 
x 
x 
x 
x 
DLQI h 
x 
 
x 
 
 
x 
x 
UCT h 
x 
 
x 
 
 
x 
x 
U-AIM h 
x 
 
x 
 
 
x 
x 
ISI h 
x 
 
x 
 
 
x 
x 
GAD-7 h 
x 
 
x 
 
 
x 
x 
WPAI h 
x 
 
x 
 
 
x 
x 
P-GIC scale h 
x 
 
x 
 
 
 
 

APPENDIX 3 (cont’d) 
Schedule of Assessments for Patients Who Transition to Open-Label Omalizumab After Randomization 
Omalizumab—Genentech, Inc. 
95/Protocol ML29510, Version 2 
Post-Randomization 
Open-Label Treatment Period a 
Follow-Up Period b 
First Day of
Transition 
Every 4 Weeks 
Until 48 Weeks 
of Total Treatment
Week 48 c 
Week 52 c
Week 56 c 
Week 60 c
ET 
Visit Window (days)
 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
IC-UAS h  
x 
 
x 
 
 
x 
x 
C-GIC scale h 
x 
 
x 
 
 
 
 
Laboratory tests i 
Hematology j 
x 
 
x 
 
 
 
x 
Blood samples for storage 
x 
 
x 
 
 
x 
x 
Blood RNA (optional) k 
x 
 
x 
 
 
x 
x 
C-GIC = Clinical Global Impression of Change; DLQI = Dermatology Life Quality Index; eDiary = electronic diary; ET=early termination; 
GAD-7 = Generalized Anxiety Disorder Assessment 7-Item Scale; IC-UAS = in-clinic Urticaria Activity Score; IgE = immunoglobulin E; ISI = Insomnia 
Severity Index; IxRS = interactive voice and web response systems; P-GIC = Patient Global Impression of Change; PRO = patient-reported 
outcome; U-AIM = Urticaria Activity and Impact Measure; UAS = Urticaria Activity Score; UCT = Urticaria Control Test; WPAI = Work Productivity 
and Activity Index. 
Note:  Unless otherwise indicated, all assessments should be performed prior to study drug administration. 
a Patients will complete a variable number of study visits during this time period, depending upon when they have transitioned to open-label 
omalizumab.  For example, if a patient transitioned to open-label omalizumab 10 weeks after randomization (Week 34), this patient would 
complete study visits at day of transition (Week 34), 4 weeks after transition (Week 38), 8 weeks after transition (Week 42), and 12 weeks after 
transition (Week 46) and subsequently, at Week 48 would enter the follow-up period, during which time omalizumab would be withdrawn. 
b The 12-week follow-up period applies only to patients who have completed the first 48 weeks of the study. 
c The Week 48 and Week 60 visits will take place at the study site.  The Week 52 and Week 56 visits will take place by telephone by the study 
site personnel to include collection of adverse event and concomitant medication information.  Patients will continue to be assessed via eDiary 
during this period.  No study treatment will be given during the follow-up period. 
d Vital signs include measurements of pulse, and systolic and diastolic blood pressure while the patient is in a seated position.  Record 
abnormalities on the Adverse Event eCRF. 
e All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal women 
and women who have had a hysterectomy will not be required to have pregnancy testing.  If a local urine pregnancy test shows a positive result, 

APPENDIX 3 (cont’d) 
Schedule of Assessments for Patients Who Transition to Open-Label Omalizumab After Randomization 
Omalizumab—Genentech, Inc. 
96/Protocol ML29510, Version 2 
then study drug and/or open-label omalizumab will not be administered that day.  Other study procedures should also be postponed and the 
result must be confirmed by a serum pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
f 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.  After initiation of study drug, all adverse events will be reported until 112 days (approximately 5 drug half-lives) 
after the last dose of study drug or study discontinuation/termination, whichever is later.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that are believed to be related to prior study drug treatment (see Section 5.6).  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. 
g Includes UAS7 (itch score, number of hives), largest size of hives, sleep interference score, activity interference question, rescue medication 
(diphenhydramine) use, angioedema episodes, and number of calls to doctor or nurse.  Daily eDiary is to be completed twice a day by the 
patient.  The eDiary will be given to patients on Day −14. 
h All PROs, including the DLQI, UCT, U-AIM, ISI, GAD-7, WPAI, P-GIC scale, IC-UAS (itch score + number of hives score), and C-GIC scale 
must be completed prior to administration of study drug. 
i Samples for laboratory tests will be taken pre-dose on dosing days. 
j Hematology to include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent, and absolute differential count (neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
k Blood RNA to be collected only in patients providing a separate, specific signature on the Informed Consent Form to document the patient's 
agreement to participate in this optional procedure. 

 
Omalizumab—Genentech, Inc. 
97/Protocol ML29510, Version 2 
Appendix 4  
Study Drug Preparation and Administration 
An unblinded pharmacist or other qualified designated individual will prepare the study 
drug (omalizumab or placebo) injection as outlined below. 
RECONSTITUTION 
The supplied study drug must be reconstituted with Sterile Water for Injection (SWFI), 
USP, using the following instructions: 
1. 
Before reconstitution, determine the number of vials that will need to be 
reconstituted (each vial delivers 150 mg of study drug). 
2. 
Draw 1.4 mL SWFI, USP, into a 3-mL syringe equipped with a 1-inch, 
18-gauge needle. 
3. 
Place the vial upright on a flat surface and, using standard aseptic technique, insert 
the needle and inject the SWFI, USP, directly onto the product. 
4. 
Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to 
evenly wet the powder.  Do not shake. 
5. 
Gently swirl the vial for 5 to 10 seconds approximately every 5 minutes in order to 
dissolve any remaining solids.  The lyophilized product takes 15 to 20 minutes to 
dissolve.  If it takes longer than 20 minutes to dissolve completely, gently swirl the 
vial for 5 to 10 seconds approximately every 5 minutes until there are no visible 
gel-like particles in the solution.  Do not use if the contents of the vial do not dissolve 
completely in 40 minutes. 
6. 
After reconstitution, the study drug solution is somewhat viscous and will appear 
clear or slightly opalescent.  It is acceptable if there are a few small bubbles or foam 
around the edge of the vial; there should be no visible gel-like particles in the 
reconstituted solution.  Do not use if foreign particles are present. 
7. 
Invert the vial for 15 seconds to allow the solution to drain toward the stopper. 
8. 
Use the study drug solution within 8 hours following reconstitution when 
stored in the vial at 2 to 8°C (36 to 46°F), or within 4 hours of reconstitution 
when stored at room temperature.  Reconstituted study drug vials should be 
protected from sunlight. 
9. 
Using a new 3-mL syringe equipped with a 1-inch, 18-gauge needle, insert the 
needle into the inverted vial.  Position the needle tip at the very bottom of the 
solution in the vial stopper when drawing the solution into the syringe.  The 
reconstituted product is somewhat viscous; in order to obtain the full 1.2-mL dose, 
all of the product must be withdrawn from the vial before expelling any air or 
excess solution from the syringe.  Before removing the needle from the vial, pull the 
plunger all the way back to the end of the syringe barrel to remove all of the solution 
from the inverted vial. 
10. Replace the 18-gauge needle with a 25-gauge needle for subcutaneous (SC) 
injection. 

APPENDIX 4 (cont’d) 
Study Drug Preparation and Administration 
Omalizumab—Genentech, Inc. 
98/Protocol ML29510, Version 2 
11. Expel air, large bubbles, and any excess solution in order to obtain the required 
1.2-mL dose.  A thin layer of small bubbles may remain at the top of the solution in 
the syringe.   
 
ADMINISTRATION 
Administer study drug by SC injection.  The injection may take 5−10 seconds to 
administer because the solution is slightly viscous.  Do not administer more than 150 mg 
(contents of one vial) per injection site.   
Cap the syringe.  Label the syringe with the patient number, kit number details, and 
protocol number (ML29510).  The syringe is now ready for use. 
 

 
Omalizumab—Genentech, Inc. 
99/Protocol ML29510, Version 2 
Appendix 5  
Study Drug Dosing and Scheduling Table 
Study Drug Dosing Schedule  
(Number of Injections and Total Injection Volumes) 
Dose (mg) 
Number of Injections 
Total Volume Injected (mL) a 
300 
2 injections:  1.2 mL omalizumab + 
1.2 mL omalizumab 
2.4 
Placebo 
2 injections:  1.2 mL placebo + 
1.2 mL placebo 
2.4 
a 1.2 mL maximum delivered volume per vial. 
 

 
Omalizumab—Genentech, Inc. 
100/Protocol ML29510, Version 2 
Appendix 6  
Patient Electronic Diary (eDiary) 
Note:  The patient eDiary is also referred to as the Urticaria Patient Daily Diary (UPDD).  
GENERAL INSTRUCTIONS 
Please answer each question to the best of your ability. 
There are no right or wrong answers.  
For each question, please choose the response that describes your experience.  
Please pay close attention to the timeframe of interest.  Some questions ask about the 
past 12 hours, while others ask about the past 24 hours. 
  
INSTRUCTIONS FOR COUNTING THE NUMBER OF HIVES AND 
MEASURING THE SIZE OF THE LARGEST HIVE 
Count each hive separately even if you have more than one hive grouped together 
with other hives.  
Please use the ruler that you have been given to measure the size of your largest hive.  
If you need help, please have someone else take this measurement for you.  Please do 
not measure a group of hives as one hive. 
 

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
101/Protocol ML29510, Version 2 
Today’s Date 
 
 
 
- 
 
 
 
-
 
 
 
 
Day 
Month 
Year 
Please complete this section every morning throughout the duration of the study. 
(Please circle only one response.)  
1. 
Thinking about the past 12 hours, please record the severity of itch and the number 
of hives you may have had associated with your skin condition.  Please count each 
hive separately even if you have more than one hive grouped together with other 
hives.  
 
Itch (severity)  
Hives (number) 
0 = none 
1 = mild 
2 = moderate 
3 = severe 
0 = none 
1 = between 1 and 6 hives 
2 = between 7 and 12 hives 
3 = greater than 12 hives 
  
This next question asks you to estimate the size of your largest hive in centimeters 
(cm).  Please use the ruler that you have been provided with to make this 
measurement.  If your largest hive is located on your back or in a place that is hard 
to reach, please have someone else take this measurement for you.  
When measuring the largest hive size, please do not measure a group of hives 
as one hive. 
Largest Hive (size) 
0 = none 
1 = less than 1.25 centimeters (cm)  
2 = between 1.25 centimeter (cm) and 2.5 centimeters (cm)  
3 = greater than 2.5 centimeters (cm)  
 

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
102/Protocol ML29510, Version 2 
Today’s Date 
 
 
 
- 
 
 
 
-
 
 
 
 
Day 
Month 
Year 
Please complete this section every evening throughout the duration of the study. 
(Please circle only one response.)  
2. 
Thinking about the past 12 hours, please record the severity of itch and the number 
of hives you may have had associated with your skin condition.  Please count each 
hive separately even if you have more one than one hive grouped together with 
other hives. 
 
Itch (severity)  
Hives (number) 
0 = none 
1 = mild 
2 = moderate 
3 = severe 
0 = none 
1 = between 1 and 6 hives 
2 = between 7 and 12 hives 
3 = greater than 12 hives 
  
This next question asks you to estimate the size of your largest hive in centimeters 
(cm).  Please use the ruler that you have been provided with to make this 
measurement.  If your largest hive is located on your back or in a place that is hard 
to reach, please have someone else take this measurement for you.  
When measuring the largest hive size, please do not measure a group of hives 
as one hive. 
Largest Hive (size) 
0 = none 
1 = less than 1.25 centimeters (cm)  
2 = between 1.25 centimeter (cm) and 2.5 centimeters (cm)  
3 = greater than 2.5 centimeters (cm)  

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
103/Protocol ML29510, Version 2 
Today’s Date 
 
 
 
- 
 
 
 
-
 
 
 
 
Day 
Month 
Year 
Please complete this section once each day throughout the duration of the study 
(preferably at the same time each day).  
(Please circle only one response.) 
3. 
Please rate how much your hives or itch interfered with your sleep during the 
past 24 hours.  
0 
No interference 
1 
Mild, little interference with sleep 
2 
Moderate, awoke occasionally, some interference with sleep 
3 
Substantial, woke up often, severe interference with sleep 
  
4. 
Please rate how much your hives or itch interfered with your daily activities during 
the past 24 hours.  This could include work, school, sports, hobbies, and activities 
with friends and family. 
0 
No interference 
1 
Mild, little interference with daily activities 
2 
Moderate, some interference with daily activities  
3 
Substantial, severe interference with daily activities 
 

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
104/Protocol ML29510, Version 2 
These next questions are about your symptoms and how you managed them 
during the past 24 hours.  
5. 
During the past 24 hours, how many pills of diphenhydramine 25 mg did you use in 
order to control symptoms of your skin condition such as itch or hives?  
0 = 0 pills 
1 = 1 pill 
2 = 2 pills 
3 = 3 pills 
  
6. 
a.  During the past 24 hours, did you have any rapid swelling on your face, 
(especially your eyelids or lips), inside your mouth (including your throat or tongue), 
or elsewhere on your body?  This rapid swelling, also called angioedema, is at a 
deeper level under your skin than hives.  
0 = No (GO TO Question 7) 
 
1 = Yes  
  
b.  If Yes, how did you treat this rapid swelling?  (Circle all that apply.) 
0 
Did nothing (GO TO Question 7) 
1 
Took some prescription or non-prescription medication  
2 
Called my doctor, nurse, or nurse practitioner 
3 
Went to see my doctor, nurse, or nurse practitioner 
4 
Went to the emergency room at the hospital 
5 
Was hospitalized 
  
7. 
During the past 24 hours, did you or someone else call your doctor, nurse, or nurse 
practitioner because of your skin condition? 
0 = No   
 
 
 
1 = Yes  
 

 
Omalizumab—Genentech, Inc. 
105/Protocol ML29510, Version 2 
Appendix 7  
Dermatology Life Quality Index (DLQI) 
 

 
Omalizumab—Genentech, Inc. 
106/Protocol ML29510, Version 2 
Appendix 8  
Urticaria Control Test (UCT) 

 
Omalizumab—Genentech, Inc. 
107/Protocol ML29510, Version 2 
Appendix 9  
Urticaria Activity and Impact Measure (U-AIM) 
This questionnaire asks you about your urticaria and how it may have affected your life 
in the past 7 days.  Please answer each question to the best of your ability.  There are 
no right or wrong answers.  For each question, mark an : in the one box that best 
describes your experience. 
1. 
Thinking about your urticaria in the past 7 days, on average, how severe was 
your itch?  
☐ 0 
None (skip to question 2) 
☐ 1 
Mild 
 
☐ 2 
Moderate 
 
☐ 3 
Severe 
 
 
 
1a. In the past 7 days, how much of the time did your itch bother you? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  
2. 
Thinking about your urticaria in the past 7 days, on average, how many hives did 
you have per day?  Count each hive separately even if you had more than one hive 
grouped together with other hives. 
☐ 0 
None (skip to question 3) 
☐ 1 
Between 1 and 6 hives 
 
☐ 2 
Between 7 and 12 hives 
 
☐ 3 
Greater than 12 hives 
 
 
 
2a. In the past 7 days, how much of the time did your hives bother you? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  

APPENDIX 9 (cont’d) 
Urticaria Activity and Impact Measure (U-AIM) 
Omalizumab—Genentech, Inc. 
108/Protocol ML29510, Version 2 
3. 
In the past 7 days, how many days did you have any rapid swelling on your face, 
(especially your eyelids or lips), inside your mouth (including your throat or tongue), 
or elsewhere on your body?  This rapid swelling, also called angioedema, is at a 
deeper level under your skin than hives.  
☐ 0 
Did not experience angioedema (skip to question 4) 
☐ 1 
1 − 2 days 
 
☐ 2 
3 − 4 days 
 
☐ 3 
5 − 6 days 
 
☐ 4 
7 days 
 
 
 
3a. In the past 7 days, how much of the time did this rapid swelling 
 
 
(angioedema) bother you? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  
4. 
In the past 7 days, how much of the time did urticaria symptoms interfere with your 
daily activities? This could include work, school, sports, hobbies, and activities with 
friends and family. 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  
5. 
In the past 7 days, how much of the time did urticaria symptoms interfere with 
your sleep? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  

APPENDIX 9 (cont’d) 
Urticaria Activity and Impact Measure (U-AIM) 
Omalizumab—Genentech, Inc. 
109/Protocol ML29510, Version 2 
6. 
How would you rate your urticaria control in the past 7 days? 
☐ 0 
Completely controlled 
☐ 1 
Well controlled 
☐ 2 
Somewhat controlled 
☐ 3 
Poorly controlled 
☐ 4 
Not controlled at all 
   
Please check that you answered every question.  Thank you for your answers! 
 

 
Omalizumab—Genentech, Inc. 
110/Protocol ML29510, Version 2 
Appendix 10  
Insomnia Severity Index (ISI) 
Subject ID:  ________________________  
 
Date:  _______________ 
 
For each question below, please circle the number corresponding most accurately to 
your sleep patterns in the last two weeks. 
For the first three questions, please rate the SEVERITY of your sleep difficulties. 
1. 
Difficulty falling asleep:  
  None 
Mild 
Moderate 
Severe 
Very Severe 
 
0 
1 
2 
3 
4 
2. 
Difficulty staying asleep: 
  None 
Mild 
Moderate 
Severe 
Very Severe 
 
0 
1 
2 
3 
4 
3. 
Problem waking up too early in the morning: 
  None 
Mild 
Moderate 
Severe 
Very Severe 
 
0 
1 
2 
3 
4 
4. 
How SATISFIED/DISSATISFIED are you with your current sleep pattern? 
   Very 
 
 
 
 
Very 
  Satisfied 
Satisfied 
Neutral 
Dissatisfied 
Dissatisfied 
 
0 
1 
2 
3 
4 
5. 
To what extent do you consider your sleep problem to INTERFERE with 
your daily functioning (e.g., daytime fatigue, ability to function at work/daily 
chores, concentration, memory, mood). 
   Not at all 
  A Little 
Somewhat 
   Much 
Very Much 
  Interfering 
Interfering 
Interfering 
Interfering 
Interfering 
 
0 
1 
2 
3 
4 
6. 
How NOTICEABLE to others do you think your sleeping problem is in terms of 
impairing the quality of your life? 
   Not at all 
  A Little 
Somewhat 
   Much 
Very Much 
  Noticeable Noticeable 
Noticeable 
Noticeable 
Noticeable 
 
0 
1 
2 
3 
4 
7. 
How WORRIED/DISTRESSED are you about your current sleep problem? 
   Not at all 
  A Little 
Somewhat 
   Much 
Very Much 
 
0 
1 
2 
3 
4 

APPENDIX 10 (cont’d) 
Insomnia Severity Index (ISI) 
Omalizumab—Genentech, Inc. 
111/Protocol ML29510, Version 2 
Guidelines for Scoring/Interpretation: 
Add scores for all seven items  =  _____   
Total score ranges from 0−28 
  0−7 
 =  No clinically significant insomnia 
  8−14 
 =  Subthreshold insomnia 
15−21 
 =  Clinical insomnia (moderate severity) 
22−28 
 =  Clinical insomnia (severe) 
© Morin, CM. (1993, 1996, 2000, 2006). 
 

 
Omalizumab—Genentech, Inc. 
112/Protocol ML29510, Version 2 
Appendix 11  
Generalized Anxiety Disorder 7 Item (GAD-7) Scale 
  
GAD-7 
 
Over the last 2 weeks, how often have you 
been bothered by the following problems? 
 
(Use “9” to indicate your answer) 
Not 
at all 
Several 
days 
More than 
half the 
days 
Nearly 
every day 
1. Feeling nervous, anxious or on edge 
0 
1 
2 
3 
2. Not being able to stop or control worrying 
0 
1 
2 
3 
3. Worrying too much about different things 
0 
1 
2 
3 
4. Trouble relaxing 
0 
1 
2 
3 
5. Being so restless that it is hard to sit still 
0 
1 
2 
3 
6. Becoming easily annoyed or irritable 
0 
1 
2 
3 
7. Feeling afraid as if something awful 
might happen 
0 
1 
2 
3 
(For office coding:  Total Score T____  =  ____  +   ____  +   ____ )
 
 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke and colleagues, 
with an educational grant from Pfizer Inc.  No permission required to reproduce, 
translate, display or distribute.

 
Omalizumab—Genentech, Inc. 
113/Protocol ML29510, Version 2 
Appendix 12  
Work Productivity and Activity Impairment Questionnaire:  
Chronic Urticaria V2.0 (WPAI:CU) 
The following questions ask about the effect of your chronic urticaria on your ability to 
work and perform regular activities.  Please fill in the blanks or circle a number, as 
indicated. 
1. 
Are you currently employed (working for pay)?  ____ No  ____ Yes 
If NO, check “NO” and skip to question 6. 
 
The next questions are about the past seven days, not including today. 
 
2. 
During the past seven days, how many hours did you miss from work because of 
problems associated with your chronic urticaria?  Include hours you missed on sick 
days, times you went in late, left early, etc., because of your chronic urticaria.  Do 
not include time you missed to participate in this study. 
_____ HOURS 
 
3. 
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
_____ HOURS 
 
4. 
During the past seven days, how many hours did you actually work? 
_____ HOURS  (If “0”, skip to question 6.) 
 

APPENDIX 12 (cont’d) 
Work Productivity and Activity Impairment Questionnaire:   
Chronic Urticaria V2.0 (WPAI:CU) 
Omalizumab—Genentech, Inc. 
114/Protocol ML29510, Version 2 
5. 
During the past seven days, how much did your chronic urticaria affect your 
productivity while you were working?   
 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual.  If chronic urticaria affected your work only a little, choose a low 
number.  Choose a high number if chronic urticaria affected your work a great deal.   
 
Consider only how much chronic urticaria affected  
productivity while you were working. 
 
 
 
 
 
 
 
 
 
 
 
Chronic urticaria 
had no effect on 
my work 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Chronic urticaria 
completely 
prevented me 
from working 
CIRCLE A NUMBER 
 
6. 
During the past seven days, how much did your chronic urticaria affect your ability to 
do your regular daily activities, other than work at a job? 
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If chronic urticaria affected your activities only a little, 
choose a low number.  Choose a high number if chronic urticaria affected your 
activities a great deal.   
 
Consider only how much chronic urticaria affected your ability  
to do your regular daily activities, other than work at a job. 
 
 
 
 
 
 
 
 
 
 
 
Chronic urticaria 
had no effect on 
my daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Chronic urticaria 
completely prevented 
me from doing my 
daily activities 
CIRCLE A NUMBER 

 
Omalizumab—Genentech, Inc. 
115/Protocol ML29510, Version 2 
Appendix 13  
Patient Global Impression of Change (P-GIC) Scale 
Please rate how your chronic idiopathic urticaria has changed since the beginning of 
the study: 
1. 
☐ Very much improved 
2. 
☐ Much improved 
3. 
☐ Minimally improved 
4. 
☐ No change 
5. 
☐ Minimally worse 
6. 
☐ Much worse 
7. 
☐ Very much worse 
 

 
Omalizumab—Genentech, Inc. 
116/Protocol ML29510, Version 2 
Appendix 14  
In-Clinic Urticaria Activity Score (IC-UAS) (Max 6) 
The physician or the person he or she designates will provide the sum of the score of the 
patient’s urticaria lesions (number of hives) and pruritus (itch) reflective of the patient's 
condition over the 12 hours prior to the visit using the following rating scale: 
Pruritus: 
0 = None 
1 = Mild – minimal awareness, easily tolerated 
2 =  Moderate – definite awareness, bothersome but tolerable 
3 = Severe – difficult to tolerate 
Number of Hives: 
0 = none 
1 = 1−6  
2 = 7−12 
3 =  > 12 
 

 
Omalizumab—Genentech, Inc. 
117/Protocol ML29510, Version 2 
Appendix 15  
Clinician Global Impression of Change (C-GIC) Scale 
Please rate how patient’s chronic idiopathic urticaria has changed since the beginning of 
the study: 
1. 
☐ Very much improved 
2. 
☐ Much improved 
3. 
☐ Minimally improved 
4. 
☐ No change 
5. 
☐ Minimally worse 
6. 
☐ Much worse 
7. 
☐ Very much worse 
 

 
Omalizumab—Genentech, Inc. 
118/Protocol ML29510, Version 2 
Appendix 16  
Sampson’s Criteria of Anaphylaxis 
ANAPHYLAXIS:  Sampson definition of anaphylaxis (clinical definition) is the acute 
onset of illness which involves SKIN, MUCOSAL TISSUE, or BOTH (e.g., generalized 
hives, pruritus or flushing, swollen lips- tongue uvula)  with one OR more of the 
following: 
• 
RESPIRATORY: Airway compromise (e.g. dyspnea, wheeze, or bronchospasm, 
stridor and reduced PEF) 
• 
CIRCULATORY: Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope) 
 
OR 
TWO or MORE of the following that occur rapidly after exposure: 
• 
SKIN, MUCOSAL TISSUE:  e.g. generalized hives, itch-flush, swollen lips- tongue-
uvula 
• 
RESPIRATORY:  Airway compromise (e.g. dyspnea, wheeze, or bronchospasm, 
stridor and reduced PEF) 
• 
CIRCULATORY:  Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope) 
• 
GASROINTESTINAL:  Persistent gastrointestinal symptoms (e.g., crampy 
abdominal pain, vomiting, nausea, diarrhea) 
 
 
 

 
Title
17-Dec-2014 19:57:48
Date and Time (UTC)
Company Signatory
Approver's Name
FINAL PROTOCOL 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. 
 
Omalizumab—Genentech, Inc. 
Protocol ML29510, Version 1 
PROTOCOL 
TITLE: 
XTEND-CIU (XOLAIR TREATMENT EFFICACY OF 
LONGER DURATION IN CHRONIC IDIOPATHIC 
URTICARIA):  A PHASE IV, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF OMALIZUMAB 
THROUGH 48 WEEKS IN PATIENTS WITH 
CHRONIC IDIOPATHIC URTICARIA 
PROTOCOL NUMBER: ML29510 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
101,612 
TEST PRODUCT: 
Omalizumab (RO5489789) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
See electronic date stamp below 

Omalizumab—Genentech, Inc. 
2/Protocol ML29510, Version 1 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 8 
PROTOCOL SYNOPSIS ...................................................................................... 9 
1. 
BACKGROUND .......................................................................................... 19 
1.1 
Chronic Idiopathic Urticaria.................................................... 19 
1.2 
Omalizumab .......................................................................... 19 
1.2.1 
Clinical Experience with Omalizumab in Patients 
with CIU................................................................................. 20 
1.2.2 
Summary of Omalizumab Clinical Efficacy in 
Patients with CIU................................................................... 21 
1.2.3 
Summary of Omalizumab Clinical Safety in 
Patients with CIU................................................................... 23 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 23 
2. 
OBJECTIVES.............................................................................................. 24 
2.1 
Primary Objective .................................................................. 24 
2.2 
Secondary Objectives............................................................ 24 
2.3 
Exploratory Objectives........................................................... 24 
3. 
STUDY DESIGN ......................................................................................... 25 
3.1 
Description of Study .............................................................. 25 
3.2 
End of Study.......................................................................... 29 
3.3 
Rationale for Study Design.................................................... 29 
3.3.1 
Omalizumab Dose and Schedule .......................................... 30 
3.4 
Outcome Measures ............................................................... 30 
3.4.1 
Primary Efficacy Outcome Measure ...................................... 30 
3.4.2 
Secondary Efficacy Outcome Measures................................ 30 
3.4.3 
Safety Outcome Measures .................................................... 31 
3.4.4 
Pharmacokinetic/Pharmacodynamic Outcome 
Measures............................................................................... 31 
3.4.5 
Exploratory Outcome Measures ............................................ 31 
4. 
MATERIALS AND METHODS .................................................................... 32 
4.1 
Patients.................................................................................. 32 

Omalizumab—Genentech, Inc. 
3/Protocol ML29510, Version 1 
4.1.1 
Inclusion Criteria.................................................................... 32 
4.1.2 
Exclusion Criteria................................................................... 33 
4.2 
Method of Treatment Assignment and Blinding..................... 34 
4.3 
Study Treatment.................................................................... 35 
4.3.1 
Formulation............................................................................ 35 
4.3.2 
Dosage, Administration, and Storage .................................... 35 
4.3.3 
Investigational Medicinal Product Accountability ................... 36 
4.3.4 
Post-Trial Access to Omalizumab.......................................... 37 
4.4 
Concomitant Therapy ............................................................ 37 
4.4.1 
Permitted Therapy ................................................................. 37 
4.4.2 
Prohibited Therapy ................................................................ 38 
4.5 
Study Assessments ............................................................... 39 
4.5.1 
Informed Consent Forms and Screening Log........................ 39 
4.5.2 
Medical History and Demographic Data ................................ 39 
4.5.3 
Vital Signs.............................................................................. 39 
4.5.4 
Physical Examinations........................................................... 39 
4.5.5 
Laboratory Assessments ....................................................... 40 
4.5.6 
Exploratory Blood RNA and Blood Biomarker 
Samples................................................................................. 41 
4.5.7 
Patient eDiary........................................................................ 41 
4.5.8 
Patient-Reported Outcomes .................................................. 42 
4.5.9 
Clinician-Reported Outcomes................................................ 43 
4.5.10 
Samples for Roche Clinical Repository.................................. 44 
4.5.10.1 
Overview of the Roche Clinical Repository............................ 44 
4.5.10.2 
Sample Collection.................................................................. 44 
4.5.10.3 
Confidentiality........................................................................ 45 
4.5.10.4 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 45 
4.5.10.5 
Withdrawal from the Roche Clinical Repository..................... 46 
4.5.10.6 
Monitoring and Oversight....................................................... 46 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 47 
4.6.1 
Patient Discontinuation.......................................................... 47 
4.6.2 
Study Treatment Discontinuation........................................... 47 

Omalizumab—Genentech, Inc. 
4/Protocol ML29510, Version 1 
4.6.3 
Study and Site Discontinuation.............................................. 47 
5. 
ASSESSMENT OF SAFETY....................................................................... 48 
5.1 
Safety Plan ............................................................................ 48 
5.1.1 
Anaphylaxis ........................................................................... 49 
5.1.2 
Clinical Trial Experience with Omalizumab in 
Patients with CIU................................................................... 50 
5.1.3 
Management of Specific Adverse Events .............................. 53 
5.2 
Safety Parameters and Definitions ........................................ 54 
5.2.1 
Adverse Events ..................................................................... 54 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 54 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 55 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 56 
5.3.1 
Adverse Event Reporting Period ........................................... 56 
5.3.2 
Eliciting Adverse Event Information ....................................... 56 
5.3.3 
Assessment of Severity of Adverse Events ........................... 57 
5.3.4 
Assessment of Causality of Adverse Events ......................... 57 
5.3.5 
Procedures for Recording Adverse Events............................ 58 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 58 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 59 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 59 
5.3.5.4 
Abnormal Laboratory Values ................................................. 59 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 60 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 61 
5.3.5.7 
Deaths ................................................................................... 61 
5.3.5.8 
Preexisting Medical Conditions.............................................. 62 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic 
Idiopathic Urticaria................................................................. 62 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 62 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 63 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 63 

Omalizumab—Genentech, Inc. 
5/Protocol ML29510, Version 1 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 63 
5.4.1 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 64 
5.4.1.1 
Events That Occur prior to Study Drug Initiation.................... 64 
5.4.1.2 
Events That Occur after Study Drug Initiation........................ 64 
5.4.2 
Reporting Requirements for Pregnancies.............................. 64 
5.4.2.1 
Pregnancies in Female Patients............................................ 64 
5.4.2.2 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 65 
5.4.3 
Medical Contact..................................................................... 65 
5.5 
Follow-Up of Patients after Adverse Events .......................... 65 
5.5.1 
Investigator Follow-Up........................................................... 65 
5.5.2 
Sponsor Follow-Up ................................................................ 66 
5.6 
Post-Study Adverse Events................................................... 66 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 66 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 67 
6.1 
Determination of Sample Size ............................................... 67 
6.2 
Summaries of Conduct of Study............................................ 67 
6.3 
Summaries of Treatment Group Comparability ..................... 67 
6.4 
Efficacy Analyses .................................................................. 67 
6.4.1 
Missing Data for Efficacy Analyses........................................ 68 
6.4.2 
Primary Efficacy Endpoint...................................................... 68 
6.4.3 
Secondary Efficacy Endpoints............................................... 68 
6.5 
Safety Analyses..................................................................... 69 
6.6 
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 69 
6.7 
Exploratory Analyses............................................................. 69 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 69 
7.1 
Data Quality Assurance......................................................... 69 
7.2 
Electronic Case Report Forms............................................... 70 

Omalizumab—Genentech, Inc. 
6/Protocol ML29510, Version 1 
7.3 
Electronic Patient-Reported Outcome Data........................... 70 
7.4 
Source Data Documentation.................................................. 71 
7.5 
Use of Computerized Systems .............................................. 71 
7.6 
Retention of Records............................................................. 72 
8. 
ETHICAL CONSIDERATIONS.................................................................... 72 
8.1 
Compliance with Laws and Regulations ................................ 72 
8.2 
Informed Consent .................................................................. 72 
8.3 
Institutional Review Board or Ethics Committee.................... 73 
8.4 
Confidentiality........................................................................ 74 
8.5 
Financial Disclosure .............................................................. 74 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 74 
9.1 
Study Documentation ............................................................ 74 
9.2 
Protocol Deviations................................................................ 75 
9.3 
Site Inspections ..................................................................... 75 
9.4 
Administrative Structure......................................................... 75 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 75 
9.6 
Protocol Amendments ........................................................... 76 
10. REFERENCES ........................................................................................... 77 
 
 
LIST OF TABLES 
Table 1 
Twice Daily Assessment of Disease Activity in Patients with 
Chronic Idiopathic Urticaria (Urticaria Activity Score).................. 41 
Table 2 
Adverse Reactions Occurring in ≥ 2% in Omalizumab-
Treated Patients and More Frequently than in Patients 
Treated with Placebo (Day 1 to Week 12) in CIU Trials.............. 50 
Table 3 
Guidelines for Management of Specific Adverse Events ............ 53 
Table 4 
Adverse Event Severity Grading Scale ....................................... 57 
Table 5 
Causal Attribution Guidance ....................................................... 58 
 

Omalizumab—Genentech, Inc. 
7/Protocol ML29510, Version 1 
 
LIST OF FIGURES 
Figure 1 
Change from Baseline in Mean UAS7:  Study Q4881g 
(ASTERIA I; Placebo versus 24 Weeks Omalizumab)................ 22 
Figure 2 
Study Schema............................................................................. 28 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments for Screening and Open-Label 
Treatment Period ........................................................................ 79 
Appendix 2 
Schedule of Assessments for Double-Blind Randomization 
Period and Follow-Up Period ...................................................... 83 
Appendix 3 
Schedule of Assessments for Patients Who Transition to 
Open-Label Omalizumab after Randomization ........................... 86 
Appendix 4 
Study Drug Preparation and Administration................................ 89 
Appendix 5 
Study Drug Dosing and Scheduling Table .................................. 91 
Appendix 6 
Patient Electronic Diary (eDiary)................................................. 92 
Appendix 7 
Dermatology Life Quality Index (DLQI) ....................................... 97 
Appendix 8 
Urticaria Control Test (UCT) ....................................................... 98 
Appendix 9 
Urticaria Activity and Impact Measure (U-AIM) ........................... 99 
Appendix 10 Insomnia Severity Index (ISI).................................................... 102 
Appendix 11 Generalized Anxiety Disorder 7 Item (GAD-7) Scale ................ 104 
Appendix 12 Work Productivity and Activity Impairment Questionnaire:  
Chronic Urticaria V2.0 (WPAI:CU) ............................................ 105 
Appendix 13 Patient Global Impression of Change (P-GIC) Scale ................ 107 
Appendix 14 In-Clinic Urticaria Activity Score (IC-UAS) (Max 6) ................... 108 
Appendix 15 Clinician Global Impression of Change (C-GIC) Scale.............. 109 
Appendix 16 Sampson’s Criteria of Anaphylaxis ........................................... 110 

Omalizumab—Genentech, Inc. 
8/Protocol ML29510, Version 1 
 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
XTEND-CIU (XOLAIR TREATMENT EFFICACY OF 
LONGER DURATION IN CHRONIC IDIOPATHIC 
URTICARIA):  A PHASE IV, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF OMALIZUMAB 
THROUGH 48 WEEKS IN PATIENTS WITH 
CHRONIC IDIOPATHIC URTICARIA 
PROTOCOL NUMBER: ML29510 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
101,612 
TEST PRODUCT: 
Omalizumab (RO5489789) 
MEDICAL MONITOR: 
, M.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 as 
instructed by the CRO. 
 

 
Omalizumab—Genentech, Inc. 
9/Protocol ML29510, Version 1 
PROTOCOL SYNOPSIS 
TITLE: 
XTEND-CIU (XOLAIR TREATMENT EFFICACY OF LONGER 
DURATION IN CHRONIC IDIOPATHIC URTICARIA):  A PHASE IV, 
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF OMALIZUMAB THROUGH 48 WEEKS IN PATIENTS 
WITH CHRONIC IDIOPATHIC URTICARIA 
PROTOCOL NUMBER: 
ML29510 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
101,612 
TEST PRODUCT: 
Omalizumab (RO5489789) 
PHASE: 
IV 
INDICATION: 
Chronic idiopathic urticaria 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Primary Objective 
The primary objective for this study is to evaluate the level of control of chronic idiopathic 
urticaria (CIU) symptoms through 48 weeks, among patients continuing omalizumab as 
compared to those receiving placebo after an initial 24 weeks of omalizumab treatment. 
Secondary Objectives 
The secondary objectives for this study are as follows: 
• 
To evaluate the response to retreatment with omalizumab in patients with CIU who have 
responded to omalizumab, but experienced recurrence or clinical worsening of disease after 
withdrawal of therapy  
• 
To evaluate whether patients who have achieved response to omalizumab after 24 weeks 
of therapy demonstrate similar levels of response after 48 weeks of therapy 
• 
To evaluate the safety of omalizumab therapy through 48 weeks in patients with CIU 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To compare the level of control of CIU symptoms, over 12 weeks after withdrawal of 
omalizumab, subsequent to completing 48 weeks versus 24 weeks of omalizumab therapy, 
among patients with CIU who have responded to omalizumab therapy 
• 
To obtain additional data on patient-reported outcome (PRO) response to omalizumab 
Study Design 
Description of Study 
This is a Phase IV, multicenter, randomized, double-blind, placebo controlled study to evaluate 
the efficacy and safety of subcutaneous (SC) omalizumab through 48 weeks as an add-on 
therapy for the treatment of refractory CIU in adolescent and adult patients (12−75 years of age) 
who remain symptomatic despite standard H1 antihistamine treatment (including doses up to 
four times above the approved dose), H2 blockers, and/or leukotriene receptor antagonists 

 
Omalizumab—Genentech, Inc. 
10/Protocol ML29510, Version 1 
(LTRAs).  The study will enroll approximately 207 patients at approximately 40 study sites in 
the U.S. 
The study will consist of the following study periods with a total duration of 62 weeks 
(see Figure 2): 
• 
Screening Period:  Day  −14 to Baseline (Week −2 to Baseline) 
• 
Open-Label Treatment Period:  Day 1 to Day 168 (Baseline to Week 24) 
• 
Double-Blind Randomization Period:  Day 169 to Day 336 (Week 24 to Week 48) 
• 
Follow-Up Period:  Day 337 to Day 420 (Week 48 to end of Week 60) 
The screening period will consist of visits at Day −14 and Day −7.  Day 1 (baseline) will mark 
the commencement of the 24-week open-label treatment period.  Patients must meet all of the 
following criteria prior to receiving treatment in the open-label treatment period: 
• 
Non-electronic diary-based Urticaria Activity Score (UAS) ≥ 4 established in the clinic 
(i.e., in-clinic UAS [IC-UAS]) based on the patient’s condition over 12 hours prior to either 
Day −14, Day −7, or Day 1 despite being on H1 antihistamine therapy 
• 
Use of H1 antihistamine treatment (up to four times the approved dose) for CIU at Day −14 
and for at least the 3 consecutive days immediately prior to Day −14 (see Section 4.4.1 for 
a list of H1 antihistamines available for use in this study) 
• 
Willing and able to complete a symptom electronic diary (eDiary), also referred to as the 
Urticaria Patient Daily Diary (UPDD), twice daily throughout the screening period to 
establish the patient’s UAS7  
Patients will have the 2-week screening period to establish their eligibility for the study and 
baseline symptom scores.  For the duration of the screening period, patients must maintain 
stable doses of their pre-screening H1 antihistamine treatment.  To be eligible for treatment 
during the open-label treatment period, patients must have no missing eDiary entries, a UAS7 
symptom score of ≥ 16 during the 7 days prior to baseline (equivalent to moderate to severe 
CIU symptoms for at least 4 out of 7 days in a week), and a weekly itch score (a component of 
the UAS7) of ≥ 8 during the 7 days prior to baseline. 
Only in exceptional circumstances, when information concerning eligibility is outstanding 
(e.g., pending laboratory data), will a screening period longer than 2 weeks be permitted.  
Patients may be re-screened upon approval from the Medical Monitor.  Circumstances that may 
permit re-screening include, but are not limited to, an IC-UAS or laboratory test results that do 
not meet eligibility requirements.  
On Day 1, eligible patients will begin open-label omalizumab 300 mg SC every 4 weeks (Q4W) 
and will continue on treatment during the 24-week open-label treatment period.  During this 
period, patients will continue reporting twice daily their UAS-related symptoms through the 
eDiary, necessary for the weekly calculation of UAS7 (which is based on the last 7 days of 
symptoms).  At the end of the open-label treatment period, patients who have responded to 
omalizumab will be randomized in a double-blinded fashion to either continue omalizumab or to 
transition to placebo for a further 24 weeks.  Patients will be eligible for randomization if they 
meet both of the following criteria: 
• 
Achieve UAS7 ≤ 6 in the final 2 weeks of the open-label treatment period (Week 23 
and Week 24) 
 
AND 
• 
Comply with omalizumab dosing for at least 5 out of the 6 planned doses, including a 
dosage at Week 20, during the initial 24-week open-label treatment period (i.e., patients 
may only be randomized if they have missed at most one dosage of omalizumab during the 
initial open-label treatment period AND did not miss their Week 20 dosage) 
Patients who meet the criteria for randomization will be randomized at a ratio of 3:2 
(omalizumab:placebo).  Randomization to treatment groups will be stratified by UAS7 at the 
point of randomization (UAS 7 = 0 vs. UAS7 > 0) and study site.  Efficacy, safety, 
pharmacokinetic (PK), and pharmacodynamic (PD) data will be collected.  Subsequent to 
randomization, patients will continue to be evaluated twice daily using the eDiary for weekly 
calculation of UAS7, which includes a weekly itch score. 

 
Omalizumab—Genentech, Inc. 
11/Protocol ML29510, Version 1 
Throughout the study (Day −14 to Week 60), patients must maintain stable doses of their 
pre-randomization combination therapy with H1 antihistamine treatment, H2 blockers, and/or 
LTRAs.  Patients will be prohibited from using non-study-drug omalizumab during the study 
(Day −14 to Week 60) (e.g., commercially available omalizumab is not permitted during the 
study).  Patients receiving non-study-drug omalizumab during the study, for any indication, will 
be discontinued from the study. 
Patients who do not meet the criteria for randomization (e.g., because of non-response to 
omalizumab during the open-label treatment period) should return for a final follow-up visit 
12 weeks after the Week 24 visit, which will include a blood draw for PK/PD measurement, and 
assessments for adverse events and PROs (see Appendix 1).  Patients will not be required to 
complete the eDiary during this 12-week period. 
Subsequent to randomization, patients may, at the discretion of the investigator, be transitioned 
from blinded study drug to open-label omalizumab at 300 mg SC Q4W if they experience 
clinically significant worsening in their CIU (as judged by the investigator); clinical worsening 
must also be accompanied by UAS7 ≥ 12 for at least 2 consecutive weeks.  That is, patients 
may potentially be transitioned to open-label omalizumab if this is deemed by the investigator to 
be clinically indicated based on clinical worsening CIU and if, after the investigator has made 
this assessment, patients are confirmed to have experienced UAS7 ≥ 12 for at least 
2 consecutive weeks as determined by eDiary entries.  Patients who are transitioned to 
open-label omalizumab will not be unblinded with respect to the treatment they had received 
between randomization and transition to open-label omalizumab.  Patients who are transitioned 
to open-label omalizumab will continue to receive open-label omalizumab as study drug until 
Week 48, after which omalizumab will be discontinued. 
The primary endpoint for this study is the percentage of patients who experience clinical 
worsening in CIU defined as UAS7 ≥ 12 for at least 2 consecutive weeks.   
After completion of the randomization period (end of Week 48), all patients will enter a 12-week 
follow-up period to allow for further characterization of the pharmacokinetics and 
pharmacodynamics of omalizumab and collection of additional efficacy and safety data.  
Patients will continue to visit the study site at 4-week intervals.  The Week 48 and Week 60 
visits will take place at the study site.  The Week 52 and Week 56 visits will take place by 
telephone by the study site personnel to include collection of adverse events and concomitant 
medication information.  Patients will continue to be assessed via eDiary during this period.  No 
study treatment will be given during the follow-up period. 
The double blindness of randomization to treatment groups should be maintained for the full 
post-randomization period of the study (until the end of the study).   
Schedule of assessments are provided in Appendix 1, Appendix 2, and Appendix 3. 
Number of Patients 
Approximately 207 patients are planned to be enrolled in this study at approximately 40 study 
sites in the U.S.  Approximately 117 patients will be randomized in this study after accounting 
for dropout, non-adherence, and non-response during the open-label treatment period.  
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 12−75 years 
• 
Diagnosis of CIU refractory to H1 antihistamines at baseline, as defined by all of 
the following: 
− 
The presence of itch and hives for ≥ 8 consecutive weeks at any time prior to enrollment 
despite current use of H1 antihistamine treatment (up to four times the approved dose) 
during this time period 
− 
UAS7 score (range 0−42) ≥ 16 and itch component of UAS7 (range 0−21) ≥ 8 during 
7 days prior to baseline 
− 
IC-UAS ≥ 4 on at least one of the screening visit days (Day −14, Day  −7, or Day 1) 
(see Section 4.5.9 for details on IC-UAS) 

 
Omalizumab—Genentech, Inc. 
12/Protocol ML29510, Version 1 
− 
Patients must have been on H1 antihistamine treatment (up to four times the approved 
dose) for CIU for at least the 3 consecutive days immediately prior to the Day −14 
screening visit and must document current use on the day of the initial screening visit. 
− 
CIU diagnosis for ≥ 6 months.  The methods used to confirm duration of CIU diagnosis 
may include patient report of onset of CIU symptoms, and the duration of CIU diagnosis 
may be made based on the initial date of these symptoms even if the diagnosis of CIU 
was made at a later date. 
• 
Willing to give written informed consent, adhere to the visit schedules, and meet study 
requirements 
− 
For patients below the legal age of consent, the child must be willing to give written 
informed assent and the parent(s)/guardian(s) must be willing to give written informed 
consent. 
− 
For patients below the legal age of consent, both child and parent must be able to 
adhere to dose and visit schedules and meet study requirements. 
• 
Willing and able to complete a daily symptom eDiary for the duration of the study 
• 
Patients must not have any missing eDiary entries in the 7 days prior to baseline. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Treatment with an investigational agent within 30 days of Day −14 
• 
Weight less than 20 kg (44 lbs) 
• 
Clearly defined underlying etiology for chronic urticarias other than CIU (main manifestation 
being physical urticaria).  This includes the following urticarias: 
− 
Acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure, or contact 
Any of the following diseases, which may have symptoms of urticaria or angioedema:  
urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary 
or acquired angioedema, lymphoma, leukemia, or generalized cancer 
• 
Evidence of parasitic infection defined as having the following three items:  
− 
Risk factors for parasitic disease (chronic gastrointestinal [GI] symptoms, travel within 
the last 6 months to an endemic area, and/or chronic immunosuppression)  
AND 
− 
An absolute eosinophil count more than twice the upper limit of normal (ULN)  
AND 
− 
Evidence of parasitic colonization or infection on stool evaluation for ova and parasites.  
Stool ova and parasite evaluation will only be conducted in patients with both risk 
factors and an eosinophil count more than twice the ULN. 
• 
Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or other skin 
disease associated with itch 
• 
Previous treatment with omalizumab within 1 year prior to Day −14 
• 
Routine (daily/every other day during 5 or more consecutive days) doses of the following 
medications within 30 days prior to Day −14:  systemic corticosteroids, hydroxychloroquine, 
methotrexate, mycophenolate, cyclosporine, or cyclophosphamide 
• 
Intravenous immunoglobulin G (IVIG) or plasmapheresis within 30 days prior to Day −14 
• 
Regular (daily/every other day) doxepin (oral) use within 14 days prior to Day −14 
• 
Patients with current malignancy, history of malignancy, or currently under work-up for 
suspected malignancy except non-melanoma skin cancer that has been treated or excised 
and is considered resolved 
• 
Hypersensitivity to omalizumab or any component of the formulation 
• 
History of anaphylactic shock 

 
Omalizumab—Genentech, Inc. 
13/Protocol ML29510, Version 1 
• 
Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, or 
other pathological conditions that could interfere with the interpretation of the study results 
and or compromise the safety of the patients 
• 
Medical examination or laboratory findings that suggest the possibility of decompensation of 
co-existing conditions for the duration of the study.  Any items that are cause for uncertainty 
must be reviewed with the Medical Monitor.  
• 
Inability to comply with study and follow-up procedures 
• 
Evidence of current drug or alcohol abuse 
• 
Nursing women or women of childbearing potential, defined as all women physiologically 
capable of becoming pregnant, including women whose career, lifestyle, or sexual 
orientation precludes intercourse with a male partner and women whose partners have 
been sterilized by vasectomy or other means, UNLESS they meet the following definition of 
post-menopausal:  12 months of natural (spontaneous) amenorrhea or 6 months of 
spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL 
or 6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) or 
hysterectomy OR are using one or more of the following acceptable methods of 
contraception:  surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception 
(implantable, patch, oral), and double-barrier methods (any double combination of:  
intrauterine device, male or female condom with spermicidal gel, diaphragm, sponge, or 
cervical cap)  
• 
Contraindications to diphenhydramine 
Length of Study 
The total duration of the study is anticipated to be 62 weeks consisting of a 2-week screening 
period, a 24-week open-label treatment period, a 24-week double-blind randomization period, 
and a 12-week follow-up period. 
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.  LPLV is expected to 
occur 60 weeks after the last patient is enrolled. 
Outcome Measures 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the percentage of patients who experience clinical 
worsening in CIU as assessed by UAS7.  The specific threshold for clinical worsening in CIU 
symptoms will be UAS7 ≥ 12, maintained for at least 2 consecutive weeks, from randomization 
(Week 24) to Week 48. 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Time to clinical worsening in CIU, defined based on the same criteria as the primary 
endpoint (maintaining UAS7 ≥ 12 for at least 2 consecutive weeks), from randomization 
(Week 24) to Week 48 
• 
Percentage of patients who experience clinical worsening in CIU assessed by UAS7, where 
the threshold for clinical worsening is UAS7 > 6 for at least 2 consecutive weeks, from 
randomization (Week 24) to Week 48 
• 
UAS7 (24- vs. 48-week value) among patients who have responded to omalizumab 
treatment at 24 weeks and completed a further 24 weeks of omalizumab (48 weeks total), 
which will be assessed by the change from randomization (Week 24) to Week 48 in UAS7 
• 
Retreatment efficacy, defined by change in UAS7 from time of retreatment to 12 weeks 
after retreatment, among patients randomized to the placebo arm who are retreated with 
open-label omalizumab after randomization and receive at least 12 weeks of omalizumab 
therapy as retreatment 

 
Omalizumab—Genentech, Inc. 
14/Protocol ML29510, Version 1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in vital signs 
• 
Clinical laboratory evaluations 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
Serum total omalizumab, and total and free immunoglobulin E (IgE) concentrations will be 
measured at: 
• 
Baseline (pre dose), Week 24 (pre-dose), Week 48, and Week 60 or early termination 
• 
The time of discontinuation from blinded treatment (i.e., start of open-label treatment 
post-randomization [pre-dose]), among patients who make the post-randomization transition 
to open-label omalizumab 
• 
The end of follow-up (i.e., 12 weeks after stopping the initial 24-week course of open-label 
omalizumab), among patients not responding to the initial 24-week course of open-label 
omalizumab 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
The proportion of patients experiencing clinical worsening in CIU (defined as maintaining 
UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 48 and 60 among patients 
randomized to continue omalizumab (i.e., during the 12 weeks after discontinuing a 
48-week course of omalizumab)  
• 
The proportion of patients experiencing clinical worsening in CIU (defined as maintaining 
UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 24 and 36 among patients 
randomized to placebo 
• 
Change from randomization (Week 24) to Week 48 in weekly itch score 
• 
Change from randomization (Week 24) to Week 48 in UAS7 
• 
Change from randomization (Week 24) to Week 48 in health-related quality-of-life as 
measured by the Dermatology Life Quality Index (DLQI) total score  
• 
Insomnia Severity Index (ISI); General Anxiety Disorder 7-Item (GAD-7) scale; and Work 
Productivity and Activity Index (WPAI) will be assessed as: 
− 
Change from baseline to Week 24 
− 
Change from randomization to Week 48  
− 
Change from the end of the randomization period (Week 48) to the end of the study 
(end of Week 60) 
• 
Proportion of angioedema days, evaluated through patient self-reports via eDiary, from 
Week 24 to Week 48 
• 
Urticaria Control Test (UCT) response and correlation with UAS7 
− 
Change in UCT from baseline to Week 24 
− 
Change in UCT from randomization to Week 48 
− 
Correlation between UCT and UAS7 from baseline to Week 24 
• 
Urticaria Activity and Impact Measure (U-AIM) response and correlation with UAS7 
− 
Change in U-AIM from baseline to Week 24 
− 
Change in U-AIM from randomization to Week 48 
− 
Correlation between U-AIM and UAS7 from baseline to Week 24 
• 
Patient Global Impression of Change (P-GIC) scale and Clinician Global Impression of 
Change (C-GIC) scale assessed at Week 24 and Week 48 

 
Omalizumab—Genentech, Inc. 
15/Protocol ML29510, Version 1 
Investigational Medicinal Products 
Study Drug 
Omalizumab will be supplied by the Sponsor.  Omalizumab is a sterile, white, preservative-free, 
lyophilized powder, contained in a single-use, 5-mL vial that will be reconstituted with Sterile 
Water for Injection (SWFI), USP, and administered as a SC injection.  Each omalizumab vial 
contains 202.5 mg of omalizumab, 145.5 mg sucrose, 2.8 mg L-histidine hydrochloride 
monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20.  Each vial is designed to deliver 
150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP. 
For additional details, see the pharmacy manual and the Omalizumab Investigator's Brochure. 
Patients will receive omalizumab 300 mg or placebo administered SC Q4W at the study site.  
Missed doses will not be replaced.  Each patient will receive two injections of study medication 
at every treatment visit.  
Placebo 
The placebo contains the same ingredients as the omalizumab formulation listed above, 
excluding omalizumab. 
Non-Investigational Medicinal Products 
See Section 4.4.1 for the long-acting H1 antihistamines, H2 blockers, and LTRAs allowed 
during the study. 
All patients will be allowed to take study-defined H1 antihistamine medications at up to four 
times the approved dose, H2 blockers, and/or LTRAs during the screening, treatment, and 
follow-up periods.  Patients should remain on a stable H1 antihistamine, H2 blocker, and/or 
LTRA treatment regimen throughout the randomization period (Week 24 to Week 48).  
Diphenhydramine (25 mg) may also be used on an as-needed basis (maximum three times/day) 
during the screening, treatment, and follow-up periods.  
Statistical Methods 
Efficacy Analyses 
Efficacy analyses will be based on the modified intent-to-treat (mITT) principle.  All patients 
meeting criteria for randomization, who are also randomized and receive at least one dosage of 
blinded study drug, will be included in analyses.  Analyses groups will be defined according to 
the patients’ assigned treatments regardless of the actual treatment received.   
Analyses comparing rates of clinical worsening CIU after randomization, including the primary 
analysis, will include the counts and proportions of the response among all patients as well as in 
the treatment groups being compared.  The 95% confidence intervals will be presented for each 
within-group proportion and for the difference in proportions between treatment groups.  The 
2-sided chi-square p-value will be presented to compare the treatment group proportions.   
Analyses comparing changes in UAS7 or any other continuous outcome measure will include 
the means, standard deviations, and 95% confidence intervals for all patients, for each 
treatment group, and for the difference between groups accompanied by p-values whenever 
applicable. 
For all efficacy analyses, statistical significance will be declared if the p-value for the 
comparison is less than 0.05. 
Missing Data for Efficacy Analyses 
For the purposes of comparing clinical worsening CIU rates, any patient who discontinues from 
the study before the end of the applicable observation period will be considered to have 
experienced clinical worsening, as defined by the primary endpoint.  For analyses related to 
continuous endpoints, any patient who discontinues from the study may have their endpoints 
imputed whenever appropriate.  Further details related to imputations for missing data will be 
outlined in the Statistical Analysis Plan (SAP) before the database is locked. 
Safety Analyses 
Safety analyses will be performed for all patients treated with study drug.  Safety will be 
assessed by adverse events, vital signs, and clinical laboratory evaluations.  
Adverse events will be collected from the time of the first study-specific procedure through the 
last observation visit.  Verbatim descriptions of adverse events will be coded and analyzed 

 
Omalizumab—Genentech, Inc. 
16/Protocol ML29510, Version 1 
using appropriate thesaurus terms.  A treatment-emergent adverse event is defined as any 
adverse event reported, or worsening of an existing condition on or after the first dose of study 
drug.  Treatment-emergent adverse events will be summarized by treatment group.  Clinical 
laboratory data (e.g., serum chemistry and hematology evaluations) and vital signs will be 
summarized by descriptive statistics for each treatment group. 
Pharmacokinetic and Pharmacodynamic Analyses 
Serum total omalizumab, and total and free IgE concentration versus time data will be tabulated 
by treatment group and summarized using descriptive statistics (e.g., mean, standard deviation, 
minimum, and maximum).  Additional PK and PD analyses may be conducted as appropriate. 
Exploratory Analyses 
For details on how each exploratory analysis will be conducted, see the SAP. 
Determination of Sample Size 
Assuming a 60% rate of clinical worsening in CIU assessed by UAS7 in the placebo group 
(including 10% dropout imputed as worsening CIU) and a rate of 30% in the omalizumab 
continuation group (including 10% dropout imputed as clinical worsening CIU) in the period up 
to 24 weeks post-randomization, a total of 117 patients will need to be randomized at a 3:2 ratio 
(3 omalizumab continuation group patients for every 2 placebo patients) to ensure 90% power 
to detect a difference in clinical worsening CIU rates as a primary analysis comparison at the 
0.05 alpha level (2-sided test).  In addition, as it is estimated that 15% of patients will either drop 
out during the open-label treatment period or not meet the adherence criteria, and that 66.5% of 
those who do not drop out or fail adherence criteria will be responders, this study will need to 
enroll at least 207 (117 / [0.665 • 0.85]) patients to ensure adequate randomization numbers for 
the primary analysis.  This sample size will also ensure at least 80% power for each of the 
secondary analyses.   

 
Omalizumab—Genentech, Inc. 
17/Protocol ML29510, Version 1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartase transaminase 
BID 
twice per day 
BUN 
blood urea nitrogen 
C-GIC 
Clinician Global Impression of Change (scale) 
CIU 
chronic idiopathic urticaria 
CRO 
contract research organization 
CSU 
chronic spontaneous urticaria 
DLQI 
Dermatology Life Quality Index 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eDiary 
electronic diary (also referred to as the UPDD) 
FcεRI 
high-affinity IgE receptor 
FDA 
U.S. Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GAD-7 
General Anxiety Disorder 7-Item (scale) 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
IC-UAS 
in-clinic Urticaria Activity Score 
ICH 
International Conference on Harmonisation 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
IVIG 
intravenous immunoglobulin G 
IxRS 
interactive voice and web response system 
LDH 
lactate dehydrogenase 
LPLV 
last patient, last visit 
LTRA 
leukotriene receptor antagonist 

 
Omalizumab—Genentech, Inc. 
18/Protocol ML29510, Version 1 
Abbreviation 
Definition 
MID 
minimally important difference 
mITT 
modified intent-to-treat (principle) 
P-GIC 
Patient Global Impression of Change (scale) 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
Q4W 
every 4 weeks 
QD 
once per day 
QID 
four times per day 
RBC 
red blood cell 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SWFI 
Sterile Water for Injection 
U-AIM 
Urticaria Activity and Impact Measure 
UAS 
Urticaria Activity Score 
UAS7 
Urticaria Activity Score over 7 days 
UCT 
Urticaria Control Test 
ULN 
upper limit of normal 
UPDD 
Urticaria Patient Daily Diary 
USPI 
U.S. Package Insert 
WBC 
white blood cell 
WPAI 
Work Productivity and Activity Index 

 
Omalizumab—Genentech, Inc. 
19/Protocol ML29510, Version 1 
1. 
BACKGROUND 
1.1 
CHRONIC IDIOPATHIC URTICARIA 
Chronic idiopathic urticaria (CIU; also referred to as chronic spontaneous urticaria [CSU]) 
is defined as the spontaneous occurrence of daily, or almost daily, hives and itching for 
at least 6 weeks without an obvious cause (Greaves 2003).  The majority of patients with 
CIU achieve symptomatic control with conventional H1 antihistamine therapy.  In some 
patients, CIU can be a debilitating condition because of a lack of clinical response as 
well as the unpredictable course of the disease, both of which can have a profound 
negative influence on the patient’s quality of life (Tilles 2005). 
Some patients may remain symptomatic despite ongoing H1 antihistamine treatment, 
and for this group of patients, therapies such as immunosuppressants 
(including cyclosporine, corticosteroids, intravenous immunoglobulin G [IVIG], 
and methotrexate) and plasmapheresis have been used (Kozel and Sabroe 2004).  
These agents have variable success and may be associated with severe adverse effects. 
The etiology of CIU is not clear.  There are several theories, including one proposing an 
infectious origin and another related to an autoimmune origin.  Some studies have found 
that approximately 30−60% of patients with CIU have an autoimmune component 
(Fiebiger et al. 1995; Tong et al. 1997; Zweiman et al. 1998).  In patients suspected of 
having an autoimmune etiology for their CIU, symptoms result from mediator release 
following the cross-linking of high-affinity immunoglobulin E (IgE) receptors on mast cells 
and basophils.  Anti-IgE antibodies and functional antibodies against the alpha chain of 
the high-affinity IgE receptor found on mast cells, basophils, and antigen-presenting cells 
have been isolated from the serum of patients with CIU (Grattan et al. 1991; 
Hide et al. 1993; Niimi et al. 1996).  Given the association of high-affinity receptor 
activation, mediator release, and CIU, several studies have been conducted to 
determine if omalizumab could be a useful therapy for this disease. 
1.2 
OMALIZUMAB 
Omalizumab (Xolair®) is a humanized anti-IgE recombinant monoclonal antibody 
approved to treat allergic asthma by inhibiting the binding of IgE to the high-affinity IgE 
receptor (FcεRI) on the surface of mast cells and basophils.  Reduction in surface-bound 
IgE on the FcεRI-expressing cells limits the degree of release of mediators in the allergic 
response.  Omalizumab has been studied for safety and efficacy in over 5000 adult and 
adolescent (≥ 12 years of age) patients with moderate to severe asthma, and more 
recently, in patients with CIU.  Omalizumab was approved by the U.S. Food and Drug 
Administration (FDA) for CIU in March 2014.  More than 60,000 patients have been 
treated with omalizumab worldwide.  
There are two hypotheses for the mechanism of action of omalizumab in patients with 
CIU.  One hypothesis is that the density of IgE receptors at the surface of mast cells and 
basophils is proportional to the plasma IgE level.  Lowering free IgE to near undetectable 

 
Omalizumab—Genentech, Inc. 
20/Protocol ML29510, Version 1 
levels should therefore down regulate the IgE receptors so that the immunoglobulin G 
(IgG) autoantibody cannot cross-link FcεRI.  Cell activation would be suppressed, and all 
the subsequent inflammatory processes (complement activation, cellular infiltration) 
would be suppressed as well.  As a consequence, the frequency and severity of 
symptoms of chronic urticaria should be markedly diminished.  It has also been 
hypothesized that the down regulation of FcεRI may be accompanied by an increase in 
the threshold above which degranulation of mast cells is triggered.  This may be an 
independent mechanism of action, unrelated to prevention of cross-linkage of surface 
receptors, or the two mechanisms might be complementary.  The exact mechanism for 
how omalizumab may work for patients with CIU is, however, unknown. 
Omalizumab is indicated for the treatment of adults and adolescents (12 years of age 
and above) with CIU who remain symptomatic despite H1 antihistamine treatment.  The 
FDA-approved dose for patients with CIU is 150 or 300 mg administered by 
subcutaneous (SC) injection every 4 weeks (Q4W). 
1.2.1 
Clinical Experience with Omalizumab in Patients with CIU 
The Phase III clinical program for omalizumab consisted of three studies: 
• 
Study Q4881g (ASTERIA I; Saini et al. 2014) and Study Q4882g (ASTERIA II; 
Maurer et al. 2013) evaluated patients with CIU who were refractory to 
H1 antihistamines at approved doses. 
• 
Study Q4883g (GLACIAL; Kaplan et al. 2013) evaluated patients with CIU who 
were refractory to H1 antihistamines at up to four times approved doses, 
H2 blockers, and/or leukotriene receptor antagonists (LTRAs). 
 
Studies Q4881g and Q4882g were both global, Phase III, multicenter, randomized, 
double-blind, placebo-controlled, parallel-group studies to evaluate the efficacy and 
safety of omalizumab, administered SC Q4W as add-on therapy for the treatment of 
adolescent and adult patients (12−75 years of age) with CIU refractory to conventional 
H1 antihistamines, as demonstrated by:  the presence of itch and hives for 
≥ 8 consecutive weeks at any time prior to enrollment, Urticaria Activity Score (UAS) over 
7 days (UAS7) confirming uncontrolled symptoms prior to randomization, and a CIU 
diagnosis for ≥ 6 months.  The studies evaluated the comparative efficacy between three 
doses of omalizumab (75 mg, 150 mg, and 300 mg) and placebo as well as the time to 
onset of clinical effect for patients with CIU who remained symptomatic despite 
treatment with approved doses of H1 antihistamine therapy.  The 150-mg dose, which 
was not studied in the Phase II study (Q4577g; Saini et al. 2011), was included as an 
intermediate between the 75- and 300-mg dose in order to better define the dose 
response.  The inclusion of the 75-mg dose served to characterize the lower end of the 
dose response after multiple doses, since only a single dose was tested in 
Study Q4577g. 

 
Omalizumab—Genentech, Inc. 
21/Protocol ML29510, Version 1 
Studies Q4481g and Q4882g differed in duration of treatment (24 weeks compared to 
12 weeks for Studies Q4881g and Q4882g, respectively).  The primary efficacy outcome 
measure was change from baseline in weekly itch score (a component of the UAS7) at 
Week 12.  In total, 319 patients were randomized from 53 centers globally, and 
323 patients were randomized from 55 centers globally in Studies Q4881g and Q4882g, 
respectively. 
Study Q4883g was a global Phase III, multicenter, randomized, double-blind, placebo-
controlled, parallel-group study to evaluate the safety and efficacy of omalizumab 
300 mg administered SC Q4W as an add-on therapy for the treatment of adolescent and 
adult patients (12−75 years of age) who have been diagnosed with CIU who remain 
symptomatic despite H1 antihistamine treatment doses up to four times above the 
approved dose, H2 blockers, and/or LTRAs.  The duration of treatment for 
Study Q4883g was 24 weeks.  The primary safety outcome measure was the incidence 
and severity of adverse events and serious adverse events.  Efficacy, a secondary 
objective, was measured in a similar manner as Studies Q4881g and Q4882g.  In total, 
336 patients were randomized from 65 centers globally. 
1.2.2 
Summary of Omalizumab Clinical Efficacy in Patients with CIU  
Consistent treatment effects were observed in all omalizumab-treated groups across all 
three pivotal studies (Q4881g, Q4882g, and Q4883g), similar to that noted in the 
Phase II dose-ranging study (Q4577g) (Saini et al. 2011; Kaplan et al. 2013; 
Maurer et al. 2013; Saini et al. 2014). 
Both the 150-mg and 300-mg groups met the primary efficacy endpoint of change from 
baseline to Week 12 in weekly itch score in all three pivotal studies (in Study Q4883g, 
only the 300-mg dose was studied), supporting the use of omalizumab for the treatment 
of adults and adolescents (12 years of age and above) with CIU who remain 
symptomatic despite H1 antihistamine treatment.  For the 300-mg group, the mean 
change from baseline in weekly itch score at Week 12 showed statistically significant 
improvements compared with placebo (−9.4 vs. −3.6, −9.8 vs. −5.1, and −8.6 vs. −4.0 for 
Studies Q4881g, Q4882g, and Q4883g, respectively).  The 75-mg group met the primary 
endpoint in Study Q4881g only. 
Studies Q4881g and Q4882g showed consistent evidence of a dose response with the 
300-mg dose demonstrating greater therapeutic benefit relative to 150 mg for the 
primary endpoint (formal statistical comparisons were not performed between 
omalizumab groups). 
At the 300-mg dose, the proportion of patients achieving a therapeutic response at 
Week 12 (secondary efficacy endpoint) was as follows:  52%, 66%, and 52% with 
UAS7 ≤ 6; and 36%, 44%, and 24% with UAS7 = 0 for Studies Q4881g, Q4882g, and 
Q4883g, respectively.  In addition, the proportion of patients at the 300-mg dose 

 
Omalizumab—Genentech, Inc. 
22/Protocol ML29510, Version 1 
achieving UAS7 ≤ 6 at both Weeks 23 and 24 was 67.6% and 65.5% for Studies Q4881g 
and Q4883g, respectively. 
As noted in Studies Q4881g and Q4883g, the decreases in mean weekly itch score and 
UAS7 with omalizumab treatment at Week 12 were maintained for up to 24 weeks of 
treatment suggesting there was no tolerance or tachyphylaxis to prolonged omalizumab 
dosing.   
After cessation of treatment, mean weekly itch score and UAS7 increased to reach 
values similar to the placebo group mean values, but did not return to baseline values for 
the duration of the 16-week follow-up period in any of the omalizumab treatment groups 
in all three pivotal studies.  The mean weekly itch score and UAS7 in the 300-mg group 
appeared to take longer to reach a similar level to that in the placebo group than was the 
case for lower omalizumab doses.  This suggests a longer lasting effect of the 300-mg 
dose. 
Figure 1 shows UAS7 scores over time in Study Q4881g (ASTERIA I), where the 
duration of potential omalizumab therapy was 24 weeks (Saini et al. 2014; Genentech 
data on file).  Study Q4883g (GLACIAL) showed a similar pattern of return to placebo 
group mean after the 24-week omalizumab treatment period (Kaplan et al. 2013). 
Figure 1 Change from Baseline in Mean UAS7:  Study Q4881g (ASTERIA I; 
Placebo versus 24 Weeks Omalizumab) 
 
UAS7 = Urticaria Activity Score over 7 days. 
 

 
Omalizumab—Genentech, Inc. 
23/Protocol ML29510, Version 1 
1.2.3 
Summary of Omalizumab Clinical Safety in Patients with CIU  
The overall safety profile of omalizumab in patients with CIU, across all four studies 
comprising the clinical development program (Q4577g, Q4881g, Q4882g, and Q4883g), 
revealed no unexpected safety signals or concerns different than the known safety 
profile of omalizumab in patients with allergic asthma (Saini et al. 2011; 
Kaplan et al. 2013; Maurer et al. 2013; Saini et al. 2014). 
Few serious adverse events were reported (< 2% of patients reported serious adverse 
events during the 12-week treatment period and < 4% during the 24-week treatment 
period) and no deaths were observed in any of the studies.  The most frequent adverse 
events demonstrating imbalances were common conditions such as nasopharyngitis, 
headache, and sinusitis.  The safety profile was similar between 12 weeks and 24 weeks.  
In general, the majority of adverse events were mild or moderate in intensity.  Overall, 
omalizumab was well tolerated with few adverse events leading to study discontinuation 
(< 2%) or withdrawal of treatment (< 4%) during the study period.  A treatment 
comparison of the main safety endpoints over the entire study period for all three 
Phase III studies pooled showed no major differences in the safety profile between the 
150- and 300-mg groups.  Treatment differences indicating greater risk in omalizumab-
treated patients were small and associated with a higher level of uncertainty.  Those 
differences that were observed were expected given the known safety profile of 
omalizumab in allergic asthma.  Specifically, a dose-dependent increase in suspected 
adverse events was observed for injection site reactions, which has been previously 
described (Xolair U.S. Package Insert 2014).  Such reactions were infrequent, occurring 
in < 3% of patients among those treated at the higher 300-mg dose, and none were 
considered severe.  Although an imbalance in hypersensitivity events for the 300-mg 
dose group was observed over the entire study, this imbalance was not observed during 
either the 12- or 24-week treatment period.  For the majority of patients suffering from 
moderate to severe CIU, the benefit of treatment with omalizumab would likely outweigh 
these risks. 
See the Omalizumab Investigator's Brochure for additional details on clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The three pivotal studies (Q4881g, Q4882g, and Q4883g) examined the safety and 
efficacy of omalizumab administered over 12 to 24 weeks.  Currently, there is limited 
clinical trial experience on the long-term treatment beyond 24 weeks (or approximately 
6 months) in patients with CIU.  The U.S. Package Insert (USPI) for omalizumab notes 
that the appropriate duration of therapy for CIU has not been evaluated and advises 
health practitioners to periodically reassess the need for continued therapy.     
This study will assess the safety and potential benefits of continuing omalizumab beyond 
24 weeks of dosing (through 48 weeks of dosing, or approximately 1 year).  Through the 
primary outcome, as well as the secondary and exploratory outcomes, this study should 

 
Omalizumab—Genentech, Inc. 
24/Protocol ML29510, Version 1 
assist healthcare providers in weighing the relative benefits of omalizumab continuation 
beyond 24 weeks by elucidating the extent to which omalizumab might be expected to 
maintain control of CIU and related symptoms.      
In Studies Q4881g (ASTERIA I) and Q4883g (GLACIAL), all patients discontinued 
omalizumab after 24 weeks and, in Study Q4882g (ASTERIA II), all patients 
discontinued omalizumab after 12 weeks.  Moreover, patients were unblinded at 
discontinuation (i.e., patients knew they were discontinuing omalizumab).  In 
Studies Q4881g and Q4883g, the mean weekly itch score and UAS7 after omalizumab 
discontinuation increased to reach values similar to that of the placebo arms 
(Kaplan et al. 2013; Maurer et al. 2013; Saini et al. 2014).  This study will evaluate 
whether continuation of omalizumab beyond 24 weeks might be expected to maintain 
control of CIU and related symptoms in the context of being blinded to omalizumab 
continuation versus discontinuation.   
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective for this study is to evaluate the level of control of CIU symptoms 
through 48 weeks, among patients continuing omalizumab as compared to those 
receiving placebo after an initial 24 weeks of omalizumab treatment. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives for this study are as follows: 
• 
To evaluate the response to retreatment with omalizumab in patients with CIU who 
have responded to omalizumab, but experienced recurrence or clinical worsening of 
disease after withdrawal of therapy 
• 
To evaluate whether patients who have achieved response to omalizumab after 
24 weeks of therapy demonstrate similar levels of response after 48 weeks of 
therapy 
• 
To evaluate the safety of omalizumab therapy through 48 weeks in patients with CIU 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To compare the level of control of CIU symptoms, over 12 weeks after withdrawal of 
omalizumab, subsequent to completing 48 weeks versus 24 weeks of omalizumab 
therapy, among patients with CIU who have responded to omalizumab therapy 
• 
To obtain additional data on patient-reported outcome (PRO) response to 
omalizumab 
 

 
Omalizumab—Genentech, Inc. 
25/Protocol ML29510, Version 1 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a Phase IV, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of SC omalizumab through 48 weeks as an add-on 
therapy for the treatment of refractory CIU in adolescent and adult patients (12−75 years 
of age) who remain symptomatic despite standard H1 antihistamine treatment (including 
doses up to four times above the approved dose), H2 blockers, and/or LTRAs.  The 
study will enroll approximately 207 patients at approximately 40 study sites in the U.S. 
The study will consist of the following study periods with a total duration of 62 weeks 
(see Figure 2): 
• 
Screening Period:  Day −14 to Baseline (Week −2 to Baseline) 
• 
Open-Label Treatment Period:  Day 1 to Day 168 (Baseline to Week 24) 
• 
Double-Blind Randomization Period:  Day 169 to Day 336 (Week 24 to Week 48) 
• 
Follow-Up Period:  Day 337 to Day 420 (Week 48 to end of Week 60) 
 
The screening period will consist of visits at Day −14 and Day −7.  Day 1 (baseline) will 
mark the commencement of the 24-week open-label treatment period.  Patients must 
meet all of the following criteria prior to receiving treatment in the open-label treatment 
period: 
• 
Non-electronic diary-based UAS ≥ 4 established in the clinic (i.e., in-clinic UAS 
[IC-UAS]) based on the patient’s condition over 12 hours prior to either Day −14, 
Day −7, or Day 1 despite being on H1 antihistamine therapy 
• 
Use of H1 antihistamine treatment (up to four times the approved dose) for CIU at 
Day −14 and for at least the 3 consecutive days immediately prior to Day −14 
(see Section 4.4.1 for a list of H1 antihistamines available for use in this study) 
• 
Willing and able to complete a symptom electronic diary (eDiary), also referred to as 
the Urticaria Patient Daily Diary (UPDD), twice daily throughout the screening period 
to establish the patient’s UAS7  
 
Patients will have the 2-week screening period to establish their eligibility for the study 
and baseline symptom scores.  For the duration of the screening period, patients must 
maintain stable doses of their pre-screening H1 antihistamine treatment.  To be eligible 
for treatment during the open-label treatment period, patients must have no missing 
eDiary entries, a UAS7 symptom score of ≥ 16 during the 7 days prior to baseline 
(equivalent to moderate to severe CIU symptoms for at least 4 out of 7 days in a week), 
and a weekly itch score (a component of the UAS7) of ≥ 8 during the 7 days prior to 
baseline. 
Only in exceptional circumstances, when information concerning eligibility is outstanding 
(e.g., pending laboratory data), will a screening period longer than 2 weeks be permitted.  
Patients may be re-screened upon approval from the Medical Monitor.  

 
Omalizumab—Genentech, Inc. 
26/Protocol ML29510, Version 1 
Circumstances that may permit re-screening include, but are not limited to, an IC-UAS or 
laboratory test results that do not meet eligibility requirements.  
On Day 1, eligible patients will begin open-label omalizumab 300 mg SC Q4W and will 
continue on treatment during the 24-week open-label treatment period.  During this 
period, patients will continue reporting twice daily their UAS-related symptoms through 
the eDiary, necessary for the weekly calculation of UAS7 (which is based on the last 
7 days of symptoms).  At the end of the open-label treatment period, patients who have 
responded to omalizumab will be randomized in a double-blinded fashion to either 
continue omalizumab or to transition to placebo for a further 24 weeks.  Patients will be 
eligible for randomization if they meet both of the following criteria: 
• 
Achieve UAS7 ≤ 6 in the final 2 weeks of the open-label treatment period (Week 23 
and Week 24) 
AND 
• 
Comply with omalizumab dosing for at least 5 out of the 6 planned doses, including 
a dosage at Week 20, during the initial 24-week open-label treatment period 
(i.e., patients may only be randomized if they have missed at most one dosage of 
omalizumab during the initial open-label treatment period AND did not miss their 
Week 20 dosage) 
 
Patients who meet the criteria for randomization will be randomized at a ratio of 3:2 
(omalizumab:placebo).  Randomization to treatment groups will be stratified by UAS7 at 
the point of randomization (UAS 7 = 0 vs. UAS7 > 0) and study site.  Efficacy, safety, 
pharmacokinetic (PK), and pharmacodynamic (PD) data will be collected.  Subsequent 
to randomization, patients will continue to be evaluated twice daily using the eDiary for 
weekly calculation of UAS7, which includes a weekly itch score. 
Throughout the study (Day −14 to Week 60), patients must maintain stable doses of their 
pre-randomization combination therapy with H1 antihistamine treatment, H2 blockers, 
and/or LTRAs.  Patients will be prohibited from using non-study-drug omalizumab during 
the study (Day −14 to Week 60) (e.g., commercially available omalizumab is not 
permitted during the study).  Patients receiving non-study-drug omalizumab during the 
study, for any indication, will be discontinued from the study. 
Patients who do not meet the criteria for randomization (e.g., because of non-response 
to omalizumab during the open-label treatment period) should return for a final follow-up 
visit 12 weeks after the Week 24 visit, which will include a blood draw for PK/PD 
measurement, and assessments for adverse events and PROs (see Appendix 1).  
Patients will not be required to complete the eDiary during this 12-week period. 
Subsequent to randomization, patients may, at the discretion of the investigator, be 
transitioned from blinded study drug to open-label omalizumab at 300 mg SC Q4W if 
they experience clinically significant worsening in their CIU (as judged by the 
investigator); clinical worsening must also be accompanied by UAS7 ≥ 12 for at least 

 
Omalizumab—Genentech, Inc. 
27/Protocol ML29510, Version 1 
2 consecutive weeks.  That is, patients may potentially be transitioned to open-label 
omalizumab if this is deemed by the investigator to be clinically indicated based on 
clinical worsening CIU and if, after the investigator has made this assessment, patients 
are confirmed to have experienced UAS7 ≥ 12 for at least 2 consecutive weeks as 
determined by eDiary entries.  Patients who are transitioned to open-label omalizumab 
will not be unblinded with respect to the treatment they had received between 
randomization and transition to open-label omalizumab.  Patients who are transitioned to 
open-label omalizumab will continue to receive open-label omalizumab as study drug 
until Week 48, after which omalizumab will be discontinued. 
The primary endpoint for this study is the percentage of patients who experience clinical 
worsening in CIU defined as UAS7 ≥ 12 for at least 2 consecutive weeks.   
After completion of the randomization period (end of Week 48), all patients will enter a 
12-week follow-up period to allow for further characterization of the pharmacokinetics 
and pharmacodynamics of omalizumab and collection of additional efficacy and safety 
data.  Patients will continue to visit the study site at 4-week intervals.  The Week 48 and 
Week 60 visits will take place at the study site.  The Week 52 and Week 56 visits will 
take place by telephone by the study site personnel to include collection of adverse 
events and concomitant medication information.  Patients will continue to be assessed 
via eDiary during this period.  No study treatment will be given during the follow-up 
period. 
The double blindness of randomization to treatment groups should be maintained for the 
full post-randomization period of the study (until the end of the study).   
Schedule of assessments are provided in Appendix 1, Appendix 2, and Appendix 3. 

 
Omalizumab—Genentech, Inc. 
29/Protocol ML29510, Version 1 
3.2 
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.  LPLV is 
expected to occur 60 weeks after the last patient is enrolled. 
3.3 
RATIONALE FOR STUDY DESIGN 
The pivotal studies demonstrated efficacy and safety of omalizumab through 24 weeks 
of treatment.  Efficacy and safety beyond 24 weeks of treatment was not examined, as 
will be addressed in this study.   Because of the previously demonstrated efficacy 
through 24 weeks, this study will begin with an initial 24-week open-label treatment 
period before any possibility of randomization to placebo.   
The primary outcome of this study is clinical worsening in CIU as assessed by UAS7.  
The specific threshold for clinical worsening in CIU symptoms is UAS7 ≥ 12, maintained 
for at least 2 consecutive weeks.  The threshold of UAS7 ≥ 12 (lower than the inclusion 
criteria of UAS7 ≥ 16) was chosen to allow patients to restart omalizumab at a lower 
threshold than that required to initiate omalizumab for the first time.  Based on advisor 
input, this is believed to mirror general clinical practice for reinitiating therapies after 
withdrawal.  Moreover, a requirement for patients to return to their baseline prior to 
reinitiating therapy is believed to be unreasonable, especially in the context of prior 
control established by omalizumab.  The specific threshold of UAS7 ≥ 12 was chosen 
because of the precedent established in the CIU Phase II study in which this was used 
as an inclusion criterion (Saini et al. 2011).  Additionally, all patients who are randomized 
will have a UAS7 ≤ 6 at time of randomization; therefore, a UAS7 ≥ 12 would confirm that 
the UAS7 score has at least doubled since randomization, representing an intuitive 
clinical threshold for reinitiating omalizumab.  The secondary outcome of this study will 
also assess time to clinical worsening as well as the level of control of CIU symptoms 
assessed by whether or not patients maintain UAS7 ≤ 6 during the randomization period 
(Week 24 to Week 48).  Separately, patients who have demonstrated a UAS7 ≥ 12 
(maintained for at least 2 consecutive weeks), who are also clinically assessed as 
having worsening CIU warranting a transition to open-label omalizumab, will be offered 
such a transition to ensure that patients do not remain symptomatic for an undue period 
of time. 
The inclusion and exclusion criteria for this study allow for up to four times the approved 
doses of H1 antihistamines, as well as H2 blockers and/or LTRAs.  These 
inclusion/exclusion criteria reflect the reality that such medications are often used at 
these doses before advancing therapy to omalizumab, as discussed in practice 
parameters and guidelines (Bernstein et al. 2014; Zuberbier et al. 2014). 
This study examines several secondary and exploratory endpoints, including PRO 
measures.  The PRO instruments used in this study include those used in the pivotal trial 
data (e.g., Dermatology Life Quality Index [DLQI]) as well as new PROs, such as anxiety 

 
Omalizumab—Genentech, Inc. 
30/Protocol ML29510, Version 1 
symptoms and work productivity that may be related to CIU and response to therapy.  In 
addition, this study will examine the validity of intermittently assessed PROs, such as the 
Urticaria Control Test (UCT) and Urticaria Activity and Impact Measure (U-AIM), 
compared with the twice daily eDiary device, in providing a clinical evaluation of patients 
with CIU.   
3.3.1 
Omalizumab Dose and Schedule 
The FDA-approved dose for patients with CIU is 150 or 300 mg SC Q4W.  In this CIU 
Phase IV study, only the 300-mg dose will be examined.  The 300-mg dose was the only 
dosage to meet both the primary outcome as well as all secondary outcomes in both 
pivotal efficacy studies (Q4881g and Q4882g).  Additionally, as shown in Figure 1, the 
average efficacy observed was numerically better with the 300-mg dose than for other 
doses.  Also, relapse to mean placebo values after cessation of the 300-mg dose of 
omalizumab took longer, on average, than after other doses of omalizumab.  
3.4 
OUTCOME MEASURES  
3.4.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the percentage of patients who experience 
clinical worsening in CIU as assessed by UAS7.  The specific threshold for clinical 
worsening in CIU symptoms will be UAS7 ≥ 12, maintained for at least 2 consecutive 
weeks, from randomization (Week 24) to Week 48. 
3.4.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
Time to clinical worsening in CIU, defined based on the same criteria as the primary 
endpoint (maintaining UAS7 ≥ 12 for at least 2 consecutive weeks), from 
randomization (Week 24) to Week 48 
• 
Percentage of patients who experience clinical worsening in CIU assessed by UAS7, 
where the threshold for clinical worsening is UAS7 > 6 for at least 2 consecutive 
weeks, from randomization (Week 24) to Week 48 
• 
UAS7 (24- vs. 48-week value) among patients who have responded to omalizumab 
treatment at 24 weeks and completed a further 24 weeks of omalizumab (48 weeks 
total), which will be assessed by the change from randomization (Week 24) to 
Week 48 in UAS7 
• 
Retreatment efficacy, defined by change in UAS7 from time of retreatment to 
12 weeks after retreatment, among patients randomized to the placebo arm who are 
retreated with open-label omalizumab after randomization and receive at least 
12 weeks of omalizumab therapy as retreatment 
 

 
Omalizumab—Genentech, Inc. 
31/Protocol ML29510, Version 1 
3.4.3 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence and severity of adverse events and serious adverse events 
• 
Changes in vital signs 
• 
Clinical laboratory evaluations 
 
3.4.4 
Pharmacokinetic/Pharmacodynamic Outcome Measures 
Serum total omalizumab, and total and free IgE concentrations will be measured at: 
• 
Baseline (pre-dose), Week 24 (pre-dose), Week 48, and Week 60 or early 
termination 
• 
The time of discontinuation from blinded treatment (i.e., start of open-label treatment 
post-randomization [pre-dose]), among patients who make the post-randomization 
transition to open-label omalizumab 
• 
The end of follow-up (i.e., 12 weeks after stopping the initial 24-week course of 
open-label omalizumab), among patients not responding to the initial 24-week 
course of open-label omalizumab  
 
3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
The proportion of patients experiencing clinical worsening in CIU (defined as 
maintaining UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 48 and 60 
among patients randomized to continue omalizumab (i.e., during the 12 weeks after 
discontinuing a 48-week course of omalizumab)  
• 
The proportion of patients experiencing clinical worsening in CIU (defined as 
maintaining UAS7 ≥ 12 for at least 2 consecutive weeks) between Weeks 24 and 36 
among patients randomized to placebo 
• 
Change from randomization (Week 24) to Week 48 in weekly itch score 
• 
Change from randomization (Week 24) to Week 48 in UAS7 
• 
Change from randomization (Week 24) to Week 48 in health-related quality-of-life as 
measured by the DLQI total score  
• 
Insomnia Severity Index (ISI); General Anxiety Disorder 7-Item (GAD-7) scale; and 
Work Productivity and Activity Index (WPAI) will be assessed as: 
− 
Change from baseline to Week 24 
− 
Change from randomization to Week 48  
− 
Change from the end of the randomization period (Week 48) to the end of the 
study (end of Week 60) 
• 
Proportion of angioedema days, evaluated through patient self-reports via eDiary, 
from Week 24 to Week 48 

 
Omalizumab—Genentech, Inc. 
32/Protocol ML29510, Version 1 
• 
UCT response and correlation with UAS7 
− 
Change in UCT from baseline to Week 24 
− 
Change in UCT from randomization to Week 48 
− 
Correlation between UCT and UAS7 from baseline to Week 24 
• 
U-AIM response and correlation with UAS7 
− 
Change in U-AIM from baseline to Week 24 
− 
Change in U-AIM from randomization to Week 48 
− 
Correlation between U-AIM and UAS7 from baseline to Week 24 
• 
Patient Global Impression of Change (P-GIC) scale and Clinician Global Impression 
of Change (C-GIC) scale assessed at Week 24 and Week 48 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 207 patients are planned to be enrolled in this study at approximately 
40 study sites in the U.S.  Approximately 117 patients will be randomized in this study 
after accounting for dropout, non-adherence, and non-response during the open-label 
treatment period.  
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 12−75 years 
• 
Diagnosis of CIU refractory to H1 antihistamines at baseline, as defined by all of the 
following: 
− 
The presence of itch and hives for ≥ 8 consecutive weeks at any time prior to 
enrollment despite current use of H1 antihistamine treatment (up to four times 
the approved dose) during this time period 
− 
UAS7 score (range 0−42) ≥ 16 and itch component of UAS7 (range 0−21) ≥ 8 
during 7 days prior to baseline 
− 
IC-UAS ≥ 4 on at least one of the screening visit days (Day −14, Day  −7, or 
Day 1) (see Section 4.5.9 for details on IC-UAS) 
− 
Patients must have been on H1 antihistamine treatment (up to four times the 
approved dose) for CIU for at least the 3 consecutive days immediately prior to 
the Day −14 screening visit and must document current use on the day of the 
initial screening visit. 
− 
CIU diagnosis for ≥ 6 months.  The methods used to confirm duration of CIU 
diagnosis may include patient report of onset of CIU symptoms, and the duration 
of CIU diagnosis may be made based on the initial date of these symptoms 
even if the diagnosis of CIU was made at a later date. 

 
Omalizumab—Genentech, Inc. 
33/Protocol ML29510, Version 1 
• 
Willing to give written informed consent, adhere to the visit schedules, and meet 
study requirements 
− 
For patients below the legal age of consent, the child must be willing to give 
written informed assent and the parent(s)/guardian(s) must be willing to give 
written informed consent. 
− 
For patients below the legal age of consent, both child and parent must be able 
to adhere to dose and visit schedules and meet study requirements. 
• 
Willing and able to complete a daily symptom eDiary for the duration of the study 
• 
Patients must not have any missing eDiary entries in the 7 days prior to baseline. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Treatment with an investigational agent within 30 days of Day −14 
• 
Weight less than 20 kg (44 lbs) 
• 
Clearly defined underlying etiology for chronic urticarias other than CIU (main 
manifestation being physical urticaria).  This includes the following urticarias: 
− 
Acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure, or contact 
Any of the following diseases, which may have symptoms of urticaria or 
angioedema:  urticarial vasculitis, urticaria pigmentosa, erythema multiforme, 
mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or 
generalized cancer 
• 
Evidence of parasitic infection defined as having the following three items:  
− 
Risk factors for parasitic disease (chronic gastrointestinal [GI] symptoms, travel 
within the last 6 months to an endemic area, and/or chronic immunosuppression)  
AND 
− 
An absolute eosinophil count more than twice the upper limit of normal (ULN)  
AND 
− 
Evidence of parasitic colonization or infection on stool evaluation for ova and 
parasites.  Stool ova and parasite evaluation will only be conducted in patients 
with both risk factors and an eosinophil count more than twice the ULN. 
• 
Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or 
other skin disease associated with itch 
• 
Previous treatment with omalizumab within 1 year prior to Day −14 
• 
Routine (daily/every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to Day −14:  systemic corticosteroids, 
hydroxychloroquine, methotrexate, mycophenolate, cyclosporine, or 
cyclophosphamide 
• 
IVIG or plasmapheresis within 30 days prior to Day −14 
• 
Regular (daily/every other day) doxepin (oral) use within 14 days prior to Day −14 

 
Omalizumab—Genentech, Inc. 
34/Protocol ML29510, Version 1 
• 
Patients with current malignancy, history of malignancy, or currently under work-up 
for suspected malignancy except non-melanoma skin cancer that has been treated 
or excised and is considered resolved 
• 
Hypersensitivity to omalizumab or any component of the formulation 
• 
History of anaphylactic shock 
• 
Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, 
or other pathological conditions that could interfere with the interpretation of the 
study results and or compromise the safety of the patients 
• 
Medical examination or laboratory findings that suggest the possibility of 
decompensation of co-existing conditions for the duration of the study.  Any items 
that are cause for uncertainty must be reviewed with the Medical Monitor.  
• 
Inability to comply with study and follow-up procedures 
• 
Evidence of current drug or alcohol abuse 
• 
Nursing women or women of childbearing potential, defined as all women 
physiologically capable of becoming pregnant, including women whose career, 
lifestyle, or sexual orientation precludes intercourse with a male partner and women 
whose partners have been sterilized by vasectomy or other means, UNLESS they 
meet the following definition of post-menopausal:  12 months of natural 
(spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum 
follicle-stimulating hormone (FSH) levels > 40 mIU/mL or 6 weeks post-surgical 
bilateral oophorectomy (with or without hysterectomy) or hysterectomy OR are using 
one or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, 
oral), and double-barrier methods (any double combination of:  intrauterine device, 
male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap)  
• 
Contraindications to diphenhydramine 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
At the Week 24 visit, patients who completed the 24-week open-label treatment period 
and have met the criteria for response (UAS7 ≤ 6 for both Weeks 23 and 24) and also 
met the omalizumab compliance criteria (5 out of 6 planned doses, including a dosage at 
Week 20) will be randomized to 300 mg omalizumab or placebo at an approximately 3:2 
ratio using an interactive voice and web response system (IxRS).  Patients, all study 
personnel, the designated evaluating physician(s), and the Sponsor and its agents (with 
the exception of the IxRS service provider, the remote unblinded monitoring staff ,the 
unblinding statistician, the unblinded pharmacists at the sites, the independent Data 
Monitoring Committee [iDMC] members, and the independent Data Coordinating Center 
[iDCC] personnel) will be blinded to treatment assignment.  Only the IxRS provider, the 
Sponsor’s unblinding statistician, and the iDCC statistician will have access to the 
unblinding code during the study.    

 
Omalizumab—Genentech, Inc. 
35/Protocol ML29510, Version 1 
A pharmacist or other qualified individual designated by the study site will prepare and 
administer the study drug as outlined in Section 4.3.2 and Appendix 4.  While blinded 
treatment kits will be used during the randomization phase of the study (Week 24 to 
Week 48), and because of potential differences in the viscosity of the omalizumab and 
placebo preparations, unblinding of the study site personnel responsible for 
reconstituting and/or administering study drug is possible.  To minimize the risk of 
potential bias, study site personnel who are responsible for reconstituting and/or 
administering study drugs will not be permitted to conduct any safety or efficacy 
evaluations.  Additionally, personnel administering study drug should apply bandages 
over injections sites to help maintain blinding.  To minimize risk of potential bias arising 
from access to laboratory results that could potentially unblind treatment assignments 
(e.g., free IgE levels and serum omalizumab concentrations), the Sponsor and sites will 
be restricted from accessing such laboratory results.  
4.3 
STUDY TREATMENT 
4.3.1 
Formulation 
Study Drug 
Omalizumab will be supplied by the Sponsor.  Omalizumab is a sterile, white, 
preservative-free, lyophilized powder, contained in a single-use, 5-mL vial that will be 
reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a SC 
injection.  Each omalizumab vial contains 202.5 mg of omalizumab, 145.5 mg sucrose, 
2.8 mg L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg 
polysorbate 20.  Each vial is designed to deliver 150 mg of omalizumab in 1.2 mL after 
reconstitution with 1.4 mL SWFI, USP. 
For additional details, see the pharmacy manual and the Omalizumab Investigator's 
Brochure. 
Placebo 
The placebo contains the same ingredients as the omalizumab formulation listed above, 
excluding omalizumab.   
4.3.2 
Dosage, Administration, and Storage 
Patients will receive omalizumab 300 mg or placebo administered SC Q4W at the study 
site.  Missed doses will not be replaced. 
Each patient will receive two injections of study medication at every treatment visit.  For 
details regarding study drug preparation and administration, and the study drug dosing 
schedule, please refer to Appendix 4 and Appendix 5, respectively. 
Doses will be divided among more than one injection site to limit injections to not more 
than 150 mg per site.  

 
Omalizumab—Genentech, Inc. 
36/Protocol ML29510, Version 1 
The reconstituted vial is to be used for single-dose administration only.  Study drug will 
be administered SC to patients in the deltoid region of the right or left arm.  Alternatively, 
the injections can be administered in the thigh if medically significant reasons preclude 
administration in the deltoid region.   
Prior to randomization, during the initial open-label treatment period, study drug will be 
administered open-label as known omalizumab.  After randomization, subjects will be 
assigned to either active or placebo medication.  As described in Section 3.1, certain 
patients meeting prespecified criteria may, at the discretion of the investigator, be 
transitioned to open-label omalizumab. 
Study drug must be stored in refrigerated conditions (2°C−8°C; 36°F−46°F) in a limited 
access area and/or a locked refrigerator.  Study drug should be stored according to the 
storage instructions on the box immediately upon receipt but no later than 24 hours after 
receipt.  
Study drug should not be frozen or shaken.  Study drug is for single use only 
and contains no preservatives.  The solution should be used for SC injection within 
8 hours following reconstitution if stored in the vial at 2°C−8°C (36°F−46°F), or within 
4 hours of reconstitution if stored at room temperature.  Reconstituted vials should be 
protected from direct sunlight. 
Patients should be closely observed after administration of open-label omalizumab and 
blinded study drug for signs and symptoms of anaphylaxis.  This observation should be 
for a period of time that is judged to be appropriate by the investigator.  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. 
Guidelines for treatment interruption or discontinuation are provided in Section 5.1.3.   
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  See Section 5.3.5.11 for guidance on adverse 
events associated with an overdose. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(omalizumab) will be provided by the Sponsor where required by local health authority 
regulations.  The study site will acknowledge receipt of IMPs, using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced.  

 
Omalizumab—Genentech, Inc. 
37/Protocol ML29510, Version 1 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any 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 
Post-Trial Access to Omalizumab 
The Sponsor (Genentech) may offer continued access to the study drug after study 
completion, in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  All concomitant medications should be 
reported to the investigator and recorded on the appropriate eCRF.  Patients will be 
encouraged to use the minimal dose required to control their symptoms. 
The long-acting H1 antihistamines, H2 blockers, and LTRAs allowed during the study 
are as follows.  Note that the H1 antihistamines may be used at up to four times the 
approved dose listed below: 
• 
H1 antihistamines 
− 
Cetirizine 5 or 10 mg once per day (QD) 
− 
Levocetirizine dihydrochloride 2.5 or 5 mg QD 
− 
Fexofenadine 60 mg twice per day (BID), or 180 mg QD 
− 
Loratadine 10 mg QD 
− 
Desloratadine 5 mg QD  
• 
H2 blockers  
− 
Cimetidine 800 mg BID, or 400 mg four times per day (QID) 
− 
Famotidine 40 mg QD, or 20 mg QD or BID 

 
Omalizumab—Genentech, Inc. 
38/Protocol ML29510, Version 1 
− 
Nizatidine 150 mg QD 
− 
Ranitadine 150 mg BID 
• 
LTRAs  
− 
Montelukast 10 mg QD 
− 
Zafirlukast 20 mg BID 
 
All patients will be allowed to take study-defined H1 antihistamine medications at 
up to four times the approved dose, H2 blockers, and/or LTRAs during the screening, 
treatment, and follow-up periods.  Patients should remain on a stable H1 antihistamine, 
H2 blocker, and/or LTRA treatment regimen throughout the randomization period 
(Week 24 to Week 48).  Diphenhydramine (25 mg) may also be used on an as-needed 
basis (maximum three times/day) during the screening, treatment, and follow-up periods.  
4.4.2 
Prohibited Therapy 
The following medications and treatments will be restricted as specified below: 
• 
Routine (daily or every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to Day −14 and during the study period 
(baseline to Week 60):  systemic corticosteroids, hydroxychloroquine, methotrexate, 
mycophenolate, cyclosporine, or cyclophosphamide.  Additionally, during the study 
period (baseline to Week 60), prohibited routine usage also includes usage for 
greater than 10 total days during any 30-day period. 
− 
Note:  inhaled asthma controllers, including inhaled corticosteroids, are 
permitted during the study. 
• 
Routine (daily or every other day during 5 or more consecutive days) doses of 
doxepin within 14 days prior to Day −14 and during the study period (baseline to 
Week 60) 
• 
Omalizumab within 1 year prior to screening and during the study period (baseline 
to Week 60), except as provided by this study   
• 
Either IVIG or plasmapheresis within 30 days prior to Day −14 and during the study 
period (baseline to Week 60) 
 
Patients who receive any excluded therapy during screening should be considered a 
screen failure.  Patients who receive any excluded therapy after randomization will be 
discontinued from study treatment; if a patient has received at least one dose of 
omalizumab following enrollment, the patient should enter the 12-week follow-up period 
(see Appendix 2).   

 
Omalizumab—Genentech, Inc. 
39/Protocol ML29510, Version 1 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1, Appendix 2, and Appendix 3 for the schedule of assessments 
performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent from the patient or a legally authorized representative, and 
patient assent, if applicable, for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for 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 randomization.  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. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases (including onset of CIU symptoms, 
date of diagnosis, and therapies received for CIU), surgeries, reproductive status, 
smoking history, and all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to the screening visit.  In addition, the following specific medications used by 
the patient within 1 year prior to the screening visit will be collected:  systemic 
corticosteroids, cutaneous (topical) corticosteroids, hydroxychloroquine, methotrexate, 
cyclosporine, and cyclophosphamide. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Vital Signs 
Vital signs include measurements of pulse, and systolic and diastolic blood pressure 
while the patient is in a seated position.   
4.5.4 
Physical Examinations 
A complete physical examination performed at screening 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. 
During the study, 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. 

 
Omalizumab—Genentech, Inc. 
40/Protocol ML29510, Version 1 
4.5.5 
Laboratory Assessments 
All blood draws should be performed prior to study drug administration. 
The following laboratory tests will be performed at the study site’s local laboratory: 
• 
Stool ova and parasite evaluation:  This test should be conducted in patients who 
have risk factors for parasitic disease (e.g., living in an endemic area, travel to an 
endemic area within the last 6 months, chronic GI symptoms, or chronic 
immunosuppression) AND an eosinophil count > 2 times the ULN.  This test should 
be conducted anytime during the screening period after the Day −14 results are 
available for applicable patients. 
• 
Urine pregnancy test:  All women of childbearing potential (including those who 
have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal 
women and women who have had a hysterectomy will not be required to have 
pregnancy testing.  If a local urine pregnancy test shows a positive result, then study 
drug and/or open-label omalizumab will not be administered that day.  Other study 
procedures should also be postponed and the result must be confirmed by a serum 
pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  Please refer to the laboratory manual for additional details on central 
laboratory assessments and sample handling.  The assessments listed below will be 
performed at a central laboratory or at Genentech: 
• 
Hematology:  hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, 
white blood cell (WBC) count, percent and absolute differential count (neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells) 
• 
Serum chemistries:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen (BUN), creatinine, calcium, phosphorus, magnesium, total and direct 
bilirubin, total protein, albumin, alanine transaminase (ALT), aspartase 
transaminase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), 
creatine phosphokinase, and uric acid 
• 
Serum pregnancy test:  If a local urine pregnancy test shows a positive result, then 
the result must be confirmed by a serum pregnancy test (performed by central 
laboratory). 
• 
Urinalysis:  dipstick (pH, specific gravity, glucose, protein, ketones, blood) and 
microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria) 
• 
PK assessments:  serum total omalizumab 
• 
PD assessments:  total serum IgE and free serum IgE levels 
• 
Blood RNA for exploratory research (see Section 4.5.6) 
• 
Blood samples for biomarker and biochemical analyses for exploratory research 
(see Section 4.5.6) 
 

 
Omalizumab—Genentech, Inc. 
41/Protocol ML29510, Version 1 
4.5.6 
Exploratory Blood RNA and Blood Biomarker Samples 
Blood samples for biomarkers and biochemical analyses will be collected from all 
patients at selected visits and stored for exploratory research and markers of drug 
response. 
Optional blood RNA samples will be collected from those patients who specifically 
consent to this optional collection.  These samples will be stored for future exploratory 
research. 
4.5.7 
Patient eDiary 
The patient eDiary (see Appendix 6), also referred to as the Urticaria Patient Daily Diary 
(UPDD), consists of questions (with specific recall periods) about the following:  itch 
severity (12 hours, twice daily), number of hives (12 hours, twice daily), largest hive size 
(12 hours, twice daily), sleep interference (24 hours), daily activity interference 
(24 hours), diphenhydramine use (24 hours), and the occurrence of angioedema 
(24 hours).  In addition, management of angioedema occurrences (24 hours) and calls to 
a doctor, nurse, or nurse practitioner because of CIU (24 hours) will be recorded.  The 
eDiary will be given to each patient at the Day −14 visit. 
Patients will be instructed to complete the eDiary twice a day for the entire duration of 
the study, beginning at Day −14.  Patients should be encouraged to make every effort to 
stay current with their eDiary entries, even when travelling or in a location where data 
reception connectivity will not allow daily transfer of eDiary entries to the central server.  
When data reception connectivity is not available, data entries will be stored locally on 
the eDiary device and transferred at the time that such connectivity becomes available. 
The UAS is a composite score (recorded via eDiary) that reflects daily itch severity and 
daily number of hives.  The daily itch score (range 0−3) comprises the average of the 
two scores of itch severity (12-hour recall each morning and evening; see Table 1).  The 
daily number of hives score (range 0−3) comprises the average of the two scores 
(12-hour recall each morning and evening; see Table 1) associated with number of hives.  
The daily UAS (range 0−6) is the sum of the daily itch score and the daily number of 
hives score.  The UAS7 is the sum of the daily UAS during the last 7 days. 
Table 1 
Twice Daily Assessment of Disease Activity in Patients with 
Chronic Idiopathic Urticaria (Urticaria Activity Score) 
Score 
Wheals (Hives) 
Pruritus (Itch) 
0 
None 
None 
1 
Mild (1−6 hives/12 hour) 
Mild 
2 
Moderate (7−12 hives/12 hour) 
Moderate 
3 
Intense (> 12 hives/12 hour) 
Severe 
 

 
Omalizumab—Genentech, Inc. 
42/Protocol ML29510, Version 1 
4.5.8 
Patient-Reported Outcomes 
The following PRO instruments will be administered as specified in Appendix 1, 
Appendix 2, and Appendix 3: 
• 
Dermatology Life Quality Index (DLQI) 
The DLQI (see Appendix 7) is a 10-item dermatology-specific health-related quality 
of life measure (Finlay and Khan 1994).  Patients rate their dermatology symptoms 
and the impact of their skin condition on various aspects of their health-related 
quality of life.  An overall score will be calculated as well as separate scores for the 
following domains:  symptoms and feelings, daily activities, leisure, work and 
school, personal relationships, and treatment.  The minimally important difference 
(MID) of overall DLQI score for patients with CIU is estimated at 2.24−3.10 
(Shikiar et al. 2005).   
• 
Urticaria Control Test (UCT) 
The UCT (see Appendix 8) is 4-item instrument, designed as a brief and 
easy-to-use tool; it may be utilized to assess urticarial control and to screen urticaria 
patients with poorly controlled disease (Weller et al. 2014).  The UCT questionnaire 
has a 4-week recall period.  Low scores indicate poorly controlled urticaria.  The 
developers recommended a value of 12 for controlled disease (i.e., all patients 
exhibiting UCT values of  ≤ 11 are considered to have poorly controlled disease).  
• 
Urticaria Activity and Impact Measure (U-AIM) 
The U-AIM (see Appendix 9) is a 9-item instrument designed to assess the patient’s 
urticaria activity and impact during the past 7 days (Genentech data on file).  The 
questionnaire asks about the severity of the CIU symptoms (itch, hives, and 
angioedema) and how much these symptoms bothered the patient.  It also inquires 
about how much CIU symptoms interfered with the patient’s daily activities and 
sleep.  It concludes by asking the patient to rate the extent to which their urticaria 
was under control.  
• 
Insomnia Severity Index (ISI)  
The ISI (see Appendix 10) is a 7-item questionnaire measuring self-perceptions of 
insomnia symptoms and the impact of these symptoms on patient health and daily 
life (Morin 1993).  It encompasses sleep onset, sleep maintenance, awakening, 
sleep pattern satisfaction, interference with daily functioning, noticeability of sleep 
problem to others, and distress caused by sleep problem.  The total score ranges 
from 0−28 points (higher scores indicate greater insomnia severity).  The developers 
provided the following guidance to the score interpretation; however, this guidance 
needs further empirical validation:  0−7 = no clinically significant insomnia, 
8−14 = sub-threshold insomnia, 15−21 = clinical insomnia (moderate severity), and 
22−28 = clinical insomnia (severe).  The recommended MID for ISI score is 6 
(Bastien 2001; Yang et al. 2009).  

 
Omalizumab—Genentech, Inc. 
43/Protocol ML29510, Version 1 
• 
Generalized Anxiety Disorder 7-Item (GAD-7) scale 
The GAD-7 scale (see Appendix 11) is a 7-item questionnaire with good reliability as 
well as criterion, construct, factorial, and procedural validity.  The total score ranges 
from 0−21, with higher scores indicating greater anxiety.  Cut points of 5, 10, and 15 
might be interpreted as representing mild, moderate, and severe levels of anxiety, 
respectively (Spitzer et al. 2006). 
• 
Work Productivity and Activity Index (WPAI) 
The WPAI (see Appendix 12) is a 6-item questionnaire that measures four domains 
of health-related quality of life associated with reduced productivity:  absenteeism, 
presenteeism, work productivity loss, and activity impairment.  The absenteeism is 
assessed as a percentage of total work time that a patient missed due to a health 
problem.  The presenteeism is evaluated as the extent to which a health problem 
affected patient’s productivity while working.  The total productivity loss is the 
product of absenteeism and presenteeism combined.  The impact on activities of 
daily living represents to what extent a health problem affected the patient’s 
activities of daily living outside of work.  The scores are generated as percentages 
for each of the abovementioned domains, with higher scores indicating more 
productivity problems associated with the health state (Reilly et al. 1993). 
• 
Patient Global Impression of Change (P-GIC) scale 
The P-GIC (see Appendix 13) is a one-item scale asking patients to rate the change 
in their CIU they experienced since the beginning of the study (Genentech data on 
file).  The questionnaire is intended to understand how patients subjectively 
perceive the change in their CIU. 
 
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 5.3.5. 
4.5.9 
Clinician-Reported Outcomes 
• 
In-Clinic Measured Urticaria Activity Score (IC-UAS) 
The IC-UAS (see Appendix 14) is a paper-based, in-clinic measured UAS based on 
the patient’s condition during the 12 hours prior to the visit.  This score will be 
recorded every 4 weeks as outlined in the schedule of assessments 
(see Appendix 1, Appendix 2, and Appendix 3).  The IC-UAS should be completed 
by a healthcare professional based on an interview of the patient.  
The IC-UAS is a composite score with numeric severity intensity ratings (0 = none to 
3 = intense/severe) for the number of wheals (hives) and the severity of the itch.  
The maximum IC-UAS value is 6. 
• 
Clinician Global Impression of Change (C-GIC) scale 
The C-GIC (see Appendix 15) is a one-item scale asking clinicians to rate the 
change in the patient’s CIU since the beginning of the study (Genentech data on 
file).  The questionnaire is intended to understand how clinicians subjectively 
perceive the change in the patient’s CIU. 

 
Omalizumab—Genentech, Inc. 
44/Protocol ML29510, Version 1 
 
4.5.10 
Samples for Roche Clinical Repository 
Genentech is a member of the Roche group and participates in the collection and/or 
submission of biological samples to the Roche Clinical Repository (RCR).  Collection 
and submission of biological samples to the RCR is contingent upon the review and 
approval of the RCR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site is not granted the necessary approval for RCR sampling, this 
section of the protocol will not be applicable at that site. 
4.5.10.1 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future. 
RCR specimens will be used to achieve the following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Sample Collection 
The following samples will be collected and stored in the RCR for research purposes, 
including but not limited to research on dynamic (non-inherited) biomarkers related to 
omalizumab or CIU: 
• 
Blood for biomarker and biochemical analyses (required for patients consenting to 
participate in this study) 
• 
Whole blood for RNA extraction (optional) 
• 
Remaining blood samples from study-related procedures (optional) 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 

 
Omalizumab—Genentech, Inc. 
45/Protocol ML29510, Version 1 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.10.3 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is “double-coded” by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A “linking key” between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens 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. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.10.4 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate in the study ML29510.  Patients may also 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to 
provide optional blood RNA samples and remaining blood samples from study-related 

 
Omalizumab—Genentech, Inc. 
46/Protocol ML29510, Version 1 
procedures for storage in the RCR.  Patients who decline to participate in the collection 
of these optional samples will not provide a separate signature.  A separate, specific 
signature is not required for submission of blood for biomarker and biochemical analyses 
to the RCR.   
The investigator should document whether or not the patient has given consent to 
participate in optional blood RNA samples and remaining blood samples from study-
related procedures for storage in the RCR by completing the appropriate section of the 
RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
 
4.5.10.5 
Withdrawal from the Roche Clinical Repository 
Patients have the right to withdraw their specimens from the RCR at any time for any 
reason.  If a patient wishes to withdraw consent to the testing of his or her specimens, 
the investigator must inform the Medical Monitor in writing of the patient's wishes through 
use of the RCR Subject Withdrawal Form and, if the trial is ongoing, must enter the date 
of withdrawal on the RCR Research Sample Withdrawal of Informed Consent eCRF.  
The patient will be provided with instructions on how to withdraw consent after the trial is 
closed.  A patient's withdrawal from Study ML29510 does not, by itself, constitute 
withdrawal of specimens from the RCR.  Likewise, a patient's withdrawal from the RCR 
does not constitute withdrawal from Study ML29510. 
4.5.10.6 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 

 
Omalizumab—Genentech, Inc. 
47/Protocol ML29510, Version 1 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
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 withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
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 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site 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 indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
• 
In addition, the Sponsor may decide to discontinue the study based on the iDMC 
recommendation. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
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 Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 

 
Omalizumab—Genentech, Inc. 
48/Protocol ML29510, Version 1 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Omalizumab (Xolair) is currently registered in over 90 countries and is indicated for 
adults and children (6 years of age and above in the E.U.) with moderate to severe 
persistent allergic asthma whose symptoms are inadequately controlled with inhaled 
corticosteroids. 
As of 30 June 2014, Xolair is currently registered in over 40 countries, including the U.S., 
for adults and adolescents (12 years of age and above) with chronic spontaneous 
(idiopathic) urticaria refractory to standard of care.  Consult local prescribing information 
for more information. 
The adverse event profile of omalizumab observed during the allergic asthma clinical 
development program was very similar to placebo with the most commonly reported 
adverse reactions were injection site reactions, including injection site pain, swelling, 
erythema, pruritus, and headaches.  
Of the adverse events of special interest, anaphylactic reactions were observed but were 
rare and typically occurring within 2 hours of the first injection.  
Although a numerical imbalance in malignancy was observed in the omalizumab 
treatment group compared with the control group, the short exposure duration is not 
consistent with the biology of solid organ pathogenesis; additionally, the diversity in the 
type of cancers observed and the clinical features of the individual cases render a causal 
relationship unlikely. 
The overall adverse event profile in the pooled Phase III CSU studies was consistent 
with the known safety profile of omalizumab in patients with allergic asthma, with the 
exception of adverse events that were specifically related to the respective indications.  
The overall incidence of adverse events across the omalizumab treatment groups was 
broadly similar to that seen with placebo.  In general, omalizumab at the proposed doses 
of 150 mg and 300 mg was well tolerated in the treatment of patients with severe, 
refractory CSU/CIU, including in patients with multiple concomitant medications.  Both 
doses appeared to be well tolerated, with no evidence of dose-related adverse events.  
Injection site reactions are a known side effect of omalizumab treatment, and those 
observed in CSU/CIU patients were consistent with those observed in allergic asthma.  
There were no subsets of patients identified who had increased risks of serious adverse 
events or adverse events of special interest. 
During the conduct of the study, a treatment assignment may be unblinded only in the 
event of a life-threatening medical emergency that requires immediate 
unblinding/unmasking.  In such cases, unblinding will be implemented following standard 

 
Omalizumab—Genentech, Inc. 
49/Protocol ML29510, Version 1 
procedures, and only following agreement by both the investigator and Medical Monitor 
that unblinding is necessary. 
The Sponsor Safety Reporting Department (independent from the study team) will break 
the treatment code for all unexpected serious adverse events that are considered by the 
investigator to be related to study drug for the purpose of regulatory reporting.  The 
study team will remain blinded to study treatment. 
Safety data, including serious and non-serious adverse events and laboratory test 
results, will be reviewed internally on a periodic basis during the conduct of the study.   
An iDMC will review blinded and unblinded safety data provided by an iDCC every 
6 months for the duration of the study. 
Events described in Section 5.1.1 through Section 5.1.3 will be closely monitored and 
represent selected adverse events for this study. 
Please refer to the Omalizumab Investigator’s Brochure for additional information on 
safety risks.  
5.1.1 
Anaphylaxis 
Anaphylaxis has been reported to occur after administration of omalizumab in 
premarketing clinical trials and in postmarketing spontaneous reports.  Signs and 
symptoms in these reported cases have included bronchospasm, hypotension, syncope, 
urticaria, and/or angioedema of the throat or tongue.  Some of these events have been 
life-threatening.  In premarketing clinical trials in patients with asthma, anaphylaxis was 
reported in 3 of 3507 (0.1%) patients. 
In postmarketing spontaneous reports, the frequency of anaphylaxis attributed to 
omalizumab use was estimated to be at least 0.2% of patients based on an estimated 
exposure of about 57,300 patients from June 2003 through December 2006.  
Anaphylaxis has occurred as early as after the first dose of omalizumab, but also has 
occurred beyond 1 year after beginning regularly scheduled treatment.  
The analysis of all cases of anaphylaxis submitted to Novartis show that, the majority of 
anaphylactic-type reactions have been reported to occur after the first dose with 
numbers decreasing with subsequent doses.  As expected for an anaphylactic-type 
reaction (Type I), events were reported to occur predominantly within the first 2 hours 
post-dosing with few reports occurring as far as > 36 hours post-dose.  

 
Omalizumab—Genentech, Inc. 
50/Protocol ML29510, Version 1 
Warning 
Because of the risk of anaphylaxis, patients should be closely observed for an 
appropriate period of time after omalizumab administration, and healthcare providers 
administering omalizumab should be prepared to manage anaphylaxis that can be 
life-threatening.  Patients should also be informed of the signs and symptoms of 
anaphylaxis and instructed to seek immediate medical care should symptoms occur. 
Please refer to the Omalizumab Investigator’s Brochure for additional information. 
5.1.2 
Clinical Trial Experience with Omalizumab in Patients with CIU 
The safety of omalizumab for the treatment of CIU was assessed in three placebo-
controlled, multiple-dose clinical trials of 12 weeks (CIU Trial 2) and 24 weeks in duration 
(CIU Trials 1 and 3).  The data described in Table 2 below reflect omalizumab 
exposure for 733 patients enrolled and receiving at least one dose of omalizumab in 
the three clinical trials, including 684 patients exposed for 12 weeks and 427 
exposed for 24 weeks. 
Table 2 
Adverse Reactions Occurring in ≥ 2% in Omalizumab-Treated 
Patients and More Frequently than in Patients Treated with 
Placebo (Day 1 to Week 12) in CIU Trials 
CIU Trials 1, 2, and 3 Pooled 
Adverse Reactions a 
Omalizumab
150 mg 
(n = 175) 
Omalizumab 
300 mg 
(n = 412) 
Placebo 
(n = 242) 
Gastrointestinal disorders 
 
Nausea 
2 (1.1%) 
11 (2.7%) 
6 (2.5%) 
Infections and infestations 
 
Nasopharyngitis 
16 (9.1%) 
27 (6.6%) 
17 (7.0%) 
 
Sinusitis 
2 (1.1%) 
20 (4.9%) 
5 (2.1%) 
 
Upper respiratory tract infection 
2 (1.1%) 
14 (3.4%) 
5 (2.1%) 
 
Viral upper respiratory tract infection 
4 (2.3%) 
2 (0.5%) 
(0.0%) 
Musculoskeletal and connective tissue disorders 
 
Arthralgia 
5 (2.9%) 
12 (2.9%) 
1 (0.4%) 
Nervous system disorders 
 
Headache 
21 (12.0%) 
25 (6.1%) 
7 (2.9%) 
Respiratory, thoracic, and mediastinal disorders 
 
Cough 
2 (1.1%) 
9 (2.2%) 
3 (1.2%) 
CIU = chronic idiopathic urticaria. 
a by MedDRA (15.1) System Organ Class and Preferred Term. 
 

 
Omalizumab—Genentech, Inc. 
51/Protocol ML29510, Version 1 
Malignancies 
A small numerical imbalance (0.5% vs. 0.2%) in malignant neoplasms was observed in 
clinical studies of adults and adolescents (≥ 12 years of age) with asthma and other 
allergic disorders.  The observed malignancies in omalizumab-treated patients were a 
variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid 
occurring more than once, and five other types occurring once each.  The majority of 
patients were observed for less than 1 year.  
A subsequent observational study, A Epidemiologic Study of Xolair (Omalizumab): 
Evaluating Clinical Effectiveness and Long-Term Safety in Patients with Moderate to 
Severe Asthma (EXCELS), was done as a post-marketing commitment to the FDA.  This 
study’s pre-specified primary outcomes measures were all malignancy, all malignancies 
excluding non-melanoma skin carcinoma, and overall serious adverse events.  This 
study enrolled 5007 omalizumab-treated and 2829 non-omalizumab-treated 
patients  ≥ 12 years old with moderate to severe persistent asthma and followed them for 
up to 5 years, with mean follow-up of 3.7 years.  Patients were not randomized or 
blinded and were assigned to omalizumab or non-omalizumab cohorts based on clinical 
decisions related to initiation and continuation of omalizumab.  In EXCELS, the 
incidence rates of primary malignancies (per 1000 patient years) were similar among 
omalizumab-treated (12.3) and non-omalizumab-treated patients (13.0).  However, study 
limitations preclude definitively ruling out a malignancy risk with omalizumab.  Study 
limitations include:  the observational study design, the bias introduced by allowing 
enrollment of patients previously exposed to omalizumab (88%), enrollment of patients 
(56%) while a history of cancer or a premalignant condition were study exclusion criteria, 
and the high study discontinuation rate (44%). 
Cardiovascular and Cerebrovascular Events from Clinical Studies in 
Patients with Asthma 
In the observational EXCELS study, a higher incidence rate of overall cardiovascular 
and cerebrovascular serious adverse events was observed in omalizumab-treated 
patients (13.4) compared to non-omalizumab-treated patients (8.1).  Increases in rates 
were observed for transient ischemic attack (0.7 vs. 0.1), myocardial infarction (2.1 vs. 
0.8), pulmonary hypertension (0.5 vs. 0), pulmonary embolism/venous thrombosis (3.2 
vs. 1.5), and unstable angina (2.2 vs. 1.4), while the rates observed for ischemic stroke 
and cardiovascular death were similar among both study cohorts.  
In the observational EXCELS study, patients were not randomized or blinded and were 
assigned to omalizumab or non-omalizumab cohorts based on clinical decisions related 
to initiation and continuation of omalizumab.  Omalizumab and non-omalizumab cohorts 
were balanced for smoking history and age.  However, baseline cardiovascular risk 
factors were higher in the omalizumab-treated cohort than the non-omalizumab-treated 
cohort (Food and Drug Administration 2014).  More omalizumab-treated patients were 
diagnosed with severe asthma (50%) compared to the non-omalizumab-treated 
patients (23%). 

 
Omalizumab—Genentech, Inc. 
52/Protocol ML29510, Version 1 
Interpretation of the EXCELS study results related to cardiovascular and 
cerebrovascular events has been limited by the observational study design, the inclusion 
of patients previously exposed to omalizumab (88%), baseline imbalances in 
cardiovascular risk factors between the treatment groups, an inability to adjust for 
unmeasured risk factors, and the high study discontinuation rate.  
A separate pooled analysis of 25 randomized double-blind, placebo-controlled clinical 
trials of 8 to 52 weeks in duration included 3342 omalizumab-treated patients and 2895 
placebo-treated patients.  The primary outcomes of interest included cardiovascular 
death, myocardial infarction, arrhythmias, heart failure, stroke, transient ischemic attack, 
pulmonary hypertension, pulmonary embolism, and unstable angina.  Across all the 
studies, a total of 8 events occurred in the omalizumab-treated patients compared with 
15 in the placebo patients, and no notable differences were observed in the rates of 
specific cardiovascular events (Food and Drug Administration 2014).  However, the 
results of the pooled analysis were based on a low number of events, slightly younger 
patients, and shorter duration of follow-up than the observational EXCELS study; 
therefore, the results are insufficient to confirm or reject the findings noted in the 
observational EXCELS study.  

 
Omalizumab—Genentech, Inc. 
53/Protocol ML29510, Version 1 
5.1.3 
Management of Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 3.   
Table 3 
Guidelines for Management of Specific Adverse Events 
Event 
Action to Be Taken 
Anaphylaxis 
• 
Administer omalizumab only in a healthcare setting by 
healthcare providers prepared to manage anaphylaxis that can 
be life-threatening.  
• 
Observe patients closely for an appropriate period of time after 
administration of omalizumab. 
• 
Inform patients of the signs and symptoms of anaphylaxis, and 
instruct them to seek immediate medical care should signs or 
symptoms occur. 
Acute asthma symptoms 
• 
Omalizumab has not been shown to alleviate asthma 
exacerbations acutely. 
• 
Do not use omalizumab to treat acute bronchospasm or status 
asthmaticus. 
Angioedema 
• 
Patients with CIU can have angioedema as part of their 
symptoms. 
− 
When angioedema poses a risk to the airway, the 
emergent use of systemic corticosteroids is indicated. 
− 
Patients who need to be treated with systemic 
corticosteroids will be discontinued from study treatment 
and followed for safety for the remainder of the study. 
− 
Patients will be provided emergency contact information 
and advised to contact a physician during the entire study, 
in case of angioedema. 
Serum sickness 
• 
In post-approval use, some patients have experienced a 
constellation of signs and symptoms including 
arthritis/arthralgia, rash, fever, and lymphadenopathy with an 
onset 1 to 5 days after the first or subsequent injections of 
omalizumab. 
− 
These signs and symptoms have recurred after additional 
doses in some patients. 
− 
Although circulating immune complexes or a skin biopsy 
consistent with a Type III reaction were not seen with 
these cases, these signs and symptoms are similar to 
those seen in patients with serum sickness. 
− 
Physicians should stop omalizumab if a patient develops 
this constellation of signs and symptoms. 
Parasitic infections 
• 
Monitor patients at high risk of geohelminth infection while on 
omalizumab therapy.  Insufficient data are available to 
determine the length of monitoring required for geohelminth 
infections after stopping omalizumab treatment. 
 

 
Omalizumab—Genentech, Inc. 
54/Protocol ML29510, Version 1 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious 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 Good Clinical Practice, 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), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram, 
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 5.3.5.10) 

 
Omalizumab—Genentech, Inc. 
55/Protocol ML29510, Version 1 
• 
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 criteria; 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 5.4.1 for 
reporting instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious 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 Section 5.4.1 for reporting instructions).  Adverse events of special interest 
for this study include the following: 
• 
Suspected anaphylaxis due to omalizumab, as defined by Sampson’s criteria 
(Sampson et al. 2006; see Appendix 16) 
• 
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. 
• 
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 5.3.5.6). 
 

 
Omalizumab—Genentech, Inc. 
56/Protocol ML29510, Version 1 
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 Section 5.4, Section 5.5, and 
Section 5.6. 
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 5.4.1 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 112 days 
(approximately 5 drug half-lives) after the last administration of study drug or study 
discontinuation/termination, whichever is later.  After this period, the investigator should 
report any serious adverse events that are believed to be related to prior study drug 
treatment (see Section 5.6). 
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?”  
 

 
Omalizumab—Genentech, Inc. 
57/Protocol ML29510, Version 1 
5.3.3 
Assessment of Severity of Adverse Events 
Table 4 provides guidance for assessing adverse event severity. 
Table 4 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see 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 or 
not an adverse event is considered to be related to the study drug, indicating “yes” or 
“no” accordingly.  The following guidance should be taken into consideration (see also 
Table 5): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 
 

 
Omalizumab—Genentech, Inc. 
58/Protocol ML29510, Version 1 
Table 5 
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 
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. 

 
Omalizumab—Genentech, Inc. 
59/Protocol ML29510, Version 1 
5.3.5.2 
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. 
5.3.5.3 
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 5.4.1 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. 
5.3.5.4 
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., dosage modification, treatment 
interruption, or treatment discontinuation) 

 
Omalizumab—Genentech, Inc. 
60/Protocol ML29510, Version 1 
• 
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  
– 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
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., ALP 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 if 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.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
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., dosage modification, treatment 
interruption, or 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. 

 
Omalizumab—Genentech, Inc. 
61/Protocol ML29510, Version 1 
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 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
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 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 a non-serious adverse event of special interest 
(see Section 5.4.1). 
5.3.5.7 
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 5.4.1).  This 
includes death attributed to progression of CIU. 
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.  The term “sudden death” should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  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. 
If the death is attributed to progression of CIU, “chronic idiopathic urticaria progression” 
should be recorded on the Adverse Event eCRF.   

 
Omalizumab—Genentech, Inc. 
62/Protocol ML29510, Version 1 
5.3.5.8 
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”). 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic Idiopathic Urticaria 
Medical occurrences or symptoms of deterioration that are anticipated as part of CIU 
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 CIU on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., “accelerated chronic idiopathic urticaria”). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient 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.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
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 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available 
 

 
Omalizumab—Genentech, Inc. 
63/Protocol ML29510, Version 1 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded 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 5.4.1). 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
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 using the contact information provided in 
Section 5.4.1.1; 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 (see Section 5.4.1 for further details) 
• 
Non-serious adverse events of special interest (see Section 5.4.1 for further details) 
• 
Pregnancies (see Section 5.4.2 for further details) 
 
The investigator must report new significant follow-up information for these events 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 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 

 
Omalizumab—Genentech, Inc. 
64/Protocol ML29510, Version 1 
5.4.1 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
5.4.1.1 
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 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 
below. 
Genentech Drug Safety Department 
Fax No.:  
 
 
650-225-4630 
Alternate Fax No: 
650-225-4682 
Email: 
 
 
 
us_drug.safety@gene.com 
  
5.4.1.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 112 days (approximately 5 drug half-lives) after the 
last administration of study drug or study discontinuation/termination, whichever is later.  
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 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 in Section 5.4.1.1.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.2 
Reporting Requirements for Pregnancies 
5.4.2.1 
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 112 days after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should counsel the patient, discussing the risks of the 

 
Omalizumab—Genentech, Inc. 
65/Protocol ML29510, Version 1 
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 the event that the EDC system is unavailable, the Clinical Trial Pregnancy 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 pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided in Section 5.4.1.1.  Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system. 
5.4.2.2 
Congenital Anomalies/Birth Defects and Abortions 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male 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 5.4.1).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant). 
5.4.3 
Medical Contact 
Genentech Medical Monitor:  
, M.D. 
Genentech, Inc. 
Telephone No.: 
 
  
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.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.2.1. 

 
Omalizumab—Genentech, Inc. 
66/Protocol ML29510, Version 1 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
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 (defined as 
112 days [approximately 5 drug half-lives] after the last administration of study drug or 
study discontinuation/termination, whichever is later), if the event is believed to be 
related to prior study drug treatment.   
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided in 
Section 5.4.1.1. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious 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 U.S. prescribing information for 
omalizumab, found in the USPI.   
 
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. 

 
Omalizumab—Genentech, Inc. 
67/Protocol ML29510, Version 1 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
Assuming a 60% rate of clinical worsening in CIU assessed by UAS7 in the placebo 
group (including 10% dropout imputed as worsening CIU) and a rate of 30% in the 
omalizumab continuation group (including 10% dropout imputed as clinical worsening 
CIU) in the period up to 24 weeks post-randomization, a total of 117 patients will need to 
be randomized at a 3:2 ratio (3 omalizumab continuation group patients for every 
2 placebo patients) to ensure 90% power to detect a difference in clinical worsening CIU 
rates as a primary analysis comparison at the 0.05 alpha level (2-sided test).  In addition, 
as it is estimated that 15% of patients will either drop out during the open-label treatment 
period or not meet the adherence criteria, and that 66.5% of those who do not drop out 
or fail adherence criteria will be responders, this study will need to enroll at least 207 
(117 / [0.665 • 0.85]) patients to ensure adequate randomization numbers for the primary 
analysis.  This sample size will also ensure at least 80% power for each of the 
secondary analyses. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The disposition of patients for each study period will be summarized by treatment group 
with respect to the number of patients randomized, treated, and completing each study 
period.  Patient discontinuation and the reason for discontinuation will be summarized by 
treatment group for each study period.  The number of patients who complete each 
scheduled dose will be summarized by treatment group.  The number of patients who 
violate key eligibility criteria as well as those who have major protocol deviations will be 
summarized by treatment group for each study period. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Treatment groups entering the double-blind randomization period of the study will be 
assessed for comparability with respect to demographic (e.g., age, sex, race/ethnicity) 
and baseline characteristics (e.g., body weight, total IgE levels, UAS7).  
6.4 
EFFICACY ANALYSES 
Efficacy analyses will be based on the modified intent-to-treat (mITT) principle.  All 
patients meeting criteria for randomization, who are also randomized and receive at 
least one dosage of blinded study drug, will be included in analyses.  Analyses groups 
will be defined according to the patients’ assigned treatments regardless of the actual 
treatment received.   
Analyses comparing rates of clinical worsening CIU after randomization, including the 
primary analysis, will include the counts and proportions of the response among all 
patients as well as in the treatment groups being compared.  The 95% confidence 
intervals will be presented for each within-group proportion and for the difference in 

 
Omalizumab—Genentech, Inc. 
68/Protocol ML29510, Version 1 
proportions between treatment groups.  The 2-sided chi-square p-value will be 
presented to compare the treatment group proportions.   
Analyses comparing changes in UAS7 or any other continuous outcome measure will 
include the means, standard deviations, and 95% confidence intervals for all patients, for 
each treatment group, and for the difference between groups accompanied by p-values 
whenever applicable. 
For all efficacy analyses, statistical significance will be declared if the p-value for the 
comparison is less than 0.05. 
6.4.1 
Missing Data for Efficacy Analyses 
For the purposes of comparing clinical worsening CIU rates, any patient who 
discontinues from the study before the end of the applicable observation period will be 
considered to have experienced clinical worsening, as defined by the primary endpoint.  
For analyses related to continuous endpoints, any patient who discontinues from the 
study may have their endpoints imputed whenever appropriate.  Further details related 
to imputations for missing data will be outlined in the Statistical Analysis Plan (SAP) 
before the database is locked. 
6.4.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the percentage of patients who experience 
a clinical worsening of CIU as defined by UAS7 ≥ 12 for at least 2 consecutive weeks 
post-randomization between Weeks 24 and 48.  The analysis of the primary endpoint will 
consist of comparisons made using a simple chi-square test which will include the 
p-value for the comparison between treatment groups as well as the 95% confidence 
interval for the difference.  
6.4.3 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Time to clinical worsening in CIU, defined based on the same criteria as the primary 
endpoint (UAS7 ≥ 12 for at least 2 consecutive weeks), from randomization 
(Week 24) to Week 48 will consist of treatment comparisons using the log-rank 
p-value and 95% confidence interval for the difference in the survival estimates from 
a corresponding Kaplan-Meier survival analysis. 
• 
Percentage of patients who experience a clinical worsening of CIU as defined by 
UAS7 > 6 for at least 2 consecutive weeks post-randomization between Weeks 24 
and 48.  The analysis of this secondary endpoint will consist of comparisons made 
using a simple chi-square test which will include the p-value for the comparison 
between treatment groups as well as the 95% confidence interval for the difference. 
• 
UAS7 (24- vs. 48-week value) among patients who have responded to omalizumab 
treatment at 24 weeks and completed a further 24 weeks of omalizumab (48 weeks 
total) will be assessed by the change from randomization (Week 24) to Week 48 in 

 
Omalizumab—Genentech, Inc. 
69/Protocol ML29510, Version 1 
UAS7 and analyzed in the context of a non-inferiority hypothesis test with 
non-inferiority margin 5.  The p-value from the non-inferiority test will be used to 
determine the value of continued treatment in this study. 
• 
Retreatment efficacy, defined by change in UAS7 from time of retreatment to 
12 weeks after retreatment, among patients randomized to the placebo arm who are 
retreated with open-label omalizumab after randomization and receive at least 
12 weeks of omalizumab therapy as retreatment, will be analyzed using a 2-sided, 
one sample t-test.  The p-value from this test will be used to evaluate the superiority 
of retreating after experiencing clinical worsening among these patients. 
 
6.5 
SAFETY ANALYSES 
Safety analyses will be performed for all patients treated with study drug.  Safety will be 
assessed by adverse events, vital signs, and clinical laboratory evaluations.  
Adverse events will be collected from the time of the first study-specific procedure 
through the last observation visit.  Verbatim descriptions of adverse events will be coded 
and analyzed using appropriate thesaurus terms.  A treatment-emergent adverse event 
is defined as any adverse event reported, or worsening of an existing condition on or 
after the first dose of study drug.  Treatment-emergent adverse events will be 
summarized by treatment group.  Clinical laboratory data (e.g., serum chemistry and 
hematology evaluations) and vital signs will be summarized by descriptive statistics for 
each treatment group. 
6.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Serum total omalizumab, and total and free IgE concentration versus time data will be 
tabulated by treatment group and summarized using descriptive statistics (e.g., mean, 
standard deviation, minimum, and maximum).  Additional PK and PD analyses may be 
conducted as appropriate. 
6.7 
EXPLORATORY ANALYSES 
For details on how each exploratory analysis will be conducted, see the SAP. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) 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 CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data or other electronic data will be sent 

 
Omalizumab—Genentech, Inc. 
70/Protocol ML29510, Version 1 
directly to the CRO, using the CRO's standard procedures to handle and process the 
electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.   
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures.  
Patient eDiary data will be collected through 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 eDiary device data will be available for view access only via 
secure access to a web server.  Only identified and trained users may view the data, and 
their actions become part of the audit trail.  The Sponsor and study sites will have view 
access only to the web server.  System backups for data stored by the Sponsor and 
records retention for the study data will be consistent with the Sponsor’s standard 
procedures. 
Paper PRO questionnaires will be faxed or couriered from the site to the data entry 
center.  Scanned paper PROs will be transferred via a secure email system. 
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 CRO and should be handled in accordance 
with instructions from the CRO. 
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. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Once the study is complete, the eDiary 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 on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 

 
Omalizumab—Genentech, Inc. 
71/Protocol ML29510, Version 1 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification 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. 
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, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC 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. 

 
Omalizumab—Genentech, Inc. 
72/Protocol ML29510, Version 1 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO completed forms, eDiary data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the 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).  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 E.U. or European 
Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  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/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
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. 

 
Omalizumab—Genentech, Inc. 
73/Protocol ML29510, Version 1 
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/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  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 
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 of 1996 (HIPAA).  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 OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
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/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 

 
Omalizumab—Genentech, Inc. 
74/Protocol ML29510, Version 1 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, 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. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
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 (i.e., LPLV). 
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/EC 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. 

 
Omalizumab—Genentech, Inc. 
75/Protocol ML29510, Version 1 
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. 
9.3 
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/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and a CRO.  The CRO will provide clinical operations 
management, data management, and medical monitoring.  An IxRS will be used to 
assign patient numbers, monitor enrollment and patient status, and to manage study 
treatment requests and shipments. 
Patient data will be recorded via an EDC system using eCRFs (see Section 7.2).  
A blinded external adjudication committee will review potential events of anaphylaxis. 
9.5 
PUBLICATION 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, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.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 
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 

 
Omalizumab—Genentech, Inc. 
76/Protocol ML29510, Version 1 
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. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC 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). 

 
Omalizumab—Genentech, Inc. 
77/Protocol ML29510, Version 1 
10. 
REFERENCES 
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an 
outcome measure for insomnia research. Sleep Med 2001;2:297−307. 
Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and 
chronic urticaria: 2014 update. J Allergy Clin Immunol 2014;133:1270−7. 
Fiebiger E, Maurer D, Holub H, et al. Serum IgG autoantibodies directed against the 
alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a 
distinct subset of chronic urticaria patients? J Clin Invest 1995;96:2606−12. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure 
for routine clinical use. Clin Exp Dermatol 1994;19:210−16. 
Food and Drug Administration. FDA Drug Safety Communication: FDA approves label 
changes for asthma drug Xolair (omalizumab), including describing slightly higher 
risk of heart and brain adverse events. 26 September 2014 [cited 24 October 
2014]. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm414911.htm. 
Grattan CE, Francis DM, Hide M, et al. Detection of circulating histamine releasing 
autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp 
Allergy 1991;21:695−704. 
Greaves MW. Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol 2003;3:363−8. 
Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE 
receptor as a cause of histamine release in chronic urticaria. N Engl J Med 
1993;328:1599−604. 
Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic 
idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy 
Clin Immunol 2013;132:101−9. 
Kozel MM, Sabroe RA. Chronic urticaria: aetiology, management and current and future 
treatment options. Drugs 2004;64:2515−36. 
Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic 
or spontaneous urticaria. N Engl J Med. 2013;368:924−35. 
Morin CM. Insomnia: Psychological Assessment and Management. New York, NY: 
Guilford Press; 1993. 
Niimi N, Francis DM, Kermani F, et al. Dermal mast cell activation by autoantibodies 
against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 
1996;106:1001−6. 
Reilly MC, Zbrozek AS, Dukes E. The validity and reproducibility of a work productivity 
and activity impairment measure.  PharmacoEconomics 1993;4:353−65. 

 
Omalizumab—Genentech, Inc. 
78/Protocol ML29510, Version 1 
Saini SS, Bindslev-Jensen C, Maurer M. Efficacy and safety of omalizumab in patients 
with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 
antihistamines: a randomized, placebo-controlled study. J Invest Dermatol 2014 
Jul 21. doi: 10.1038/jid.2014.306. [Epub ahead of print] 
Saini S, Rosen KE, Hsieh HJ. A randomized, placebo-controlled, dose-ranging study of 
single-dose omalizumab in patients with H1-antihistamine-refractory chronic 
idiopathic urticaria. J Allergy Clin Immunol 2011;128:567−73. 
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;117:391−7. 
Shikiar R, Harding G, Leahy M, et al. Minimal Important Difference (MID) of the 
Dermatology Life Quality Index (DLQI): results from patients with chronic idiopathic 
urticaria. Health Qual Life Outcomes 2005;3:36.  
Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized 
anxiety disorder: the GAD-7. Arch Intern Med 2006;166:1092−7. 
Tilles SA. Approach to therapy in chronic urticaria: when benadryl is not enough. Allergy 
Asthma Proc 2005;26:9−12. 
Tong LJ, Balakrishnan G, Kochan JP, et al. Assessment of autoimmunity in patients with 
chronic urticaria. J Allergy Clin Immunol 1997;99:461−5. 
Weller K, Groffik A, Church MK, et al. Development and validation of the Urticaria 
Control Test: a patient-reported outcome instrument for assessing urticaria control. 
J Allergy Clin Immunol. 2014;133:1365−72. 
XOLAIR® (omalizumab) U.S. Package Insert, Genentech USA, Inc. and Novartis 
Pharmaceuticals Corporation. 2014 Mar [cited 2014 Apr 15]. Available from 
http://www.gene.com/download/pdf/xolair_prescribing.pdf. 
Yang M, Morin CM, Schaefer K, et al. Interpreting score differences in the Insomnia 
Severity Index: using health-related outcomes to define the minimally important 
difference. Curr Med Res Opin. 2009;25:2487−94 
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for 
the definition, classification, diagnosis, and management of urticaria: the 2013 
revision and update. Allergy 2014;69:868−87. 
Zweiman B, Valenzano M, Atkins PC. Modulation of serum histamine releasing activity in 
chronic idiopathic urticaria. Immunopharmacology 1998;39:225−34. 
 

APPENDIX 1 (cont’d) 
Schedule of Assessments for Screening and Open-Label Treatment Period 
Omalizumab—Genentech, Inc. 
80/Protocol ML29510, Version 1 
 
Screening a 
Open-Label Treatment Period (Baseline to Week 24)
End of Study Week
 
 
Baseline
4 
8 
12  
16 
20 
24 b 
Follow-Up 
Visit for 
Non-Responders c
ET d 
Day
(Window)
−14 
(−4/+2)
−7 
(± 3) 
1 
 
29 
(± 3) 
57 
(± 3) 
85 
(± 3) 
113
(± 3) 
141
(± 3) 
169
(± 3) 
Day 253 
(± 7) 
 
Visit #
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
 
U-AIM k 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
ISI k 
 
 
x 
 
 
x 
 
 
x 
x 
x 
GAD-7 k 
 
 
x 
 
 
x 
 
 
x 
x 
x 
WPAI k 
 
 
x 
 
 
x 
 
 
x 
x 
x 
P-GIC scale k 
 
 
 
 
 
 
 
 
x 
 
 
IC-UAS k  
x 
x 
x 
 
 
 
 
 
x 
x 
x 
C-GIC scale k 
 
 
 
 
 
 
 
 
x 
 
 
Laboratory tests l 
Hematology m 
x 
 
 
 
 
 
 
 
x 
 
x 
Stool ova and parasite evaluation n 
 
x 
 
 
 
 
 
 
 
 
 
Chemistry o 
x 
 
 
 
 
 
 
 
 
 
 
Urinalysis p 
x 
 
 
 
 
 
 
 
 
 
 
Thyroperoxidase antibody 
x 
 
 
 
 
 
 
 
 
 
 
CU index 
x 
 
 
 
 
 
 
 
 
 
 
PK sample (serum total 
omalizumab) 
x 
 
 
 
 
 
 
 
x 
x 
x 
PD samples (total serum IgE and 
free serum IgE) 
x 
 
 
 
 
 
 
 
x 
x 
x 
Blood samples for storage  
x 
 
 
 
 
 
 
 
x 
 
x 

APPENDIX 1 (cont’d) 
Schedule of Assessments for Screening and Open-Label Treatment Period 
Omalizumab—Genentech, Inc. 
81/Protocol ML29510, Version 1 
 
Screening a 
Open-Label Treatment Period (Baseline to Week 24)
End of Study Week
 
 
Baseline
4 
8 
12  
16 
20 
24 b 
Follow-Up 
Visit for 
Non-Responders c
ET d 
Day
(Window)
−14 
(−4/+2)
−7 
(± 3) 
1 
 
29 
(± 3) 
57 
(± 3) 
85 
(± 3) 
113
(± 3) 
141
(± 3) 
169
(± 3) 
Day 253 
(± 7) 
 
Visit #
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
 
Blood RNA (optional) q 
x 
 
 
 
 
 
 
 
x 
 
x 
C-GIC = Clinical Global Impression of Change; CU = chronic urticaria; DLQI = Dermatology Life Quality Index; eDiary = electronic diary; ET = early 
termination; GAD-7 = Generalized Anxiety Disorder Assessment 7-Item Scale; IC-UAS = in-clinic Urticaria Activity Score; IgE = immunoglobulin E; 
ISI = Insomnia Severity Index; IxRS = interactive voice and web response systems; P-GIC = Patient Global Impression of Change; 
PD = pharmacodynamic; PK = pharmacokinetic; PRO = patient-reported outcome; U-AIM = Urticaria Activity and Impact Measure; UAS = Urticaria 
Activity Score; UCT = Urticaria Control Test; WPAI = Work Productivity and Activity Index. 
Note:  Unless otherwise indicated, all assessments should be performed prior to study drug administration. 
a The screening period should be 12 to 18 days long.  Day −14 and Day −7 are provided for reference.  The Day −14 visit should be conducted 
18 to 12 days prior to baseline (Day 1).  Complete eDiary information must be collected on 7 consecutive days prior to the Day 1 visit.  The 
Day −7 visit is intended for review of screening labs collected on Day −14, assessment of IC-UAS score, evaluation of patients’ eDiary use, and 
additional eDiary training if necessary.   
b The Week 24 visit is the end of the open-label treatment period and the start of the double-blind randomization period.  This visit should be 
scheduled on Day 169 (not Day 168) in order to collect eDiary data of Day 168.  A 3-day window is allowed.  Patients who meet criteria for 
randomization will be randomized and receive their first dose of blinded study drug at this visit; this is the only assessment (noted by gray 
shading) being performed as part of the double-blind randomization period (see Appendix 2).    
c Patients who do not meet the criteria for randomization (e.g., because of non-response to omalizumab during the open-label treatment period) 
should return for a final follow-up visit 12 weeks after the Week 24 visit, which will include a blood draw for PK/PD measurement, and 
assessments for adverse events and PROs.  Patients will not be required to complete the eDiary during this 12-week period. 
d Patients who discontinue study treatment early (after baseline, but before Week 24 [Day 169]) should return for an early termination visit.  
These assessments do NOT apply to non-responders who discontinue study treatment before the Day 253 visit.  Non-responders who 
complete the Week 24 visit but discontinue study treatment before Day 253 should instead complete the assessments listed under the column 
“Follow-Up Visit for Non-Responders.” 
e Medical history includes clinically significant diseases (including onset of CIU symptoms, date of diagnosis, and therapies received for CIU), 
surgeries, reproductive status, smoking history, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to the screening visit. 

APPENDIX 1 (cont’d) 
Schedule of Assessments for Screening and Open-Label Treatment Period 
Omalizumab—Genentech, Inc. 
82/Protocol ML29510, Version 1 
f Vital signs include measurements of pulse, and systolic and diastolic blood pressure while the patient is in a seated position.  Record 
abnormalities on the Adverse Event eCRF. 
g A complete physical examination performed at screening 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. 
h All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal women 
and women who have had a hysterectomy will not be required to have pregnancy testing.  If a local urine pregnancy test shows a positive result, 
then study drug and/or open-label omalizumab will not be administered that day.  Other study procedures should also be postponed and the 
result must be confirmed by a serum pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
i 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.  After initiation of study drug, all adverse events will be reported until 112 days (approximately 5 drug half-lives) 
after the last dose of study drug or study discontinuation/termination, whichever is later.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that are believed to be related to prior study drug treatment (see Section 5.6).  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. 
j Includes UAS7 (itch score, number of hives), largest size of hives, sleep interference score, activity interference question, rescue medication 
(diphenhydramine) use, angioedema episodes, and number of calls to doctor or nurse.  Daily eDiary is to be completed twice a day by the 
patient.  The eDiary will be given to patients on Day −14. 
k All PROs, including the DLQI, UCT, U-AIM, ISI, GAD-7, WPAI, P-GIC scale, IC-UAS (itch score + number of hives score), and C-GIC scale 
must be completed prior to  administration of study drug. 
l Samples for laboratory tests will be taken pre-dose on dosing days. 
m Hematology to include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count (e.g., neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
n Note that stool ova and parasite examination should be performed on Day −7 in patients with an eosinophil count > 2 times the ULN on Day −14 
AND risk factors for parasitic disease. Stool ova and parasite examination will be performed by a local laboratory. 
o Serum chemistries to include sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and 
direct bilirubin, total protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatine phosphokinase, and uric acid. 
p Urinalysis to include dipstick (i.e., pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (e.g., sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria). 
q Blood RNA to be collected only in patients providing a separate, specific signature on the Informed Consent Form to document the patient's 
agreement to participate in this optional procedure. 

APPENDIX 2 (cont’d) 
Schedule of Assessments for Double-Blind Randomization Period and Follow-Up Period 
Omalizumab—Genentech, Inc. 
85/Protocol ML29510, Version 1 
f Vital signs include measurements of pulse, and systolic and diastolic blood pressure while the patient is in a seated position.  Record 
abnormalities on the Adverse Event eCRF. 
g All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal women 
and women who have had a hysterectomy will not be required to have pregnancy testing.  If a local urine pregnancy test shows a positive result, 
then study drug and/or open-label omalizumab will not be administered that day.  Other study procedures should also be postponed and the 
result must be confirmed by a serum pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
h 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.  After initiation of study drug, all adverse events will be reported until 112 days (approximately 5 drug half-lives) 
after the last dose of study drug or study discontinuation/termination, whichever is later.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that are believed to be related to prior study drug treatment (see Section 5.6).  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. 
i Includes UAS7 (itch score, number of hives), largest size of hives, sleep interference score, activity interference question, rescue medication 
(diphenhydramine) use, angioedema episodes, and number of calls to doctor or nurse.  Daily eDiary is to be completed twice a day by the 
patient.  The eDiary will be given to patients on Day −14. 
j All PROs, including the DLQI, UCT, U-AIM, ISI, GAD-7, WPAI, P-GIC scale, IC-UAS (itch score + number of hives score), and C-GIC scale 
must be completed prior to administration of study drug. 
k Samples for laboratory tests will be taken pre-dose on dosing days. 
l Hematology to include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count 
(e.g., neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
m Blood RNA to be collected only in patients providing a separate, specific signature on the Informed Consent Form to document the patient's 
agreement to participate in this optional procedure. 

 
Omalizumab—Genentech, Inc. 
86/Protocol ML29510, Version 1 
Appendix 3  
Schedule of Assessments for Patients Who Transition to Open-Label Omalizumab 
after Randomization 
Post-Randomization 
Open-Label Treatment Period a 
Follow-Up Period b 
First Day of
Transition 
Every 4 Weeks 
Until 48 Weeks 
of Total Treatment
Week 48 c 
Week 52 c
Week 56 c 
Week 60 c
ET 
Visit Window (days)
 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
Vital signs (blood pressure 
and pulse) d 
x 
x 
x 
 
 
x 
x 
Weight/height 
 
 
 
 
 
x 
x 
Pregnancy test e 
x 
x 
 
 
 
 
 
Concomitant medication usage 
x 
x 
x 
x 
x 
x 
x 
Adverse events f 
x 
x 
x 
x 
x 
x 
x 
Open-label omalizumab 
x 
x 
 
 
 
 
 
Site to contact IxRS 
x 
x 
 
 
 
x 
x 
PROs 
Patient eDiary g 
x 
x 
x 
x 
x 
x 
x 
DLQI h 
x 
 
x 
 
 
x 
x 
UCT h 
x 
 
x 
 
 
x 
x 
U-AIM h 
x 
 
x 
 
 
x 
x 
ISI h 
x 
 
x 
 
 
x 
x 
GAD-7 h 
x 
 
x 
 
 
x 
x 
WPAI h 
x 
 
x 
 
 
x 
x 
P-GIC scale h 
x 
 
x 
 
 
 
 

APPENDIX 3 (cont’d) 
Schedule of Assessments for Patients Who Transition to Open-Label Omalizumab After Randomization 
Omalizumab—Genentech, Inc. 
87/Protocol ML29510, Version 1 
Post-Randomization 
Open-Label Treatment Period a 
Follow-Up Period b 
First Day of
Transition 
Every 4 Weeks 
Until 48 Weeks 
of Total Treatment
Week 48 c 
Week 52 c
Week 56 c 
Week 60 c
ET 
Visit Window (days)
 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
 ± 3 
IC-UAS h  
x 
 
x 
 
 
x 
x 
C-GIC scale h 
x 
 
x 
 
 
 
 
Laboratory tests i 
Hematology j 
x 
 
x 
 
 
 
x 
PK sample (serum total 
omalizumab) 
x 
 
x 
 
 
x 
x 
PD samples (total serum IgE and 
free serum IgE) 
x 
 
x 
 
 
x 
x 
Blood samples for storage 
x 
 
x 
 
 
x 
x 
Blood RNA (optional) k 
x 
 
x 
 
 
x 
x 
C-GIC = Clinical Global Impression of Change; DLQI = Dermatology Life Quality Index; eDiary = electronic diary; ET=early termination; 
GAD-7 = Generalized Anxiety Disorder Assessment 7-Item Scale; IC-UAS = in-clinic Urticaria Activity Score; IgE = immunoglobulin E; ISI = Insomnia 
Severity Index; IxRS = interactive voice and web response systems; P-GIC = Patient Global Impression of Change; PD = pharmacodynamic; 
PK = pharmacokinetic; PRO = patient-reported outcome; U-AIM = Urticaria Activity and Impact Measure; UAS = Urticaria Activity Score; 
UCT = Urticaria Control Test; WPAI = Work Productivity and Activity Index. 
Note:  Unless otherwise indicated, all assessments should be performed prior to study drug administration. 
a Patients will complete a variable number of study visits during this time period, depending upon when they have transitioned to open-label 
omalizumab.  For example, if a patient transitioned to open-label omalizumab 10 weeks after randomization (Week 34), this patient would 
complete study visits at day of transition (Week 34), 4 weeks after transition (Week 38), 8 weeks after transition (Week 42), and 12 weeks after 
transition (Week 46) and subsequently, at Week 48 would enter the follow-up period, during which time omalizumab would be withdrawn. 
b The 12-week follow-up period applies only to patients who have completed the first 48 weeks of the study. 

APPENDIX 3 (cont’d) 
Schedule of Assessments for Patients Who Transition to Open-Label Omalizumab After Randomization 
Omalizumab—Genentech, Inc. 
88/Protocol ML29510, Version 1 
c The Week 48 and Week 60 visits will take place at the study site.  The Week 52 and Week 56 visits will take place by telephone by the study 
site personnel to include collection of adverse event and concomitant medication information.  Patients will continue to be assessed via eDiary 
during this period.  No study treatment will be given during the follow-up period. 
d Vital signs include measurements of pulse, and systolic and diastolic blood pressure while the patient is in a seated position.  Record 
abnormalities on the Adverse Event eCRF. 
e All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test.  Post-menopausal women 
and women who have had a hysterectomy will not be required to have pregnancy testing.  If a local urine pregnancy test shows a positive result, 
then study drug and/or open-label omalizumab will not be administered that day.  Other study procedures should also be postponed and the 
result must be confirmed by a serum pregnancy test (test to be conducted by central laboratory) prior to proceeding. 
f 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.  After initiation of study drug, all adverse events will be reported until 112 days (approximately 5 drug half-lives) 
after the last dose of study drug or study discontinuation/termination, whichever is later.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that are believed to be related to prior study drug treatment (see Section 5.6).  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. 
g Includes UAS7 (itch score, number of hives), largest size of hives, sleep interference score, activity interference question, rescue medication 
(diphenhydramine) use, angioedema episodes, and number of calls to doctor or nurse.  Daily eDiary is to be completed twice a day by the 
patient.  The eDiary will be given to patients on Day −14. 
h All PROs, including the DLQI, UCT, U-AIM, ISI, GAD-7, WPAI, P-GIC scale, IC-UAS (itch score + number of hives score), and C-GIC scale 
must be completed prior to administration of study drug. 
i Samples for laboratory tests will be taken pre-dose on dosing days. 
j Hematology to include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent, and absolute differential count (neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
k Blood RNA to be collected only in patients providing a separate, specific signature on the Informed Consent Form to document the patient's 
agreement to participate in this optional procedure. 

 
Omalizumab—Genentech, Inc. 
89/Protocol ML29510, Version 1 
Appendix 4  
Study Drug Preparation and Administration 
An unblinded pharmacist or other qualified designated individual will prepare the study 
drug (omalizumab or placebo) injection as outlined below. 
RECONSTITUTION 
The supplied study drug must be reconstituted with Sterile Water for Injection (SWFI), 
USP, using the following instructions: 
1. 
Before reconstitution, determine the number of vials that will need to be 
reconstituted (each vial delivers 150 mg of study drug). 
2. 
Draw 1.4 mL SWFI, USP, into a 3-mL syringe equipped with a 1-inch, 
18-gauge needle. 
3. 
Place the vial upright on a flat surface and, using standard aseptic technique, insert 
the needle and inject the SWFI, USP, directly onto the product. 
4. 
Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to 
evenly wet the powder.  Do not shake. 
5. 
Gently swirl the vial for 5 to 10 seconds approximately every 5 minutes in order to 
dissolve any remaining solids.  The lyophilized product takes 15 to 20 minutes to 
dissolve.  If it takes longer than 20 minutes to dissolve completely, gently swirl the 
vial for 5 to 10 seconds approximately every 5 minutes until there are no visible 
gel-like particles in the solution.  Do not use if the contents of the vial do not dissolve 
completely in 40 minutes. 
6. 
After reconstitution, the study drug solution is somewhat viscous and will appear 
clear or slightly opalescent.  It is acceptable if there are a few small bubbles or foam 
around the edge of the vial; there should be no visible gel-like particles in the 
reconstituted solution.  Do not use if foreign particles are present. 
7. 
Invert the vial for 15 seconds to allow the solution to drain toward the stopper. 
8. 
Use the study drug solution within 8 hours following reconstitution when 
stored in the vial at 2 to 8°C (36 to 46°F), or within 4 hours of reconstitution 
when stored at room temperature.  Reconstituted study drug vials should be 
protected from sunlight. 
9. 
Using a new 3-mL syringe equipped with a 1-inch, 18-gauge needle, insert the 
needle into the inverted vial.  Position the needle tip at the very bottom of the 
solution in the vial stopper when drawing the solution into the syringe.  The 
reconstituted product is somewhat viscous; in order to obtain the full 1.2-mL dose, 
all of the product must be withdrawn from the vial before expelling any air or 
excess solution from the syringe.  Before removing the needle from the vial, pull the 
plunger all the way back to the end of the syringe barrel to remove all of the solution 
from the inverted vial. 
10. Replace the 18-gauge needle with a 25-gauge needle for subcutaneous (SC) 
injection. 

APPENDIX 4 (cont’d) 
Study Drug Preparation and Administration 
Omalizumab—Genentech, Inc. 
90/Protocol ML29510, Version 1 
11. Expel air, large bubbles, and any excess solution in order to obtain the required 
1.2-mL dose.  A thin layer of small bubbles may remain at the top of the solution in 
the syringe.   
 
ADMINISTRATION 
Administer study drug by SC injection.  The injection may take 5−10 seconds to 
administer because the solution is slightly viscous.  Do not administer more than 150 mg 
(contents of one vial) per injection site.   
Cap the syringe.  Label the syringe with the patient number, kit number details, and 
protocol number (ML29510).  The syringe is now ready for use. 
 

 
Omalizumab—Genentech, Inc. 
91/Protocol ML29510, Version 1 
Appendix 5  
Study Drug Dosing and Scheduling Table 
Study Drug Dosing Schedule  
(Number of Injections and Total Injection Volumes) 
Dose (mg) 
Number of Injections 
Total Volume Injected (mL) a 
300 
2 injections:  1.2 mL omalizumab + 
1.2 mL omalizumab 
2.4 
Placebo 
2 injections:  1.2 mL placebo + 
1.2 mL placebo 
2.4 
a 1.2 mL maximum delivered volume per vial. 
 

 
Omalizumab—Genentech, Inc. 
92/Protocol ML29510, Version 1 
Appendix 6  
Patient Electronic Diary (eDiary) 
Note:  The patient eDiary is also referred to as the Urticaria Patient Daily Diary (UPDD).  
GENERAL INSTRUCTIONS 
Please answer each question to the best of your ability. 
There are no right or wrong answers.  
For each question, please choose the response that describes your experience.  
Please pay close attention to the timeframe of interest.  Some questions ask about the 
past 12 hours, while others ask about the past 24 hours. 
  
INSTRUCTIONS FOR COUNTING THE NUMBER OF HIVES AND 
MEASURING THE SIZE OF THE LARGEST HIVE 
Count each hive separately even if you have more than one hive grouped together 
with other hives.  
Please use the ruler that you have been given to measure the size of your largest hive.  
If you need help, please have someone else take this measurement for you.  Please do 
not measure a group of hives as one hive. 
 

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
93/Protocol ML29510, Version 1 
Today’s Date 
 
 
 
- 
 
 
 
-
 
 
 
 
Day 
Month 
Year 
Please complete this section every morning throughout the duration of the study. 
(Please circle only one response.)  
1. 
Thinking about the past 12 hours, please record the severity of itch and the number 
of hives you may have had associated with your skin condition.  Please count each 
hive separately even if you have more than one hive grouped together with other 
hives.  
 
Itch (severity)  
Hives (number) 
0 = none 
1 = mild 
2 = moderate 
3 = severe 
0 = none 
1 = between 1 and 6 hives 
2 = between 7 and 12 hives 
3 = greater than 12 hives 
  
This next question asks you to estimate the size of your largest hive in centimeters 
(cm).  Please use the ruler that you have been provided with to make this 
measurement.  If your largest hive is located on your back or in a place that is hard 
to reach, please have someone else take this measurement for you.  
When measuring the largest hive size, please do not measure a group of hives 
as one hive. 
Largest Hive (size) 
0 = none 
1 = less than 1.25 centimeters (cm)  
2 = between 1.25 centimeter (cm) and 2.5 centimeters (cm)  
3 = greater than 2.5 centimeters (cm)  
 

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
94/Protocol ML29510, Version 1 
Today’s Date 
 
 
 
- 
 
 
 
-
 
 
 
 
Day 
Month 
Year 
Please complete this section every evening throughout the duration of the study. 
(Please circle only one response.)  
2. 
Thinking about the past 12 hours, please record the severity of itch and the number 
of hives you may have had associated with your skin condition.  Please count each 
hive separately even if you have more one than one hive grouped together with 
other hives. 
 
Itch (severity)  
Hives (number) 
0 = none 
1 = mild 
2 = moderate 
3 = severe 
0 = none 
1 = between 1 and 6 hives 
2 = between 7 and 12 hives 
3 = greater than 12 hives 
  
This next question asks you to estimate the size of your largest hive in centimeters 
(cm).  Please use the ruler that you have been provided with to make this 
measurement.  If your largest hive is located on your back or in a place that is hard 
to reach, please have someone else take this measurement for you.  
When measuring the largest hive size, please do not measure a group of hives 
as one hive. 
Largest Hive (size) 
0 = none 
1 = less than 1.25 centimeters (cm)  
2 = between 1.25 centimeter (cm) and 2.5 centimeters (cm)  
3 = greater than 2.5 centimeters (cm)  

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
95/Protocol ML29510, Version 1 
Today’s Date 
 
 
 
- 
 
 
 
-
 
 
 
 
Day 
Month 
Year 
Please complete this section once each day throughout the duration of the study 
(preferably at the same time each day).  
(Please circle only one response.) 
3. 
Please rate how much your hives or itch interfered with your sleep during the 
past 24 hours.  
0 
No interference 
1 
Mild, little interference with sleep 
2 
Moderate, awoke occasionally, some interference with sleep 
3 
Substantial, woke up often, severe interference with sleep 
  
4. 
Please rate how much your hives or itch interfered with your daily activities during 
the past 24 hours.  This could include work, school, sports, hobbies, and activities 
with friends and family. 
0 
No interference 
1 
Mild, little interference with daily activities 
2 
Moderate, some interference with daily activities  
3 
Substantial, severe interference with daily activities 
 

APPENDIX 6 (cont’d) 
Patient Electronic Diary (eDiary) 
Omalizumab—Genentech, Inc. 
96/Protocol ML29510, Version 1 
These next questions are about your symptoms and how you managed them 
during the past 24 hours.  
5. 
During the past 24 hours, how many pills of diphenhydramine 25 mg did you use in 
order to control symptoms of your skin condition such as itch or hives?  
0 = 0 pills 
1 = 1 pill 
2 = 2 pills 
3 = 3 pills 
  
6. 
a.  During the past 24 hours, did you have any rapid swelling on your face, 
(especially your eyelids or lips), inside your mouth (including your throat or tongue), 
or elsewhere on your body?  This rapid swelling, also called angioedema, is at a 
deeper level under your skin than hives.  
0 = No (GO TO Question 7) 
 
1 = Yes  
  
b.  If Yes, how did you treat this rapid swelling?  (Circle all that apply.) 
0 
Did nothing (GO TO Question 7) 
1 
Took some prescription or non-prescription medication  
2 
Called my doctor, nurse, or nurse practitioner 
3 
Went to see my doctor, nurse, or nurse practitioner 
4 
Went to the emergency room at the hospital 
5 
Was hospitalized 
  
7. 
During the past 24 hours, did you or someone else call your doctor, nurse, or nurse 
practitioner because of your skin condition? 
0 = No   
 
 
 
1 = Yes  
 

 
Omalizumab—Genentech, Inc. 
97/Protocol ML29510, Version 1 
Appendix 7  
Dermatology Life Quality Index (DLQI) 
 

 
Omalizumab—Genentech, Inc. 
98/Protocol ML29510, Version 1 
Appendix 8  
Urticaria Control Test (UCT) 

 
Omalizumab—Genentech, Inc. 
99/Protocol ML29510, Version 1 
Appendix 9  
Urticaria Activity and Impact Measure (U-AIM) 
This questionnaire asks you about your urticaria and how it may have affected your life 
in the past 7 days.  Please answer each question to the best of your ability.  There are 
no right or wrong answers.  For each question, mark an : in the one box that best 
describes your experience. 
1. 
Thinking about your urticaria in the past 7 days, on average, how severe was 
your itch?  
☐ 0 
None (skip to question 2) 
☐ 1 
Mild 
 
☐ 2 
Moderate 
 
☐ 3 
Severe 
 
 
 
1a. In the past 7 days, how much of the time did your itch bother you? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  
2. 
Thinking about your urticaria in the past 7 days, on average, how many hives did 
you have per day?  Count each hive separately even if you had more than one hive 
grouped together with other hives. 
☐ 0 
None (skip to question 3) 
☐ 1 
Between 1 and 6 hives 
 
☐ 2 
Between 7 and 12 hives 
 
☐ 3 
Greater than 12 hives 
 
 
 
2a. In the past 7 days, how much of the time did your hives bother you? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  

APPENDIX 9 (cont’d) 
Urticaria Activity and Impact Measure (U-AIM) 
Omalizumab—Genentech, Inc. 
100/Protocol ML29510, Version 1 
3. 
In the past 7 days, how many days did you have any rapid swelling on your face, 
(especially your eyelids or lips), inside your mouth (including your throat or tongue), 
or elsewhere on your body?  This rapid swelling, also called angioedema, is at a 
deeper level under your skin than hives.  
☐ 0 
Did not experience angioedema (skip to question 4) 
☐ 1 
1 − 2 days 
 
☐ 2 
3 − 4 days 
 
☐ 3 
5 − 6 days 
 
☐ 4 
7 days 
 
 
 
3a. In the past 7 days, how much of the time did this rapid swelling 
 
 
(angioedema) bother you? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  
4. 
In the past 7 days, how much of the time did urticaria symptoms interfere with your 
daily activities? This could include work, school, sports, hobbies, and activities with 
friends and family. 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  
5. 
In the past 7 days, how much of the time did urticaria symptoms interfere with 
your sleep? 
☐ 0 
None of the time 
☐ 1 
A little of the time 
☐ 2 
Some of the time 
☐ 3 
Most of the time 
☐ 4 
All of the time 
  

APPENDIX 9 (cont’d) 
Urticaria Activity and Impact Measure (U-AIM) 
Omalizumab—Genentech, Inc. 
101/Protocol ML29510, Version 1 
6. 
How would you rate your urticaria control in the past 7 days? 
☐ 0 
Completely controlled 
☐ 1 
Well controlled 
☐ 2 
Somewhat controlled 
☐ 3 
Poorly controlled 
☐ 4 
Not controlled at all 
   
Please check that you answered every question.  Thank you for your answers! 
 

 
Omalizumab—Genentech, Inc. 
102/Protocol ML29510, Version 1 
Appendix 10  
Insomnia Severity Index (ISI) 
Subject ID:  ________________________  
 
Date:  _______________ 
 
For each question below, please circle the number corresponding most accurately to 
your sleep patterns in the last two weeks. 
For the first three questions, please rate the SEVERITY of your sleep difficulties. 
1. 
Difficulty falling asleep:  
  None 
Mild 
Moderate 
Severe 
Very Severe 
 
0 
1 
2 
3 
4 
2. 
Difficulty staying asleep: 
  None 
Mild 
Moderate 
Severe 
Very Severe 
 
0 
1 
2 
3 
4 
3. 
Problem waking up too early in the morning: 
  None 
Mild 
Moderate 
Severe 
Very Severe 
 
0 
1 
2 
3 
4 
4. 
How SATISFIED/DISSATISFIED are you with your current sleep pattern? 
   Very 
 
 
 
 
Very 
  Satisfied 
Satisfied 
Neutral 
Dissatisfied 
Dissatisfied 
 
0 
1 
2 
3 
4 
5. 
To what extent do you consider your sleep problem to INTERFERE with 
your daily functioning (e.g., daytime fatigue, ability to function at work/daily 
chores, concentration, memory, mood). 
   Not at all 
  A Little 
Somewhat 
   Much 
Very Much 
  Interfering 
Interfering 
Interfering 
Interfering 
Interfering 
 
0 
1 
2 
3 
4 
6. 
How NOTICEABLE to others do you think your sleeping problem is in terms of 
impairing the quality of your life? 
   Not at all 
  A Little 
Somewhat 
   Much 
Very Much 
  Noticeable Noticeable 
Noticeable 
Noticeable 
Noticeable 
 
0 
1 
2 
3 
4 
7. 
How WORRIED/DISTRESSED are you about your current sleep problem? 
   Not at all 
  A Little 
Somewhat 
   Much 
Very Much 
 
0 
1 
2 
3 
4 

APPENDIX 10 (cont’d) 
Insomnia Severity Index (ISI) 
Omalizumab—Genentech, Inc. 
103/Protocol ML29510, Version 1 
Guidelines for Scoring/Interpretation: 
Add scores for all seven items  =  _____   
Total score ranges from 0−28 
  0−7 
 =  No clinically significant insomnia 
  8−14 
 =  Subthreshold insomnia 
15−21 
 =  Clinical insomnia (moderate severity) 
22−28 
 =  Clinical insomnia (severe) 
© Morin, CM. (1993, 1996, 2000, 2006). 
 

 
Omalizumab—Genentech, Inc. 
104/Protocol ML29510, Version 1 
Appendix 11  
Generalized Anxiety Disorder 7 Item (GAD-7) Scale 
  
GAD-7 
 
Over the last 2 weeks, how often have you 
been bothered by the following problems? 
 
(Use “9” to indicate your answer) 
Not 
at all 
Several 
days 
More than 
half the 
days 
Nearly 
every day 
1. Feeling nervous, anxious or on edge 
0 
1 
2 
3 
2. Not being able to stop or control worrying 
0 
1 
2 
3 
3. Worrying too much about different things 
0 
1 
2 
3 
4. Trouble relaxing 
0 
1 
2 
3 
5. Being so restless that it is hard to sit still 
0 
1 
2 
3 
6. Becoming easily annoyed or irritable 
0 
1 
2 
3 
7. Feeling afraid as if something awful 
might happen 
0 
1 
2 
3 
(For office coding:  Total Score T____  =  ____  +   ____  +   ____ )
 
 
Developed by Drs. Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke and colleagues, 
with an educational grant from Pfizer Inc.  No permission required to reproduce, 
translate, display or distribute.

 
Omalizumab—Genentech, Inc. 
105/Protocol ML29510, Version 1 
Appendix 12  
Work Productivity and Activity Impairment Questionnaire:  
Chronic Urticaria V2.0 (WPAI:CU) 
The following questions ask about the effect of your chronic urticaria on your ability to 
work and perform regular activities.  Please fill in the blanks or circle a number, as 
indicated. 
1. 
Are you currently employed (working for pay)?  ____ No  ____ Yes 
If NO, check “NO” and skip to question 6. 
 
The next questions are about the past seven days, not including today. 
 
2. 
During the past seven days, how many hours did you miss from work because of 
problems associated with your chronic urticaria?  Include hours you missed on sick 
days, times you went in late, left early, etc., because of your chronic urticaria.  Do 
not include time you missed to participate in this study. 
_____ HOURS 
 
3. 
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
_____ HOURS 
 
4. 
During the past seven days, how many hours did you actually work? 
_____ HOURS  (If “0”, skip to question 6.) 
 

APPENDIX 12 (cont’d) 
Work Productivity and Activity Impairment Questionnaire:   
Chronic Urticaria V2.0 (WPAI:CU) 
Omalizumab—Genentech, Inc. 
106/Protocol ML29510, Version 1 
5. 
During the past seven days, how much did your chronic urticaria affect your 
productivity while you were working?   
 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual.  If chronic urticaria affected your work only a little, choose a low 
number.  Choose a high number if chronic urticaria affected your work a great deal.   
 
Consider only how much chronic urticaria affected  
productivity while you were working. 
 
 
 
 
 
 
 
 
 
 
 
Chronic urticaria 
had no effect on 
my work 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Chronic urticaria 
completely 
prevented me 
from working 
CIRCLE A NUMBER 
 
6. 
During the past seven days, how much did your chronic urticaria affect your ability to 
do your regular daily activities, other than work at a job? 
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If chronic urticaria affected your activities only a little, 
choose a low number.  Choose a high number if chronic urticaria affected your 
activities a great deal.   
 
Consider only how much chronic urticaria affected your ability  
to do your regular daily activities, other than work at a job. 
 
 
 
 
 
 
 
 
 
 
 
Chronic urticaria 
had no effect on 
my daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Chronic urticaria 
completely prevented 
me from doing my 
daily activities 
CIRCLE A NUMBER 

 
Omalizumab—Genentech, Inc. 
107/Protocol ML29510, Version 1 
Appendix 13  
Patient Global Impression of Change (P-GIC) Scale 
Please rate how your chronic idiopathic urticaria has changed since the beginning of 
the study: 
1. 
☐ Very much improved 
2. 
☐ Much improved 
3. 
☐ Minimally improved 
4. 
☐ No change 
5. 
☐ Minimally worse 
6. 
☐ Much worse 
7. 
☐ Very much worse 
 

 
Omalizumab—Genentech, Inc. 
108/Protocol ML29510, Version 1 
Appendix 14  
In-Clinic Urticaria Activity Score (IC-UAS) (Max 6) 
The physician or the person he or she designates will provide the sum of the score of the 
patient’s urticaria lesions (number of hives) and pruritus (itch) reflective of the patient's 
condition over the 12 hours prior to the visit using the following rating scale: 
Pruritus: 
0 = None 
1 = Mild – minimal awareness, easily tolerated 
2 =  Moderate – definite awareness, bothersome but tolerable 
3 = Severe – difficult to tolerate 
Number of Hives: 
0 = none 
1 = 1−6  
2 = 7−12 
3 =  > 12 
 

 
Omalizumab—Genentech, Inc. 
109/Protocol ML29510, Version 1 
Appendix 15  
Clinician Global Impression of Change (C-GIC) Scale 
Please rate how patient’s chronic idiopathic urticaria has changed since the beginning of 
the study: 
1. 
☐ Very much improved 
2. 
☐ Much improved 
3. 
☐ Minimally improved 
4. 
☐ No change 
5. 
☐ Minimally worse 
6. 
☐ Much worse 
7. 
☐ Very much worse 
 

 
Omalizumab—Genentech, Inc. 
110/Protocol ML29510, Version 1 
Appendix 16  
Sampson’s Criteria of Anaphylaxis 
ANAPHYLAXIS:  Sampson definition of anaphylaxis (clinical definition) is the acute 
onset of illness which involves SKIN, MUCOSAL TISSUE, or BOTH (e.g., generalized 
hives, pruritus or flushing, swollen lips- tongue uvula)  with one OR more of the 
following: 
• 
RESPIRATORY: Airway compromise (e.g. dyspnea, wheeze, or bronchospasm, 
stridor and reduced PEF) 
• 
CIRCULATORY: Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope) 
 
OR 
TWO or MORE of the following that occur rapidly after exposure: 
• 
SKIN, MUCOSAL TISSUE:  e.g. generalized hives, itch-flush, swollen lips- tongue-
uvula 
• 
RESPIRATORY:  Airway compromise (e.g. dyspnea, wheeze, or bronchospasm, 
stridor and reduced PEF) 
• 
CIRCULATORY:  Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope) 
• 
GASROINTESTINAL:  Persistent gastrointestinal symptoms (e.g., crampy 
abdominal pain, vomiting, nausea, diarrhea)