Conditions: Nasal Polyps Chronic Rhinosinusitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy and safety of omalizumab compared with placebo in adult participants with chronic rhinosinusitis with nasal polyps (CRSwNP) who have had an inadequate response to standard-of-care treatments.

Study GA39855 (POLYP 2; NCT03280537) was another Phase III study by the Sponsor with identical objectives and design and was run in parallel with this study.

Detailed description:

Arms:
arm 1: Participants received omalizumab as a subcutaneous injection once every 2 weeks (q2w) or once every 4 weeks (q4w). The dose (from 75 mg up to 600 mg) and dosing frequency (q2w or q4w) was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy. arm 2: Participants received matching placebo as a subcutaneous injection once every 2 weeks or once every 4 weeks. The dose and dosing frequency was determined by serum total IgE level and body weight using the study-drug dosing table. All participants were also treated during the entire study with intranasal corticosteroids (mometasone nasal spray) as background therapy.

Interventions: intervention 1: Omalizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received omalizumab as a subcutaneous injection once every 2 weeks (q2w) or once every 4 weeks (q4w). The dose (from 75 mg up to 600 mg) and dosing frequency (q2w or q4w) was determined by serum total IgE level and body weight using the study-drug dosing table. intervention 2: Participants received matching placebo as a subcutaneous injection once every 2 weeks or once every 4 weeks. The dose and dosing frequency was determined by serum total IgE level and body weight using the study-drug dosing table.

Protocol document:
Prot_000.pdf: 
 
 
Official Title:  
 
A PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL OF OMALIZUMAB IN 
PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS 
NCT Number: 
NCT03280550 
Document: 
Version & Date:  
PROTOCOL 
Version 2: 11-Oct-2017 
 


FINAL PROTOCOL APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (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 Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Omalizumab—F. Hoffmann-La Roche Ltd 
Protocol GA39688, Version 2 
PROTOCOL 
TITLE: 
A PHASE III, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, PLACEBO-CONTROLLED 
CLINICAL TRIAL OF OMALIZUMAB IN PATIENTS 
WITH CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS 
PROTOCOL NUMBER: GA39688 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2017-001724-22 
IND NUMBER: 
5369 
TEST PRODUCT: 
Omalizumab (IGE025) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE AMENDED: 
Version 1: 2 June 2017 
Version 2:  See electronic date stamp below 
 
11-Oct-2017 16:06:49
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Omalizumab—F. Hoffmann-La Roche Ltd 
2/Protocol GA39688, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
RATIONALE 
Protocol GA39688 has been amended to modify the study design according to the 
recommendations of the Voluntary Harmonization Procedure (VHP), the 
European-based process for obtaining a harmonized assessment of multinational clinical 
trial authorization (CTA) applications before the national process.  Changes to the 
protocol are summarized below: 
 
The inclusion criteria have been updated to specify acceptable methods of 
contraception (Section 4.1.1).  
 
An additional exclusion criterion has been added to exclude patients with a 
history of myocardial infarction, unstable angina, cerebrovascular accident, or 
transient ischemic attack or a known history of a hypercoagulable disorder 
(Section 4.1.2). 
 
Four additional urine pregnancy tests have been added to the treatment period 
such that women of childbearing potential will have urine pregnancy testing every 
4 weeks during the 24-week treatment period (Section 4.5.8, Appendix 1). 
 
Viral serologies for HIV, hepatitis B, and hepatitis C have been added during 
screening at Day -35 (Section 4.5.8, Appendix 1).  Patients with a history of HIV, 
hepatitis B, and hepatitis C were excluded in the prior version of the protocol, and 
these exclusion criteria remain in the current version of the protocol. 
 
Additional specifications have been added to the section on the Management of 
Patients Who Experience Specific Adverse Events.  While liver injury has not 
been described as a risk associated with omalizumab, this new section specifies 
how study drug should be managed for patients who experience drug induced 
liver injury (Section 5.1.4.2). 
 
Additional revisions have been made to the following statistical sections:   
– 
Section 6, Statistical Considerations and Analysis Plan 
– 
Section 6.1, Determination of Sample Size 
– 
Section 6.4, Efficacy Analyses 
 
 
The following statistical sections have been added: 
– 
Section 6.4.4, Subgroup Analyses 
– 
Section 6.4.5, Pooled Analyses 
– 
Section 6.8, Missing Data 
– 
Section 6.9, Unused and Spurious Data 
 
This amendment represents cumulative changes to the original protocol. 
 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
3/Protocol GA39688, 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 4.1.1: Inclusion Criteria 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the 
treatment period and for 60 days 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. 
– 
Acceptable methods of contraception include surgical sterilization 
(e.g., bilateral tubal ligation, vasectomized partner), hormonal contraception 
(e.g., implantable, injectable, patch, oral), and intrauterine device (IUD).  
 
Barrier methods must always be supplemented with the use of a spermicide 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result during the screening period. 
 
SECTION 4.1.2: Exclusion Criteria   
 
History of myocardial infarction, unstable angina, cerebrovascular accident, or 
transient ischemic attack or a known history of a hypercoagulable disorder 
 
SECTION 4.5.8: Laboratory and Other Biological Samples 
 
Serum and urine pregnancy test 
– 
All women of childbearing potential must have a negative serum pregnancy test 
during the screening period, prior to initiation of study drug.  Additionally, 
women should have a urine pregnancy test prior to the initiation of study drug, 
every 4 weeks during study treatment period, and at the safety follow-up visit, as 
indicated in Appendix 1.  Urine pregnancy test results must be reviewed and 
confirmed to be negative before study drug administration.  If a urine pregnancy 
test is positive or borderline, it must be confirmed by a serum pregnancy test 
(analyzed at the central laboratory) before giving study drug. 
 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
 
Viral serology (unless not permitted by local regulations or ethics committees):  
HIV, hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), hepatitis C (HCV) antibody 
 




 
Omalizumab—F. Hoffmann-La Roche Ltd 
5/Protocol GA39688, Version 2 
SECTION 6.4: EFFICACY ANALYSES 
All hypothesis tests will be two-sided.  Unless otherwise noted, all analyses of efficacy 
outcome measures will at a minimum be adjusted by geographic region through the use 
of a categorical variable and by baseline asthma comorbidity and aspirin sensitivity 
status.  Adjustment by additional covariates, if any, will be described in the SAP.  
Efficacy data on the co primary and secondary endpoints from this study may be pooled 
with external data from another trial and analyzed in the Summary of Clinical Efficacy 
(SCE), details of which will be provided in a separate SAP for the SCE. 
SECTION 6.4.4: Subgroup Analyses (NEW SECTION) 
Exploratory subgroup analyses will be performed to evaluate the consistency of the 
primary analysis results across pre-specified subgroups defined by demographic and 
baseline characteristics.  Further details on these subgroup analyses and any additional 
subgroups will be pre-specified in the SAP and finalized prior to data unblinding.  
In addition to age, sex, and race, the following subgroups (at a minimum) will be 
analyzed with respect to the co-primary efficacy endpoints (change from baseline at 
Week -24 in NPS and change from baseline at Week -24 in NCS) using the same 
methods as specified for the co-primary endpoints:  
 
Baseline comorbid asthma and aspirin sensitivity status (asthmatic and aspirin 
sensitive, asthmatic not aspirin sensitive, all other)  
 
Geographic region (North America, ex-North America) 
 
Baseline mometasone prescribed dose (daily dose of 400 g, daily dose of 200 g)  
 
If convergence problems with the statistical models arise due to a small number of 
patients per subgroup, the analysis may be simplified by combining some of the 
subgroups or by excluding baseline stratification variables from the model. 
SECTION 6.4.5: Pooled Analyses (NEW SECTION) 
Efficacy data on endpoints from this study may be pooled with external data from a 
replicate trial (GA39855).  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
6/Protocol GA39688, Version 2 
 
  
SECTION 6.8: MISSING DATA (NEW SECTION) 
Unless otherwise noted, in the analysis of all continuous co-primary, secondary, and 
exploratory endpoints (NPS, NCS, loss of smell, anterior rhinorrhea, posterior 
rhinorrhea, TNSS, SNOT-22, UPSIT, EQ-5D-5L), missing values will not be explicitly 
imputed in the analyses, which will use a mixed-effect model repeated measurement 
(MMRM) model.  The exception is for the co-primary endpoints NPS and NCS, for 
which missing values planned on or after the date of treatment failure will be imputed 
by the worst possible score of 8 for NPS and 3 for daily NCS.  Patients without post-
baseline endpoint data will not contribute to the MMRM model.  Sensitivity analysis 
concerning missing data assumptions for all continuous co-primary and secondary 
efficacy endpoints meeting nominal statistical significance will be conducted 
(i.e., tipping point analysis).  Details of these pre-specified sensitivity analyses will be 
provided in the SAP and finalized prior to data unblinding. 
In the analysis of the following categorical secondary endpoints (for which a logistic 
regression model is specified) missing data from patients who discontinue the study 
prior to their Week -24 visit without having previously met the criteria for the event 
will be imputed as having the event:  
 
Requirement of rescue treatment (systemic CS for  3 consecutive days) or 
having had surgery for nasal polyps through Week -24  
 
Requirement of rescue treatment (systemic CS for  3 consecutive days) through 
Week -24  
 
Having had surgery for nasal polyps through Week -24  
 
In the analysis of the following categorical secondary and exploratory endpoints (for 
which a logistic regression model is specified) missing data from patients who 
discontinue the study prior to Week -24 without having previously met the criteria for 
the event will be imputed as not having the event:  
 
Reduction in the need for surgery by Week -24, as defined by an NPS of  4 
(unilateral score of  2 on each side) and improvement in SNOT-22 score of 
 8.9  
 
Change from baseline at Week -24 in AQLQ of  0.5 (in patients with comorbid 
asthma only)  
 
Change from baseline at Week -24 in SNOT-22 of at least the minimal important 
difference (MID) (8.9 points). 
 
SECTION 6.9: UNUSED AND SPURIOUS DATA (NEW SECTION) 
For the efficacy analysis of continuous co-primary, secondary, and exploratory 
endpoints for which an MMRM model is used, a single data point will be assigned to a 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
7/Protocol GA39688, Version 2 
planned timepoint (e.g., Week 4, Week 8, Week 16, Week 24) according to the Schedule 
of Activities for that particular endpoint (see Appendix 1) based on the proximity of the 
date of the assessment to the planned timepoint and may include data collected as part 
of a planned, unscheduled, safety follow-up, dosing termination, or early termination 
visit.  All data points collected but not assigned to a planned timepoint in the analysis 
will be unused in the planned analysis.  Further details on the assignment of data 
points to planned timepoints for analysis will be described in the SAP and finalized 
prior to unblinding.  
Due to the nature of the data capture instruments (e.g., eCRF, eDiary, or tablet), 
spurious response data are not expected for PRO efficacy endpoints (i.e., NPS, NCS, 
SNOT-22, UPSIT, AQLQ, EQ-5D-5L).  In the event of a documented device 
malfunction leading to spurious data (i.e., a date that is recorded prior to the date of 
first patient screened or after last patient’s last visit), those data will be ignored 
(assumed missing) for the purpose of efficacy analysis and discussed in the Clinical 
Study Report (CSR).  Any spurious lab values or vital sign measurements will be 
excluded from summary tables and discussed in the CSR. 
APPENDIX 1:  Schedule of Activities  
The schedule of activities 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—F. Hoffmann-La Roche Ltd 
8/Protocol GA39688, Version 2 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15 
PROTOCOL SYNOPSIS .................................................................................... 16 
1. 
BACKGROUND .......................................................................................... 24 
1.1 
Background on Chronic Rhinosinusitis with Nasal 
Polyps .................................................................................... 24 
1.2 
Background on Omalizumab ................................................. 25 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 25 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 26 
3. 
STUDY DESIGN ......................................................................................... 28 
3.1 
Description of the Study ......................................................... 28 
3.2 
End of Study and Length of Study ......................................... 31 
3.3 
Rationale for Study Design .................................................... 31 
3.3.1 
Rationale for Omalizumab Dose and Schedule ..................... 31 
3.3.2 
Rationale for Patient Population ............................................ 32 
3.3.3 
Rationale for Control Group ................................................... 33 
3.3.4 
Rationale for Co-Primary Endpoint Selection ........................ 33 
3.3.5 
Rationale for Choice of Stratification Factors ......................... 33 
3.3.6 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 34 
4. 
MATERIALS AND METHODS .................................................................... 34 
4.1 
Patients .................................................................................. 34 
4.1.1 
Inclusion Criteria .................................................................... 35 
4.1.2 
Exclusion Criteria ................................................................... 36 
4.2 
Method of Treatment Assignment and Blinding ..................... 37 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 39 
4.3.1 
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 39 
4.3.1.1 
Omalizumab and Placebo ...................................................... 39 
4.3.1.2 
Mometasone Furoate Monohydrate Nasal Spray .................. 39 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
9/Protocol GA39688, Version 2 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 39 
4.3.2.1 
Omalizumab and Placebo ...................................................... 40 
4.3.3 
Mometasone Furoate Monohydrate Nasal Spray .................. 40 
4.3.4 
Investigational Medicinal Product Accountability ................... 41 
4.3.5 
Continued Access to Omalizumab ......................................... 41 
4.4 
Concomitant Therapy ............................................................ 41 
4.4.1 
Prohibited Therapy ................................................................ 41 
4.5 
Study Assessments ............................................................... 42 
4.5.1 
Informed Consent Forms and Screening Log ........................ 43 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 43 
4.5.3 
Physical Examinations ........................................................... 43 
4.5.4 
Vital Signs .............................................................................. 43 
4.5.5 
CRSwNP History and Comorbidities ..................................... 44 
4.5.6 
CRSwNP-Specific Assessments ........................................... 44 
4.5.7 
Physician Review eDiary Data and Compliance .................... 45 
4.5.8 
Laboratory and Other Biological Samples ............................. 45 
4.5.9 
Electrocardiograms ................................................................ 46 
4.5.10 
Patient-Reported Outcomes .................................................. 46 
4.5.10.1 
Nasal Symptoms, including Nasal Congestion 
Score ..................................................................................... 47 
4.5.10.2 
Sino-Nasal Outcome Test-22 ................................................ 47 
4.5.10.3 
University of Pennsylvania Smell Identification 
Test ....................................................................................... 47 
4.5.10.4 
EuroQol 5-Dimension 5-Level Questionnaire ........................ 47 
4.5.10.5 
Asthma Quality of Life Questionnaire (Patients 
with Comorbid Asthma Only) ................................................. 48 
4.5.11 
Optional Samples for Research Biosample 
Repository ............................................................................. 48 
4.5.11.1 
Overview of the Research Biosample Repository .................. 48 
4.5.11.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 48 
4.5.11.3 
Sample Collection .................................................................. 49 
4.5.11.4 
Confidentiality ........................................................................ 49 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
10/Protocol GA39688, Version 2 
4.5.11.5 
Consent to Participate in the Research 
Biosample Repository ............................................................ 50 
4.5.11.6 
Withdrawal from the Research Biosample 
Repository ............................................................................. 50 
4.5.11.7 
Monitoring and Oversight ....................................................... 50 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ...................................................................... 51 
4.6.1 
Study Treatment Discontinuation ........................................... 51 
4.6.2 
Patient Discontinuation from Study ........................................ 51 
4.6.3 
Study Discontinuation ............................................................ 52 
4.6.4 
Site Discontinuation ............................................................... 52 
5. 
ASSESSMENT OF SAFETY ....................................................................... 52 
5.1 
Safety Plan ............................................................................ 53 
5.1.1 
Safety and Data Monitoring ................................................... 53 
5.1.2 
Anaphylaxis Adjudication Committee .................................... 53 
5.1.3 
Risks Associated with Omalizumab ....................................... 53 
5.1.3.1 
Anaphylaxis ........................................................................... 53 
5.1.3.2 
Serum Sickness ..................................................................... 54 
5.1.3.3 
Churg-Strauss Syndrome and Hypereosinophilic 
Syndrome .............................................................................. 55 
5.1.3.4 
Thrombocytopenia ................................................................. 55 
5.1.3.5 
Malignancies .......................................................................... 55 
5.1.3.6 
Arterial Thrombotic Events .................................................... 56 
5.1.3.7 
Antibody Formation to Omalizumab ...................................... 56 
5.1.4 
Management of Patients Who Experience 
Specific Adverse Events ........................................................ 56 
5.1.4.1 
Dose Modifications and Treatment Interruption ..................... 56 
5.1.4.2 
Management of Drug Induced Liver Injuries .......................... 56 
5.2 
Safety Parameters and Definitions ........................................ 56 
5.2.1 
Adverse Events ..................................................................... 57 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 57 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 58 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
11/Protocol GA39688, Version 2 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 58 
5.3.1 
Adverse Event Reporting Period ........................................... 59 
5.3.2 
Eliciting Adverse Event Information ....................................... 59 
5.3.3 
Assessment of Severity of Adverse Events ........................... 59 
5.3.4 
Assessment of Causality of Adverse Events ......................... 60 
5.3.5 
Procedures for Recording Adverse Events ............................ 60 
5.3.5.1 
Injection-Site Reactions ......................................................... 61 
5.3.5.2 
Anaphylactic Reactions ......................................................... 61 
5.3.5.3 
Diagnosis versus Signs and Symptoms................................. 61 
5.3.5.4 
Adverse Events That Are Secondary to Other 
Events .................................................................................... 61 
5.3.5.5 
Persistent or Recurrent Adverse Events ................................ 62 
5.3.5.6 
Abnormal Laboratory Values ................................................. 62 
5.3.5.7 
Abnormal Vital Sign Values ................................................... 63 
5.3.5.8 
Abnormal Liver Function Tests .............................................. 63 
5.3.5.9 
Deaths ................................................................................... 64 
5.3.5.10 
Preexisting Medical Conditions .............................................. 64 
5.3.5.11 
Lack of Efficacy or Worsening of Nasal Polyposis ................. 64 
5.3.5.12 
Hospitalization or Prolonged Hospitalization .......................... 64 
5.3.5.13 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 65 
5.3.5.14 
Patient-Reported Outcome Data ........................................... 65 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 65 
5.4.1 
Emergency Medical Contacts ................................................ 66 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 67 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 67 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 67 
5.4.3 
Reporting Requirements for Pregnancies .............................. 67 
5.4.3.1 
Pregnancies in Female Patients ............................................ 67 
5.4.3.2 
Abortions ............................................................................... 68 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 68 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
12/Protocol GA39688, Version 2 
5.5 
Follow-Up of Patients after Adverse Events .......................... 68 
5.5.1 
Investigator Follow-Up ........................................................... 68 
5.5.2 
Sponsor Follow-Up ................................................................ 68 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 68 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 69 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 69 
6.1 
Determination of Sample Size ............................................... 70 
6.2 
Summaries of Conduct of Study ............................................ 72 
6.3 
Summaries of Treatment Group Comparability ..................... 72 
6.4 
Efficacy Analyses .................................................................. 72 
6.4.1 
Co-primary Efficacy Endpoints .............................................. 73 
6.4.2 
Secondary Efficacy Endpoints ............................................... 75 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 76 
6.4.4 
Subgroup Analyses ............................................................... 76 
6.4.5 
Pooled Analyses .................................................................... 77 
6.5 
Safety Analyses ..................................................................... 77 
6.6 
Pharmacokinetic/Pharmacodynamic Analyses ...................... 78 
6.7 
Interim Analysis ..................................................................... 78 
6.8 
Missing Data .......................................................................... 78 
6.9 
Unused and Spurious Data .................................................... 79 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 79 
7.1 
Data Quality Assurance ......................................................... 79 
7.2 
Electronic Case Report Forms ............................................... 80 
7.3 
Electronic Patient-Reported Outcome ................................... 80 
7.4 
Source Data Documentation .................................................. 81 
7.5 
Use of Computerized Systems .............................................. 81 
7.6 
Retention of Records ............................................................. 81 
8. 
ETHICAL CONSIDERATIONS .................................................................... 82 
8.1 
Compliance with Laws and Regulations ................................ 82 
8.2 
Informed Consent .................................................................. 82 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
13/Protocol GA39688, Version 2 
8.3 
Institutional Review Board or Ethics Committee .................... 83 
8.4 
Confidentiality ........................................................................ 84 
8.5 
Financial Disclosure .............................................................. 84 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 84 
9.1 
Study Documentation ............................................................ 84 
9.2 
Protocol Deviations ................................................................ 85 
9.3 
Site Inspections ..................................................................... 85 
9.4 
Administrative Structure ......................................................... 85 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 86 
9.6 
Protocol Amendments ........................................................... 86 
10. REFERENCES ........................................................................................... 88 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 27 
Table 2 
Nasal Polyps Scoring System ..................................................... 29 
Table 3 
Adverse Event Severity Grading Scale ....................................... 59 
Table 4 
Causal Attribution Guidance ....................................................... 60 
Table 5 
Summary of Studies Used for Determination of Sample Size ..... 71 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 31 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
14/Protocol GA39688, Version 2 
LIST OF APPENDICES 
 
Appendix 1 
Schedule of Activities .................................................................. 93 
Appendix 2 
Nasal Polyps Scoring System ..................................................... 98 
Appendix 3 
Nasal Symptoms Assessed Daily via Electronic Diary ................ 99 
Appendix 4 
Sino-Nasal Outcome Test-22 (SNOT-22) Questionnaire .......... 100 
Appendix 5 
Omalizumab Dosing Table for Nasal Polyps ............................. 101 
Appendix 6 
EuroQol 5-Dimension 5-Level Questionnaire ............................ 103 
Appendix 7 
Asthma Quality of Life Questionnaire ........................................ 105 
Appendix 8 
Study Drug Preparation and Administration .............................. 1 
Appendix 9 
Sampson's Criteria for Diagnosing Potential Cases of 
Anaphylaxis ............................................................................... 1 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
15/Protocol GA39688, Version 2 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, PLACEBO-CONTROLLED 
CLINICAL TRIAL OF OMALIZUMAB IN PATIENTS 
WITH CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS 
PROTOCOL NUMBER: GA39688 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2017-001724-22 
IND NUMBER: 
5369 
TEST PRODUCT: 
Omalizumab (IGE025) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
16/Protocol GA39688, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL OF OMALIZUMAB IN 
PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS 
PROTOCOL NUMBER: 
GA39688 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2017-001724-22 
IND NUMBER: 
5369 
TEST PRODUCT: 
Omalizumab (IGE025) 
PHASE: 
Phase III 
INDICATION: 
Chronic rhinosinusitis with nasal polyps 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
The purpose of this study is to determine the efficacy and safety of omalizumab compared with 
placebo in adult patients with CRSwNP who have had an inadequate response to 
standard-of-care treatments.  Specific objectives and corresponding endpoints for the study are 
outlined below. 
 
Primary Efficacy Objective 
Corresponding Co-Primary Endpoints 
• To evaluate the efficacy of 
omalizumab compared with placebo  
Co-primary endpoints: 
• Change from baseline at Week 24 in average daily nasal 
congestion score (NCS)  
• Change from baseline at Week 24 in nasal polyps score 
(NPS)  
Secondary Efficacy Objective a 
Corresponding Endpoints 
• To evaluate the efficacy of 
omalizumab compared with placebo  
• Change from baseline at Week 24 in the average daily 
total nasal symptom score (TNSS) 
• Change from baseline at Week 24 in the average daily 
sense of smell score 
• Change from baseline at Week 24 in the average daily 
posterior rhinorrhea score  
• Change from baseline at Week 24 in the average daily 
anterior rhinorrhea score 
• Change from baseline at Week 24 in patient-reported 
health-related quality of life as assessed by the total 
SNOT-22 
• Change from baseline at Week 16 in the average daily 
NCS  
• Change from baseline at Week 16 in NPS 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
17/Protocol GA39688, Version 2 
• Change from baseline at Week 24 in sense of smell, as 
assessed by the UPSIT 
• Reduction in the need for surgery by Week 24, as 
defined by an NPS of ≤ 4 (unilateral score of ≤ 2 on 
each side) and improvement in SNOT-22 score of ≥ 8.9 
• Requirement of rescue treatment (systemic CS for ≥ 3 
consecutive days) or having had surgery for nasal 
polyps through Week 24 
• Requirement of rescue treatment (systemic CS for ≥ 3 
consecutive days) through Week 24. 
• Having had surgery for nasal polyps through Week 24 
• Change from baseline at Week 24 in AQLQ of ≥ 0.5 
(in patients with comorbid asthma only) 
Exploratory Efficacy Objective 
Corresponding Endpoint 
• To evaluate the efficacy of 
omalizumab compared with placebo  
• Change from baseline at Week 24 in SNOT-22 of 
at least the MID (8.9 points). 
• To evaluate health status utility 
scores compared with placebo 
• Change from baseline at Week 24 as assessed by 
EQ-5D 
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of 
omalizumab compared with placebo  
• Incidence of adverse events  
• Incidence of serious adverse events  
• Incidence of adverse events leading to 
omalizumab/placebo discontinuation 
• Clinically significant change in laboratory values 
Pharmacokinetic and 
Pharmacodynamic Objectives 
Corresponding Endpoint 
• To evaluate the pharmacokinetics 
and pharmacodynamics of 
omalizumab  
• Serum concentration of omalizumab at specified 
timepoints outlined in the Schedule of Activities 
• Serum levels of total and free IgE at specific timepoints 
outlined in the Schedule of Activities 
AQLQ = Asthma Quality of Life Questionnaire; CS = corticosteroid; MID =  minimal important 
difference; NCS = nasal blockage/congestion score; NPS = nasal polyp score; 
SNOT-22 = Sino-Nasal Outcome Test-22; TNSS = total nasal symptom score; UPSIT = University 
of Pennsylvania Smell Identification Test. 
a Order of endpoints presented here does not determine order in a sequential type I error control 
procedure.  Details on type I error control procedures will be given in the Statistical Analysis Plan 
at a later date. 
Study Design 
Description of Study 
This study is a Phase III, randomized, multicenter, double-blind, placebo-controlled, clinical trial 
that will be run in parallel with a replicate study, under Protocol GA39855.   
The study consists of a 5-week screening/run-in period, a 24-week treatment period, and a 
4-week study follow-up period.  The 4-week follow-up period will be for all patients unless they 
enroll at Week 24 into another available sponsor-permitted study of omalizumab in nasal 
polyps. 
The screening/run-in period will include two visits (“1st screening visit” at Day -35 and 
“2nd screening visit” at Day -7), during which patients will undergo video endoscopy to quantify 
the size of the polyps and assign a nasal polyps score (NPS) prior to baseline.   


 
Omalizumab—F. Hoffmann-La Roche Ltd 
18/Protocol GA39688, Version 2 
Beginning at Day -35 (1st screening visit), patients will be asked to standardize their nasal CS 
to a regimen of mometasone, 200 µg twice a day (400 µg total daily dosage).  Patients deemed 
by the investigator to be intolerant to a BID regimen of mometasone may remain on a stable 
dosage of mometasone QD during the run-in period and throughout the duration of the 
treatment period (two sprays/nostril, both nostrils, 50 µg/spray QD for a total daily dosage of 
200 µg).  Any patient transitioned to daily mometasone should remain on this regimen for the 
remainder of study.   
After screening/run-in has been completed, eligible patients will be randomly allocated in a 
1:1 ratio to receive double-blind treatment with omalizumab or placebo.  Randomization will be 
stratified on comorbid asthma and aspirin sensitivity status at baseline (3 levels: asthmatic and 
aspirin sensitive, asthmatic not aspirin sensitive, all other) and geographic region 
(North America, ex-North America).  
A modified version of the approved E.U. Summary of Product Characteristics (SmPC) 
omalizumab dosing table will be used; the SmPC has been modified to treat only the higher 
body weights reflective of the adult population being studied.  The first dose of study drug will be 
administered on the same day as randomization ([Day 1, Week 0]).  Dosing will be repeated 
every 2 or 4 weeks during a 24-week placebo−controlled treatment period.   
Video nasal endoscopy will be performed at Day -35 (1st screening visit) and at baseline 
(Day -7), and at Weeks 4, 8, 16, and 24 (for a total of 6 endoscopies).  Change from baseline in 
NPS at Week 24 will be used as a co-primary endpoint to evaluate the benefit of omalizumab, 
where the baseline measurement is performed at Day -7 (2nd screening visit) prior to 
randomization.  
After the treatment period ends (at Week 24), patients will be followed for 4 additional weeks as 
part of safety follow-up, unless they enroll at Week 24 into another available sponsor-permitted 
study of omalizumab in nasal polyps.  
Number of Patients 
A total of approximately 120 patients with CRSwNP whose disease remains inadequately 
controlled despite daily treatment with intranasal corticosteroid (CS) therapy will be enrolled.   
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age 18−75 years, inclusive, at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
NPS ≥ 5, with a unilateral score of ≥ 2 for each nostril, at screening (Day -35), and on Day -7 
(as assessed by a central panel of independent central readers) 
• 
SNOT-22 score ≥ 20 at screening (Day -35) and at randomization (Day 1) 
• 
Treatment with nasal mometasone at least 200 µg per day, or equivalent daily dosing of 
another nasal CS, for at least 4 weeks before screening (Day -35) 
• 
Treatment with nasal mometasone 200 µg twice a day (or once a day if intolerant to twice 
daily) during the run-in period with an adherence rate of at least 70%.  
• 
Presence of nasal blockage/congestion with NCS ≥ 2 (1-week recall) at Day -35 and a 
weekly average at randomization of NCS > 1 with at least one of the following symptoms 
prior to screening:  nasal discharge (anterior/posterior nasal drip) and/or reduction or loss of 
smell 
• 
Eligibility per the study drug−dosing table (serum IgE level ≥ 30 to ≤ 1500 IU/mL and body 
weight ≥ 30 to ≤ 150 kg) and ability to be dosed per the dosing table  
• 
Willingness to maintain all background medications stable for the duration of the treatment 
and follow-up periods 
• 
Willingness and ability to use electronic device to enter study-related information in 
electronic devices (electronic diary [eDiary]/electronic tablet [eTablet]) 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
19/Protocol GA39688, Version 2 
• 
Demonstration of at least 70% adherence to eDiary daily symptom assessment during 
run-in period, with fully completed entries on at least 4 days in the week prior to 
randomization  
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the treatment 
period and for 60 days 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. 
– 
Acceptable methods of contraception include surgical sterilization (e.g., bilateral 
tubal ligation, vasectomized partner), hormonal contraception (e.g., implantable, 
injectable, patch, oral), and intrauterine device (IUD). 
– 
Women of childbearing potential must have a negative serum pregnancy test result 
during the screening period. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known history of anaphylaxis/hypersensitivity to omalizumab 
• 
Treatment with investigational drugs within 12 weeks or 5 half-lives (whichever is longer) 
prior to screening (Day -35) 
• 
Treatment with monoclonal antibodies (e.g., omalizumab, mepolizumab) for 6 months prior 
to screening (Day -35) 
• 
Current treatment with leukotriene antagonists/modifiers, unless patient has been on stable 
dosing of such medication for at least 1 month prior to screening (Day -35) 
• 
Treatment with non-steroid immunosuppressants (e.g., cyclosporine, methotrexate, 
azathioprine, mycophenolate, siroliumus, tacrolimus) within 2 months or 5 half-lives, 
whichever is longer, prior to screening (Day -35) 
• 
Treatment with systemic corticosteroids (CS), except when used as treatment for nasal 
polyposis, within 2 months prior to screening (Day -35) 
• 
Usage of systemic CS during the run-in period.  Patients requiring systemic CS during run-
in may be rescreened after completing systemic CS.  
• 
Treatment with intranasal CS drops or CS−administering devices (e.g., OptiNose device or 
stents) within 1 month prior to screening (Day -35) or during the run-in period 
• 
History of nasal surgery (including polypectomy) within 6 months prior to screening 
• 
History of sinus or nasal surgery modifying the structure of the nose such that assessment 
of NPS is not possible 
• 
Uncontrolled epistaxis requiring surgical or procedural intervention, including nasal packing, 
within 2 months prior to screening 
• 
Known or suspected diagnosis of cystic fibrosis, primary ciliary dyskinesia (e.g., Kartagener 
syndrome) or other dyskinetic ciliary syndromes, hypogammaglobulinemia or other immune 
deficiency syndrome, chronic granulomatous disease and granulomatous vasculitis, 
granulomatosis with polyangiitis (e.g., Wegener’s Granulomatosis), or eosinophilic 
granulomatous with polyangiitis (EGPA) (e.g., Churg-Strauss syndrome) 
• 
Presence of antrochoanal polyps 
• 
Concomitant conditions that interfere with evaluation of primary endpoint: 
– 
Nasal septal deviation occluding one or both nostrils 
– 
Ongoing rhinitis medicamentosa 
– 
Acute sinusitis, nasal infection, or upper respiratory infection during the run-in period 
– 
Known or suspected invasive or expansive fungal rhinosinusitis 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
20/Protocol GA39688, Version 2 
• 
Known HIV infection at screening 
• 
Known acute and chronic infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) 
at screening 
• 
History of myocardial infarction, unstable angina, cerebrovascular accident, or transient 
ischemic attack or a known history of a hypercoagulable disorder 
• 
Infection that meets any of the following criteria: 
– 
Resulted in hospital admission within 4 weeks prior to screening 
– 
Required treatment with intravenous or intramuscular antibiotics within 4 weeks prior to 
screening 
– 
Any active infection that required treatment with oral antibiotics within 2 weeks prior to 
screening 
– 
Active parasitic infection, including nematodes (e.g., Ascaris, Ancylostoma), 
platyhelminths (e.g., Schistosoma), or Listeria monocytogenes infection within 6 months 
prior to screening 
Note:  Antibiotics are considered to include any antimicrobial therapy used to treat bacterial, 
fungal, parasitic, viral, or other infections.  
• 
Active tuberculosis requiring treatment within 12 months prior to screening (Day -35) 
Patients who have completed treatment for tuberculosis at least 12 months prior to 
screening (Day -35) and have no evidence of recurrent disease are permitted. 
• 
Initiation of or change in allergen immunotherapy within 3 months prior to screening (Day -
35) or during the run-in period 
• 
Initiation of or change in aspirin desensitization within 4 months prior to screening (Day -35) 
or during the run-in period 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 60 
days after the last dose of omalizumab 
• 
Current malignancy or history of malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix or non-melanoma skin carcinoma that 
has been treated or excised and is considered resolved 
• 
Any serious medical condition (including but not limited to significant arrhythmia, 
uncontrolled hypertension, significant pulmonary disease other than asthma) or abnormality 
in clinical laboratory tests that precludes the patient’s safe participation in and completion of 
the study 
• 
History of alcohol, drug, or chemical abuse within 6 months of screening 
 
End of Study 
The end of the study is defined as the date of the last patient's last visit (LPLV).  The LPLV is 
expected to occur at a maximum of 28 weeks after the last patient is randomized.  
Length of Study 
Each patient will be followed for up to 33 weeks (5-week screening/run-in period, 24-week 
treatment period, 4-week off-drug safety follow-up period).  The 4-week follow-up period will be 
for all patients unless they enroll into another available sponsor-permitted study of omalizumab 
in nasal polyps. 
Investigational Medicinal Products 
The investigational medicinal product (IMP) for this study is omalizumab. 
Test Product (Investigational Drug) 
Study drug will be administered subcutaneously to patients by qualified personnel who are not 
involved with conducting safety or efficacy evaluations using a disposable 25-gauge needle 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. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
21/Protocol GA39688, Version 2 
Study drug will be administered subcutaneously every 2 or 4 weeks.  Because the solution is 
slightly viscous, the injection may take 5−10 seconds to administer.  The dose (mg) and dosing 
frequency will be determined by serum total IgE level (IU/mL) (measured before the start of 
treatment) and body weight (kg) at Day -35.  Assignment of the study drug dose will be 
determined by using the study drug−dosing table.  Doses of > 150 mg are divided among more 
than one injection site to limit injections to no more than 150 mg per site.  The reconstituted vial 
is to be used for single-dose administration only. 
Comparator  
The placebo will be administered according to the same dose, route, and dosing regimen as 
omalizumab, shown above. 
Non-Investigational Medicinal Products 
In this study, mometasone furoate monohydrate nasal spray is considered a non-IMP and is 
used as background therapy only.  
Statistical Methods 
Primary Analysis 
The analysis of data from the 24-week treatment period may be performed after all patients 
have either completed the Week 24 visit or discontinued from the treatment period prematurely, 
and all data from the treatment period are in the database and have been cleaned and verified.  
Patients who discontinue early will not be replaced. 
The analysis of complete data from the study, including data from the safety follow-up period 
will be performed when all patients have either discontinued the study early or completed the 
safety follow-up period, all data from the study are in the database, and the database is cleaned 
and locked. 
Determination of Sample Size   
A total of approximately 120 patients will be enrolled in this study.  Patients will be randomly 
allocated in a 1:1 ratio to receive treatment with omalizumab or placebo, in addition to intranasal 
steroids.   
The sample size of 120 patients will provide at least 85% power to independently detect both a 
0.56-point difference between treatment groups in change from baseline at Week 24 in the 
average daily NCS and a 1.50-point difference between treatment groups in change from 
baseline at Week 24 in NPS.   
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
22/Protocol GA39688, Version 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AERD 
aspirin exacerbated respiratory disease 
AQLQ 
Asthma Quality of Life Questionnaire 
ATE 
arterial thrombotic events 
BID 
twice a day 
CIU 
chronic idiopathic urticarial 
CRO 
contract research organization 
CRS 
chronic rhinosinusitis  
CRSwNP 
chronic rhinosinusitis with nasal polyps 
CS 
corticosteroid 
CSR 
Clinical Study Report 
CSU 
chronic spontaneous urticaria 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level Questionnaire 
FAS 
full-analysis set 
FDA 
Food and Drug Administration 
FESS 
functional endoscopic sinus surgery 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IL 
interleukin 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IWRS 
interactive Web-based reponse system 
LPLV 
last patient, last visit 
MID 
minimal important difference 
MMRM 
mixed-effect model repeated measurement 
NCS 
nasal blockage/congestion score 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
23/Protocol GA39688, Version 2 
NPS 
nasal polyp score 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
QD 
once a day 
QoL 
quality of life 
RBR 
Research Biosample Repository 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SCE 
Summary of Clinical Efficacy 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SNOT-22 
Sino-Nasal Outcome Test-22 
SWFI 
Sterile Water for Injection 
TNSS 
total nasal symptom score 
ULN 
upper limit of normal 
UPSIT 
University of Pennsylvania Smell Identification Test 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
24/Protocol GA39688, Version 2 
1. 
BACKGROUND 
1.1 
BACKGROUND ON CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS  
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly adult disease with 
a prevalence estimated to be 2.1%−2.7% (Johansson et al. 2003; Klossek et al. 2005; 
We et al. 2015).  It is associated with reduced quality of life (QoL) and significant 
morbidity, including asthma, which can be severe and refractory, particularly in those 
patients with aspirin exacerbated respiratory disease (AERD) (Hulse et al. 2014; 
Stevens et al. 2016). 
The diagnosis of CRSwNP is made in patients who exhibit a combination of symptoms 
(e.g., blockage/congestion, anterior or postnasal drip, and impaired sense of smell) with 
the presence of nasal polyps (Fokkens et al. 2012; Rimmer et al. 2014).  Intranasal and 
systemic/oral corticosteroids remain the mainstay of treatment, but many patients fail to 
achieve complete therapeutic benefit with these medications and resort to functional 
endoscopic sinus surgery (FESS) and other complex sinus surgery (Fokkens et al. 2012; 
Rimmer et al. 2014).  Although FESS and intranasal and oral corticosteroids are useful 
and often effective in reducing the size of nasal polyps and associated symptoms, many 
patients do not respond sufficiently and/or polyps return rapidly after medication 
withdrawal or within months or years following surgery.  In one trial, almost 40% of 
patients who received daily intranasal corticosteroids (mometasone furoate) following 
FESS suffered a relapse within 6 months of the procedure (Stjärne et al 2009).  In another 
study, almost 50% of the patients who received oral corticosteroids in combination with 
topical therapy suffered a relapse within 12 months of treatment (Cassano et al. 1996).  
Moreover, oral corticosteroids are associated with significant side effects, and repeat 
surgical procedures become progressively more complex and risky.  In the United States, 
the only approved pharmacotherapy for nasal polyps is intranasal corticosteroids 
(mometasone furoate and/or beclomethasone).  Because of limitations in treatment 
combined with a QoL that is considerably reduced in patients with CRSwNP, nasal 
polyposis remains an important unmet medical need (Hulse et al. 2015).   
Patients with CRSwNP and most patients with asthma share a common IgE-mediated 
type 2 inflammatory response, characterized by elevated levels of interleukin (IL)-4, IL-5, 
IL-13, eosinophils, Th2 cells, and type 2 innate lymphoid cells (Wenzel et al. 1999; 
Kato 2015).  In addition, locally produced IgEoften against Staphylococcus aureus 
enterotoxinsis associated with local inflammation in CRSwNP and, in particular, with 
comorbid asthma (Bachert et al. 2010).  Because of the common type 2 inflammatory 
disease between asthma and CRSwNP, approximately 20%−30% of patients with 
asthma have CRSwNP, particularly those patients with AERD.  In addition, a substantial 
proportion of patients with CRSwNP have symptoms of asthma, with higher percentages 
associated with patients who have greater nasal polyp disease severity (Settipane 1987; 
Larsen 1996; Hedman et al. 1999; Johansson et al. 2003; Ragab et al. 2004; 
Pearlman et al. 2009; Promsopa et al. 2016).  Importantly, there appears to be a 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
25/Protocol GA39688, Version 2 
premorbid relationship between asthma and CRSwNP, with the diagnosis of asthma 
often occurring prior to that of nasal polyposis (Larsen 1996; Tan et al. 2013; 
Lam et al. 2014).  
1.2 
BACKGROUND ON OMALIZUMAB 
Omalizumab (Xolair®) is a recombinant DNA-derived humanized IgG1 monoclonal 
antibody with a molecular mass of approximately 149 kilodaltons that selectively binds to 
human IgE. 
Omalizumab is designed to treat IgE-mediated disease by reducing the concentration of 
free IgE in blood and in tissue.  Omalizumab selectively binds to human IgE at the same 
site as does the high affinity IgE receptor (FcεRI) (Schulman 2001), thereby reducing 
surface-bound IgE through this receptor on basophils and mast cells, reducing 
cross-linking of IgE to the receptor when antigen is bound and the subsequent basophil 
and mast cell triggered type 2 inflammation. 
Omalizumab is currently approved by U.S. Food and Drug Administration (FDA) for 
allergic asthma and chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria 
(CSU).  
Refer to the Omalizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
CRSwNP occurs in a subset of patients with chronic rhinosinusitis (CRS).  The polyps 
that develop in patients with CRSwNP are characterized histologically by the presence 
of large numbers of eosinophils and type 2 innate lymphoid cells as well as by mucosal 
edema and albumin containing pseudocysts with minimal extracellular matrix fibrosis 
(Huvenne et al. 2009; Mjösberg et al. 2011).  In contrast, nasal polyps associated with 
other diseases (e.g., cystic fibrosis) are associated with large numbers of neutrophils in 
the polyp tissue.  The polyps in patients with CRSwNP exhibit a type 2 cytokine profile, 
with predominant expression of IL-13, IL-5, and some IL-4 (Wang et al. 2015).  Activated 
B cells produce IgE, often against Staphylococcus aureus, in association with increased 
mucus and chemokine production.  The marked local production of IgE antibodies in 
patients with CRSwNP appears to be functional and involved in the regulation of chronic 
inflammation (Zhang et al. 2011).  Asthma and CRSwNP may share similar type 2 
cytokine profiles, such that a substantial proportion of patients with CRSwNP exhibit 
comorbid asthma.  In turn, a substantial proportion of patients with asthma have 
CRSwNP, particularly among those with more severe asthma (Settipane 1987; 
Larsen 1996; Ragab et al. 2004; Pearlman et al. 2009; Langdon and Mullol 2016). 
Omalizumab interrupts the allergic cascade triggered by cross-linking IgE on the surface 
of mast cells and basophils by 1) forming complexes with IgE and preventing the arming 
of effector cells; 2) aiding off-loading of mast cells and basophils by trapping IgE as it 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
26/Protocol GA39688, Version 2 
dissociates from the FcεRI receptor; 3) down-modulating FcεRI (in mast cells, basophils, 
and dendritic cells) as a direct consequence of the reduction in free IgE levels; 
4) reducing antigen presentation to T lymphocytes by dendritic cells; 5) reducing IgE 
stimulated synthesis and secretion of proinflammatory cytokines by human airway 
smooth muscle cells; and 6) improving interferon-α production by plasmacytoid dendritic 
cells (Presta et al.1993; Jardieu 1995; Heusser and Jardieu 1997; Boushey 2001; 
Holgate et al. 1998; Fick 1999; Jardieu and Fick 1999; Patalano 1999; Prussin et al. 
2003; Roth and Tamm 2010, Teach et al. 2015).  These events then result in the 
reduction of type 2 inflammation, including reduced production of IL-4, IL-5, and IL-13 by 
innate and adaptive cells.  Therefore, given the multiple potential mechanisms of 
omalizumab in limiting the inflammation in nasal polyps, a strategy to antagonize IgE 
with omalizumab is likely to benefit patients with CRSwNP.   
The benefit of antagonizing IgE in patients with CRSwNP has also been suggested by a 
randomized, double-blind, placebo-controlled study in patients with nasal polyps and 
comorbid asthma published in Gevaert et al. 2013.  Twenty-four patients (nasal polyp 
size ≥ 5) were included and randomized 2:1 to receive omalizumab or placebo for 
16 weeks.  Twelve of the 24 patients had the diagnosis of aspirin hypersensitivity.  
Results showed a significant reduction from baseline in total nasal endoscopic polyp 
score in patients in the omalizumab group at Week 16 (-2.67, p = 0.001) but not in 
patients in placebo group (-0.12, p = 0.99).  In addition, omalizumab treatment improved 
computed tomography image scores; reduced symptom scores for nasal congestion, 
anterior rhinorrhea, loss of sense of smell, wheeze, and dyspnea; and improved QoL 
scores, all irrespective of the presence of allergy (Gevaert et al. 2013). 
A number of other case-controlled and randomized, double-blind, placebo-controlled 
studies have been performed over the past decade examining the efficacy of 
omalizumab for the treatment of nasal polyps (Penn and Mikula 2007; Pinto et al. 2010; 
Vennera et al. 2011; Tajiri et al. 2013; Sintobin et al. 2015).  The collective and 
cumulative clinical evidence strongly suggests a potential benefit of omalizumab in 
patients with CRSwNP. 
Taken together, these studies provide evidence that anti-IgE therapy can be effective for 
patients with nasal polyps, particularly in those with large nasal polyps, suggesting that 
omalizumab therapy should be further evaluated in a large clinical trial for confirmation.  
2. 
OBJECTIVES AND ENDPOINTS 
The purpose of this study is to determine the efficacy and safety of omalizumab 
compared with placebo in adult patients with CRSwNP who have had an inadequate 
response to standard-of-care treatments.  Specific objectives and corresponding 
endpoints for the study are outlined below. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
27/Protocol GA39688, Version 2 
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Co-Primary Endpoints 
• To evaluate the efficacy of 
omalizumab compared with placebo  
Co-primary endpoints: 
• Change from baseline at Week 24 in average daily 
nasal congestion score (NCS)  
• Change from baseline at Week 24 in nasal polyps score 
(NPS)  
Secondary Efficacy Objective a 
Corresponding Endpoints 
• To evaluate the efficacy of 
omalizumab compared with placebo  
• Change from baseline at Week 24 in the average daily 
total nasal symptom score (TNSS) 
• Change from baseline at Week 24 in the average daily 
sense of smell score 
• Change from baseline at Week 24 in the average daily 
posterior rhinorrhea score  
• Change from baseline at Week 24 in the average daily 
anterior rhinorrhea score 
• Change from baseline at Week 24 in patient-reported 
HRQoL as assessed by the total SNOT-22 
• Change from baseline at Week 16 in the average daily 
NCS  
• Change from baseline at Week 16 in NPS 
• Change from baseline at Week 24 in sense of smell, as 
assessed by the UPSIT 
• Reduction in the need for surgery by Week 24, as 
defined by an NPS of ≤ 4 (unilateral score of ≤ 2 on 
each side) and improvement in SNOT-22 score of ≥ 8.9 
• Requirement of rescue treatment (systemic CS for ≥ 3 
consecutive days) or having had surgery for nasal 
polyps through Week 24 
• Requirement of rescue treatment (systemic CS for 
≥ 3 consecutive days) through Week 24 
• Having had surgery for nasal polyps through Week 24 
• Change from baseline at Week 24 in AQLQ of ≥ 0.5 
(in patients with comorbid asthma only) 
Exploratory Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of 
omalizumab compared with placebo  
• Change from baseline at Week 24 in SNOT-22 of 
at least the MID (8.9 points). 
• To evaluate health status utility 
scores compared with placebo 
• Change from baseline at Week 24 as assessed by 
EQ-5D-5L 
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of 
omalizumab compared with placebo  
• Incidence of adverse events  
• Incidence of serious adverse events  
• Incidence of adverse events leading to 
omalizumab/placebo discontinuation 
• Clinically significant change in laboratory values 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
28/Protocol GA39688, Version 2 
Pharmacokinetic and 
Pharmacodynamic Objectives 
Corresponding Endpoint 
• To evaluate the pharmacokinetics 
and pharmacodynamics of 
omalizumab  
• Serum concentration of omalizumab at specified 
timepoints outlined in Appendix 1 
• Serum levels of total and free IgE at specified 
timepoints outlined in Appendix 1 
AQLQ = Asthma Quality of Life Questionnaire; CS = corticosteroid; EQ-5D-5L = EuroQol 
5-Dimension 5-Level Questionnaire; HRQoL = health-related quality of life; MID =  minimal 
important difference; NCS = nasal blockage/congestion score; NPS = nasal polyp score; 
SNOT-22 = Sino-Nasal Outcome Test-22; TNSS = total nasal symptom score; UPSIT = University 
of Pennsylvania Smell Identification Test. 
a Order of endpoints presented here does not determine order in a sequential type I error control 
procedure.  Details on type I error control procedures will be given in the Statistical Analysis 
Plan at a later date. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This study is a Phase III, randomized, multicenter, double-blind, placebo-controlled, 
clinical trial that will be run in parallel with a replicate study, under Protocol GA39855.  In 
this study (GA39688), a total of approximately 120 patients with CRSwNP whose 
disease remains inadequately controlled despite daily treatment with intranasal 
corticosteroid (CS) therapy will be enrolled.   
Written informed consent for participation in the study must be obtained before 
performing any study-specific tests or evaluations.  The 5-week screening/run-in period 
will include two visits (“1st screening visit” at Day -35 and “2nd screening visit” at Day -7) 
(see Figure 1).  During the screening/run-in period, at both the 1st screening visit and 
2nd screening visit, patients will undergo video endoscopy to quantify the size of the 
polyps and assign a nasal polyps score (NPS) prior to baseline.  The final NPS will be 
determined by central readers based on the criteria presented below in Table 2 and in 
Appendix 3.  The NPS ranges from 0−8 (0−4 on the left and 0−4 on the right). 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
29/Protocol GA39688, Version 2 
Table 2 
Nasal Polyps Scoring System 
Polyp Score 
Polyp Size 
0 
No polyps 
1 
Small polyps in the middle meatus not reaching below the inferior border of 
the middle turbinate 
2 
Polyps reaching below the lower border of the middle turbinate a 
3 
Large polyps reaching the lower border of the inferior turbinate or polyps 
medial to the middle turbinate 
4 
Large polyps causing complete obstruction of the inferior nasal cavity 
Note:  Scoring system is used to evaluate polyp size in each nasal passage by means of 
video nasal endoscopy.  Nasal polyp score is the sum of unilateral polyp scores for each 
nasal passage.   
a The scoring is modified to accommodate patients who have had a middle turbinectomy, 
such that the polyp must reach the top of the inferior turbinate to be graded as Score 2.   
Source:  Gevaert et al. 2013. 
 
During the screening/run-in period, beginning at Day -35 (1st screening visit), patients 
will be asked to standardize their nasal CS to a regimen of mometasone, 200 µg twice a 
day (BID) (400 µg total daily dosage).  Patients deemed by the investigator to be 
intolerant to a BID regimen of mometasone may remain on a stable dosage of 
mometasone once a day (QD) during the run-in period and throughout the duration of 
the treatment period (two sprays/nostril, both nostrils, 50 µg/spray QD for a total daily 
dosage of 200 µg).  Any patient transitioned to daily mometasone should remain on this 
regimen for the remainder of study.  At Day -35 (1st screening visit), patients should 
receive appropriate training on proper self-administration of mometasone nasal spray.   
Other assessments and activities occurring during the screening/run-in period are 
presented in Appendix 1.   
If patients do not meet the inclusion criteria (e.g., development of an acute infection at 
the time of screening necessitating treatment with antibiotics), they may be eligible for 
re-screening up to two times, after discussion with a Medical Monitor.  Additionally, if 
video endoscopy at Day -7 (2nd screening visit) is determined to be of insufficient quality 
to allow for scoring of NPS, patients may repeat nasal endoscopy if sufficient time 
remains to allow for central reading of that endoscopy prior to randomization; in such 
cases, before proceeding with repeat endoscopy, investigators should confirm that 
sufficient time does indeed remain for central reading of this endoscopy prior to 
randomization. 
After screening/run-in has been completed, approximately 120 eligible patients will be 
randomly allocated in a 1:1 ratio to receive double-blind treatment with omalizumab or 
placebo.  Randomization will be stratified on comorbid asthma and aspirin sensitivity 
status at baseline (see Section 4.2 for details) and geographic region (North America, 
ex-North America).  


 
Omalizumab—F. Hoffmann-La Roche Ltd 
30/Protocol GA39688, Version 2 
A modified version of the approved E.U. Summary of Product Characteristics (SmPC) 
omalizumab dosing table (Appendix 5) will be used; the SmPC has been modified to 
treat only the higher body weights reflective of the adult population being studied.  The 
first dose of study drug will be administered on the same day as randomization ([Day 1, 
Week 0]).  Dosing will be repeated every 2 or 4 weeks (Appendix 5) during a 24-week 
placebo−controlled treatment period.   
Patients will remain on stable doses of intranasal CS therapy (mometasone nasal spray 
200 µg BID as per Section 4.3.3) for the entire treatment period.  Patients deemed by 
the investigator to be intolerant to a BID regimen of mometasone may remain on a 
stable dosage of mometasone QD (two sprays/nostril, both nostrils, 50 µg/spray QD for 
a total daily dosage of 200 µg).  Any patient transitioned to daily mometasone should 
remain on this regimen for the remainder of the study.   
Safety, efficacy, and patient-reported outcome (PRO) measurements will be assessed 
throughout the placebo-controlled treatment period, as detailed in the schedule of 
activities.  The co-primary efficacy endpoints are changes from baseline in NPS and 
nasal blockage/congestion score (NCS) at Week 24. 
Video nasal endoscopy will be performed at Day -35 (1st screening visit) and at baseline 
(Day -7), and at Weeks 4, 8, 16, and 24 (for a total of 6 endoscopies).  Change from 
baseline in NPS at Week 24 will be used as a co-primary endpoint to evaluate the 
benefit of omalizumab, where the baseline measurement is performed at Day -7 
(2nd screening visit) prior to randomization.  
After the treatment period ends (at Week 24), patients will be followed for 4 additional 
weeks as part of safety follow-up (Appendix 1), unless they enroll at Week 24 into 
another available sponsor-permitted study of omalizumab in nasal polyps.  
All patients who discontinue study drug early during the treatment period will be asked to 
continue the planned study assessments through Week 24 and then to complete a 
4-week safety follow-up period.  Patients who are unwilling or unable to continue with the 
planned assessments in the treatment period will instead complete a dosing-termination 
visit and then enter a 4−week safety follow-up period.  Patients who require sinus 
surgery or require two or more courses of treatment with systemic CS for ≥ 3 consecutive 
days will discontinue study drug but continue in the study with assessments and 
treatments.   
NCS will be calculated as an average of daily scores.  Patients will complete an NCS 
assessment every morning (on a daily basis) via an electronic device, and change from 
baseline at Week 24 in the average daily NCS will be used as a co-primary endpoint to 
evaluate the benefit of omalizumab.  
A schedule of activities is provided in Appendix 1. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
31/Protocol GA39688, Version 2 
Figure 1 Study Schema 
 
1°EP = co-primary end point; Q2W = every 2 weeks; Q4W = every 4 weeks; SFU = safety follow-up; 
wk = week. 
Note:  All patients will be treated during the entire study with intranasal corticosteroids 
(mometasone nasal spray as per Section 4.3.4) as background therapy.   
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date of the last patient's last visit (LPLV).  The 
LPLV is expected to occur at a maximum of 28 weeks after the last patient is 
randomized.  
Each patient will be followed for up to 33 weeks (5-week screening/run-in period, 
24-week treatment period, 4-week safety follow-up period).  The 4-week follow-up period 
will be for all patients unless they enroll into another available sponsor-permitted study of 
omalizumab in nasal polyps. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Omalizumab Dose and Schedule 
Omalizumab will be dosed in this trial based on a dosing table that provides at least 
0.016 mg/kg for every IU/mL of IgE, within a 4-week interval (see Appendix 5).  The 
dosing algorithm used as the basis of the dosing table is consistent with the approach 
used in published studies for the treatment of CRSwNP and with the approach used for 
the treatment of allergic asthma.  The range of IgE values (30 IU/mL to 1,500 IU/mL) 
used in the dosing table comes from the asthma E.U. SmPC dosing table.  This asthma 
E.U SmPC has been modified to remove lower patient weights because this trial will 
include only adult patients, whereas the asthma E.U. SmPC is also intended to treat 
pediatric patients.  As with the E.U. SmPC, omalizumab will be administered every 
4 weeks for doses up to and including 600 mg and every 2 weeks for those patients 
requiring higher doses (Appendix 5).  In this trial, patient weights and IgE values used to 
determine study drug dosing will be based only on the Day -35 (1st screening visit) 
values.   


 
Omalizumab—F. Hoffmann-La Roche Ltd 
32/Protocol GA39688, Version 2 
3.3.2 
Rationale for Patient Population  
CRSwNP occurs in a subset of patients with CRS.  The polyps that develop in patients 
with CRSwNP are characterized histologically by the presence of large numbers of 
eosinophils and type 2 innate lymphoid cells and by mucosal edema and 
albumin-containing pseudocysts with minimal extracellular matrix fibrosis 
(Huvenne et al. 2009; Mjosberg et al. 2011).  The polyps in patients with CRSwNP 
exhibit a type 2 cytokine profile, with predominant expression of IL-13, IL-5, and 
some IL-4 (Wang et al. 2015).  Activated B cells produce IgE, in association with 
increased mucus, and chemokines.  The marked local production of IgE antibodies in 
patients with CRSwNP appears to be functional and involved in the regulation of chronic 
inflammation (Zhang et al. 2011).  Asthma and CRSwNP may share similar type 2 
cytokine profiles, such that a substantial proportion of patients with CRSwNP exhibit 
comorbid asthma and, in turn, a substantial proportion of patients with asthma have 
CRSwNP, particularly among those with more severe asthma (Settipane 1987; 
Larsen 1996; Ragab et al. 2004, Pearlman et al. 2009; Langdon and Mullol 2016).  
Patients with and without a diagnosis of asthma will be eligible for this trial.  During 
screening, it will be important to record in the eCRF any previous or current diagnosis of 
asthma.  It is acknowledged that patients with more severe CRSwNP are more likely to 
have asthma.  Previous trials with omalizumab in CRSwNP have generally focused on 
treating patients with a comorbid diagnosis of asthma, and there is less information 
about the efficacy in patients who do not have a diagnosis of asthma. 
The target population for this study will include patients who have an inadequate 
response to standard of care.  Standard of care for this study is defined as including 
at least 8 weeks of intranasal corticosteroids and may also include systemic/oral 
corticosteroids and/or surgery. 
Patients who have required oral corticosteroids for treatment of their nasal polyposis will 
be eligible for this study.  At the same time, requirement for systemic corticosteroids 
during the treatment period will be evidence of treatment failure, as detailed in 
Section 6.4.2.  As such, clinical stability will be necessary at the time of randomization, 
and patients who have required oral/systemic corticosteroids during the run-in period will 
be required to complete their course of such corticosteroids and re-initiate the run-in and 
screening period prior to randomization.   
The target population is defined based on currently available therapies that form the 
basis of standard of care for nasal polyps.  These patients will have bilateral polyps with 
an NPS of ≥ 5, with a baseline Sino-Nasal Outcome Test-22 (SNOT-22) score of 20 or 
greater (indicating moderate to severe symptoms).  Omalizumab will be evaluated in 
these patients as an add-on therapy to intranasal corticosteroids.  Patients meeting 
these entry criteria (having large polyps obstructing their nasal passage and causing 
significant impairment to their QoL) represent a significant unmet medical need.   


 
Omalizumab—F. Hoffmann-La Roche Ltd 
33/Protocol GA39688, Version 2 
This CRSwNP target population is thought to exhibit type 2 inflammation in particular, 
with predominant expression of IL-13, IL-5, and some IL-4 (Wang et al. 2015).  
As discussed in Section 1.3, such patients with CRSwNP have marked local production 
of IgE antibodies, often in response to Staphylococcus aureus, which appears to be 
functional and involved in the regulation of chronic inflammation (Zhang et al. 2011).  
Furthermore, prior studies including a proof-of-concept study (Gevaert et al. 2013) 
demonstrated that omalizumab reduces nasal polyp size and symptoms in patients with 
CRSwNP.  Therefore, by reducing circulating free IgE, preventing IgE cross-linking on 
the surface of mast cells and basophils, and interrupting the type 2 inflammatory 
cascade initiated by these events, omalizumab has the potential to offer significant 
clinical benefit for patients with CRSwNP and can very favourably address this 
significant unmet medical need in the target patient population.  
3.3.3 
Rationale for Control Group  
The proposed design includes a placebo group to eliminate reporting and ascertainment 
biases in the data analysis.  Patients in the placebo group will receive subcutaneous (SC) 
placebo injections at each treatment visit.  
Per standard of care in clinical practice for this patient population, all patients regardless 
of the treatment group will remain on intranasal CS therapy (e.g., mometasone furoate 
nasal spray as specified in Section 4.3.4) throughout the study.  
3.3.4 
Rationale for Co-Primary Endpoint Selection 
The two co-primary endpoints capture the important signs and symptoms of the disease 
and have regulatory precedence.  The endpoints assess major clinical features of 
nasal polyps and were used as the basis for the registration of mometasone furoate 
monohydrate spray (NASONEX USPI and E.U. SmPC for the treatment of nasal 
polyps).  Of note, in the response from FDA dated 9 February 2017 
(Reference ID: 4053742), the Agency noted that the selection of co-primary efficacy 
endpoints and proposed approach to consider patients who undergo surgery or use 
rescue medications to have experienced treatment failure (imputing with worst outcomes 
that are not in favor of the treatment) is reasonable. 
3.3.5 
Rationale for Choice of Stratification Factors 
The similarity between the pathophysiology of asthma and CRSwNP suggests that 
asthma comorbidity and aspirin sensitivity status may be prognostic of nasal polyp size 
and nasal polyp symptoms (see Sections 1.1 and 1.3 for background).  Stratification by 
asthma comorbidity status will minimize the chance of imbalance of this characteristic 
between treatment groups.  Due to the subjective nature of the NCS and variability of 
medical practices by geographic region, the Sponsor anticipates that maintaining 
balance across geographic regions within the treatment groups will minimize the chance 
of biased estimation of the treatment effect.  North America and ex−North America are 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
34/Protocol GA39688, Version 2 
the factors chosen to maximize the similarity of culture and medical practice within these 
regions, balanced by the expected number of patients that will fall within a given strata.   
3.3.6 
Rationale for Patient-Reported Outcome Assessments 
Change in nasal symptoms (i.e., patient-reported nasal congestion, sense of smell, 
anterior rhinorrhea, and posterior rhinorrhea) will provide important information to 
clinicians and patients regarding reduction in symptom burden.  In fact, CRSwNP has 
been shown to have a negative impact on several aspects of QoL and has a greater 
impact on social functioning, than chronic heart failure, angina, or back pain 
(Gliklich and Metson 1995).  Reduced symptom burden may improve patients' QoL and 
reduce economic burden of the disease (e.g., decreased work productivity) 
(Schalek 2011; Dietz de Loos et al. 2013; Chung et al. 2015).  
The SNOT-22 will be employed to assess the impact of treatment on patient-reported 
symptoms and health-related quality of life (HRQoL).  SNOT-22 was the recommended 
outcome tool by Fokkens et al. (2012) in their European position paper.  This tool rates 
highly in terms of psychometric quality and has been used in a number of published 
studies performed in the European Union and the United States (Hopkins et al. 2006, 
2009c; Kennedy et al. 2013; Yeolekar et al. 2013).  Treatment benefit will be assessed 
by change from baseline at Week 24 in the SNOT-22 total score.   
The University of Pennsylvania Smell Identification Test (UPSIT) is a standardized, 
40-item “scratch-and-sniff” measure of olfactory function (Doty et al. 1984).  It was 
developed using over 1,600 patients in a series of experiments designed to test the 
ability of the UPSIT to differentiate between patients with and without olfactory disorders.  
The UPSIT is widely used and is recommended by the BMJ Best Practice Guidelines 
(2015) to assess olfactory function in nasal polyps.  The UPSIT will be employed to 
assess smell.  
The four brief nasal symptom items will be completed by patients on a daily basis.  
Completion of these items is estimated to require < 2 minutes each day.  The SNOT-22 
and UPSIT will be completed at a minimal number of study visits in order to reduce 
patient burden. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The study will enroll patients with difficult-to-treat CRSwNP.  These will be patients with 
large bilateral nasal polyps that remain uncontrolled despite daily treatment with 
intranasal CS for at least 8 weeks, as demonstrated by an NPS score of ≥ 5.   
Approximately 120 patients will be enrolled in this Phase III study at approximately 
50−70 sites located globally.   


 
Omalizumab—F. Hoffmann-La Roche Ltd 
35/Protocol GA39688, Version 2 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age 18−75 years, inclusive, at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
NPS ≥ 5, with a unilateral score of ≥ 2 for each nostril (see Appendix 2), at 
screening (Day -35), and on Day -7 (as assessed by a central panel of 
independent central readers) 
• 
SNOT-22 score ≥ 20 at screening (Day -35) and at randomization (Day 1) 
• 
Treatment with nasal mometasone at least 200 µg per day, or equivalent daily 
dosing of another nasal CS, for at least 4 weeks before screening (Day -35) 
• 
Treatment with nasal mometasone 200 µg BID (or QD if intolerant to twice daily) 
during the run-in period with an adherence rate of at least 70%.  
• 
Presence of nasal blockage/congestion with NCS ≥ 2 (1-week recall) at Day -35 
and a weekly average at randomization of NCS  > 1 with at least one of the 
following symptoms prior to screening:  nasal discharge (anterior/posterior nasal 
drip) and/or reduction or loss of smell 
• 
Eligibility per the study drug−dosing table (serum IgE level ≥ 30 to ≤ 1500 IU/mL 
and body weight ≥ 30 to ≤ 150 kg) and ability to be dosed per the dosing table 
(see Appendix 5) 
• 
Willingness to maintain all background medications stable for the duration of the 
treatment and follow-up periods 
• 
Willingness and ability to use electronic device to enter study-related information 
in electronic devices (electronic diary [eDiary]/electronic tablet [eTablet]) 
• 
Demonstration of at least 70% adherence to eDiary daily symptom assessment 
during run-in period, with fully completed entries on at least 4 days in the week 
prior to randomization  
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the 
treatment period and for 60 days 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. 
– 
Acceptable methods of contraception include surgical sterilization 
(e.g., bilateral tubal ligation, vasectomized partner), hormonal contraception 
(e.g., implantable, injectable, patch, oral), and intrauterine device (IUD). 
– 
Women of childbearing potential must have a negative serum pregnancy test 
result during the screening period. 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
36/Protocol GA39688, Version 2 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known history of anaphylaxis/hypersensitivity to omalizumab 
• 
Treatment with investigational drugs within 12 weeks or 5 half-lives (whichever is 
longer) prior to screening (Day -35) 
• 
Treatment with monoclonal antibodies (e.g., omalizumab, mepolizumab) for 
6 months prior to screening (Day -35) 
• 
Current treatment with leukotriene antagonists/modifiers, unless patient has been 
on stable dosing of such medication for at least 1 month prior to screening (Day -
35) 
• 
Treatment with non-steroid immunosuppressants (e.g., cyclosporine, 
methotrexate, azathioprine, mycophenolate, siroliumus, tacrolimus) within 2 
months or 5 half-lives, whichever is longer, prior to screening (Day -35) 
• 
Treatment with systemic corticosteroids (CS), except when used as treatment for 
nasal polyposis, within 2 months prior to screening (Day -35) 
• 
Usage of systemic CS during the run-in period.  Patients requiring systemic CS 
during run-in may be rescreened after completing systemic CS.  
• 
Treatment with intranasal CS drops or CS−administering devices (e.g., 
OptiNose device or stents) within 1 month prior to screening (Day -35) or during 
the run-in period 
• 
History of nasal surgery (including polypectomy) within 6 months prior to 
screening 
• 
History of sinus or nasal surgery modifying the structure of the nose such that 
assessment of NPS is not possible 
• 
Uncontrolled epistaxis requiring surgical or procedural intervention, including 
nasal packing, within 2 months prior to screening 
• 
Known or suspected diagnosis of cystic fibrosis, primary ciliary dyskinesia 
(e.g., Kartagener syndrome) or other dyskinetic ciliary syndromes, 
hypogammaglobulinemia or other immune deficiency syndrome, chronic 
granulomatous disease and granulomatous vasculitis, granulomatosis with 
polyangiitis (e.g., Wegener’s Granulomatosis), or eosinophilic granulomatous with 
polyangiitis (EGPA) (e.g., Churg-Strauss syndrome) 
• 
Presence of antrochoanal polyps 
• 
Concomitant conditions that interfere with evaluation of primary endpoint: 
– 
Nasal septal deviation occluding one or both nostrils 
– 
Ongoing rhinitis medicamentosa 
– 
Acute sinusitis, nasal infection, or upper respiratory infection during the run-in 
period 
– 
Known or suspected invasive or expansive fungal rhinosinusitis 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
37/Protocol GA39688, Version 2 
• 
Known HIV infection at screening 
• 
Known acute and chronic infections with hepatitis C virus (HCV) and hepatitis B 
virus (HBV) at screening 
• 
History of myocardial infarction, unstable angina, cerebrovascular accident, or 
transient ischemic attack or a known history of a hypercoagulable disorder 
• 
Infection that meets any of the following criteria: 
– 
Resulted in hospital admission within 4 weeks prior to screening 
– 
Required treatment with intravenous or intramuscular antibiotics within 4 weeks 
prior to screening 
– 
Any active infection that required treatment with oral antibiotics within 2 weeks 
prior to screening 
– 
Active parasitic infection, including nematodes (e.g., Ascaris, Ancylostoma), 
platyhelminths (e.g., Schistosoma), or Listeria monocytogenes infection within 
6 months prior to screening 
Note:  Antibiotics are considered to include any antimicrobial therapy used to treat 
bacterial, fungal, parasitic, viral, or other infections.  
• 
Active tuberculosis requiring treatment within 12 months prior to screening 
(Day -35) 
Patients who have completed treatment for tuberculosis at least 12 months 
prior to screening (Day -35) and have no evidence of recurrent disease are 
permitted. 
• 
Initiation of or change in allergen immunotherapy within 3 months prior to 
screening (Day -35) or during the run-in period 
• 
Initiation of or change in aspirin desensitization within 4 months prior to screening 
(Day -35) or during the run-in period 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 60 days after the last dose of omalizumab 
• Current malignancy or history of malignancy within 5 years prior to screening, 
except for appropriately treated carcinoma in situ of the cervix or non-melanoma 
skin carcinoma that has been treated or excised and is considered resolved 
• 
Any serious medical condition (including but not limited to significant arrhythmia, 
uncontrolled hypertension, significant pulmonary disease other than asthma) or 
abnormality in clinical laboratory tests that precludes the patient’s safe 
participation in and completion of the study 
• 
History of alcohol, drug, or chemical abuse within 6 months of screening 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
At the Day 1 visit, after verification of inclusion/exclusion criteria, patients will be 
randomized to receive either omalizumab or placebo at approximately a 1:1 ratio using 
an interactive Web-based response system (IWRS).  Randomization will be stratified by 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
38/Protocol GA39688, Version 2 
comorbid asthma and aspirin sensitivity status at baseline (3 levels: asthmatic and 
aspirin sensitive, asthmatic not aspirin sensitive, all other) and geographic region 
(North America, ex-North America).  
The following individuals/groups will be blinded to treatment assignment throughout the 
study: patients, the designated evaluating physician(s) and study nurses, the central 
image readers, and the Sponsor and its agents.  The following are exceptions to the 
blinding:  IWRS service provider, unblinded pharmacist at the sites, and bioanalytical 
laboratory personnel.  To minimize risk of potential bias arising from access to laboratory 
results that could potentially unblind treatment assignments (e.g., free IgE levels), 
access to these results will be restricted to the site and the sponsor until study 
completion.  Treatment assignment may be unblinded to the personnel analyzing the 
data from the treatment period when all data through Week 24 are in the database and 
the data have been cleaned and verified.   
Study drug supplies will be shipped blinded to each site.  To minimize the risk of 
potential bias, study site personnel who are responsible for reconstituting and/or 
administering study drug will not be permitted to conduct any safety or efficacy 
evaluations.  Each center will identify an individual (e.g., pharmacist) responsible for the 
reconstitution procedures.  This individual will prepare the study drug for each patient 
prior to administration.  An individual not involved with evaluating the patient must be 
identified to administer the study drug. 
While pharmacokinetic (PK) samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK results for these 
patients are generally not needed for the safe conduct or proper interpretation of this 
study.  Laboratories responsible for performing study drug PK assays will be unblinded 
to patients' treatment assignments to identify appropriate samples to be analyzed.  
PK samples from patients assigned to the comparator arm will not be analyzed for 
study drug PK concentration except by request (e.g., to evaluate a possible error in 
dosing).   
As per local health authorities (HA) reporting requirements, the Sponsor will break the 
treatment code for all SUSARs (suspected unexpected serious adverse reactions).  For 
more details on expedited reporting to HA, investigators, IRBs, and ethics committees, 
see Section 5.7.  The internal study team will remain blinded to treatment assignment, 
and the patient may continue to receive treatment per protocol.  
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IWRS).  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly.  The investigator should document and 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
39/Protocol GA39688, Version 2 
provide an explanation for any premature unblinding (e.g., accidental unblinding or 
unblinding due to a serious adverse event). 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is omalizumab. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Omalizumab and Placebo 
Omalizumab will be supplied by the Sponsor.  Omalizumab is a sterile, white, 
preservative-free, lyophilized powder, contained in a single-use vial that will be 
reconstituted with Sterile Water for Injection (SWFI), USP, and administered as 
an 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. 
The placebo contains the same ingredients as the omalizumab formulation listed above, 
excluding omalizumab. 
4.3.1.2 
Mometasone Furoate Monohydrate Nasal Spray 
In this study, mometasone furoate monohydrate nasal spray is considered a non-IMP 
and is used as background therapy only. 
Each spray delivers 50 µg of mometasone furoate monohydrate per actuation. For 
information on the formulation, handling, and storage of mometasone furoate 
monohydrate nasal spray, see the local prescribing information.   
Any adverse events associated with an overdose or incorrect administration of 
mometasone furoate monohydrate nasal spray should be recorded on the 
Adverse Event electronic Case Report Form (eCRF).   
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Any overdose or incorrect administration of omalizumab should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of any of the study treatments should be recorded on the 
Adverse Event eCRF. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.4.1. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
40/Protocol GA39688, Version 2 
4.3.2.1 
Omalizumab and Placebo 
Study drug will be administered subcutaneously to patients by qualified personnel who 
are not involved with conducting safety or efficacy evaluations using a disposable 
25-gauge needle 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. 
Patients should be observed after administration of omalizumab for signs and symptoms 
of anaphylaxis.  More details are provided in Section 5.1.3.1.  In addition, the study staff 
should be prepared to manage anaphylaxis.  Patients should also be informed of the 
signs and symptoms of anaphylaxis and be instructed to seek immediate care should 
symptoms occur. 
Study drug will be administered subcutaneously every 2 or 4 weeks.  Because the 
solution is slightly viscous, the injection may take 5−10 seconds to administer.  The 
dose (mg) and dosing frequency will be determined by serum total IgE level (IU/mL) 
(measured before the start of treatment via central laboratory) and body weight (kg) as 
specified in Appendix 1.  Assignment of the study drug dose will be determined by using 
the study drug−dosing table (see Appendix 5).  Doses of > 150 mg are divided among 
more than one injection site to limit injections to no more than 150 mg per site.  The 
reconstituted vial is to be used for single-dose administration only. 
Study drug kits must be stored at 2°C−8°C (36°F−46°F) in refrigerated conditions in a 
limited access area and/or a locked refrigerator.  Study drug should not be frozen or 
shaken.  Study drug should be stored immediately upon receipt but no later than 
24 hours after receipt.  Omalizumab is for single-use only and contains no preservatives.  
The solution may be used for SC administration 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.  For further details on drug handling, see the pharmacy manual. 
4.3.3 
Mometasone Furoate Monohydrate Nasal Spray  
All patients will be required to take mometasone furoate nasal spray (e.g., Nasonex) 
starting at Day -35 (1st screening visit) (two sprays/nostril, both nostrils, 50 µg/spray BID 
for a total daily dose of 400 µg) and remain on this medication at this dose throughout 
the study until Week 24.  Patients deemed by the investigator to be intolerant to a BID 
regimen of mometasone may be treated with a stable dosage of mometasone QD 
(two sprays/nostril, both nostrils, 50 µg/spray QD for a total daily dosage of 200 µg).  
Any patient transitioned to daily mometasone should remain on this regimen for the 
remainder of the study.   
Patients who have not been sufficiently adherent to mometasone during the run-in 
period, as specified in inclusion criteria and measured by eDiary (Section 4.1.1), will be 
prohibited from enrollment.   


 
Omalizumab—F. Hoffmann-La Roche Ltd 
41/Protocol GA39688, Version 2 
Patients will confirm daily mometasone use in the eDiary during the run-in period only.  
During the treatment period, patient adherence to prescribed mometasone regimen will 
be assessed by the investigator at clinic visits and recorded in the eCRF. 
For more information on formulation, dosing, and product safety, see the local 
prescribing information for mometasone furoate nasal spray. 
4.3.4 
Investigational Medicinal Product Accountability 
The IMP (omalizumab) required for completion of this study will be provided by the 
Sponsor.  The study site will acknowledge receipt of the IMP using the IWRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced. 
IMPs either will be disposed of at the study site according to the study site's institutional 
standard operating procedure or will be 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. 
4.3.5 
Continued Access to Omalizumab 
Patients may be eligible to receive omalizumab as part of another available sponsor-
permitted study of omalizumab in nasal polyps.  The Roche Global Policy on Continued 
Access to Investigational Medicinal Product is available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy will consist of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from Day -35 
(1st screening visit).  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF.  
4.4.1 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
• 
Investigational therapy other than the study drug  
• 
Sino-nasal surgical procedures, including polypectomies 
These procedures, if performed will be considered rescue treatment and 
evidence of treatment failure.  Patients requiring sino-nasal surgery (e.g., nasal 
polypectomy) during the study should have their reasons for surgery 
documented and reviewed by the Medical Monitor.  Should surgery occur 
during the treatment phase, study medication should be discontinued, although 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
42/Protocol GA39688, Version 2 
study assessments should continue.  Should the patient elect to withdraw from 
study medication, the safety follow-up visits should be scheduled.  Details of the 
surgical procedure should be recorded on the eCRF. 
• 
Any intranasal corticosteroids other than that required by the protocol  
• 
Any parenteral steroid injections such as triamcinolone 
• 
Use of verapamil, cyclosporine, methotrexate, azathioprine, or mycophenolate 
and chronic use of systemic corticosteroids  
Acute courses of oral or systemic corticosteroids must be justified and reasons 
documented.  Use of oral or systemic corticosteroids for  ≥  3 consecutive days 
will be considered rescue treatment and evidence of treatment failure.  Patients 
who require two or more single courses of systemic corticosteroids 
for  ≥ 3 consecutive days should discontinue study medication, although study 
assessments should continue.  Should the patient elect to withdraw from study 
medication, the safety follow-up visits should be scheduled.  
• 
Changes in allergen immunotherapy or initiation of new allergen immunotherapy 
within 3 months prior to screening and throughout the study  
• 
Changes in aspirin desensitization therapy or initiation of new aspirin 
desensitization therapy within 4 months prior to screening and throughout the 
study  
• 
Use of systemic antibiotics for > 14 days 
• 
Intranasal medication that may interfere with the symptoms of diseases 
(antihistamines, nasal atropine, ipratropium bromide, nasal cromolyn, intranasal 
antibiotics like mupirocin irrigation), except nasal saline 
• 
Nasal decongestants except when administered by study personnel on the day of 
endoscopy immediately prior to such endoscopy 
 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  To ensure 
PRO instrument validity and that data standards meet health authority requirements, the 
questionnaires that will be completed at certain site visits (SNOT-22, EQ-5D-5L, Asthma 
Quality of Life Questionnaire [AQLQ; for patients with comorbid asthma only]) must be 
administered before the patient receives any information on disease status, prior to the 
performance of non-PRO assessments and prior to the administration of study treatment, 
unless otherwise specified. 
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and laboratory test values are acceptable. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
43/Protocol GA39688, Version 2 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
consent forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, surgeries, cancer history, 
reproductive status, and smoking history will be recorded at screening.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient prior to Day -35 
(1st screening visit) will be recorded.  At the time of each follow-up physical examination, 
an interval medical history should be obtained and any changes in medications and 
allergies should be recorded. 
In particular, any history of anaphylaxis, cardiovascular disease, eosinophilic disease, 
inflammatory or autoimmune disease, parasitic disease, and diseases commonly 
associated with CRSwNP, including asthma, AERD, and fungal infections/allergies, 
should be recorded on the eCRF. 
Demographic data to be collected will include age, sex, and self-reported race/ethnicity.  
4.5.3 
Physical Examinations 
A complete physical examination, performed at the 1st screening visit (Day -35) 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. 
Limited, symptom-directed physical examinations should be performed at specified visits 
and as clinically indicated.  Changes from baseline abnormalities should be recorded in 
patient notes.  New or worsened clinically significant abnormalities should be recorded 
as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of pulse rate, and systolic and diastolic blood 
pressure while the patient is in a seated position.   Blood pressure and pulse rate should 
be assessed prior to all study drug administrations, including administrations at Weeks 2, 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
44/Protocol GA39688, Version 2 
6, 10, 14, 18, and 22 in patients receiving study drug every 2 weeks, as determined by 
screening IgE and weight. 
4.5.5 
CRSwNP History and Comorbidities 
Specific clinical history and physical examination findings related to CRSwNP will be 
recorded at the 1st screening visit (Day -35).  These will include the date of first 
diagnosis, number of prior surgeries, and the date and nature of the most recent surgical 
procedure.   
The Medical History eCRF will collect specific information pertaining to diseases 
commonly associated with CRSwNP, including but not limited to asthma, allergic rhinitis, 
AERD, and allergic fungal rhinitis.  
In addition, specific clinical history for the conditions listed below will be recorded at 
screening. 
Asthma 
Time since diagnosis, whether asthma is active or inactive, assessment of disease 
severity (mild, moderate, or severe), and dose and frequency of all asthma-targeted 
therapies (including but not limited to inhalers or oral medications) will be collected. 
Aspirin-Exacerbated Respiratory Disease 
Time since diagnosis, an assessment of disease severity (mild, moderate, or severe), 
and treatments given prior to the study will be collected.  
Allergic Fungal Sinusitis 
A history of sino-nasal fungal infections will be recorded on the eCRF.  Any historic or 
ongoing treatments, including past surgeries, will be collected.  
4.5.6 
CRSwNP-Specific Assessments 
The following measures of CRSwNP will be collected during the study: 
• 
NPS will be assessed by video nasal endoscopy (0−4 scale on each side).  Nasal 
endoscopy (including use of decongestants before the procedure) will be 
performed after all other efficacy assessments have been completed for each 
visit.  In cases where nasal endoscopy is performed at a different location than 
the primary principal investigator site, endoscopy can be performed subsequent 
to the main site visit (within 3 days).  Standardized video files will be uploaded by 
the investigator or the assigned nasal endoscopist to the central reader's secured 
Internet site (see Appendix 2 for nasal polyp scoring system and the nasal 
endoscopy site manual for more details).   
• 
Nasal symptoms including NCS (see Section 4.5.10.2 and Appendix 3)   
• 
SNOT-22 (see Section 4.5.10.2 and Appendix 4) 
• 
UPSIT (see Section 4.5.10.3) 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
45/Protocol GA39688, Version 2 
4.5.7 
Physician Review eDiary Data and Compliance 
Electronic data from the eDiary will be transferred to a web-based platform for review.  
Study site personnel (e.g., investigator) should review eDiary adherence to completion of 
eDiary at least once every 4 weeks.  Sites should be especially vigilant in providing a 
reminder about importance of adherence at the Week 20 visit, 4 weeks before the 
assessment of the primary outcomes.   
4.5.8 
Laboratory and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Serum and urine pregnancy test 
– 
All women of childbearing potential must have a negative serum pregnancy test 
during the screening period, prior to initiation of study drug.  Additionally, 
women should have a urine pregnancy test prior to the initiation of study drug, 
every 4 weeks during study treatment period, and at the safety follow-up visit, as 
indicated in Appendix 1.  Urine pregnancy test results must be reviewed and 
confirmed to be negative before study drug administration.  If a urine pregnancy 
test is positive or borderline, it must be confirmed by a serum pregnancy test 
(analyzed at the central laboratory) before giving study drug. 
• 
Stool ova and parasite evaluation 
This test should be conducted locally 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 upper limit of normal.  This test should be 
conducted anytime during the screening period after the Day −35 eosinophil 
count results are available for applicable patients. 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• Total IgE for study eligibility and dosing determination 
• 
Standard hematology, including but not limited to:  WBC count, RBC count, 
hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells) 
• 
Standard chemistry panel (serum or plasma), including but not limited to: sodium, 
potassium, chloride, bicarbonate, glucose, BUN/urea, creatinine, total protein, 
albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, 
ALT, AST, uric acid, LDH 
• 
Coagulation:  INR, aPTT, PT 
• 
Viral serology (unless not permitted by local regulations or ethics committees):  
HIV, hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), hepatitis C (HCV) antibody 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
46/Protocol GA39688, Version 2 
• 
Urinalysis, including but not limited to: dipstick (pH, specific gravity, glucose, 
protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria) 
 
Samples for the following laboratory tests will be sent to the sponsor or a designee for 
analysis: 
• Serum samples for PK analysis.  PK samples may also be used for additional drug 
level/anti-drug antibody (ADA) testing.  PK samples need to be drawn before 
administration of omalizumab. 
• Serum samples for determination of trough serum free-IgE and serum total-IgE.  
The IgE samples may also be used for specific IgE testing, including but not 
limited to specific IgE to Staphylococcus aureus enterotoxin.  The samples from 
PK and IgE testing will be destroyed no later than 5 years after the final Clinical 
Study Report has been completed, unless the patient gives specific consent for 
his or her residual samples to be donated for optional exploratory research (see 
Section 4.5.11).  Samples need to be drawn before administration of omalizumab. 
 
4.5.9 
Electrocardiograms 
A single ECG recording will be obtained at the 1st screening (Day -35), as outlined in the 
schedule of activities (see Appendix 1).  Lead placement should be as consistent as 
possible.  The ECG recording must be performed after the patient has been resting in a 
supine position for at least 10 minutes.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
and should not be obtained within 3 hours after any meal.  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 
recording. 
For safety purposes, the investigator must review, sign, and date the ECG tracings.  
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at 
the site.  The following should be recorded in the appropriate eCRF:  heart rate, 
RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected. 
4.5.10 
Patient-Reported Outcomes 
PRO data will be collected to document the treatment benefit of omalizumab.  The 
questionnaires, translated into the local language as appropriate, will be completed in 
their entirety at specified timepoints during the study, as outlined in Appendix 1.  
To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires will be self-administered early in the clinic visit, before the 
patient receives any information on his or her disease status and prior to the 
performance of non-PRO assessments (e.g., endoscopy, UPSIT), unless otherwise 
specified.  Additionally, PROs should be collected prior to the administration of study 
treatment. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
47/Protocol GA39688, Version 2 
Patients will complete specific PRO assessments on a daily basis in the morning.  
For such daily PRO assessments, patients will use an electronic device (eDiary).  
Patients will be instructed to complete the questions in their eDiary in the morning, within 
approximately 1 hour of awakening.  The device will be programmed to lock data entry in 
the afternoon.  The electronic device and/or instructions for completing the 
questionnaires electronically will be provided by site staff.  The data will be transmitted to 
a centralized database maintained by the electronic device vendor.  The data will be 
available for access by appropriate study personnel. 
4.5.10.1 
Nasal Symptoms, including Nasal Congestion Score  
Patient-reported nasal symptoms (nasal congestion, sense of smell, anterior rhinorrhea, 
posterior rhinorrhea) will be scored as not at all, mild, moderate, or severe (scores of 0, 
1, 2, or 3, respectively).  Total nasal symptom score (TNSS) consists of nasal 
congestion, loss of smell, and rhinorrhea.  Symptoms will be reported by patients daily 
(in the morning) on an eDiary, from screening through treatment period.  The nasal 
symptom questions, which include NCS, are provided in Appendix 3.   
4.5.10.2 
Sino-Nasal Outcome Test-22 
SNOT-22 (Hopkins et al. 2009) utilizes a 2-week recall period to measure common 
symptoms of CRS with and without nasal polyps (nasal blockage, facial pain, sense of 
smell, drainage, need to blow nose, sneezing, runny nose, and sleep and emotional 
issues; see Appendix 4).  The 22 items are summed to provide a total score, with a 
lower score indicating fewer problems and better HRQoL.  The SNOT-22 will be 
completed electronically at specified timepoints, as outlined in the schedule of activities. 
4.5.10.3 
University of Pennsylvania Smell Identification Test 
The UPSIT (Doty et al. 1984) is a 40-item objective assessment of sense of olfactory 
function.  It is a self-administered "scratch-and-sniff" test.  The UPSIT is provided in 
booklets that have 40 microencapsulated odorants, each with a multiple-choice option 
for the response.  The number of correct responses is summed to provide a total score.  
The UPSIT will be completed at clinic visits at specified timepoints, as outlined in the 
schedule of activities. 
4.5.10.4 
EuroQol 5-Dimension 5-Level Questionnaire 
The EuroQol 5-Dimension 5-level Questionnaire (EQ-5D-5L) is a self-reported health 
status questionnaire that consists of six questions that are used to calculate a health 
utility score for use in health economic analysis (EuroQol Group 1990; Brooks 1996; 
Herdman et al. 2011; Janssen et al. 2013; Appendix 6).  Patients will complete the 
EQ-5D-5L at specific visits as specified in the schedule of activities.  
There are two components to the EuroQol EQ-5D-5L:  a 5-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression 
as well as a visual analogue scale that measures health state.  Published weighting 
systems allow for creation of a single summary score.  Overall scores range from 0 to 1, 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
48/Protocol GA39688, Version 2 
with low scores representing a higher level of dysfunction.  The EQ-5D-5L will be utilized 
in this study for economic modelling.   
4.5.10.5 
Asthma Quality of Life Questionnaire (Patients with Comorbid 
Asthma Only) 
The standardized AQLQ (AQLQ[S]) will be completed by patients with comorbid asthma 
in order to assess the patients' asthma-specific HRQoL (Juniper et al. 1999).  The 
32-item questionnaire contains 4 domains:  activity limitations, symptoms, emotional 
function, and environmental stimuli.  The AQLQ(S) has a recall specification of 2 weeks.  
Items are scored on a 7-point scale ranging from 1 (severe impairment) to 7 (no 
impairment).  A copy of the AQLQ(S) is provided in Appendix 7.  The AQLQ(S) will be 
administered at the randomization visit (Week 0), Week 16, and Week 24. 
4.5.11 
Optional Samples for Research Biosample Repository 
4.5.11.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) 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, 
storage, and analysis of RBR 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. 
Specimens for the RBR will be collected from patients who give specific consent to 
donate samples for research. RBR 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 
 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR 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 has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.11) will not be 
applicable at that site. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
49/Protocol GA39688, Version 2 
4.5.11.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research related to omalizumab or Chronic Rhinosinusitis 
with Nasal Polyps and related diseases: 
• 
Blood samples for DNA analysis  
• 
Residual blood, serum, and any derivatives thereof (e.g., DNA, RNA, proteins, 
peptides), including residual PK serum 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing (NGS), or other genomic analysis methods.   
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.11.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR 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. 
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
50/Protocol GA39688, Version 2 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may 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 RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.11.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR 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 appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR 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 GA39688 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study GA39688. 
4.5.11.7 
Monitoring and Oversight 
RBR 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.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
51/Protocol GA39688, Version 2 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the investigator or Sponsor determines may 
jeopardize the patient's safety if he or she continues to receive study treatment 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.  
Patients who discontinue study treatment should continue with remaining study 
assessments as per Appendix 1. 
Patients who do not wish to continue with study assessments will return to the clinic for a 
dosing termination visit within 28 days after the last dose of study drug and will then 
subsequently return for a safety follow-up visit (see Appendix 1 for additional details).   
4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
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 discontinue from the 
study.  The patient should be asked to return for a study discontinuation visit within 
28 days after the last dose of study drug and then return for a safety follow-up visit.  The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF.  If a patient requests to be withdrawn from the study, this request must be 
documented in the source documents and signed by the investigator.  Patients who 
withdraw from the study will not be replaced. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
52/Protocol GA39688, Version 2 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations 
have been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
Omalizumab is not approved for the treatment of adult patients with CRSwNP who have 
had an inadequate response to standard-of-care treatments.  The safety plan for 
patients in this study is based on the extensive clinical and post-marketing experience 
with omalizumab for the last 13 years.   Omalizumab is marketed in over 90 countries for 
allergic asthma and 80 countries for chronic idiopathic urticaria (CIU)/chronic 
spontaneous urticaria (CSU) as of 31 December 2016.  The estimated cumulative 
omalizumab exposure is 31,000 Patient-Years in clinical trials and 819,000 
Patient-Years in the postmarketing setting as of 31 December 2016. 
The clinical safety of omalizumab has been well documented in a number of clinical trials 
that involve adults and children with moderate to severe allergic asthma.  The adverse 
event profile of omalizumab observed during the clinical development program of allergic 
asthma was similar to placebo, with the most commonly reported adverse events being 
headaches and injection site reactions, including injection site pain, swelling, erythema, 
pruritus.  Anaphylactic reactions were observed but were rare and typically occurred 
within 2 hours of the first injection.  The overall adverse event profile in CIU/CSU studies 
was consistent with the known safety profile of omalizumab.  Omalizumab has also been 
investigated in patients with seasonal allergic rhinitis, perennial allergic rhinitis, atopic 
dermatitis, and peanut allergy.  The safety profile of omalizumab in non-asthma trials 
has not differed from the safety profile of omalizumab in asthma trials.  


 
Omalizumab—F. Hoffmann-La Roche Ltd 
53/Protocol GA39688, Version 2 
The Sponsor does not anticipate a difference in the safety profile of omalizumab in the 
population with nasal polyps from the existing safety profile in asthma and CIU/CSU 
where the safety profile of the molecule is already well defined.  No specific safety 
concerns were identified in the published literature for the similar indication and study 
population with omalizumab. 
5.1 
SAFETY PLAN 
The anticipated important safety risks for omalizumab are outlined below.  Please refer 
to the omalizumab Investigator's Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for treatment interruption or discontinuation is provided 
appropriately (see Section 4.6.1). 
5.1.1 
Safety and Data Monitoring 
All safety events will be closely monitored by the study team.  The sponsor followed the 
U.S. Food and Drug Administration (FDA) guidance (FDA 2006; 
https://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm) to evaluate the 
need for an independent data monitoring committee (iDMC) and decided not to have 
an iDMC for this study based on the criteria mentioned in the guidance.  Given the 
established safety record of omalizumab, the nature of nasal polyposis, and the 
outcomes being examined, an iDMC is not indicated in this study. 
5.1.2 
Anaphylaxis Adjudication Committee 
All potential anaphylaxis cases reported by investigators to the Sponsor will be 
subsequently submitted for adjudication to a blinded 3-member anaphylaxis adjudication 
committee composed of external experts in allergic diseases.  The committee will assess 
whether the reported event is a true anaphylaxis event (based on Sampson's criteria) 
and whether the reported anaphylaxis event is causally related to blinded study drug.  
Further details will be provided in the Anaphylaxis Adjudication Charter. 
5.1.3 
Risks Associated with Omalizumab 
5.1.3.1 
Anaphylaxis 
Anaphylaxis has been reported to occur after administration of omalizumab in clinical 
trials and in post-marketing spontaneous reports.  Anaphylactic reactions were rare in 
clinical trials (0.1%) and estimated as 0.2% from post-marketing reporting.  The reported 
signs and symptoms included but were not limited to bronchospasm, hypotension, 
syncope, urticaria, and/or angioedema of the throat or tongue.  Some of these events 
have been reported as life threatening. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
54/Protocol GA39688, Version 2 
The majority of anaphylactic-type reactions have been reported to occur after the 
first dose, with numbers decreasing with subsequent doses, but such reactions were 
also reported beyond 1 year after starting scheduled treatment.  The events were 
reported to occur predominantly within the first 2 hours post-dose, with few reports 
occurring as far as > 36 hours post-dose.  
Details regarding management of these events are provided below: 
• 
Administer omalizumab only in a healthcare setting by healthcare providers 
prepared to manage anaphylaxis that can be life-threatening; medications for the 
treatment of anaphylactic reactions should be available for immediate use 
following administration of omalizumab.  
• 
Patients should be observed for at least 2 hours after the first 3 study drug doses 
and at least 30 minutes after subsequent doses.  However, some patients may 
require longer observation periods, depending on investigator judgment taking 
into account the time to onset of anaphylaxis seen in clinical trials and 
postmarketing spontaneous reports.   The American College of Allergy, Asthma, 
and Immunology guideline on the observation period after omalizumab 
administration (Kim et al. 2010) recommends 2 hours of monitoring in the clinic 
after the first 3 injections and 30 minutes or an appropriate time agreed upon by 
the individual patient and healthcare professional for subsequent injections.  
However, a delayed onset of symptoms and protracted progression of 
anaphylaxis should be taken into account when administering omalizumab (Limb 
et al. 2007).   
• 
Inform patients of the signs and symptoms of anaphylaxis, and instruct them to 
seek immediate medical care should signs or symptoms occur. 
• 
Discontinue omalizumab in patients who experience a severe hypersensitivity 
(anaphylactic) reaction.  
 
5.1.3.2 
Serum Sickness 
Serum sickness and serum sickness−like reactions, which are delayed allergic type III 
reactions, have rarely been seen in patients treated with humanized monoclonal 
antibodies including omalizumab in the post-approval use.  The onset has typically been 
1−5 days after administration of the first or subsequent injections, also after long 
duration of treatment.  Symptoms suggestive of serum sickness include 
arthritis/arthralgia, rash (urticaria or other forms), fever, and lymphadenopathy.  
Antihistamines and corticosteroids may be useful for preventing or treating this disorder. 
• 
Patients should be informed and advised to report any suspected symptoms of 
serum sickness−like reactions. 
• 
Physicians should stop omalizumab if a patient develops this constellation of 
signs and symptoms. 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
55/Protocol GA39688, Version 2 
5.1.3.3 
Churg-Strauss Syndrome and Hypereosinophilic Syndrome  
Patients with severe asthma may rarely present systemic hypereosinophilic syndrome or 
allergic eosinophilic granulomatous vasculitis (Churg-Strauss syndrome), both of which 
are usually treated with systemic corticosteroids.  In rare cases, patients on therapy with 
anti-asthma medicinal products, including omalizumab, may present or develop systemic 
eosinophilia and vasculitis.  These events are commonly associated with the reduction of 
oral corticosteroid therapy and alerted to the development of marked eosinophilia, 
vasculitic rash, worsening pulmonary symptoms, paranasal sinus abnormalities, 
cardiac complications, and/or neuropathy.  
Abrupt discontinuation of systemic or inhaled corticosteroids after initiation of 
omalizumab therapy is not recommended.  Decreases in corticosteroids should be 
performed under the direct supervision of a physician and may need to be performed 
gradually.  Patients with known or suspected Churg-Strauss syndrome should be 
excluded from the study. 
5.1.3.4 
Thrombocytopenia  
In nonclinical studies, a dose-dependent and reversible circulating platelet reduction was 
observed.  In clinical studies, few patients experienced platelet counts below the lower 
limit of the normal laboratory range.  None of these changes was associated with 
bleeding episodes or a decrease in hemoglobin.   
5.1.3.5 
Malignancies 
During initial clinical trials in adults and adolescents 12 years of age and older with 
allergic asthma, there was a numerical imbalance in cancers arising in the active 
treatment group, compared with the control group.  The number of observed cases was 
uncommon (< 1/100) in both the active and the control group.  In a subsequent 
observational study (EXCELS) comparing 5007 omalizumab-treated patients and 
2829 non-omalizumab-treated patients followed for up to 5 years, the incidence rates of 
primary malignancies per 1000 patient years were 16.01 (295/18,426 patient years) and 
19.07 (190/9963 patients years), respectively, which does not indicate an increased 
malignancy risk (rate ratio 0.84, 95% CI: 0.62−1.13).  In a further analysis of randomized 
double-blind placebo-controlled clinical trials, including 4254 patients on omalizumab 
and 3178 patients on placebo, omalizumab treatment was not associated with an 
increased malignancy risk based on incidence rates per 1000 patient years of 4.14 
(14/3382 patient years) for omalizumab-treated patients and 4.45 (11/2474 patient years) 
for placebo patients (rate ratio 0.93, 95% CI: 0.39−2.27).  The overall observed 
incidence rate of malignancy in the omalizumab clinical trial program was comparable to 
that reported in the general population.  There were no cases of malignancy in clinical 
trials in allergic asthma in the 6 to < 12 years-of-age group with omalizumab; there were 
2 cases of malignancy in the control group (medulloblastoma and nephroblastoma). 
In the Phase III CIU/CSU program (733 patients enrolled and receiving at least 1 dose of 
omalizumab, including 684 patients exposed for 12 weeks and 427 exposed for 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
56/Protocol GA39688, Version 2 
24 weeks), there was 1 case of malignancy in the placebo group (242 patients) and 
1 case in the omalizumab 300-mg group (412 patients) in a patient with a pre-existing 
history. 
5.1.3.6 
Arterial Thrombotic Events 
In controlled clinical trials in allergic asthma and during interim analyses of EXCELS (an 
observational study), a numerical imbalance of arterial thrombotic events (ATEs) was 
observed.  ATEs included stroke, transient ischemic attack, myocardial infarction, 
unstable angina, and cardiovascular death (including death from unknown cause).  
The results from the EXCELS revealed the rate of ATEs per 1000 patient years was 
7.52 (115/15286 patient years) for omalizumab-treated patients and 5.12 
(51/9963 patient years) for control patients.  Although there was no consistent evidence 
of an association between omalizumab use and risk of ATEs, the 95% CIs were wide 
and could not definitively exclude an elevated risk. 
5.1.3.7 
Antibody Formation to Omalizumab 
Omalizumab is a humanized monoclonal anti-IgE antibody.  The formation of 
anti-omalizumab antibodies (also called anti-drug antibodies [ADAs]) after omalizumab 
administration is a rare event.  There were 3 ADA-positive cases out of 23,375 serum 
samples tested in the Allergic Asthma and CSU/CIU programs following omalizumab 
administration.  These cases were not associated with any severe adverse events. 
There was no case of drug-induced ADAs recorded across the entire CSU/CIU 
development program. 
5.1.4 
Management of Patients Who Experience Specific Adverse 
Events 
5.1.4.1 
Dose Modifications and Treatment Interruption 
No dose modification or treatment interruption is allowed during the conduct of the study.  
Omalizumab should be discontinued in patients who experience a severe 
hypersensitivity reaction. 
5.1.4.2 
Management of Drug Induced Liver Injuries 
Liver injury has not been described as a risk associated with omalizumab.  However, 
1) if the patient's AST or ALT is > 8× ULN, or 2) if the patient's ALT or 
AST > 3× ULN and total bilirubin > 2× ULN or clinical jaundice occurs, study drug 
should be discontinued, liver test should be repeated, and an evaluation for causes for 
the liver test abnormality should be initiated. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events (including 
serious adverse events and adverse events of special interest), performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
57/Protocol GA39688, Version 2 
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 5.2.2. 
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 5.3.5.11 
• 
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., ECG, X-ray) that 
is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., nasal endoscopy) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places 
the patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.12) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
58/Protocol GA39688, Version 2 
• 
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; see Section 5.3.3); 
the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
• 
Suspected anaphylaxis/anaphylactoid reactions identified based on Sampson's 
criteria (see Appendix 9) 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.8) 
• 
Suspected transmission of an infectious agent by the study drug, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 and 5.6. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
59/Protocol GA39688, Version 2 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until the end of the 
safety follow-up period (Week 28).  Instructions for reporting adverse events that occur 
after the adverse event reporting period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 3 will be used for assessing severity of adverse events. 
Table 3 
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). 
  


 
Omalizumab—F. Hoffmann-La Roche Ltd 
60/Protocol GA39688, Version 2 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event 
Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
61/Protocol GA39688, Version 2 
5.3.5.1 
Injection-Site Reactions 
Local adverse events that occur during (or within 24 hours) after study drug 
administration and are judged to be related to study drug injection should be captured as 
a diagnosis (e.g., "injection-site reaction" on the Adverse Event eCRF).  Associated 
signs and symptoms should be recorded on the dedicated Injection-Site Reaction eCRF.  
If a patient experiences both a local and systemic reaction to the same dose of study 
drug, each reaction should be recorded separately on the Adverse Event eCRF, with 
signs and symptoms also recorded separately on the dedicated Injection-Site 
Reaction eCRF. 
5.3.5.2 
Anaphylactic Reactions 
The investigator should use Sampson's criteria (Appendix 9) to identify the potential 
cases of anaphylaxis and report as a diagnosis on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  Any case of known or suspected 
anaphylaxis will require the completion of a dedicated eCRF to record the specific signs 
and symptoms associated with this event.   
5.3.5.3 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.4 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
62/Protocol GA39688, Version 2 
• 
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. 
5.3.5.5 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.6 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
63/Protocol GA39688, Version 2 
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 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., 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. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.8 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.6) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
64/Protocol GA39688, Version 2 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.9 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period, 
regardless of relationship to study drug, must be recorded on the Adverse Event eCRF 
and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.10 
Preexisting Medical Conditions 
A pre-existing 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 pre-existing 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 pre-existing condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.11 
Lack of Efficacy or Worsening of Nasal Polyposis 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
nasal polyposis 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 nasal polyposis on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "worsening of nasal polyposis as 
compared to baseline"). 
5.3.5.12 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
65/Protocol GA39688, Version 2 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol if required by site (e.g., for study 
drug administration or nasal endoscopy)  
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.13 
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 5.4.2). 
5.3.5.14 
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; under no circumstances should reporting take 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
66/Protocol GA39688, Version 2 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
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 Institutional Review Board or Ethics Committee 
(IRB/EC). 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information (Primary) 
Medical Monitor:  
 
 
 
 
 
 
, M.D. 
 Medical Monitor 
 
Telephone No. (24/7) North America: 
 
Telephone No. (24/7) Europe: 
 
 
Additional contact information will be provided by the Sponsor as needed. 
Questions and issues related to medical monitoring may be directed to the above 
numbers, which are available 24 hours per day, 7 days per week. 
Roche Medical Monitor Contact Information (Secondary) 
Roche Medical Responsible: 
, M.D.   
Telephone No.: 
 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
67/Protocol GA39688, Version 2 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, all adverse events including serious adverse events, non-
serious events, and adverse events of special interest will be reported until completion of 
the safety follow-up period (Week 28).  Investigators should record all case details that 
can be gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  
A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur post-study are provided in 
Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 60 days after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
68/Protocol GA39688, Version 2 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.   
5.4.3.2 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
study completion date), if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
69/Protocol GA39688, Version 2 
the Sponsor or its designee, either by faxing or by scanning and emailing the paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Omalizumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of data from the 24-week treatment period may be performed after all 
patients have either completed the Week 24 visit or discontinued from the treatment 
period prematurely, and all data from the treatment period are in the database and have 
been cleaned and verified.  Patients who discontinue early will not be replaced. 
The analysis of complete data from the study, including data from the safety follow-up 
period, will be performed when all patients have either discontinued the study early or 
completed the safety follow-up period, all data from the study are in the database, and 
the database is cleaned and locked. 
Throughout this Section the term “descriptive statistics” is defined as follows, unless 
otherwise noted:  
• 
For continuous variables descriptive statistics will include at a minimum: 
number of subjects, mean, standard deviation, median, minimum, and maximum.  
• 
For categorical variables descriptive statistics will include at a minimum: 
number of patients and percentage of patients. 
 
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP).  The SAP will be reviewed by health authorities and finalized prior 




 
Omalizumab—F. Hoffmann-La Roche Ltd 
71/Protocol GA39688, Version 2 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
72/Protocol GA39688, Version 2 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Descriptive statistics will be used to evaluate the conduct of the study.  The number of 
patients randomized will be tabulated by country, study site, and treatment arm in 
all patients with data.  Patient disposition (the number of patients randomized, treated, 
and completing each study period) will be tabulated by treatment arm in all patients with 
data.  Premature study drug discontinuation and study discontinuation, as well as 
reasons for discontinuations, will be summarized.  Eligibility criteria deviations and other 
major protocol deviations will be summarized. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, NPS, NCS, 
sense of smell, anterior rhinorrhea, posterior rhinorrhea, UPSIT, and SNOT-22 will be 
summarized with descriptive statistics by treatment arm in all patients with data.  
Baseline disease characteristics will be defined as the last measurement (or average in 
the case of daily nasal symptom scores) prior to randomization.  Exposure to study drug 
(number of study drug treatments and duration of treatment) will be summarized by 
treatment arm in all patients with data. 
6.4 
EFFICACY ANALYSES 
There are two distinct and equally important estimands of interest in this trial.  The first 
estimand is the treatment group difference in mean change from baseline at Week 24 in 
NPS in patients with CRwNP, where the need for rescue medication or nasal 
polypectomy is accounted for as an unfavorable (worst) outcome.  The second estimand 
is the treatment group difference in mean change from baseline at Week 24 in the 
average daily NCS in patients with CRwNP, where the need for rescue medication or 
nasal polypectomy is accounted for as an unfavorable (worst) outcome. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
73/Protocol GA39688, Version 2 
Hypothesis testing for all efficacy endpoints will be conducted in the full-analysis set 
(FAS).  The FAS will include all randomized patients who received at least one dose of 
study drug grouped according to the treatment assigned at randomization.   
The study level type-1 error for the family of primary and select secondary efficacy 
hypotheses will be controlled at α = 0.05.  Details for the type-1 error control procedures 
for the co-primary endpoints are provided below, while further type-1 error control 
procedures for secondary efficacy endpoints will be provided in the SAP. 
All hypothesis tests will be two-sided.  Unless otherwise noted, all analyses of efficacy 
outcome measures will at a minimum be adjusted by geographic region through the use 
of a categorical variable and by baseline asthma comorbidity and aspirin sensitivity 
status.  Adjustment by additional covariates, if any, will be described in the SAP.   
Treatment Failure and Missing Data 
In NPS, NCS, and nasal symptoms analyses, a patient is considered to have 
experienced treatment failure if they initiate rescue treatment (i.e., use of systemic CS 
for ≥ 3 consecutive days or nasal polypectomy) at any point during the interval between 
randomization and their Week 24 visit inclusive.  Unless otherwise noted, handling of 
missing data, treatment failure, and handling of observed data post-treatment failure will 
be detailed in the SAP. 
6.4.1 
Co-primary Efficacy Endpoints 
As NCS and NPS are co-primary endpoints, both null hypotheses for NCS and NPS 
need to be rejected for the study to be deemed positive.  The primary analysis will 
separately test the null hypotheses that no treatment group difference exists in each of 
the co-primary endpoints: 
• 
Change from baseline at Week 24 in NPS in the FAS 
• 
Change from baseline at Week 24 in the average daily NCS in the FAS 
 
Because both NCS and NPS hypotheses need to be rejected to demonstrate efficacy of 
omalizumab in patients with CRSwNP, there is no adjustment for multiple endpoints and 
each will be tested at the two-sided α = 0.05 level.   
Nasal Polyp Score 
Polyp size in each nasal opening will be graded through an assessment of the video 
nasal endoscopy (0−4 integer scale, see Appendix 2; Gevaert et al. 2013) by a central 
panel of independent sinus surgeons who are blinded to treatment assignment.  NPS is 
the sum of the polyp scores in both nostrils (maximum score of 8).  For patients who 
have had a relatively common surgical procedure called middle turbinectomy, scoring 
will be modified (see Appendix 2).  NPS will be assessed during screening at Day -35 
and Day -7 and post-randomization on Weeks 4, 8, 16, and 24.  Baseline NPS is defined 
as the last measurement performed before the first dose of study drug.  The absolute 
change from baseline NPS values will be defined as the NPS at the timepoint minus the 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
74/Protocol GA39688, Version 2 
NPS at baseline.  The absolute change from baseline in NPS will be summarized by 
treatment arm and timepoint. 
Treatment group comparisons of absolute change from baseline at Week 24 in NPS 
between treatment groups will be assessed using a mixed-effect model repeated 
measurement (MMRM) model.  The model will use absolute change from baseline as 
the response variable and will be adjusted for the covariates mentioned in Section 6.4, 
as well as timepoint (Weeks 4, 8, 16, and 24), baseline NPS, treatment by timepoint 
interaction, and baseline NPS by timepoint interaction.  Further details about the model 
and additional covariates, if any, will be described in the SAP.  Point estimates, 
95% confidence intervals, and p-values for the treatment effect (omalizumab vs. placebo) 
on absolute change from baseline in NPS will be calculated on the basis of the model for 
all post-baseline study visits, including Week 24, using appropriate contrasts.   
Nasal Congestion Score 
NCS will be scored by patients as not at all, mild, moderate, or severe (a score of 0, 1, 2, 
or 3, respectively; see Appendix 3; Fairley et al. 1993) every morning through Week 24 
via eDiary.  Details on the calculation of the average daily NCS (i.e., number of days 
included) at baseline and at each timepoint will be provided in the SAP.  For each patient 
and monthly post-baseline assessment study visit (i.e., Weeks 4, 8, 12, 16, 20, and 24), 
the post-baseline NCS for that study visit will be defined as the average of the daily 
scores leading up to that timepoint.  The absolute change from baseline in the average 
daily NCS values will be defined as the average NCS at the timepoint minus the average 
daily NCS at baseline.  Through ongoing monitoring of eDiary compliance, we will aim to 
obtain at least 4 of the 7 days of data for NCS in any given week.   
Treatment group comparisons of absolute change from baseline at Week 24 in NCS 
between treatment groups will be assessed using a MMRM model.  The model will use 
absolute change from baseline as the response variable and will be adjusted for the 
covariates mentioned in Section 6.4, as well as timepoint (Weeks 4, 8, 12, 16, 20, 
and 24), baseline NCS, treatment by time point interaction, and baseline NCS by 
timepoint interaction.  Further details about the model and additional covariates will be 
described in the SAP.  Point estimates, 95% confidence intervals, and p-values for the 
treatment effect (omalizumab vs. placebo) on absolute change from baseline in NCS will 
be calculated on the basis of the model for all post-baseline study visits, including Week 
24, using appropriate contrasts.   
Handling of Treatment Failure and Missing Data 
In patients classified as having experienced treatment (i.e., use of systemic CS for 
≥ 3 consecutive days or nasal polypectomy), the worst possible score of 8 for NPS and 3 
for average daily NCS will be imputed for all timepoints on or after the initiation of rescue 
medication or nasal polypectomy.  Sensitivity analysis concerning missing data 
assumptions for all efficacy endpoints meeting nominal significance will be conducted 
(i.e., tipping point analysis) and details will be provided in the SAP. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
75/Protocol GA39688, Version 2 
6.4.2 
Secondary Efficacy Endpoints 
Change from Baseline at Week 24 in Nasal Symptoms  
In addition to nasal congestion, the following patient-reported nasal symptom scores will 
be measured every morning: loss of smell, posterior rhinorrhea, and anterior rhinorrhea.  
Each symptom is scored on the integer scale ranging from 0 [not at all] to 3 [severe].  
The treatment group difference in absolute change from baseline at Week 24 in each of 
the daily nasal symptom scores will be estimated using separate MMRM models with 
absolute change from baseline as the response variable and adjusted for timepoint 
(Weeks 4, 8, 12, 16, 20, and 24), baseline covariates as described in Section 6.4, as 
well as the respective nasal symptom score at baseline.  The TNSS, a composite of 
nasal congestion, loss of smell, and rhinorrhea, will be analyzed separately using the 
same methods.  Further details, including the calculation of TNSS, will be described in 
the SAP. 
Change from Baseline at Week 24 in Sino-Nasal Outcome Test-22 
The SNOT-22, a disease-specific HRQoL measure, has a range 0–110 (lower score 
indicating less disease and better HRQoL).  The treatment group difference in absolute 
change from baseline at Week 24 in SNOT-22 will be estimated using an MMRM model 
with absolute change from baseline as the response variable, adjusted for timepoint 
(Weeks 4, 8, 16, and 24), baseline covariates as described in Section 6.4, as well as 
baseline SNOT-22.  Further details will be described in the SAP. 
Change from Baseline at Week 16 in Nasal Congestion Score 
The MMRM model used for the primary analysis of absolute change from baseline at 
Week 24 in average daily NCS will be used to estimate the treatment group difference in 
absolute change from baseline at Week 16 in NCS. 
Change from Baseline at Week 16 in Nasal Polyp Score 
The MMRM model used for the primary analysis of absolute change from baseline at 
Week 24 in NPS will be used to estimate the treatment group difference in absolute 
change from baseline at Week 16 in NPS. 
Change from Baseline at Week 24 in University of Pennsylvania Smell 
Identification Test 
The UPSIT is a 40-question instrument that measures an individual's ability to detect 
odors and ranges from 0−40.  The treatment group difference in absolute change from 
baseline at Week 24 in UPSIT will be estimated using MMRM model with absolute 
change from baseline as the response variable and adjusted for timepoint (Weeks 4, 8, 
16, and 24) baseline covariates as described in Section 6.4 as well as baseline UPSIT.  
Further details will be described in the SAP. 
Reduction in the Need for Surgery at Week 24  
A reduced need for surgery by Week 24 is defined by a reduction in NPS to ≤ 4 
(unilateral score of ≤ 2 on each side) and with improvement from baseline at Week 24 in 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
76/Protocol GA39688, Version 2 
SNOT-22 score of ≥ 8.9 without treatment failure.  The treatment group difference in 
proportion of patients at Week 24 with a reduced need for surgery will be estimated 
using a logistic regression model analysis adjusted for baseline covariates as described 
in Section 6.4, as well as baseline NPS and SNOT-22.  Further details will be described 
in the SAP. 
Requirement of Rescue Treatment through Week 24 
Requiring rescue treatment is defined here as having taken systemic CS for 
≥ 3 consecutive days or having had sinus surgery for nasal polyps at any point between 
randomization and Week 24 inclusive.  The treatment group difference in proportion of 
patients requiring rescue treatment will be estimated using a logistic regression model 
analysis adjusted for baseline covariates as described in Section 6.4.  Similarly, 
requirement of systemic CS and sinus surgery will be analyzed separately.  Further 
details will be described in the SAP. 
Change from Baseline at Week 24 in Asthma Quality of Life Questionnaire 
of ≥ 0.5 Points 
The AQLQ is a 32-item measure of asthma-related QoL with a total score ranging 
from 1 to 7; a higher score indicates a better QoL.  The treatment group difference in 
proportion of patients with comorbid asthma with a change from baseline at Week 24 in 
AQLQ score of ≥ 0.5 points will be estimated using a logistic regression model analysis 
adjusted for baseline covariates as described in Section 6.4, as well as baseline AQLQ.  
Further details will be described in the SAP. 
6.4.3 
Exploratory Efficacy Endpoints 
Details on analysis of exploratory efficacy endpoints will be provided in the SAP. 
6.4.4 
Subgroup Analyses 
Exploratory subgroup analyses will be performed to evaluate the consistency of the 
primary analysis results across pre-specified subgroups defined by demographic and 
baseline characteristics.  Further details on these subgroup analyses and any additional 
subgroups will be pre-specified in the SAP and finalized prior to data unblinding.  
In addition to age, sex, and race, the following subgroups (at a minimum) will be 
analyzed with respect to the co-primary efficacy endpoints (change from baseline at 
Week -24 in NPS and change from baseline at Week -24 in NCS) using the same 
methods as specified for the co-primary endpoints:  
• 
Baseline comorbid asthma and aspirin sensitivity status (asthmatic and aspirin 
sensitive, asthmatic not aspirin sensitive, all other)  
• 
Geographic region (North America, ex-North America) 
• 
Baseline mometasone prescribed dose (daily dose of 400 µg, daily dose of 200 µg)  
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
77/Protocol GA39688, Version 2 
If convergence problems with the statistical models arise due to a small number of 
patients per subgroup, the analysis may be simplified by combining some of the 
subgroups or by excluding baseline stratification variables from the model. 
6.4.5 
Pooled Analyses 
Efficacy data on endpoints from this study may be pooled with external data from a 
replicate trial (GA39855).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received.  
Safety summaries will be presented by treatment group for all treated patients. 
Safety will be assessed through the summary of adverse events, laboratory test results, 
and vital signs.  
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events will be coded, and their 
incidence will be summarized.  A treatment-emergent adverse event is defined as any 
new adverse event reported or any worsening of an existing condition on or after the first 
dose of study drug.  In addition, separate summaries will be generated for serious 
adverse events, deaths, adverse event of special interest, and adverse events leading to 
discontinuation of study drug. 
Vital Signs 
Vital signs (pulse rate, systolic and diastolic blood pressure while the patient is in a 
seated position) will be summarized by descriptive statistics by timepoint.  


 
Omalizumab—F. Hoffmann-La Roche Ltd 
78/Protocol GA39688, Version 2 
Clinical Laboratory Evaluations 
Clinical laboratory data (serum chemistry, hematology evaluations including CBC with 
differential and platelet counts, and urinalysis values) will be summarized by descriptive 
statistics by timepoint. 
6.6 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES  
Serum omalizumab and total and free IgE concentrations will be measured predose 
(Cmin) and at Weeks 16 and 24 during the treatment period, and at Week 28 during the 
safety follow-up period according to the schedule of activities (see Appendix 1).  These 
concentrations will be summarized using descriptive statistics (mean, SD, coefficient of 
variation, median, minimum, and maximum) by treatment group and timepoint based on 
the safety analysis population.  
Additional PK analyses will be conducted as appropriate. 
6.7 
INTERIM ANALYSIS 
There are no planned interim efficacy analyses. 
6.8 
MISSING DATA 
Unless otherwise noted, in the analysis of all continuous co-primary, secondary, and 
exploratory endpoints (NPS, NCS, loss of smell, anterior rhinorrhea, posterior 
rhinorrhea, TNSS, SNOT-22, UPSIT, EQ-5D-5L), missing values will not be explicitly 
imputed in the analyses, which will use a mixed-effect model repeated measurement 
(MMRM) model.  The exception is for the co-primary endpoints NPS and NCS, for 
which missing values planned on or after the date of treatment failure will be imputed 
by the worst possible score of 8 for NPS and 3 for daily NCS.  Patients without post-
baseline endpoint data will not contribute to the MMRM model.  Sensitivity analysis 
concerning missing data assumptions for all continuous co-primary and secondary 
efficacy endpoints meeting nominal statistical significance will be conducted 
(i.e., tipping point analysis).  Details of these pre-specified sensitivity analyses will be 
provided in the SAP and finalized prior to data unblinding. 
In the analysis of the following categorical secondary endpoints (for which a logistic 
regression model is specified) missing data from patients who discontinue the study 
prior to their Week -24 visit without having previously met the criteria for the event 
will be imputed as having the event:  
• 
Requirement of rescue treatment (systemic CS for ≥ 3 consecutive days) or 
having had surgery for nasal polyps through Week -24  
• 
Requirement of rescue treatment (systemic CS for ≥ 3 consecutive days) through 
Week -24  
• 
Having had surgery for nasal polyps through Week -24  
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
79/Protocol GA39688, Version 2 
In the analysis of the following categorical secondary and exploratory endpoints (for 
which a logistic regression model is specified) missing data from patients who 
discontinue the study prior to Week -24 without having previously met the criteria for 
the event will be imputed as not having the event:  
• 
Reduction in the need for surgery by Week -24, as defined by an NPS of ≤ 4 
(unilateral score of ≤ 2 on each side) and improvement in SNOT-22 score of 
≥ 8.9  
• 
Change from baseline at Week -24 in AQLQ of ≥ 0.5 (in patients with comorbid 
asthma only)  
• 
Change from baseline at Week -24 in SNOT-22 of at least the minimal important 
difference (MID) (8.9 points). 
 
6.9 
UNUSED AND SPURIOUS DATA 
For the efficacy analysis of continuous co-primary, secondary, and exploratory 
endpoints for which an MMRM model is used, a single data point will be assigned to a 
planned timepoint (e.g., Week 4, Week 8, Week 16, Week 24) according to the Schedule 
of Activities for that particular endpoint (see Appendix 1) based on the proximity of the 
date of the assessment to the planned timepoint and may include data collected as part 
of a planned, unscheduled, safety follow-up, dosing termination, or early termination 
visit.  All data points collected but not assigned to a planned timepoint in the analysis 
will be unused in the planned analysis.  Further details on the assignment of data 
points to planned timepoints for analysis will be described in the SAP and finalized 
prior to unblinding.  
Due to the nature of the data capture instruments (e.g., eCRF, eDiary, or tablet), 
spurious response data are not expected for PRO efficacy endpoints (i.e., NPS, NCS, 
SNOT-22, UPSIT, AQLQ, EQ-5D-5L).  In the event of a documented device 
malfunction leading to spurious data (i.e., a date that is recorded prior to the date of 
first patient screened or after last patient’s last visit), those data will be ignored 
(assumed missing) for the purpose of efficacy analysis and discussed in the Clinical 
Study Report (CSR).  Any spurious lab values or vital sign measurements will be 
excluded from summary tables and discussed in the CSR. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
80/Protocol GA39688, Version 2 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory, central imaging, 
eDiary/ePRO, and IWRS data will be sent directly to the Sponsor, using the Sponsor's 
standard procedures 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 by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
Some PRO data will be collected through the use of an electronic device provided by a 
vendor (see Section 7.3 for details). 
Some PRO data (i.e., the UPSIT) will be collected on paper.  The data from the UPSIT 
will be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
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  
Patients will use an electronic device to capture PRO data.  The device is designed for 
entry of data in a way that is attributable, secure, and accurate, in compliance with 
U.S. FDA regulations for electronic records (21 CFR Part 11).  The data will be 
transmitted to a centralized database maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure Web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats 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 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
81/Protocol GA39688, Version 2 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, 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 and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/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, electronic or paper PRO data (if applicable), Informed Consent 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
82/Protocol GA39688, Version 2 
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 European Union 
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 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. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
83/Protocol GA39688, Version 2 
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. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD 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 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
84/Protocol GA39688, Version 2 
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. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/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—F. Hoffmann-La Roche Ltd 
85/Protocol GA39688, 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.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
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 
Omalizumab in the treatment of nasal polyposis is a joint development project between 
F. Hoffmann-La Roche Ltd and Novartis Pharmaceuticals.  This study is sponsored by 
F. Hoffmann-La Roche Ltd and will be managed by F. Hoffmann-La Roche Ltd and a 
contract research organization (CRO).  The CRO will manage clinical site operations and 
medical monitoring.  
Approximately 50−70 sites globally will participate to enroll approximately 120 patients.  
An IWRS will be used for study drug inventory management and to randomize patients 
to study drug.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
Samples for urine pregnancy tests will be analyzed at the local laboratory.  Samples for 
PD, PK, and antibody tests will be sent to the Sponsor or a designee for analysis.  
All other samples will be sent to one of several central laboratories for analysis.  
PRO data will be recorded electronically via devices supplied by a PRO vendor.  
Patients will be provided an eDiary device for answering questions on controller 
medication and rescue use. 
Endoscopy reads will be read centrally and managed by a central reading vendor. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
86/Protocol GA39688, Version 2 
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: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
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 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
87/Protocol GA39688, Version 2 
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—F. Hoffmann-La Roche Ltd 
88/Protocol GA39688, Version 2 
10. 
REFERENCES 
Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal 
polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized 
clinical Trial. JAMA 2016;315:469−79. 
Bachert C, Zhang N, Holtappels G, et al. Presence of IL-5 protein and IgE antibodies to 
staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. 
J Allergy Clin Immunol 2010;126:962−8. 
BMJ Best Practice. BMJ Best Practice Guidelines [resource on the Internet]. 2015 [cited 
April 2017]. Available from: http://bestpractice.bmj.com/best-practice/verify-user-
north-american-access.html. 
Boushey HA Jr. Experiences with monoclonal antibody therapy for allergic asthma. J 
Allergy Clin Immunol 2001;108:S77−83. 
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53−72. 
Cassano P, Marini F, Indraccolo AS, et al. Corticosteroid therapy in the prevention of 
recurrent post-surgical nasal polyposis. Acta Otorhinolaryngol Ital 1996;16:334−8. 
Chung, Hung SH, Lin HC, et al. Dementia is associated with chronic rhinosinusitis: a 
population-based case-controlled study. Am J Rhinol Allergy. 2015;29:44−7. doi: 
10.2500/ajra.2015.29.4113. 
Dietz de Loos DAE, Hopkins C, Fokkens WJ. Symptoms in chronic rhinosinusitis with 
and without nasal polyps. Laryngoscope 2013;123:57−63. 
Doty RL, Shaman P, Kimmelman CP, et al. University of Pennsylvania Smell 
Identification Test: a rapid quantitative olfactory function test for the clinic. 
Laryngoscope 1984;94(2 Pt 1):176−8. 
The European Parliament and the Council of the European Union. Directive 2001/20/EC 
of the European Parliament and of the Council. Official Journal of the European 
Communities 2001. Available from: https://www.eortc.be/services/doc/clinical-eu-
directive-04-april-01.pdf. 
EuroQol Group. EuroQola new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199−208. 
Fairley JW, Yardley MPJ, Durham LH, et al. Reliability and validity of a nasal symptom 
questionnaire for use as an outcome measure in clinical research and audit of 
functional endoscopic sinus surgery. Clin Otolaryngol 1993;18:436−42. 
Fick RB. Therapy of allergic pulmonary diseases with anti-IgE antibodies. A review. 
Pediatr Pulmonol Suppl 1999;18:115−7. 
Fokkens WJ, Lund VJ, Mullol J, et al. Europeanp position paper on rhinosinusitis and 
nasal polyps 2012. Rhinology 2012;50:Supplement [23]: 1−298. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
89/Protocol GA39688, Version 2 
Food and Drug Administration. Guidance for Clinical Trial Sponsors: Establishment and 
Operation of Clinical Trial Data Monitoring Committees. U.S. Department of Health 
and Human Services. (2006). OMB Control No. 0910-0581. Expiration Date: 
12/31/2018 
Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, 
as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 
2011;128(5):989−95.  doi:10.1016/j.jaci.2012.07.047. Epub 27 September 2012. 
Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic 
patients with nasal polyps and asthma. J Allergy Clin Immunol 2013;131:110−6 e1. 
Gliklich RE, Metson R.  The health impact of chronic sinusitis in patients seeking 
otolaryngologic care.  Otolaryngol Head Neck Surg 1995;113:104−9. 
Hedman J, Kaprio J, Poussa T, et al. Prevalence of asthma, aspirin intolerance, nasal 
polyposis and chronic obstructive pulmonary disease in a population-based study. 
Int J Epidemiol 1999; 28:717−22  
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727−36.  
Heusser C, Jardieu P. Therapeutic potential of anti-IgE antibodies. Curr Opin in Immunol 
1997;9:805−13. 
Holgate ST, Corne J, Jardieu P, et al. Treatment of allergic airways disease with anti-IgE. 
Allergy 1998;53:83−8. 
Hopkins C, Borwne JP, Slack R, et al. The national comparative audit of surgery for 
nasal polyposis and chronic rhinosinusitis. Clin Otolaryngol 2006;31:390−8. 
Hopkins C, Gillett S, Slack R, et al. Psychometric validity of the 22-item Sinonasal 
Outcome Test. Clin Otolaryngol 2009;34:44−54. 
Hulse KE, Chaung K, Seshadri S, et al. Suppressor of cytokine signaling 3 expression is 
diminished in sinonasal tissues from patients with chronic rhinosinusitis with nasal 
polyps. J Allergy Clin Immunol 2014;133:275−7. 
Hulse KE, Stevens WW, Tan BK, et al. Pathogenesis of nasal polyposis. Clin Exp 
Allergy 2015;45:328−46. 
Huvenne W, van Bruaene N, Zhang N, et al. Chronic rhinosinusitis with and without 
nasal polyps: what is the difference? Curr Allergy Asthma Rep 2009;9:213−20. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:1717−27. 
Jardieu P. Anti-IgE therapy. Curr Opin Immunol 1995;7:779−82.  
Jardieu PM, Fick RB Jr. IgE inhibition as a therapy for allergic disease. Int Arch Allergy 
Immunol 1999;118:112−15.  


 
Omalizumab—F. Hoffmann-La Roche Ltd 
90/Protocol GA39688, Version 2 
Johansson L, Akerlund A, Melen I, et al. Prevalence of nasal polyps in adults: the 
Skovde population-based study. Ann Otol Rhinol Laryngol 2003;112:625−9. 
Juniper EF, Buist AS, Cox FM, et al. Validation of a standardized version of the Asthma 
Quality of Life Questionnaire. Chest 1999;115:1265−70.  
Kato A. Immunopathology of chronic rhinosiusitis. Allergol Int 2015;64:121−30. 
Kennedy JL, Hubbard MA, Huyett P, et al. Sino-Nasal Outcome Test (SNOT-22): a 
predictor of post-surgical improvement in patients with chronic sinusitis. Ann 
Allerrgy Asthma Immunol 2013;111:246−51.  
Kim HL, Leigh RL, Becker A. Omalizumab: practical considerations regarding the risk of 
anaphylaxis. Allergy Asthma Clin Immunol 2010;6:32 
Klossek JM, Chidiac C, Serrano E. Current position of the management of 
community-acquired acute maxillary sinusitis or rhinosinusitis in France and 
literature review. Rhinol Suppl 2005;(19):4−33. 
Lam K, Hirsch AG, Tan BK. The association of premorbid diseases with chronic 
rhinosinusitis with and without polyps. Curr Opin Otolaryngol Head Neck Surg 
2014;22:231−41.  
Langdon C, Mullol J. Nasal polyps in patients with asthma: prevalence, impact, and 
management challenges. J Asthma Allergy 2016;9:45−53. 
Larsen K. The clinical relationship of nasal polyps to asthma. Allergy Asthma Proc 
1996;17:243−9. 
Limb SL, Starke PR, Lee CE, et al. Delayed onset and protracted progression of 
anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin 
Immunol 2007;120:1378−81. 
Mjösberg JM, Trifari S, Crellin NK, et al. Human IL-25- and IL-33-responsive type 2 
innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat 
Immunol 2011;12:1055−62. 
Patalano F. Injection of anti-IgE antibodies will suppress IgE and allergic symptoms. 
Allergy 1999;54:103−10. 
Pearlman AN, Chandra RK, Chang D, et al. Relationships between severity of chronic 
rhinosinusitis and nasal polyposis, asthma, and atopy. Am J Rhinol Allergy 
2009;23:145−8. doi: 10.2500/ajra.2009.23.3284. 
Penn R, Mikula S. The role of anti-IgE immunoglobulin therapy in nasal polyposis: a pilot 
study. Am J Rhinol 2007;21:428−32. 
Piccirillo JF, Merritt MG Jr, Richards ML. Psychometric and clinimetric validity of the 
20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg 
2002;126:41−7. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
91/Protocol GA39688, Version 2 
Pinto JM, Mehta N, DiTineo M, et al. A randomized, double-blind, placebo-controlled trial 
of anti-IgE for chronic rhinosinusitis. Rhinology 2010;48:318−24. 
doi:10.4193/Rhin09.144. 
Presta LG, Lahr SJ, Shields RL, et al. Humanization of an antibody directed against IgE. 
J Immunol 1993;151:2623−32. 
Promsopa C, Kansara S, Citardi MJ, et al. Prevalence of confirmed asthma varies in 
chronic rhinosinusitis subtypes. Int Forum Allergy Rhinol 2016;6:373−7. Epub 2015: 
17 December 2005. 
Prussin C, Griffith DT, Boesel KM, et al. Omalizumab treatment downregulates dendritic 
cell FcεRI expression. J Allergy Clin Immunol 2003;112:1147−54. 
Ragab SM, Lund VJ, Scadding G. Evaluation of the medical and surgical treatment of 
chronic rhinosinusitis: a prospective, randomised, controlled 
trial. Laryngoscope 2004;114:923−30. 
Rimmer J, Fokkens W, Chong LY, et al. Surgical versus medical interventions for 
chronic rhinosinusitis with nasal polyps. Cochrane Database Syst Rev 
2014;(12):CD006991.   
Roth M, Tamm M. The effects of omalizumab on IgE-induced cytokine synthesis by 
asthmatic airway smooth muscle cells. Ann Allergy Asthma Immunol 
2010;104:152−60. 
Schalek P. RhinosinusitisIts impact on quality of life. In: Marseglia GL, Caimmi DP, 
editors. Peculiar aspects of rhinosinusitis.  InTech (online), 2011:3−26. 
Schulman ES. Development of a monoclonal anti-immunoglobulin E antibody 
(omalizumab) for the treatment of allergic respiratory disorders. Am J Respir Crit 
Care Med 2001;164:S6−11. 
Settipane GA. Nasal polyps: epidemiology, pathology, immunology, and treatment. Am J 
Rhinol 1987;1:119−26. 
Sintobin I, Vennera Mdel C, Mullol J, et al. Influence of the diagnosis chronic 
rhinosinusitis on asthma response to omalizumab in severe, uncontrolled 
asthmatics. Clin Transl Allergy 2015;5(Suppl 4):O11. 
doi:10.1186/2045-7022-5-S4-O11. Epub 26 June 2015. 
Stjärne P, Olsson P, Alenius M. Use of mometaone furoate to prevent polyp relapse 
after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg 
2009;135:296−302. 
Stevens WW, Schleimer RP. Aspirin-exacerbated respiratory disease as an endotype of 
chronic rhinosinusitis. Immunol Allergy Clin North Am 2016;36:669−80. 
Tajiri T, Matsumoto H, Hiraumi H, et al. Efficacy of omalizumab in eosinophilic chronic 
rhinosinusitis patients with asthma. Ann Allergy Asthma Immunol 2013;110:387−8. 
doi:10.1016/j.anai.2013.01.024. Epub 23 February 2013. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
92/Protocol GA39688, Version 2 
Tan BK, Rakesh CK, Pollak J, et al. Incidence and associated pre-morbid diagnoses of 
patients with chronic rhinosinusitis. J Allergy Clin Immunol 2013;131:1350−60. 
Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an 
inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin 
Immunol 2015;136:1476−85. 
Vennera Mdel C, Picado C, Mullol J, et al. Efficacy of omalizumab in the treatment of 
nasal polyps. Thorax 2011;66:824−5. doi:10.1136/thx.2010.152835. Epub 25 
November 2010. 
Wang M, Wang X, Zhang N. Association of periostin expression with eosinophilic 
inflammation in nasal polyps. Letter to the Editor. J Allergy Clin Immunol 
2015;1700−3. 
We J, Lee WH, Tan KL, et al. Prevalence of nasal polyps and its risk factors: Korean 
National Health and Nutrition Examination Survey 2009-2011. Am J Rhinol 
Allergy 2015;29:e24−8. doi: 10.2500/ajra.2015.29.4131. 
Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be 
divided pathologically into two inflammatory subtypes with distinct physiologic and 
clinical characteristics. Am J Respir Crit Care Med 1999 Sep;160(3):1001−8. 
XOLAIR (omalizumab) Summary of product characteristics, Genentech Inc. 2003 [cited 
17 October 2016]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000606/WC500057298.pdf  
Yeolekar AM, Dasgupta KS, Khode S, et al. A study of SNOT 22 scores in adults with no 
sinonasal disease. J Rhinol-Otol 2013;1:6−10. 
Zhang N, Holtappels G, Gevaert P, et al. Mucosal tissue polycolnal IgE is functional in 
response to alergen and SEB. Allergy 
2011;66:141−8.  doi: 10.1111/j.1398-9995.2010.02448.x. 








 
 
Appendix 1 Schedule of Activities (cont.) 
Omalizumab—F. Hoffmann-La Roche Ltd 
96/Protocol GA39688, Version 2 
ADA = anti-drug antibody; AQLQ = Asthma Quality of Life Questionnaire; BID = twice a day; BP = blood pressure; CS = corticosteroid; d = day; 
eDiary = electronic diary; EQ-5D-5L = EuroQol 5-Dimension 5-Level Questionnaire; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface 
antigen; HCV = hepatitis C virus; IWRS = interactive web-based response system; NCS = nasal blockage/congestion score; NPS = nasal polyp 
score; PK = pharmacokinetic; Q2W = every 2 weeks; RBR = Roche Biosample Repository; SNOT-22 = Sino-Nasal Outcome Test-22; SFU = safety 
follow-up; Term. = termination; UPSIT = University of Pennsylvania Smell Identification Test; UV = unplanned visit; W = week. 
Notes:  Cells shaded in gray pertain to patients on Q2W dosing schedule only. 
a Patients requiring omalizumab dosing every 2 weeks, based on IgE levels and weight as in dosing table (see Appendix 5), will return to clinic 
every 2 weeks for study drug administration between baseline and Week 22.  Vital signs (blood pressure and pulse rate) should be assessed 
prior to all study drug administration, including administration at Weeks 2, 6, 10, 14, 18, and 22 in patients receiving study drug every 2 weeks. 
b 4-week safety follow-up period for patients unless they enroll at Week 24 into another available sponsor-permitted study of omalizumab in 
nasal polyps. 
c Baseline/Day 1 visit should be targeted for 7 days after the Day -7 visit but may occur as late as 14 days after the Day -7 visit.   
d The 1st screening visit at Day -35 is defined as Visit 1 (V1) and the 2nd screening visit at Day -7 is defined as Visit 2 (V2).  Thereafter, 
because some patients will require visits every 2 weeks and other patients every 4 weeks (depending on frequency of study drug administration), 
all remaining visits are referenced by their timing in relationship to baseline (e.g., Week 0 [W0], Week 2 [W2], Week 4 [W4]). 
e Patients will remain on mometasone intranasally throughout the study as specified in Section 4.3.3.  At each visit the investigator must ensure 
that the patient has the necessary doses up to the next visit. 
f 
Patients will be instructed to complete the questions in their eDiary in the morning, within approximately 1 hour of awakening.  NCS (1-week 
recall) at Day -35 used for inclusion criteria will be collected via the EDC system. 
g Video endoscopy will be read centrally.  
h If initial video endoscopy done during visit is of insufficient quality to allow for assessment of nasal polyps score, patient should return to clinic 
within 10 working days to repeat video endoscopy. 
i 
AQLQ assessed only in patients with asthma 
j 
For women of childbearing potential 
k PK samples should be obtained prior to study drug administration.  Residual PK samples will be stored and may be used for further PK 
analysis and/or ADA analysis.  See Section 4.5.8 for further details. 
l 
Dosing of omalizumab should be based on IgE and weight levels from Day -35, and patients must meet criteria for dosing based on dosing 
table in Appendix 5 using the IgE value from Day -35.  Exceptions to the specific timing of IgE measurement may be made for cases in which 
there are problems with sample processing (e.g., sample destroyed in shipment requiring repeat phlebotomy).   
m Total IgE and free IgE samples need to be drawn before study drug administration.  Residual samples will be stored and may be used for 
specific IgE testing.  See Section 4.5.8 for further details. 


 
 
Appendix 1 Schedule of Activities (cont.) 
Omalizumab—F. Hoffmann-La Roche Ltd 
97/Protocol GA39688, Version 2 
n Hematology, including:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
o Chemistry panel (serum or plasma), including:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, 
albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH 
p Coagulation:  INR, aPTT, PT 
q Viral serology:  HIV, HBsAg, total HBcAb, HCV antibody.  Viral serology will not be assessed if prohibited by local regulations or ethics 
committees.  
r Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria) 
s Stool ova and parasite examination should be performed on Day -7 in patients with an eosinophil count > 2 times the upper limit of normal on 
Day -35 and risk factors for parasitic disease, as per Section 4.5.8.  Stool ova and parasite examination will be performed by a local laboratory. 
t Optional DNA collection for donation to RBR.  These samples will only be collected from patients who give specific consent for his or her 
samples to be stored for optional exploratory research 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
98/Protocol GA39688, Version 2 
Appendix 2  
Nasal Polyps Scoring System 
Polyp Score 
Polyp Size 
0 
No polyps 
1 
Small polyps in the middle meatus not reaching below the inferior border of 
the middle turbinate 
2 
Polyps reaching below the lower border of the middle turbinate a 
3 
Large polyps reaching the lower border of the inferior turbinate or polyps 
medial to the middle turbinate 
4 
Large polyps causing complete obstruction of the inferior nasal cavity 
Note:  Scoring system is used to evaluate polyp size in each nasal passage by means of 
video nasal endoscopy.  Nasal polyp score is the sum of unilateral polyp scores for each 
nasal passage.   
a The scoring is modified to accommodate patients who have had a middle turbinectomy, 
such that the polyp must reach the top of the inferior turbinate to be graded as Score 2.   
Source:  Gevaert et al. 2013. 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
99/Protocol GA39688, Version 2 
Appendix 3  
Nasal Symptoms Assessed Daily via Electronic Diary 
 
1. Is your nose blocked? a 
0 = Not at all  
1 = Mild  
2 = Moderate  
3 = Severe 
2. Is your sense of smell reduced?  
0 = Not at all  
1 = Mild  
2 = Moderate  
3 = Severe 
3. Do you have a runny nose?  
0 = Not at all  
1 = Mild  
2 = Moderate  
3 = Severe 
4. Do you feel dripping at the back of the nose?  
0 = Not at all  
1 = Mild  
2 = Moderate  
3 = Severe 
 
 a The Nasal Congestion Score (NCS) will be assessed with Question 1 only.   
 
NOTE: This is an example of the content; formatting may be adjusted for adaptation to the 
tablet electronic patient-reported outcome device. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
100/Protocol GA39688, Version 2 
Appendix 4  
Sino-Nasal Outcome Test-22 (SNOT-22) Questionnaire 
Below you will find a list of symptoms and social/emotional consequences of your nasal disorder.  
We would like to know more about these problems and would appreciate you answering the 
following question to the best of your ability.  There are no right or wrong answers, and only you 
can provide us with this information.  Please rate your problems, as they have been over the past 
2 weeks.  Thank you for your participation. 
 
Considering how severe the 
problem is when you experience 
it and how frequently it happens, 
please rate each item below on 
how 'bad' it is by circling the 
number that corresponds with 
how you feel using this scale:  
No 
problem 
Very 
mild 
problem 
Mild or 
slight 
problem 
Moderate 
problem 
Severe 
problem 
Problem 
as bad 
as it can 
be 
1. 
Need to blow nose 
0 
1 
2 
3 
4 
5 
2. 
Sneezing 
0 
1 
2 
3 
4 
5 
3. 
Runny nose 
0 
1 
2 
3 
4 
5 
4. 
Cough 
0 
1 
2 
3 
4 
5 
5. 
Post nasal discharge 
(dripping at the back of your nose) 
0 
1 
2 
3 
4 
5 
6. 
Thick nasal discharge 
0 
1 
2 
3 
4 
5 
7. 
Ear fullness 
0 
1 
2 
3 
4 
5 
8. 
Dizziness 
0 
1 
2 
3 
4 
5 
9. 
Ear pain 
0 
1 
2 
3 
4 
5 
10. Facial pain/pressure 
0 
1 
2 
3 
4 
5 
11. Difficulty falling asleep 
0 
1 
2 
3 
4 
5 
12. Waking up at night 
0 
1 
2 
3 
4 
5 
13. Lack of a good night's sleep 
0 
1 
2 
3 
4 
5 
14. Waking up tired 
0 
1 
2 
3 
4 
5 
15. Fatigue 
0 
1 
2 
3 
4 
5 
16. Reduced productivity 
0 
1 
2 
3 
4 
5 
17. Reduced concentration 
0 
1 
2 
3 
4 
5 
18. Frustrated/restless/irritable 
0 
1 
2 
3 
4 
5 
19. Sad 
0 
1 
2 
3 
4 
5 
20. Embarrassed 
0 
1 
2 
3 
4 
5 
21. Sense of taste/smell 
0 
1 
2 
3 
4 
5 
22. Blockage/congestion of nose 
0 
1 
2 
3 
4 
5 
 
NOTE: This is an example of the content; formatting may be adjusted for adaptation to the 
tablet electronic patient-reported outcome device. 




 
Omalizumab—F. Hoffmann-La Roche Ltd 
102/Protocol GA39688, Version 2 
Appendix 5  
Omalizumab Dosing Table for Nasal Polyps (cont.)  
Table 2 
Blinded Study Drug Dosing Schedule (Number of Injections and Total Injection Volumes) 
Dose (mg) 
Number of Vials (mL) 
Number of Injections 
Total Volume Injected (mL) a 
75 
1 
1 
0.6 
150 
1 
1 
1.2 
225 
2 
2 
1.8 
300 
2 
2 
2.4 
375 
3 
3 
3.0 
450 
3 
3 
3.6 
525 
4 
4 
4.2 
600 
4 
4 
4.8 
a 
1.2 mL maximum delivered volume per vial. 
 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
103/Protocol GA39688, Version 2 
Appendix 6 EuroQol 5-Dimension 5-Level Questionnaire 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g., work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN/DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY/DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 
 


 
 
 
Appendix 6 EuroQol 5-Dimension 5-Level Questionnaire (cont.) 
Omalizumab—F. Hoffmann-La Roche Ltd 
104/Protocol GA39688, Version 2 
The worst health 
you can imagine 
 
 
• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the box below. 
 
  
 
 
The best health 
you can imagine 
YOUR HEALTH TODAY = 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
NOTE: This is an example of the content; formatting may be adjusted for 
adaptation to the tablet electronic patient-reported outcome device. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
105/Protocol GA39688, Version 2 
Appendix 7 Asthma Quality of Life Questionnaire 
 














 
Omalizumab—F. Hoffmann-La Roche Ltd 
112/Protocol GA39688, Version 2 
Appendix 8 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.  Study drug for subcutaneous 
(SC) administration should be prepared using Sterile Water for Injection (SWFI), 
USP only. 
To minimize the risk of potential bias, study site personnel who are responsible for 
reconstituting and/or administering study drug will not be permitted to conduct any safety 
or efficacy evaluations.  An individual not involved with evaluating the patient must be 
identified to administer the study drug. 
Study drug is for single use only and contains no preservatives.  The solution should be 
used for SC administration within 8 hours following reconstitution when stored in the vial 
at 2°C−8°C (36°F−46°F), or within 4 hours of reconstitution when stored at room 
temperature. 
The lyophilized product will take 15−20 minutes to dissolve.  The fully reconstituted 
product will appear clear or slightly opalescent and may have a few small bubbles or 
foam around the edge of the vial.  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. 
Administration 
1. 
Draw 1.4 mL SWFI, USP into a 3-cc syringe equipped with a 1-inch, 18-gauge 
needle. 
2. 
Place the vial upright on a flat surface and, using standard aseptic technique, insert 
the needle and inject the SWFI directly onto the product. 
3. 
Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to 
evenly wet the powder.  Do not shake. 
4. 
Gently swirl the vial for 5−10 seconds approximately every 5 minutes in order to 
dissolve any remaining solids.  Vials typically take 10−20 minutes to solubilize.  
Longer reconstitution times may be required.  Continue to swirl the vial occasionally 
during this time to aid in solubilization.  There should be no visible gel-like particles 
in the solution.  Do not use if foreign particles are present.  Note: It is acceptable to 
have small bubbles or foam around the edge of the vial.  Do not use if the contents 
of the vial do not dissolve completely in 40 minutes. 
5. 
Invert the vial for 15 seconds to allow the solution to drain toward the stopper.  
Using a new 3-cc 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.  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. 
6. 
Replace the 18-gauge needle with a 25-gauge needle for SC administration. 


 
 
 
Appendix 8 Study Drug Preparation and Administration(cont.) 
Omalizumab—F. Hoffmann-La Roche Ltd 
113/Protocol GA39688, Version 2 
7. 
Expel air, large bubbles, and any excess solution to obtain the required 0.6−1.2 mL 
dose.  A thin layer of small bubbles may remain at the top of the solution in the 
syringe.  Because the solution is slightly viscous, the injection may take 
5−10 seconds to administer. 
8. 
A vial delivers 1.2 mL (150 mg) of study drug.  For a 75-mg dose, draw up 
all contents of the vial and dispel the contents of the syringe until only 0.6 mL of the 
contents remains in the syringe. 
9. 
Cap the syringe.  Label the syringe with the patient number, kit number details (Kit 1 
or 2), and protocol number (GA39688).  The syringe is now ready for use. 


 
Omalizumab—F. Hoffmann-La Roche Ltd 
114/Protocol GA39688, Version 2 
Appendix 9 Sampson's Criteria for Diagnosing Potential Cases 
of Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia) 
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence) 
 
2) Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
c) 
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
 
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a) Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person's baseline 
 
 
 

SAP_001.pdf: 
 
 
Official Title:  
 
A PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL OF OMALIZUMAB IN 
PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS 
NCT Number: 
NCT03280550 
Document: 
Version & Date:  
STATISTICAL ANALYSIS PLAN 
Version 2: 15-Apr-2019 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Omalizumab (IGE025)—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan GA39688
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, 
DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL 
TRIAL OF OMALIZUMAB IN PATIENTS WITH CHRONIC 
RHINOSINUSITIS WITH NASAL POLYPS
PROTOCOL NUMBER:
GA39688
STUDY DRUG:
Omalizumab (IGE025) RO5489789
VERSION NUMBER:
2
IND NUMBER:
5369
EUDRACT NUMBER:
2017-003450-28
SPONSOR:
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
24 January 2019
DATE AMENDED:
See electronic date stamp below.
Name                                                             Reason for Signing                              Date and Time
(UTC)
15-Apr-2019 17:04:31
Company Signatory


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GA39688
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
Changes to Section 4.2.4 analysis of Daily eDiary Assessments were made to reflect 
that symptom evaluation would occur only through Day 186 (last day of Week 24 
window), the point in time of the primary endpoint, but not through a later date as 
indicated in the prior version.
Changes in Section 4.3.1 (Intra-Reader Reliability of Nasal Polyp Score Assessments) 
were made to add the missing data imputation rules.
Changes to Section 4.5.1.1.1 were made to address an inconsistency between the 
definition of the estimand for co-primary endpoints (Section 4.5.1.1.1) and the estimator 
(Section 4.5.1.1.3).
Changes to Section 4.5.1.1.3 were made to clarify the data handling for patients with 
complete baseline and no post-baseline values in the primary analysis.
Changes to Section 4.5.1.1.4.1 were made to add one sensitivity analysis to evaluate 
the robustness of the primary endpoint results using different imputation rules for data 
after intercurrent events.
Changes to Section 4.5.3 were made to add four exploratory endpoints.
Changes to Section 4.7.2 were made to clarify that some events identified as risks 
associated with omalizumab will first be captured by broad search criteria or broad 
Standardized MedDRA Query and then confirmed by a Sponsor scientist during medical 
reviews.
Additional minor changes have been made to improve clarity and consistency.  


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GA39688
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 8
2.
STUDY DESIGN........................................................................................... 8
2.1
Protocol Synopsis.................................................................. 11
2.2
Endpoints............................................................................... 11
2.2.1
Co-Primary Efficacy Endpoints.............................................. 11
2.2.2
Secondary Efficacy Endpoints............................................... 11
2.2.3
Exploratory Efficacy Endpoints.............................................. 12
2.2.4
Safety Endpoints ................................................................... 12
2.2.5
Pharmacokinetic/Pharmacodynamic Endpoints..................... 12
2.3
Determination of Sample Size ............................................... 12
2.4
Analysis Timing ..................................................................... 15
3.
STUDY CONDUCT..................................................................................... 15
3.1
Randomization....................................................................... 15
3.2
Anaphylaxis Adjudication Committee .................................... 15
3.3
Early Study Drug Discontinuation and Early 
Study Withdrawal................................................................... 15
4.
STATISTICAL METHODS .......................................................................... 16
4.1
Analysis Populations ............................................................. 16
4.1.1
Full-Analysis Set.................................................................... 16
4.1.2
Pooled Full-Analysis Set........................................................ 16
4.1.3
Safety Analysis Set................................................................ 16
4.2
Data Handling Conventions................................................... 16
4.2.1
Treatment Failure .................................................................. 16
4.2.2
Definition of Study Day .......................................................... 17
4.2.3
Definition of Baseline............................................................. 17
4.2.4
Daily eDiary Assessments..................................................... 18
4.2.5
Assessment Intervals and Assigning Timepoints................... 19
4.3
Analysis of Study Conduct..................................................... 19
4.3.1
Intra-Reader Reliability of Nasal Polyp Score 
Assessments ......................................................................... 20


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan GA39688
4.3.2
Inter-Reader Reliability of Nasal Polyp Score 
Assessments ......................................................................... 21
4.4
Analysis of Treatment Group Comparability .......................... 22
4.5
Efficacy Analysis.................................................................... 22
4.5.1
Co-Primary Efficacy Endpoints.............................................. 23
4.5.1.1
Nasal Congestion Score........................................................ 24
4.5.1.2
Nasal Polyp Score................................................................. 28
4.5.2
Secondary Efficacy Endpoints............................................... 28
4.5.2.1
Type 1 Error Control for Co-Primary and 
Secondary Endpoints ............................................................ 28
4.5.2.2
Type 1 Error Control for Co-Primary and 
Secondary Endpoints for EMA............................................... 30
4.5.2.3
Change from Baseline at Week 24 in Sino-Nasal 
Outcome Test-22................................................................... 31
4.5.2.4
Change from Baseline at Week 24 in Nasal 
Symptoms Other than NCS ................................................... 31
4.5.2.5
Change from Baseline at Week 24 in Total Nasal 
Symptom Score..................................................................... 32
4.5.2.6
Change from Baseline at Week 16 in the 
Average Daily NCS................................................................ 32
4.5.2.7
Change from Baseline at Week 16 in the NPS...................... 32
4.5.2.8
Change from Baseline at Week 24 in UPSIT......................... 32
4.5.2.9
Reduction in the Need for Nasal Polypectomy by 
Week 24, as Defined by an NPS of 4 (Unilateral 
Score of 2 on Each Side) and Improvement in 
SNOT-22 Score of 8.9 ......................................................... 32
4.5.2.10
Requirement of Rescue Treatment (Systemic 
Corticosteroids for 3 Consecutive Days or 
Having Had Nasal Polypectomy) through 
Week 24 ................................................................................ 33
4.5.2.11
Requirement of Rescue Medication (Systemic 
Corticosteroids for 3 Consecutive Days) through 
Week 24 ................................................................................ 34
4.5.2.12
Having Had Nasal Polypectomy through 
Week 24 ................................................................................ 34
4.5.2.13
Change from Baseline at Week 24 in AQLQ of 
0.5 (in Patients with Comorbid Asthma Only) ...................... 34
4.5.3
Exploratory Efficacy Endpoints.............................................. 35


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan GA39688
4.6
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 36
4.7
Safety Analyses..................................................................... 37
4.7.1
Exposure of Study Medication............................................... 37
4.7.2
Adverse Events ..................................................................... 37
4.7.3
Laboratory Data..................................................................... 39
4.7.4
Vital Signs.............................................................................. 39
4.8
Missing Data.......................................................................... 39
4.9
Interim Analyses .................................................................... 39
5.
REFERENCES ........................................................................................... 40
LIST OF TABLES
Table 1
Nasal Polyps Scoring System....................................................... 9
Table 2
Summary of Studies Used for Determination of Sample Size..... 14
Table 3
Definition of Baseline .................................................................. 17
Table 4
Analysis Timepoints and Windows.............................................. 18
Table 5
Calculation Examples for 7-Day Prior Average of NCS at 
Week 8........................................................................................ 19
Table 6
Linear Weights............................................................................ 22
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 11
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 41
Appendix 2
Schedule of Assessments........................................................... 47
Appendix 3
Omalizumab Dosing Table for Nasal Polyps............................... 51


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan GA39688
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
AAC
anaphylaxis adjudication committee
AE
adverse event
AESI
adverse event of special interest
ARS
anterior rhinorrhea score
ATE
arterial thrombotic events
AQLQ
asthma quality of life questionnaire
BID
twice a day
Comp
completers
CRSwNP
chronic rhinosinusitis with nasal polyps
CS
corticosteroid
CSS
Churg Strauss Syndrome
Day 1
study day one; defined as the day of randomization
Day -7
study day minus seven is defined as seven days prior to 
randomization
Drop
dropouts
eCRF
electronic Case Report Form
EGPA
Eosinophilic Granulomatosis with Polyangiitis
EMA
European Medicines Agency
EQ-5D-5L
EuroQol 5-Dimension 5-level Questionnaire
FAS
full analysis set
FDA
U.S. Food and Drug Administration
HES
Hyper Eosinophilic Syndrome
HGLT
High Level Group Term
HLT
High Level Term
HRQoL
health-related quality of life
ICC
intraclass correlation coefficient
IWRS
interactive Web-based response system
LOE
lack of efficacy
LS
least squares
M
mometasone
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimal important difference
MMRM
mixed-effect model repeated measurement
MNAR
missing not at random
NCS
nasal congestion score


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan GA39688
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
NPS
nasal polyp score
OLE
open label extension
PD
progressive disease
PFAS
pooled full-analysis set
PRS
posterior rhinorrhea score
PT
Preferred Term
QD
once a day
QoL
quality of life
Rx
prescription
SAE
serious adverse event
SAP
Statistical Analysis Plan
SFU
safety follow-up
SSLD
Serum Sickness Like Disease
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SNOT-22
Sino-Nasal Outcome Test-22
SSS
sense of smell score
SOA
schedule of assessments
TNSS
total nasal symptom score
TEAE
treatment emergent adverse event
UPSIT
University of Pennsylvania Smell Identification Test
V1
Visit 1 (see SOA)
V2
Visit 2 (see SOA)
VAS
visual analogue scale
Study drug
placebo or omalizumab


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan GA39688
1.
BACKGROUND
The purpose of the analyses outlined in this Statistical Analysis Plan (SAP) is to evaluate 
the efficacy and safety of omalizumab compared with placebo in adult patients with 
chronic rhinosinusitis with nasal polyps (CRSwNP) who have had an inadequate 
response to standard-of-care treatments.
This SAP is based on Section 6 (Statistical Considerations and Analysis Plan) of the 
protocol for Study GA39688.  However, the analyses specified in this document 
supersede the high-level analysis plan described in the protocols.  Note that 
Studies GA39688 and GA39855 are independent studies with identical study designs as 
described in the Protocol Synopsis for Study GA39688 in Appendix 1.
Prior to the initiation of Studies GA39688 and GA39855, the Sponsor requested advice 
from both the U.S. Food and Drug Administration (FDA) and 
European Medicines Agency (EMA) on the nasal polyps program for omalizumab,
including the statistical considerations for the CRSwNP program. The feedback from 
these agencies have been incorporated into a draft SAP.  After initiation of the studies, 
the Sponsor requested advice from the FDA on a draft SAP. Additional feedback 
regarding the draft SAP was obtained from the FDA and this feedback has also been 
incorporated into this document.
2.
STUDY DESIGN
Studies GA39688 and GA39855 are Phase III, randomized, multi-center, double-blind, 
placebo-controlled, clinical trials that are run in parallel.  In each study, a total of 
approximately 120 patients with CRSwNP whose disease remains inadequately 
controlled despite daily treatment with intranasal corticosteroid (CS) therapy will be 
enrolled.
Written informed consent for participation in the study must be obtained before 
performing any study-specific tests or evaluations.  The 5-week screening/run-in period 
will include two visits (“1st screening visit” [V1] and “2nd screening visit” [V2]) (see 
Figure 1).  During the screening/run-in period, at both the V1 and V2, patients will 
undergo video endoscopy to quantify the size of the polyps and be assigned a nasal 
polyp score (NPS) prior to randomization.  The site physician performing the nasal 
endoscopy does not score the nasal polyps.  The bilateral NPS at each assessment will 
be determined by central readers, according to a modified ‘21 paradigm’ 
(Ahmad et al. 2015) consisting of two central readers chosen from a pool of five and up 
to one central adjudicator from a pool of three based on the criteria presented below in 
Table 1.  Specifically, if the two central readers assigned disagree on NPS by 1 or more 
points, a central adjudicator will determine which of the two central reader scores is 
utilized.  The NPS ranges from 0−8 (sum of 0−4 on the left nostril and 0−4 on the right 
nostril).


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan GA39688
Table 1 Nasal Polyps Scoring System
Polyp Score
Polyp Size
0
No polyps
1
Small polyps in the middle meatus not reaching below 
the inferior border of the middle turbinate
2
Polyps reaching below the lower border of the middle 
turbinate a
3
Large polyps reaching the lower border of the inferior 
turbinate or polyps medial to the middle turbinate
4
Large polyps causing complete obstruction of the inferior 
nasal cavity
Note:  Scoring system is used to evaluate polyp size in each nasal passage by means of 
video nasal endoscopy.  Nasal polyp score is the sum of unilateral polyp scores for each 
nasal passage.  
a The scoring is modified to accommodate patients who have had a middle turbinectomy, 
such that the polyp must reach the top of the inferior turbinate to be graded as Score 2.
Source:  Gevaert et al. 2013.
During the screening/run-in period, beginning at V1, patients will be asked to standardize 
their intranasal CS to a regimen of mometasone, 200 g twice a day (BID) (400 g total 
daily dosage).  Patients deemed by the investigator to be intolerant to a BID regimen of 
mometasone may remain on a stable dosage of mometasone once a day (QD) during 
the run-in period and throughout the duration of the treatment period (two sprays/nostril, 
both nostrils, 50 g/spray QD for a total daily dosage of 200 g).  Any patient 
transitioned to QD mometasone should remain on this regimen for the remainder of 
study.  At V1, patients should receive appropriate training on proper self-administration
of mometasone nasal spray.
Other assessments and activities occurring during the screening/run-in period are 
presented in the Schedule of Assessments (SOA) (see Appendix 2).
If patients do not meet the inclusion criteria (e.g., development of an acute infection at 
the time of screening necessitating treatment with antibiotics), they may be eligible for 
re-screening up to two times, after discussion with a Medical Monitor.  Additionally, if 
video endoscopy at V2 is determined to be of insufficient quality to allow for scoring of 
NPS, patients may repeat nasal endoscopy if sufficient time remains to allow for central 
reading of that endoscopy prior to randomization; in such cases, before proceeding with 
repeat endoscopy, investigators should confirm that sufficient time does indeed remain 
for central reading of this endoscopy prior to randomization.
After screening/run-in has been completed, approximately 120 eligible patients per study 
will be randomly allocated in a 1:1 ratio to receive double-blind treatment with 
omalizumab or placebo.  Randomization will be stratified on comorbid asthma and 
aspirin sensitivity status at baseline (3 levels:  asthmatic and aspirin sensitive, asthmatic 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan GA39688
not aspirin sensitive, all other) and geographic region (North America [including Canada, 
Mexico, or USA] and ex-North America).
A modified version of the approved E.U. Summary of Product Characteristics (SmPC) 
omalizumab dosing table (see Appendix 3) will be used; the dosing table from the SmPC 
has been modified to treat only the higher body weights reflective of the adult population 
being studied.  The first dose of study drug will be administered on the same day as 
randomization Week 0 (Day 1).  Dosing will be repeated every 2 or 4 weeks during 
a 24-week placebo-controlled treatment period.
Safety and efficacy will be assessed throughout the placebo-controlled treatment period, 
as detailed in the SOA (see Appendix 2).  The co-primary efficacy endpoints are 
changes from baseline in NPS and nasal congestion score (NCS) at Week 24.
Video nasal endoscopy will be performed at V1 and V2, and at Weeks 4, 8, 16, and 24 
(for a total of 6 endoscopies).  NCS will be assessed in the mornings daily via eDiary 
throughout the study.
After the treatment period ends (at Week 24), patients will be followed for four additional 
weeks as part of safety follow-up (SFU).  However, if patients enroll at Week 24 into the 
open-label extension (OLE) Study WA40169 of omalizumab in nasal polyps, then the 
SFU will be deferred until the end of Study WA40169 and not considered a part of this 
study.
All patients who discontinue study drug early during the treatment period will be asked to 
continue the planned study assessments through Week 24 and then to complete a 
4-week SFU period.  Patients who are unwilling or unable to continue with the planned 
assessments in the treatment period will instead complete a dosing-termination visit and 
then enter a 4week SFU period.  Patients who require nasal polypectomy or require 
two or more courses of treatment with systemic CS for 3 consecutive days will 
discontinue study drug but continue in the study with assessments and treatments.
An SOA is provided in Appendix 2.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
11/Statistical Analysis Plan GA39688
Figure 1
Study Schema
1 EPco-primaryend point; Nnumber of patients; Q2Wevery 2 weeks; Q4Wevery 4 weeks; 
SFUsafety follow-up; wkweek.
Note:  All patients will be treated during the entire study with intranasal corticosteroids 
(mometasone nasal spray) as background therapy.
2.1
PROTOCOL SYNOPSIS
Studies GA39688 and GA39855 are independent studies with identical study designs.  
The Protocol Synopsis for Study GA39688 is in Appendix 1.  For additional details on 
planned study assessments, see the SOA in Appendix 2.
2.2
ENDPOINTS
Baseline is defined differently for different endpoints depending on the SOA (see
Appendix 2).  Definitions of baseline for each assessment are provided in Section 4.2.3.
2.2.1
Co-Primary Efficacy Endpoints
The co-primary efficacy endpoints are as follows:

Change from baseline at Week 24 in average daily NCS

Change from baseline at Week 24 in NPS
2.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Change from baseline at Week 24 in the average daily total nasal symptom score 
(TNSS)

Change from baseline at Week 24 in the average daily sense of smell score (SSS)

Change from baseline at Week 24 in the average daily posterior rhinorrhea score 
(PRS)

Change from baseline at Week 24 in the average daily anterior rhinorrhea score 
(ARS)

Change from baseline at Week 24 in patient-reported health-related quality of life 
(HRQoL) as assessed by the total Sino-Nasal Outcome Test-22 (SNOT-22)

Change from baseline at Week 16 in the average daily NCS


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
12/Statistical Analysis Plan GA39688

Change from baseline at Week 16 in NPS

Change from baseline at Week 24 in sense of smell, as assessed by the University 
of Pennsylvania Smell Identification Test (UPSIT)

Reduction in the need for nasal polypectomy by Week 24, as defined by an NPS of 
4 (unilateral score of 2 on each side) and improvement in SNOT-22 score of 8.9

Requirement of rescue treatment (systemic CS for 3 consecutive days or having 
had nasal polypectomy) through Week 24

Requirement of rescue medication (systemic CS for 3 consecutive days) through 
Week 24

Having had nasal polypectomy through Week 24

Change from baseline at Week 24 in Asthma Quality of Life Questionnaire (AQLQ) 
of 0.5 (in patients with comorbid asthma only)
2.2.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

Change from baseline at Week 24 in SNOT-22 of at least the minimal important 
difference (MID) (8.9 points)

Change from baseline at Week 24 as assessed by the EuroQol 5-Dimension 5-level 
Questionnaire (EQ-5D-5L)
2.2.4
Safety Endpoints
The safety endpoints are as follows:

Incidence of adverse events (AEs)

Incidence of serious adverse events (SAEs)

Incidence of AEs leading to omalizumab/placebo discontinuation

Clinically significant change in laboratory values
2.2.5
Pharmacokinetic/Pharmacodynamic Endpoints
The pharmacokinetic and pharmacodynamic endpoints are as follows:

Serum concentration of omalizumab at specified timepoints outlined in the SOA

Serum levels of total and free IgE at specified timepoints outlined in the SOA
2.3
DETERMINATION OF SAMPLE SIZE
A total of approximately 120 patients will be enrolled in this study.  Patients will be 
randomly allocated in a 1:1 ratio to receive treatment with omalizumab or placebo, in 
addition to intranasal steroids.
The sample size of 120 patients (102 patients divided by 0.85 assuming a 15% early 
withdrawal rate) will provide at least 85% power to detect both a 0.56-point difference 
between treatment groups in change from baseline at Week 24 in the average daily NCS 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
13/Statistical Analysis Plan GA39688
and a 1.50-point difference between treatment groups in change from baseline at Week 
24 in NPS. 
 
 
 
 
 
 
 
 
 
 
 
 
Without any early patient withdrawals from the study, the sample size of n102 patients 
will provide approximately 92% power to detect a 0.56-point treatment group difference 
in change from baseline at Week 24 in NCS (SD0.83) and approximately 93% power to 
detect a 1.50-point treatment group difference in change from baseline at Week 24 in 
NPS (SD2.2), for an overall power of at least 85% (0.93 0.92 0.85).  
 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
14/Statistical Analysis Plan GA39688


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
15/Statistical Analysis Plan GA39688
2.4
ANALYSIS TIMING
The analysis of complete data from the study, including data from the SFU period for 
patients not entering into the OLE Study WA40169, will be performed when all patients 
have met one of the following three criteria:  1) discontinued the study early, 2) 
completed the SFU period, or 3) enrolled in the OLE Study WA40169, and additionally 
all data from the study are in the database and the database is cleaned and locked.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
At the Day 1 visit, after verification of inclusion/exclusion criteria, patients are 
randomized to receive either omalizumab or placebo in approximately a 1:1 ratio using 
an interactive web-based response system (IWRS) provided by 
  
Randomization will be stratified by comorbid asthma and aspirin sensitivity status at 
baseline (three levels:  asthmatic and aspirin sensitive, asthmatic not aspirin sensitive, 
all other) and geographic region (two levels: North America [including Canada, Mexico, 
or USA] and ex-North America) which are crossed for a total of six strata.
3.2
ANAPHYLAXIS ADJUDICATION COMMITTEE
All potential anaphylaxis cases reported by investigators to the Sponsor will be 
subsequently submitted for adjudication to a blinded three-member anaphylaxis 
adjudication committee (AAC) composed of external experts in allergic diseases.  The 
committee will assess whether the reported event meets criteria for an anaphylaxis 
event (based on Sampson’s criteria) and whether the reported anaphylaxis event is 
causally related to blinded study drug.  Further details will be provided in the 
Anaphylaxis Adjudication Charter.
3.3
EARLY STUDY DRUG DISCONTINUATION AND EARLY STUDY 
WITHDRAWAL
The primary reason for study drug (placebo or omalizumab) discontinuation will be 
documented on the appropriate electronic Case Report Form (eCRF).  
When discontinuing study drug, the patients are encouraged to continue with all planned 
assessments through Week 28.  When patients complete the blinded treatment period 
(24 weeks) and are eligible for enrollment into the OLE Study WA40169, if they choose,
they will skip the 4-week SFU period and enter directly into the OLE Study and will be 
considered to have completed Study GA39688.  Patients who discontinue study drug 
early do not qualify for enrollment into the OLE Study WA40169.  When patients 
discontinue drug early or withdraw from the study early, the sites are instructed to enter 
the most informative reason available for early study drug discontinuation or early study 
withdrawal according to the following hierarchy from most informative to least informative:  
pregnancy, death, progressive disease (PD), AE, lack of efficacy (LOE), lost to follow-up, 
non-compliance with study drug, protocol deviation, withdrawal by subject, physician 
decision, study terminated by sponsor, other.  Free text is collected if the reason is due 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
16/Statistical Analysis Plan GA39688
to an AE, protocol deviation, withdrawal by subject, physician decision, or other, and 
every effort will be made to accurately record the reason for discontinuation.  These 
steps were taken to help ensure that missing data are handled appropriately in the 
efficacy analysis.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Full-Analysis Set
The full-analysis set (FAS) will include all randomized patients in Study GA39688
grouped according to the treatment assigned at randomization.
4.1.2
Pooled Full-Analysis Set
The pooled full-analysis set (PFAS) will include all randomized patients in both Studies 
GA39688 and GA39855 grouped according to the treatment assigned at randomization.
4.1.3
Safety Analysis Set
The safety analysis set will consist of all patients in Study GA39688 who received at 
least one dose of study drug, with patients grouped according to treatment received 
defined as:

Placebo:  Patients who received only (and at least one) placebo injections (i.e., no 
active treatment) during the treatment period.

Omalizumab:  Patients who received at least one omalizumab injection during the 
treatment period.
4.2
DATA HANDLING CONVENTIONS
4.2.1
Treatment Failure
Treatment failure is defined as a patient requiring rescue treatment.  Patients receiving 
nasal polypectomy at any time during the interval between the date of randomization and 
the planned date of their Week 24 visit inclusive will be considered to have received 
rescue treatment.  In addition, patients requiring 
 systemic CS for 
nasal polyps symptoms for 3 consecutive days 
beginning after randomization through the planned date of 
their Week 24 visit, will be considered to have received rescue treatment.  
 
Only CS administered 
, at 
least in part, to alleviate symptoms of nasal polyposis as recorded in the eCRF will be 
considered when determining treatment failure status
 
 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
17/Statistical Analysis Plan GA39688
 
Treatment failure status for each patient will be determined prior to unblinding.  
The treatment failure status, having had nasal polypectomy, concomitant systemic CS
medication use after randomization, and indication for systemic CS use for all patients 
within the FAS will be provided in a single listing.
4.2.2
Definition of Study Day
For purpose of this document, study Day 1 is defined as the day of randomization.  
The day immediately following randomization is study Day 2 and so on.  Study Day -1 is 
defined as the day that is one day prior to randomization.  There is no study Day 0 by 
this definition of study day.
4.2.3
Definition of Baseline
Baseline for safety and efficacy endpoints will be defined as below in Table 3.
Table 3
Definition of Baseline
Assessment
Baseline Definition
Nasal Polyp Score
The last assessment on or before the date of randomization 
(i.e., V2 or V1 if V2 value is missing)
Nasal Congestion, Smell, 
Anterior Rhinorrhea, 
Posterior Rhinorrhea
Average of the daily values recorded during the 7-day interval 
ending on the latest day prior to randomization such that the prior 
7-day interval includes a recorded value on at least 4 of the 7 days 
of that interval
SNOT-22
The last assessment on or before the date of randomization 
(i.e., Day 1 or V1 if Day 1 is missing)
UPSIT, EQ-5D-5L, AQLQ
The last assessment on or before the date of randomization 
(i.e., Day 1 is the only planned assessment that qualifies)
Total IgE
The first assessment before but not on the day of randomization. 
Cases where this assessment of IgE and body weight does not 
meet protocol inclusion criteria will be excluded from calculation of 
baseline value.
All other non-efficacy (i.e., 
free IgE, vital signs, lab 
assessments)
The last assessment on or before the date of first dose of study 
drug
AQLQasthma quality of life questionnaire; EQ-5D-5LEuroQol 5-Dimension 5-level 
Questionnaire; SNOT-22sino-nasal outcome test-22; UPSITUniversity of Pennsylvania Smell 
Identification Test.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
18/Statistical Analysis Plan GA39688
4.2.4
Daily eDiary Assessments
The following assessments are recorded via eDiary each morning:  NCS, SSS, ARS, 
and PRS.
Table 4
Analysis Timepoints and Windows
Analysis 
Timepoints
First Study Day 
Included
(-13 days)
Planned Timepoint Study 
Day
Last Study Day 
Included 
(+14 days)
Week 4
15
28
42
Week 8
43
56
70
Week 12
71
84
98
Week 16
99
112
126
Week 20
127
140
154
Week 24
155
168
186*
*the last day of the Week 24 interval is 4 days longer to minimize missing data at the Week 24 
timepoint.
The following calculation will be performed for each of the following:  NCS, ARS, PRS, 
SSS, and TNSS (defined as the sum of the four individual daily scores). For each study 
day (Day 1 through Day 186), a score will be calculated using an average of the prior 
7 days (among the available days within the specified window, excluding the study day 
itself) if a value has been recorded by the patient on at least 4 of the prior 7 days, 
otherwise the 7-day prior average for that study day will be considered missing.  For 
example the 7-day prior average NCS at Day 56 can be interpreted as “the average 
NCS in the 7 days prior to study Day 56. The 7-day prior average NCS will be 
calculated for study Days 1 through 186 with non-missing data in at least 4 of 7 days 
prior. (See Table 5 for examples).  Each calculated (non-missing) 7-day prior average for 
each study day will be assigned to an analysis timepoint at Weeks 4, 8, 12, 16, 20, and 
24 according to the intervals specified in Table 4.  For each analysis timepoint, one 
calculated (non-missing) 7-day prior average will be selected for analysis according to 
the study day with nearest proximity to the planned timepoint study day, with the earlier 
selected in the case of a tie. For further details on handling of missing data and 
imputation rules for analysis of NCS, SSS, PRS, ARS, and TNNS (see Section 4.5).


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
19/Statistical Analysis Plan GA39688
Table 5
Calculation Examples for 7-Day Prior Average of NCS at Week 8
Example Scenario
Calculation
A daily NCS value was collected for Days 48, 
49, 50, 51, 52, 53, 54, and 55
The 7-day prior average for study Day 56 is the 
average of the NCS on Days 49, 50, 51, 52, 
53, 54, and 55
A daily NCS value was collected for Days 48, 
49, 50, 51, 52 but missing for Days 53, 54, and 
55.
With 4 or more of the 7 days collected the 7-
day prior average for study Day 56 is the 
average of the NCS on Days 49, 50, 51, and 
52. This average is used for analysis timepoint 
at Week 8.
A daily NCS value was collected for Days 48, 
53, 54, 55, and 56 but missing for Days 49, 50, 
51, and 52.
The 7-day prior average for study Day 56 is 
missing because 3 or fewer days were 
collected.  The 7-day prior average is checked 
for Days 55 and found invalid because 4 days 
among Days 48-54 are missing. The 7-day 
prior average is checked for Days 57 and used 
and calculated as the average of Days 53, 54, 
55, and 56 and used for the analysis timepoint 
at Week 8.
A daily NCS value was collected for Days 48, 
49, 50, and 51 but missing for Days 52, 53, 54, 
and 55.
The 7-day prior average for study Day 56 is 
missing because 3 or fewer days were 
collected from Days 49 through 55. 
The 7-day prior average for study Day 55 is 
valid because at least 4 days are non-missing. 
The 7-day prior average for study Day 55 is 
calculated from Days 48, 49, 50, and 51 and 
used for analysis timepoint at Week 8.
4.2.5
Assessment Intervals and Assigning Timepoints
Data collected outside the visit intervals specified in the protocol will not necessarily be 
excluded from the analysis.  For a given safety, efficacy, pharmacodynamic, or 
pharmacokinetic assessment, all data collected within the specified window of a planned 
timepoint study day (see Table 4) will be considered for an assigned timepoint for 
analysis.  Within this interval for a given planned visit day, the assessment with the date 
nearest to the planned timepoint study day (for that assessment) will be selected with 
assessments occurring prior to the planned timepoint study day taking priority in case of 
a tie.  With respect to the last timepoint (Week 24), for patients enrolled in the OLE 
Study WA40169, assessments recorded after open-label omalizumab dosing will not be 
considered part of data collected under this study protocol and therefore will not be used 
in the analysis for this study.
4.3
ANALYSIS OF STUDY CONDUCT
Descriptive statistics will be used to evaluate the conduct of the study.  The number of 
patients randomized will be tabulated by country, study site, and randomized treatment 
arm in the FAS.  Patient disposition (the number and percentage of patients randomized, 
treated, completing the treatment, and completing the study) will be tabulated by 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
20/Statistical Analysis Plan GA39688
randomized treatment arm in the FAS.  The number and percentage of patients who 
undergo premature study drug discontinuation and study discontinuation, as well as 
reasons for discontinuations, will be summarized.  The number and percentage of 
patients with eligibility criteria deviations, dosing errors and other major protocol 
deviations will be summarized. 
4.3.1
Intra-Reader Reliability of Nasal Polyp Score Assessments
For details on the NPS assessment paradigm including adjudication, see Section 4.5.1.2.  
In order to assess the consistency of reader performance during the study, intra-reader 
reliability of NPS assessments will be evaluated using combined data from a random 
sample of 20 videos (10 from each of Studies GA39688 and GA39855).  The following 
mixed-effect model (Shrout and Fleiss 1979; Gwet 2014) will be used for the NPS 
reading  associated with video , reader 	, and replicate 
:
Where

 is the expected score,

 the random video effect, 

 the fixed reader effect due to the reader 	,

(sr) the random video-reader interaction,

and  the random error term. 

Each of 
are assumed to follow Normal distributions with variances
respectively.  
The intra-reader reliability will be assessed by the intraclass correlation coefficient (ICC):
Where r5 the number of readers and m2 the number of replications.
MSS is the mean of squares for subjects and is calculated by summing the squared 
differences 
over all n20 videos and multiplying the summation by rm (n-1). 
Note that 
is the overall average NPS while 
is the average of all NPS associated 
with video i.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
21/Statistical Analysis Plan GA39688
MSI is the mean of squares for ratersubject interaction and is calculated by summing 
the squared differences 
over all n20 videos and r5 
readers and multiplying the summation by m/[(r-1)(n-1)]. The term 
represents the 
average of all NPSs associated with reader j and video i. The term 
is the average 
of all measurements associated with reader j.
MSE is the mean of squares for errors and calculated by summing the squared 
differences 
over all rnm200 readings, and by dividing the summation by 
rn(m-1).
ICC will range from 0 to 1 where 0 represents no reliability and 1 perfect reliability.
To provide the data for the model, 10 videos will be randomly selected from each study 
from the set of videos captured in the study at the time of sampling to be re-read by the 
original readers assigned, and also read twice by the three other readers at least 
4 weeks after the initial read.  There are five readers total and all five will read videos in 
each study in approximately equal proportion.  The selected original reads, re-reads, and 
reads/re-reads from non-assigned readers for these 20 videos will be used for purpose 
of assessment of intra-rater reliability.  Scores which are the result of re-reads for 
purpose of this assessment will not be used in the primary efficacy analysis.  If a reader 
assigns a NPS for a video in one assessment, but deems this video unreadable in 
another assessment, a NPS of either 0 or 8 will be imputed for that non-evaluable 
assessment, whichever leads to the poorest intra-rater agreement for that reader and 
video.  This will provide approximately 200 reads (5 readers per video, 10 videos per
study, 2 reads per video) for calculation of an empirical estimate of ICC. 
4.3.2
Inter-Reader Reliability of Nasal Polyp Score Assessments
To further assess the reader performance in the study, the inter-reader reliability of NPS 
assessment of endoscopy videos will be assessed at each planned timepoint with point 
estimates of Fleiss’ Kappa (Fleiss 1971) with linear weights (see Table 6) using all 
available data from all randomized patients from Studies GA39688 and GA39855 pooled 
for each planned timepoint (V1, V2, Weeks 4, 8, 16, and 24).  Fleiss’ Kappa may be 
interpreted as 0‘poor reliability’, 0 to 0.20‘slight’, 0.21 to 0.40‘fair’, 0.41 to 
0.60‘moderate’, 0.61 to 0.80‘substantial’, 0.81‘almost perfect’ reliability 
(Landis and Koch 1977).




Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
23/Statistical Analysis Plan GA39688

Having had nasal polypectomy through Week 24

Change from baseline at Week 24 in Asthma Quality of Life Questionnaire (AQLQ) 
of 0.5 (in patients with comorbid asthma only)
While two-sided unadjusted p-values will be reported, the overall study-level type 1 error 
will be controlled at a two-sided 0.05 level according to the type 1 error control plan 
detailed in Section 4.5.2.
All efficacy models will be adjusted by the stratification variables used in the 
randomization procedure:  a two-level categorical covariate for geographic region (two 
levels:  North America [including Canada, Mexico, or USA] and ex-North America), a 
three-level categorical covariate for baseline asthma comorbidity/aspirin sensitivity 
status (three levels:  asthma with aspirin sensitivity, asthma without aspirin sensitivity, 
and non-asthma regardless of aspirin sensitivity).  The baseline asthma/aspirin 
sensitivity status will be derived from that collected on the eCRF, which unlike the data 
collected in the IWRS, is subject to data monitoring, query, and revision in cases when 
an error is made, and is therefore most accurate.
4.5.1
Co-Primary Efficacy Endpoints
As NCS and NPS are co-primary endpoints, both null hypotheses for NCS and NPS 
must be rejected, with parameter estimates indicating a benefit of omalizumab over 
placebo, for the study to be deemed positive.  The primary analysis will separately test 
the null hypotheses that no treatment group difference exists in terms of each of the 
co-primary endpoints:

(): ∆
()= ∆
() and 
(): ∆
()= ∆
()

∆
() and ∆
() are the change from baseline at Week 24 in the average daily NCS in 
the FAS in the omalizumab arm and in the placebo arm respectively.

∆
() and ∆
() are the change from baseline at Week 24 in NPS in the FAS in the 
omalizumab arm and in the placebo arm respectively.
The two-sided alternative hypotheses are:

(): ∆
()≠∆
() and 
(): ∆
()≠∆
()
Because both NCS and NPS hypotheses need to be rejected to demonstrate efficacy of 
omalizumab in patients with CRSwNP, there is no adjustment for multiplicity for these 
co-primary endpoints and each will be tested at the two-sided 0.05 level.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
24/Statistical Analysis Plan GA39688
4.5.1.1
Nasal Congestion Score
4.5.1.1.1
Estimand
The first of the co-primary estimands is defined as follows:

Population:  Adult patients with a physician diagnosed CRSwNP for 12 months, 
with and without comorbid asthma, who have large nasal polyps with moderate to 
severe symptoms, and an inadequate response to standard of care therapy (which 
includes at least 8 weeks of intranasal CS and may include systemic CS and/or 
nasal polypectomy)

Variable:  Change from baseline in average daily NCS at Week 24.

Intercurrent events:  (1) Had rescue treatment not been made available prior to 
Week 24; (2) regardless of study drug discontinuation due to AE/PD/LOE.  All 
values after the intercurrent event would be coded to worst observed event value 
carried forward (worst observed value post-randomization and up to and including
the day of the intercurrent event for that patient).

Population-level summary:  Difference in least squares variable means between 
omalizumab and placebo treatment groups
4.5.1.1.2
Variable Definition
NCS will be scored by patients as not at all, mild, moderate, or severe (a score of 
0, 1, 2, or 3, respectively; see Fairley et al. 1993) every morning from V1 through 
Week 28 via eDiary.  Baseline average NCS will be calculated according to the method 
previously described in Table 3 while post-baseline (Weeks 4, 8, 12, 16, 20, and 24) will 
be calculated according to the method described in Section 4.2.4 and Table 4.  The 
absolute change from baseline at Week 24 in the average daily NCS values over the 
7 days prior to the planned study visit day will be defined for each patient as the average 
NCS assigned to the Week 24 timepoint minus the average daily NCS assigned to 
baseline (and similarly for Weeks 4, 8, 12, 16, and 20).


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
25/Statistical Analysis Plan GA39688
4.5.1.1.3
Primary Estimator
Treatment group comparisons of absolute change from baseline at Week 24 in average 
daily NCS between treatment groups will be assessed using a mixed-effect model 
repeated measurement (MMRM) model with unstructured covariance.  
The variance-covariance matrices for each treatment group will be assumed equal.  
The Kenward-Rogers approximation (Kenward and Roger 1997) will be used to calculate 
the denominator degrees of freedom.  The dependent variable will be absolute change 
from baseline in average daily NCS.  In addition to adjustment for geographic region and 
asthma/aspirin sensitivity comorbidity status, the model will include terms for treatment 
group, timepoint (Weeks 4, 8, 12, 16, 20, and 24), baseline value of the dependent 
variable (baseline average daily NCS in this case), treatment by timepoint interaction, 
and baseline value of dependent variable by timepoint interaction.  Point estimates, 
95% confidence intervals, and p-values for the treatment effect (omalizumab vs. placebo) 
on absolute change from baseline at a timepoint in average daily NCS will be calculated 
on the basis of the model for all post-baseline analysis timepoints:  
Weeks 4, 8, 12, 16, 20, and 24, using appropriate difference in least square (LS)-means.  
Patients with baseline and no post-baseline data will be included in the model for the 
calculation of the LS means.  The LS-means will be calculated using the coefficients of 
the independent variables weighted according to that observed in the FAS, regardless of 
treatment assignment.  This marginal weighting of coefficients for LS-means may impact 
the estimates of the means in each treatment arm but would not impact the difference 
between means in arms because the same covariate values are applied to calculate the 
means in both arms.  The null hypothesis will be tested by the t-test arriving from the 
treatment group difference in LS-means of the change from baseline at Week 24 in 
average daily NCS.  If issues with convergence arise, the unstructured covariance 
assumption will be replaced with a heterogeneous compound symmetry covariance 
assumption and later ANCOVA at each timepoint if issues persist.
Data collected after intercurrent events will be handled as follows before calculation of 
the 7-day prior averages:
1.
Receive rescue treatment (nasal polypectomy or systemic CS) prior to Week 24:  
For patients who received rescue treatment as defined in Section 4.2.1, all data 
collected after treatment failure will be set to missing and the worst observed daily 
NCS (observed post-randomization on or before the day of rescue treatment) will be 
used to impute on each day after the date of treatment failure through the date of 
the planned Week 24 visit. The date of treatment failure is defined as the date of 
nasal polypectomy or the start date of the earliest course of systemic CS that 
qualifies as treatment failure per the criteria in Section 4.2.1.  It would be unethical 
to deny the patient rescue treatment.  Yet, assuming that rescue treatment is 
effective in lowering the NCS, incorporation of data collected post rescue treatment 
risks biasing the comparison in favor of the experimental treatment arm with higher 
rescue treatment rates (and lower efficacy).  Therefore, data collected after rescue 
treatment will not be used in the analysis model.  At the same time simply excluding 
the data would assume missing at random (MAR) which is unreasonable so a 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
26/Statistical Analysis Plan GA39688
missing not at random (MNAR) imputation rule is preferred to excluding the data.  
Although rescue treatment is temporarily effective, it is associated with clinically 
significant complications and recurrence and therefore suboptimal.  It is also 
reasonable to assume that for patients who require rescue treatment, the NCS 
would have been poor if rescue treatment was not available.  For these reasons the 
worst observed post-baseline score is chosen for imputation after rescue treatment. 
2.
Discontinuation of study drug early due to PD, AE, or LOE:  For patients who 
discontinue study drug early due to PD, AE, or LOE all data collected after the last 
dose of study drug will be set to missing and the worst observed daily NCS 
(observed post-randomization on or before the last dose of study drug) will be used 
to impute on each day after the last dose of study drug through the date of the 
planned Week 24 visit.  The rationale is that, given the severity of nasal polyposis, 
patients who discontinue drug due to PD or LOE are likely to require rescue 
treatment after dropping out of the study.  The rationale for imputing the worst 
observed post-baseline on or before last dose of study drug value of NCS for drop 
outs after discontinuing drug due to AE is to avoid potential bias in favor of an 
experimental drug associated with AEs.
Missing data not explicitly covered above will be assumed MAR (i.e., given the observed 
outcomes and other variables in the statistical model missingness is independent of the 
unobserved outcomes).  This type of missing data will not be explicitly imputed. 
Patients who have a pre-treatment value but lack at least one post-randomization value 
assigned to planned analysis timepoint to be used in the MMRM model for NCS 
assessment will only contribute to the analysis in the calculation of LS-means in each 
arm in change from baseline via their contribution to the observed marginal (within the 
FAS) coefficients for independent variables (baseline asthma/aspirin sensitivity 
comorbidity, geographic region, and baseline NCS).  This marginal weighting of 
coefficients for LS-means may impact the estimates of the means in each treatment arm 
but would not impact the difference between LS-means in arms because the same 
covariate values are applied to calculate the means in both arms.
The order of operations is as follows:
1. Assess the occurrence of intercurrent events and impute the daily NCS after the 
intercurrent event as per above at the level of study day.
2. Using all observed and imputed daily NCS data, calculate the 7-day prior average 
daily NCS for all study days up to and including Week 24 (up to and including 
Day 186) for those with at least 4 days of the 7-day prior interval are non-missing as 
per Section 4.2.4.
3. Using the calculated 7-day prior average daily NCS for the study days, assign one to 
the analysis timepoint according to proximity to the planned study day per the 
windowing rules in Section 4.2.5.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
27/Statistical Analysis Plan GA39688
4.5.1.1.4
Sensitivity Analyses of Estimand Assumptions
4.5.1.1.4.1
Handling of Missing Data
In order to test the sensitivity of the co-primary NCS estimate with respect to the MAR 
assumption for non-intermittent missing data not following an intercurrent event due to 
early study discontinuation, a tipping point sensitivity analysis will be performed if the 
percentage of patients with missing data at Week 24 not following an intercurrent event 
exceeds 5% in either treatment group.  Additional sensitivity analyses of the MAR 
assumption may be performed as deemed appropriate whether or not the 5% condition 
is met. 
In order to evaluate the sensitivity of the treatment group difference in NCS estimate with 
respect to the variability associated with single imputation following an intercurrent event 
in the primary analysis, a second tipping point analysis will be performed via multiple 
imputation. Non-intermittent missing data not preceded by an intercurrent event will be 
assumed MAR and not imputed (same as in the primary analysis). Data preceded by an 
intercurrent event will be omitted and imputed using multiple imputation with delta 
adjustment at various MNAR assumptions and with MAR as a reference. The data post 
intercurrent event will be multiply imputed in separate simple linear regression 
imputation models in each arm using the same baseline covariates as used in the 
primary analysis (baseline NCS value, asthma/aspirin status, geographic region) and 
NCS at prior timepoints. Each of the imputed and MNAR adjusted (tipped) datasets will 
be analyzed with the same MMRM model as used in the primary analysis. Estimates 
grouped according to distinct tipping point assumptions will be combined 
separately according to Rubins rules and the estimate and nominal p-value will be 
reported for each distinct tipping point assumption.
4.5.1.1.4.2
Sensitivity Analyses on Baseline Covariates
Baseline mometasone treatment and anti-leukotriene treatment may explain some of the 
variability in the change from baseline in NCS, but the number of patients with 
prescribed anti-leukotriene treatment at baseline or baseline mometasone dose 400 g 
per day is expected to be small.  Therefore, pending sufficient data for model 
convergence, the same model as specified for the primary estimator will be fitted with 
two additional baseline categorical covariates defined as the mometasone dose 
prescribed at baseline (2 levels: 400 , 400 g per day) and prescribed anti-leukotriene
treatment at baseline (2 levels:  Yes, No).
4.5.1.1.5
Supplementary Analysis
4.5.1.1.5.1
Cumulative Proportion of Responders Analysis Graph
No minimal important difference in the change from baseline in the average daily NCS 
has been identified; therefore there is no generally accepted definition of a responder.  In 
order to aid in the interpretation of the results, cumulative proportion of responders 
analysis graphs (Farrar et al. 2006) will be provided with responder defined separately 
as having achieved a change from baseline at Weeks 16 and 24 in 7-day prior average 
daily NCS X without having been classified as a treatment failure, using the same 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
28/Statistical Analysis Plan GA39688
augmented dataset (same imputation rules) as those specified for the primary estimator.  
Curves will be displayed for both treatment groups with proportion of responders on the 
y-axis and X on the x-axis ranging from the maximum to the minimum change from 
baseline at Weeks 16 and 24 (in separate figures) in 7-day prior daily average NCS.  
Patients with missing Week 16 or 24 values not due to an intercurrent event will be 
excluded from these graphs.
4.5.1.2
Nasal Polyp Score
The estimand and primary estimator method as well as all sensitivity and supplementary 
analyses for NPS will follow those used for NCS.  The variable for NPS is defined below.
Polyp size in each nostril will be graded through an assessment of the video nasal 
endoscopy (04 integer scale per nostril, see Table 1; Gevaert et al. 2013) for both 
pivotal studies (GA39688 and GA39855) by a central panel of five independent sinus 
surgeons who are blinded to treatment assignment and source study.  The NPS used in 
the primary analysis is determined according to a modified ‘21 paradigm’ 
(Ahmad et al. 2015).  It is modified from the example in the referenced publication 
because the NPS is determined initially by two central readers rather than one central 
reader and a site physician.  The site physician performing the endoscopy does not 
score the nasal polyp and thus does not contribute to the score used for efficacy 
analysis.  Each subject is assigned two independent central readers from a pool of five 
central readers who read that subject’s videos throughout the study including those 
obtained during screening (V1 and V2) and post-randomization (Weeks 4, 8, 16, and 24) 
when possible.  NPS is the sum of the polyp scores in both nostrils (maximum score 
of 8).  Once two central readers independently assign an NPS (08) their scores are 
then compared and if there is any difference the video and both reader’s assessments
(by nostril) are sent to one central adjudicator among a pool of three central adjudicators 
distinct from and blinded to the identity of the central readers.  The adjudicator is 
required to choose between the two reader’s assessments and the chosen score (sum 
of individual scores in each nostril) is used for efficacy analyses.  The absolute change 
from baseline at each timepoint in NPS for each patient will be defined as the NPS 
assessment assigned to the analysis timepoint as per Section 4.2.5 minus the NPS at 
baseline as per Section 4.2.3. The same intercurrent events and imputation rules that 
apply to NCS will apply to NPS, but with a NPS worst post-baseline value observed prior 
to or on the day of rescue treatment/last does of study drug will be imputed for 
post-intercurrent event analysis timepoints.
4.5.2
Secondary Efficacy Endpoints
4.5.2.1
Type 1 Error Control for Co-Primary and Secondary Endpoints 
Along with the co-primary endpoints (change from baseline at Week 24 in NPS and 
NCS), all secondary endpoints will be included in the type 1 error control. 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
29/Statistical Analysis Plan GA39688
The following hypotheses will be tested in the FAS of Study GA39688.  The 
corresponding null hypotheses are denoted as

H1:  No difference between the treatment groups for change from baseline at 
Week 24 in NPS 

H2:  No difference between the treatment groups for change from baseline at 
Week 24 in average daily NCS 

H3:  No difference between the treatment groups for change from baseline at 
Week 24 in the average daily SSS

H4:  No difference between the treatment groups for change from baseline at 
Week 24 in average daily PRS

H5: No difference between the treatment groups for change from baseline at 
Week 16 in NPS

H6:  No difference between the treatment groups for change from baseline at 
Week 16 in average daily NCS

H7:  No difference between the treatment groups for HRQoL as assessed by the 
change from baseline at Week 24 in total SNOT-22

H8 :  No difference between the treatment groups for change from baseline at 
Week 24 in average daily ARS

H13 : No difference between treatment groups for reduction in the need for nasal 
polypectomy by Week 24, as defined by an NPS of 4 (unilateral score of 2 on 
each side) and improvement in SNOT-22 score of 8.9

H14 : No difference between treatment groups for change from baseline at Week 24 
in the average daily TNSS

H15: No difference between the treatment for sense of smell, as assessed by the 
change from baseline at Week 24 in UPSIT
Studies GA39688 and GA39855 are identical in design. The following endpoints will be 
tested using the PFAS (combined data) from Studies GA39688 and GA39855 if the 
analysis findings from the two studies are consistent.  The corresponding hypotheses 
are denoted as

H9:  No difference between treatment groups for requirement of rescue medication 
(systemic CS for 3 consecutive days) through Week 24

H10: No difference between treatment groups for having had nasal polypectomy 
through Week 24

H11: No difference between treatment groups for change from baseline at Week 24 
in Asthma Quality of Life Questionnaire (AQLQ) of 0.5 (in patients with comorbid 
asthma only)

H12: No difference between treatment groups for requirement of rescue treatment 
(systemic CS or nasal polypectomy).


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
30/Statistical Analysis Plan GA39688
The alternative hypothesis is that there is a difference between treatment groups for the 
respective endpoints.
Within Study GA39688, the co-primary hypotheses (H1 and H2) are tested 
simultaneously at first.  If both of the co-primary hypotheses are rejected at a two-sided 
significance level of 0.05, then the secondary hypotheses are tested in a sequential 
order of H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14 and H15 switching 
between FAS and PFAS as specified above.  A secondary hypothesis can be tested for 
statistical significance at a two-sided significance level of 0.05 if all of the previous 
hypotheses are rejected at a two-sided significance level of 0.05.  Otherwise, testing for 
statistical significance will stop within the study.  For example, H8 can be tested at a two 
sided significance level of 0.05 if all of H1, H2, H3, H4, H5, H6, and H7 are rejected.  H9, 
H10, H11, and H12 are based on PFAS (combined data from both studies) and must 
meet the additional condition that in separate analyses in FAS of both Studies GA39688 
and GA39855 for a given endpoint, the findings must be consistent prior to formal testing 
based on PFAS (pooled data).
4.5.2.2
Type 1 Error Control for Co-Primary and Secondary Endpoints 
for EMA
The same type 1 error control procedure described in the Section 4.5.2.1 will be applied 
for EMA but with a different set (and order) of secondary endpoints as agreed with EMA.
Along with the co-primary endpoints (NPS at Week 24 and NCS at Week 24), the 
following secondary endpoints will be included in the type 1 error control:

Requirement of rescue treatment (systemic CS for 3 consecutive days) or having 
had nasal polypectomy through Week 24

Change from baseline at Week 24 in the average daily TNSS

Change from baseline at Week 24 in patient-reported HRQoL as assessed by the 
total SNOT-22

Change from baseline at Week 24 in sense of smell, as assessed by the UPSIT

Change from baseline at Week 16 in NPS

Change from baseline at Week 16 in the average daily NCS
The following hypotheses will be tested in the FAS of Study GA39688.  The 
corresponding null hypotheses are denoted as

H1:  No difference between the treatment groups for change from baseline at 
Week 24 in NPS 

H2:  No difference between the treatment groups for change from baseline at 
Week 24 in average daily NCS 

H3:  No difference between the treatment groups for change from baseline at 
Week 24 in average daily TNSS


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
31/Statistical Analysis Plan GA39688

H4:  No difference between the treatment groups for change from baseline at 
Week 24 HRQoL as assessed by the total SNOT-22

H5:  No difference between the treatment groups for change from baseline at 
Week 24 in UPSIT

H6 :  No difference between the treatment groups for change from baseline at 
Week 16 in NPS 

H7 :  No difference between the treatment groups for change from baseline at 
Week 16 in average daily NCS 
Studies GA39688 and GA39855 are identical in design. The following endpoints will be 
tested using the PFAS (combined data) from Studies GA39688 and GA39855 studies if 
the analysis findings from the two studies are consistent.  The corresponding 
hypotheses are denoted as

H8: No difference between treatment groups for requirement of rescue treatment 
(systemic CS or nasal polypectomy).
The alternative hypothesis for each of the hypotheses is that there is a difference 
between treatment groups for the respective endpoint.
Within Study GA39688 the co-primary hypotheses (H1 and H2) are tested 
simultaneously first.  If both of the co-primary hypotheses are rejected at two-sided 
significance level of 0.05, then the secondary hypotheses are tested in a sequential 
order of H3, H4, H5, H6, H7, and H8. 
4.5.2.3
Change from Baseline at Week 24 in Sino-Nasal Outcome 
Test-22
The SNOT-22, a disease specific HRQoL measure, has a range 0–110 (lower score 
indicating less disease and better HRQoL).  The same estimand and primary estimator 
method for NPS will be used for SNOT-22.  
Supplementary Analysis for EMA
The relative (percent) change from baseline at Week 24 in SNOT-22 will be analyzed 
using the same method as the absolute change from baseline at Week 24 in SNOT-22 
except that the covariates baseline SNOT-22 and baseline SNOT-22 by treatment 
interaction will be removed from the model.
4.5.2.4
Change from Baseline at Week 24 in Nasal Symptoms Other 
than NCS
In addition to daily NCS, the following nasal symptoms will be measured daily in the 
morning:

Loss of smell

Posterior rhinorrhea


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
32/Statistical Analysis Plan GA39688

Anterior rhinorrhea
As with the NCS, these symptoms are each scored on the integer scale ranging from 
0 (not at all) to 3 (severe).  For each of these symptoms, the change from baseline in 
average daily symptom score over the 7 days prior to planned study visit day at each 
timepoint will be calculated and analyzed according to the assumptions and procedures
outlined for NCS in Section 4.5.1.1.
4.5.2.5
Change from Baseline at Week 24 in Total Nasal Symptom 
Score
Patient-reported TNSS will be the sum of the four equally weighted individual daily 
symptom scores, as measured every morning:  NCS, SSS, PRS, and ARS.  Each daily 
subscore ranges on the integer scale from 0 [not at all] to 3 [severe], and the TNSS 
ranges from 0 to 12.  For the TNSS, the change from baseline for average daily TNSS 
over the 7 days prior to planned study visit day will be calculated and analyzed 
according to the estimand and primary estimator method for NCS.  The imputation for 
observations after the intercurrent events will be performed at the day level and 
according to the worst observed daily TNSS post-randomization and on or prior to 
intercurrent event as per Section 4.5.1.1.
4.5.2.6
Change from Baseline at Week 16 in the Average Daily NCS
The same MMRM model used in Section 4.5.1.1 for the change from baseline at 
Week 24 in the average daily NCS will be used for the change from baseline at Week 16 
in average daily NCS.  The null hypothesis will be tested by the t-test associated with the 
treatment group difference in LS-means (derived from the MMRM model for the 
co-primary endpoint) of the change from baseline in average daily NCS at Week 16.
4.5.2.7
Change from Baseline at Week 16 in the NPS
The same MMRM model used in Section 4.5.1.2 for the change from baseline at 
Week 24 in the NPS will be used for the change from baseline at Week 16 in the NPS.  
The null hypothesis will be tested by the t-test associated with the treatment group 
difference in LS-means (derived from the MMRM model for the co-primary endpoint) of 
the change from baseline in the NPS at Week 16.
4.5.2.8
Change from Baseline at Week 24 in UPSIT
The UPSIT is a 40-question instrument that measures an individual’s ability to detect 
odors and ranges from 040.  The same estimand and analysis methods as will be used 
for NPS will be used for UPSIT.
4.5.2.9
Reduction in the Need for Nasal Polypectomy by Week 24, as 
Defined by an NPS of 4 (Unilateral Score of 2 on Each Side) 
and Improvement in SNOT-22 Score of 8.9
The following estimand of interest will be estimated:

Population:  same as for NCS estimand


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
33/Statistical Analysis Plan GA39688

Variable:  binary response variable indicating reduction in the need for nasal 
polypectomy by Week 24, defined as if an NPS of 4 (unilateral score of 2 on each 
side) and improvement in SNOT-22 score of 8.9 then will be coded “yes”, if both 
NPS and SNOT-22 are non-missing and either NPS >4 at Week 24 or SNOT-22 is 
not improved 8.9 at Week 24 will be coded “no”

Intercurrent event: (1) Had rescue treatment not been made available prior to 
Week 24; (2) regardless of study drug discontinuation due to AE/PD/LOE.  All 
patients having an intercurrent event will be imputed as “no”, not having had the 
event

Population-level summary:  Treatment group odds-ratio.
A reduced need for nasal polypectomy by Week 24 is defined by a reduction in NPS to 
4 (unilateral score of 2 on each side) and with improvement from baseline at Week 24 
in SNOT-22 score of 8.9 without rescue treatment (systemic CS or surgery).  Patients 
who have not had an intercurrent event and without valid Week 24 assessments of both 
NPS and SNOT-22 at Week 24 will have a missing outcome.
The treatment group odds-ratio at Week 24 with a reduced need for nasal polypectomy 
will be estimated using a logistic regression model analysis adjusted for geographic 
region, asthma/aspirin sensitivity comorbidity status, as well as baseline value of the 
measures used to define the endpoint (in this case, baseline NPS and SNOT-22).  
The null hypothesis for treatment group difference in the reduction in the need for nasal 
polypectomy by Week 24 will be assessed by the Wald Chi-square test of the treatment 
term in the logistic regression model.  If model convergence is an issue, then Fisher’s 
Exact test will be used, unadjusted for baseline covariates.
4.5.2.10
Requirement of Rescue Treatment (Systemic Corticosteroids
for 3 Consecutive Days or Having Had Nasal Polypectomy) 
through Week 24
Due to the low frequency of this clinically meaningful endpoint, the analysis will be 
conducted for Study GA39688 and also conducted on pooled data from 
Studies GA39688 and GA39855 in a separate analysis if the analysis findings are 
consistent for the two studies.
The following estimand of interest will be estimated:

Population:  same as for NCS estimand

Variable:  binary event variable defined as if requirement of rescue treatment 
through Week 24 defined by having taken systemic CS for 3 consecutive days or 
having had nasal polypectomy at any point between randomization and Week 24 
inclusive then coded yes; if follow-up is 155 days and no rescue treatment is 
required then coded “no”.

Intercurrent event:  regardless of study drug discontinuation due to AE/PD/LOE.  All 
patients having an intercurrent event will be imputed as “yes”


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
34/Statistical Analysis Plan GA39688

Population-level summary:  Treatment group odds-ratio.
In this analysis, requiring rescue treatment is defined as having taken systemic CS for 
3 consecutive days or having had sinus nasal polypectomy at any point between 
randomization and Week 24, inclusive.  The treatment group odds-ratio of patients 
requiring rescue treatment will be estimated using a logistic regression model analysis 
adjusted for geographic region, asthma/aspirin sensitivity comorbidity status, and study 
(Study GA39688, Study GA39855 for pooled analysis).  Patients whose last visit falls 
prior to Day 155 (Week 24 minus 13-day interval is the first day of the Week 24 analysis 
visit window) and did not already meet the criteria for the event and intercurrent event 
will have a missing outcome.
The null hypothesis for treatment group difference in the requirement of rescue 
treatment by Week 24 will be assessed by the Wald Chi-square test of the treatment 
term in the logistic regression model.  If model convergence is an issue, then Fisher’s 
Exact test will be used.
4.5.2.11
Requirement of Rescue Medication (Systemic Corticosteroids
for 3 Consecutive Days) through Week 24
Due to the low frequency of this clinically meaningful endpoint the analysis will be 
conducted for Study GA39688 and also conducted on pooled data from 
Studies GA39688 and GA39855 in a separate analysis if the analysis findings are 
consistent for the two studies.  The same estimand, procedures, and imputation rules 
outlined in Section 4.5.2.10 will be performed with a change in definition of the event 
variable to having taken systemic CS for 3 consecutive days at any point between 
randomization and Week 24 (regardless of surgical status). A two-level study covariate 
will be added to the model for analyses of pooled data.
4.5.2.12
Having Had Nasal Polypectomy through Week 24
Due to the low frequency of this clinically meaningful endpoint the analysis will be 
conducted for Study GA39688 and also conducted on pooled data from 
Studies GA39688 and GA39855 in a separate analysis if the analysis findings are 
consistent for the two studies.  The same estimand, procedures, and imputation rules 
outlined in Section 4.5.2.10 will be performed with a change in the definition of the event 
variable to having had nasal polypectomy at any point between randomization and 
Week 24 (regardless of systemic CS usage).  A two-level study covariate will be added 
to the model for analyses of pooled data.
4.5.2.13
Change from Baseline at Week 24 in AQLQ of 0.5 (in Patients 
with Comorbid Asthma Only)
This analysis will be conducted in the subgroup of patients with comorbid asthma at 
baseline in Study GA39688 and will also be conducted on pooled data from 
Studies GA39688 and GA39855 in a separate analysis if the analysis findings are 
consistent for the two studies.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
35/Statistical Analysis Plan GA39688
The following estimand of interest will be estimated:

Population:  same as for NCS estimand

Variable:  binary response variable defined as: if a change from baseline at 
Week 24 in AQLQ of 0.5 coded as “yes; if non-missing change from baseline at 
Week 24 in AQLQ < 0.5 codes as “no”. 

Intercurrent event:  (1) Had rescue treatment not been made available prior to 
Week 24; (2) regardless of study drug discontinuation due to AE/PD/LOE.  All 
patients having an intercurrent event will be imputed as “no”, not having had the 
event

Population-level summary:  Treatment group odds-ratio.
This analysis will be conducted only in the comorbid asthma subgroup of the FAS as 
defined in Section 4.1.1.  The AQLQ is a 32-item measure of asthma-related quality of 
life (QoL) with a total score (the mean of all 32 responses) ranging from 1 to 7; a higher 
score indicates a better QoL.  Patients whose last visit falls prior to Day 155 (Week 24 
minutes 13 day interval) without assessments of AQLQ at Week 24 and have not had an 
intercurrent event will have a missing outcome.
The treatment group odds-ratio of patients with a change from baseline at Week 24 in 
AQLQ of 0.5 will be estimated using the same methods in Section 4.5.2.9 with an 
additional two-level covariate of the study (Study GA39688 or Study GA39855).  The null 
hypothesis for treatment group odds-ratio of patients with a change from baseline at 
Week 24 in AQLQ of 0.5 will be assessed by the Wald Chi-square test of the treatment 
term in the logistic regression model.  If model convergence is an issue, then Fisher’s 
Exact test will be used, unadjusted for baseline covariates.
4.5.3
Exploratory Efficacy Endpoints
There will be no type 1 error control for exploratory endpoints.  Unadjusted two-sided 
p-values will be reported.
Change from baseline at Week 24 in SNOT-22 of at least the MID (8.9 points)
The estimand and primary estimator method for change from baseline at Week 24 in 
SNOT-22 of at least the MID (8.9 points improvement) will follow those used in 
Section 4.5.2.9.
Change from baseline at Week 24 in EQ-5D-5L
The absolute value and change from baseline to Week 16 and Week 24 of the visual 
analogue scale (VAS) for the EQ-5D-5L will be summarized by treatment group using 
mean, standard deviation, median, and range.  The percentage of response to each of 
the five questions will be summarized at baseline, Week 16 and Week 24.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan GA39688
Change from baseline at Week 24 in average daily NCS of at least 0.5 and 1 point
The estimand and primary estimator method for the proportions of patients with 0.5 
and 1 point improvement in change from baseline at Week 24 of daily NCS averaged 
over the prior 7 days will follow those used in Section 4.5.2.9. Patients with baseline 
NCS that did not meet inclusion criteria of NCS 1 will be excluded from the analysis. If 
model convergence is an issue, then Fisher’s Exact test will be used.
Change from baseline at Week 24 in NPS of at least 1 and 2 points 
The estimand and primary estimator method for the proportions of patients with 1 point
and 2 point improvement in change from baseline at Week 24 of NPS will follow those 
used in Section 4.5.2.9.
4.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
The analyses of all pharmacodynamic endpoints will be based on the safety analysis set 
(see Section 4.1.3).  Serum total and free IgE concentrations will be measured at V1 
(total IgE only), Day 1, Week 16, and Week 24 during the treatment period, and at 
Week 28 during the SFU period according to the SOA (see Appendix 2).  
Descriptive summaries (mean, SD, coefficient of variation, median, minimum, and 
maximum) of these pharmacodynamic concentrations will be produced at each timepoint 
by treatment group.  Only pharmacodynamic assessments made on or prior to date of 
last dose for patients who discontinue study drug early will be considered for assignment 
to a planned timepoint for analysis per Section 4.2.5.
Serum omalizumab concentrations are measured at the following timepoints: Day 1, 
Week 16, Week 24, and Week 28 in patients randomized to omalizumab only.  
Descriptive summaries (mean, SD, coefficient of variation, median, minimum, and 
maximum) of these omalizumab concentrations will be produced at each for omalizumab 
patients only based on the safety analysis set (see Section 4.1.3).  While treatment 
groups will be defined according to the treatment received, a review of dosing 
information including dosing errors, if any, and the pharmacokinetic data for patients with 
unusual dosing patterns will be conducted to assess for any potential impact on results.  
Only pharmacokinetic assessments made on or prior to date of last dose for patients 
who discontinue study drug early will be considered for assignment to a planned 
timepoint for analysis per Section 4.2.5.
Additional pharmacokinetic analyses may be conducted as appropriate.  
Population pharmacokinetic/pharmacodynamic modeling may be performed to 
characterize inter-individual variability, which may be reported separately from the 
clinical study report.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
37/Statistical Analysis Plan GA39688
4.7
SAFETY ANALYSES
Safety will be assessed through the summary of AEs, laboratory test results (hematology 
and serum chemistry), and vital signs.  Safety summaries may include data collected at 
unscheduled visits, dosing termination visits, early termination visits, SFU visits.
Safety outcomes will be summarized based on the safety analysis set with patients 
grouped according to the actual treatment received (see Section 4.1.3).  
Safety summaries will be presented by treatment group for all treated patients.
4.7.1
Exposure of Study Medication
Patients were dosed with study drug according to their screening IgE and body weight 
based on the dosing table listed in Appendix 5 of the protocol. In cases where initial 
screening IgE, in combination with body weight, did not meet the protocol inclusion 
criteria, the IgE could be re-assessed at the investigator's discretion, with this re-
assessed level used to determine the study drug dose. The number and percentage of 
patients receiving each dose of study drug will be summarized by treatment group.  The 
overall duration of exposure (weeks), and number of doses received will be summarized 
by descriptive statistics (mean, SD, median, range).  The overall duration of exposure 
will be summarized by number of patients and percentage categorically (i.e.,
48 weeks, 812 weeks, etc.).  Duration of treatment will be defined based on the 
difference (in days) between the dates of the first and last dose of study drug plus 1 day.  
4.7.2
Adverse Events
Verbatim descriptions of treatment-emergent adverse events (TEAEs) will be coded 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).  
A TEAE is defined as any new AE or any worsening of an existing condition with an 
onset after the first study drug administration.  Summaries of treatment-emergent events 
will be provided for each of the following categories:

All AEs

All AEs by severity

AEs assessed as related to study drug by the investigator

SAEs

AEs leading to discontinuation of study drug

Adverse events of special interest (AESI) (i.e., anaphylaxis/anaphylactoid reactions, 
drug induced liver injury, and suspected transmission of an infectious agent by the 
study drug)

Deaths


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan GA39688
The AESIs will be identified as defined below.  Summaries by treatment arm will include 
tabulations by MedDRA preferred terms and/or listings, as appropriate.

Anaphylactic, anaphylactoid, and hypersensitivity reactions:  Potential cases of 
anaphylactic, anaphylactoid, and hypersensitivity reactions will be identified and 
sent for adjudication by an independent AAC (see Section 3.2).  Members of the 
AAC review blinded data to adjudicate cases as anaphylaxis per Sampson’s Criteria 
and for relatedness to study drug.  A detailed description of the process for 
identification of potential events and data flow is provided in the AAC Charter.  
Events adjudicated by the AAC as meeting Sampson’s Criteria for anaphylaxis and 
relatedness to study drug will be summarized.  Additionally, a listing of all possible 
cases of anaphylaxis will be produced.

Suspected transmission of an infectious agent by the study drug: Events will be 
identified using the Preferred Term (PT) “Suspected transmission of an infectious 
agent via product”.

Drug-induced liver injury: Events will be identified and summarized if any one of the 
following three criteria are met:  1) treatment-emergent AST or ALT3ULN in 
combination with total bilirubin 2 ULN; 2) treatment-emergent AST or 
ALT3ULN in combination with clinical jaundice as represented by any one of the 
following preferred terms:  ocular icterus, jaundice acholuric, jaundice 
hepatocellular; or 3) if the patient is reported to have the preferred term 
drug-induced liver injury. 
The following AEs identified as risks associated with omalizumab will be listed and
summarized separately:

Serum Sickness Syndrome/Serum Sickness Like Disease (SSLD) (PTs “Serum 
sickness” and “Serum sickness-like reaction”)

Antibody formation to omalizumab (PTs “Drug specific antibody present”, 
“Human anti-human antibody test”, and “Drug specific antibody”)

The following AEs identified as risks associated with omalizumab will be first 
identified according to the broad search criteria below. Events will be evaluated by 
a Sponsor scientist and only confirmed events will be summarized. Events 
identified by the broad search will be listed with the events confirmed by the sponsor 
scientist flagged:
–
Churg Strauss Syndrome (CSS)/Hyper Eosinophilic Syndrome 
(HES)/Eosinophilic Granulomatosis with Polyangiitis (EGPA) (broad search 
criteria: HLGT “Vascular inflammations” and HLT “Eosinophilic disorders”)
–
Thrombocytopenia (SMQ [Standardized MedDRA Query] “Haematopoietic 
thrombocytopenia” [Broad] and PT “Immune thrombocytopenic purpura” [ITP]).
–
Arterial Thrombotic Events (ATEs) (SMQs [broad]: “Myocardial Infarction” and 
“Other ischaemic heart disease”, SMQs [narrow]:  “Ischaemic central nervous 
system vascular conditions”, “Haemorrhagic central nervous system vascular 
conditions” and PTs “Hemiparesis”, “Hemiplegia”, “Sudden cardiac death”, 
“Sudden death”, and “Cardiac death”).


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan GA39688
–
Malignant neoplasms (SMQ “Malignancies” [broad])
–
Parasitic infections (broad search criteria: the MedDRA High Level Group 
Terms (HGLT) of “Helminthic disorders”, “Mycobacterial infectious disorders”, 
and “Protozoal infectious disorders”, MedDRA High Level Term (HLT) of 
“Listeria infections”)
4.7.3
Laboratory Data
Serum chemistry and hematology values and changes from baseline in clinical 
laboratory values will be summarized by descriptive statistics (mean, SD, median, 
minimum, maximum) at baseline and throughout the study by treatment group.  Worst 
post-baseline World Health Organization (WHO) grade for clinical laboratory values of 
platelets, hemoglobin, neutrophils, creatinine, aspartate transaminase (ALT), alanine 
transaminase (AST), total bilirubin, alkaline phosphatase, sodium, and potassium will be 
presented by treatment group. Worst post-baseline FDA Healthy Volunteers grade for 
clinical laboratory values of eosinophils and white blood cells will be presented by 
treatment group. Shift tables of highest WHO grade post-baseline by baseline grade for 
platelets, AST, ALT, and total bilirubin will be presented by treatment group.
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study drug for the treatment period (Day 1), unless otherwise 
specified.
4.7.4
Vital Signs
Vital signs (pulse rate, systolic and diastolic blood pressure while the patient is in a 
seated position) and changes from baseline will be summarized over the course of the 
study by descriptive statistics (mean, SD, median, minimum, and maximum) by 
treatment group. 
4.8
MISSING DATA
If the baseline asthma/aspirin status based on the eCRF data is missing or unknown, 
then the value entered into IWRS at randomization will be used (i.e., asthmatic and 
aspirin sensitive, asthmatic not aspirin sensitive, all other).
In all efficacy analyses, missing data handling is specific to the efficacy endpoint and 
details are given within Section 4.5 for all efficacy endpoints.  For analysis of change 
from baseline endpoints if a patient is randomized but no baseline value exists for that 
endpoint, then the patient will be excluded from the analysis of that endpoint.
4.9
INTERIM ANALYSES
No efficacy interim analyses are planned.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan GA39688
5.
REFERENCES
Ahmad H, Gottlieb K, Hussain F. The 2 + 1 paradigm; an efficient algorithm for central 
reading of Mayo endoscopic subscores in global multicenter phase 3 ulcerative 
colitis clinical trials. Gastroenterology Report 2015; 4(1): 35-38.
Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal 
polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized 
clinical Trial. JAMA 2016;315:469-79.
Fairley JW, Yardley MPJ, Durham LH, et al. Reliability and validity of a nasal symptom 
questionnaire for use as an outcome measure in clinical research and audit of 
functional endoscopic sinus surgery. Clin Otolaryngol 1993;18:43642.
Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders 
analysis graph to present pain data over a range of cut-off points: Making clinical 
trial data more understandable. Journal of Pain and Symptom 
Management. 2006;31:369–77.
Fleiss JL. Measuring nominal scale agreement among many raters. Psychological 
Bulletin 1971; 76:378.
Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, 
as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 
2011;128(5):989-95.
Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic 
patients with nasal polyps and asthma. J Allergy Clin Immunol 2013;131:110-16.
Gwet KL. Handbook of Inter-Rater Reliability. 4th ed. Gaithersburg, MD USA: Advanced 
Analytics, LLC, 2014.
Kenward MG and Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 1997, 53:983–97.
Landis JR, Koch GG. The measurement of observer agreement for categorical data. 
Biometrics 1977; 33:159–74.
Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. 
Psychological Bulletin. 1979; 86: 420-28.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan GA39688
Appendix 1
Protocol Synopsis
TITLE:
A PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED CLINICAL TRIAL OF OMALIZUMAB IN 
PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL 
POLYPS
PROTOCOL NUMBER:
GA39688
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-001718-28
IND NUMBER:
5369
TEST PRODUCT:
Omalizumab (IGE025)
PHASE:
Phase III
INDICATION:
Chronic rhinosinusitis with nasal polyps
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
The purpose of this study is to determine the efficacy and safety of omalizumab compared with 
placebo in adult patients with CRSwNP who have had an inadequate response to 
standard-of-care treatments.  Specific objectives and corresponding endpoints for the study are 
outlined below.
Primary Efficacy Objective
Corresponding Co-Primary Endpoints
To evaluate the efficacy of 
omalizumab compared with placebo 
Co-primary endpoints:
Change from baseline at Week 24 in average daily nasal 
congestion score (NCS) 
Change from baseline at Week 24 in nasal polyps score 
(NPS) 
Secondary Efficacy Objective a
Corresponding Endpoints
To evaluate the efficacy of 
omalizumab compared with placebo 
Change from baseline at Week 24 in the average daily 
total nasal symptom score (TNSS)
Change from baseline at Week 24 in the average daily 
sense of smell score
Change from baseline at Week 24 in the average daily 
posterior rhinorrhea score 
Change from baseline at Week 24 in the average daily 
anterior rhinorrhea score
Change from baseline at Week 24 in patient-reported 
health-related quality of life as assessed by the total 
SNOT-22
Change from baseline at Week 16 in the average daily 
NCS 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan GA39688
Change from baseline at Week 16 in NPS
Change from baseline at Week 24 in sense of smell, as 
assessed by the UPSIT
Reduction in the need for surgery by Week 24, as 
defined by an NPS of 4 (unilateral score of 2 on 
each side) and improvement in SNOT-22 score of 8.9
Requirement of rescue treatment (systemic CS for 3 
consecutive days) or having had surgery for nasal 
polyps through Week 24
Requirement of rescue treatment (systemic CS for 3 
consecutive days) through Week 24.
Having had surgery for nasal polyps through Week 24
Change from baseline at Week 24 in AQLQ of 0.5 
(in patients with comorbid asthma only)
Exploratory Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
omalizumab compared with placebo 
Change from baseline at Week 24 in SNOT-22 of 
at least the MID (8.9 points).
To evaluate health status utility 
scores compared with placebo
Change from baseline at Week 24 as assessed by 
EQ-5D
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
omalizumab compared with placebo 
Incidence of adverse events 
Incidence of serious adverse events 
Incidence of adverse events leading to 
omalizumab/placebo discontinuation
Clinically significant change in laboratory values
Pharmacokinetic and 
Pharmacodynamic Objectives
Corresponding Endpoint
To evaluate the pharmacokinetics
and pharmacodynamics of 
omalizumab 
Serum concentration of omalizumab at specified 
timepoints outlined in the Schedule of Activities
Serum levels of total and free IgE at specific timepoints 
outlined in the Schedule of Activities
AQLQ Asthma Quality of Life Questionnaire; CS corticosteroid; MID minimal important 
difference; NCS nasal blockage/congestion score; NPS nasal polyp score; 
SNOT-22 Sino-Nasal Outcome Test-22; TNSStotal nasal symptom score; UPSIT University 
of Pennsylvania Smell Identification Test.
a Order of endpoints presented here does not determine order in a sequential type I error control 
procedure.  Details on type I error control procedures will be given in the Statistical Analysis Plan 
at a later date.
Study Design
Description of Study
This study is a Phase III, randomized, multicenter, double-blind, placebo-controlled, clinical trial 
that will be run in parallel with a replicate study, under Protocol GA39688.  
The study consists of a 5-week screening/run-in period, a 24-week treatment period, and a 
4-week study follow-up period.  The 4-week follow-up period will be for all patients unless they 
enroll at Week 24 into another available sponsor-permitted study of omalizumab in nasal 
polyps.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan GA39688
The screening/run-in period will include two visits (“1st screening visit” at Day -35 and 
“2nd screening visit” at Day -7), during which patients will undergo video endoscopy to quantify 
the size of the polyps and assign a nasal polyps score (NPS) prior to baseline.  
Beginning at Day -35 (1st screening visit), patients will be asked to standardize their nasal CS 
to a regimen of mometasone, 200 g twice a day (400 g total daily dosage).  Patients deemed 
by the investigator to be intolerant to a BID regimen of mometasone may remain on a stable 
dosage of mometasone QD during the run-in period and throughout the duration of the 
treatment period (two sprays/nostril, both nostrils, 50 g/spray QD for a total daily dosage of 
200 g).  Any patient transitioned to daily mometasone should remain on this regimen for the 
remainder of study. 
After screening/run-in has been completed, eligible patients will be randomly allocated in a 
1:1 ratio to receive double-blind treatment with omalizumab or placebo.  Randomization will be 
stratified on comorbid asthma and aspirin sensitivity status at baseline (3 levels: asthmatic and 
aspirin sensitive, asthmatic not aspirin sensitive, all other) and geographic region 
(North America, ex-North America). 
A modified version of the approved E.U. Summary of Product Characteristics (SmPC) 
omalizumab dosing table will be used; the SmPC has been modified to treat only the higher 
body weights reflective of the adult population being studied. The first dose of study drug will be 
administered on the same day as randomization ([Day 1, Week 0]).  Dosing will be repeated 
every 2 or 4 weeks during a 24-week placebocontrolled treatment period.  
Video nasal endoscopy will be performed at Day -35 (1st screening visit) and at baseline 
(Day -7), and at Weeks 4, 8, 16, and 24 (for a total of 6 endoscopies).  Change from baseline in 
NPS at Week 24 will be used as a co-primary endpoint to evaluate the benefit of omalizumab, 
where the baseline measurement is performed at Day -7 (2nd screening visit) prior to 
randomization. 
After the treatment period ends (at Week 24), patients will be followed for 4 additional weeks as 
part of safety follow-up, unless they enroll at Week 24 into another available sponsor-permitted 
study of omalizumab in nasal polyps. 
Number of Patients
A total of approximately 120 patients with CRSwNP whose disease remains inadequately 
controlled despite daily treatment with intranasal corticosteroid (CS) therapy will be enrolled.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 1875 years, inclusive, at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

NPS 5, with a unilateral score of 2 for each nostril, at screening (Day -35), and on Day -7 
(as assessed by a central panel of independent central readers)

SNOT-22 score 20 at screening (Day -35) and at randomization (Day 1)

Treatment with nasal mometasone at least 200 g per day, or equivalent daily dosing of 
another nasal CS, for at least 4 weeks before screening (Day -35)

Treatment with nasal mometasone 200 g twice a day (or once a day if intolerant to twice 
daily) during the run-in period with an adherence rate of at least 70%. 

Presence of nasal blockage/congestion with NCS 2 (1-week recall) at Day -35 and a 
weekly average at randomization of NCS 1 with at least one of the following symptoms 
prior to screening:  nasal discharge (anterior/posterior nasal drip) and/or reduction or loss of 
smell

Eligibility per the study drugdosing table (serum IgE level 30 to 1500 IU/mL and body 
weight 30 to 150 kg) and ability to be dosed per the dosing table 

Willingness to maintain all background medications stable for the duration of the treatment 
and follow-up periods


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan GA39688

Willingness and ability to use electronic device to enter study-related information in 
electronic devices (electronic diary [eDiary]/electronic tablet [eTablet])

Demonstration of at least 70% adherence to eDiary daily symptom assessment during 
run-in period, with fully completed entries on at least 4 days in the week prior to 
randomization 

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the treatment 
period and for 60 days 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.
–
Acceptable methods of contraception include surgical sterilization (e.g., bilateral 
tubal ligation, vasectomized partner), hormonal contraception (e.g., implantable, 
injectable, patch, oral), and intrauterine device (IUD).
–
Women of childbearing potential must have a negative serum pregnancy test result 
during the screening period.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Known history of anaphylaxis/hypersensitivity to omalizumab

Treatment with investigational drugs within 12 weeks or 5 half-lives (whichever is longer) 
prior to screening (Day -35)

Treatment with monoclonal antibodies (e.g., omalizumab, mepolizumab) for 6 months prior 
to screening (Day -35)

Current treatment with leukotriene antagonists/modifiers, unless patient has been on stable 
dosing of such medication for at least 1 month prior to screening (Day -35)

Treatment with non-steroid immunosuppressants (e.g., cyclosporine, methotrexate, 
azathioprine, mycophenolate, siroliumus, tacrolimus) within 2 months or 5 half-lives, 
whichever is longer, prior to screening (Day -35)

Treatment with systemic corticosteroids (CS), except when used as treatment for nasal 
polyposis, within 2 months prior to screening (Day -35)

Usage of systemic CS during the run-in period.  Patients requiring systemic CS during run-
in may be rescreened after completing systemic CS. 

Treatment with intranasal CS drops or CSadministering devices (e.g., OptiNosedevice or 
stents) within 1 month prior to screening (Day -35) or during the run-in period

History of nasal surgery (including polypectomy) within 6 months prior to screening

History of sinus or nasal surgery modifying the structure of the nose such that assessment 
of NPS is not possible

Uncontrolled epistaxis requiring surgical or procedural intervention, including nasal packing, 
within 2 months prior to screening

Known or suspected diagnosis of cystic fibrosis, primary ciliary dyskinesia (e.g., Kartagener 
syndrome) or other dyskinetic ciliary syndromes, hypogammaglobulinemia or other immune 
deficiency syndrome, chronic granulomatous disease and granulomatous vasculitis, 
granulomatosis with polyangiitis (e.g., Wegener’s Granulomatosis), or eosinophilic 
granulomatous with polyangiitis (EGPA) (e.g., Churg-Strauss syndrome)

Presence of antrochoanal polyps

Concomitant conditions that interfere with evaluation of primary endpoint:
–
Nasal septal deviation occluding one or both nostrils
–
Ongoing rhinitis medicamentosa


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan GA39688
–
Acute sinusitis, nasal infection, or upper respiratory infection during the run-in period
–
Known or suspected invasive or expansive fungal rhinosinusitis

Known HIV infection at screening

Known acute and chronic infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) 
at screening

History of myocardial infarction, unstable angina, cerebrovascular accident, or transient 
ischemic attack or a known history of a hypercoagulable disorder

Infection that meets any of the following criteria:
–
Resulted in hospital admission within 4 weeks prior to screening
–
Required treatment with intravenous or intramuscular antibiotics within 4 weeks prior to 
screening
–
Any active infection that required treatment with oral antibiotics within 2 weeks prior to 
screening
–
Active parasitic infection, including nematodes (e.g., Ascaris, Ancylostoma), 
platyhelminths (e.g., Schistosoma), or Listeria monocytogenes infection within 6 months 
prior to screening
Note:  Antibiotics are considered to include any antimicrobial therapy used to treat bacterial, 
fungal, parasitic, viral, or other infections. 

Active tuberculosis requiring treatment within 12 months prior to screening (Day -35)
Patients who have completed treatment for tuberculosis at least 12 months prior to 
screening (Day -35) and have no evidence of recurrent disease are permitted.

Initiation of or change in allergen immunotherapy within 3 months prior to screening (Day -
35) or during the run-in period

Initiation of or change in aspirin desensitization within 4 months prior to screening (Day -35) 
or during the run-in period

Pregnant or breastfeeding, or intending to become pregnant during the study or within 60
days after the last dose of omalizumab

Current malignancy or history of malignancy within 5 years prior to screening, except for 
appropriately treated carcinoma in situ of the cervix or non-melanoma skin carcinoma that 
has been treated or excised and is considered resolved

Any serious medical condition (including but not limited to significant arrhythmia, 
uncontrolled hypertension, significant pulmonary disease other than asthma) or abnormality 
in clinical laboratory tests that precludes the patient’s safe participation in and completion of 
the study

History of alcohol, drug, or chemical abuse within 6 months of screening
End of Study
The end of the study is defined as the date of the last patient's last visit (LPLV).  The LPLV is 
expected to occur at a maximum of 28 weeks after the last patient is randomized. 
Length of Study
Each patient will be followed for up to 33 weeks (5-week screening/run-in period, 24-week 
treatment period, 4-week off-drug safety follow-up period). The 4-week follow-up period will be 
for all patients unless they enroll into another available sponsor-permitted study of omalizumab 
in nasal polyps.
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is omalizumab.
Test Product (Investigational Drug)
Study drug will be administered subcutaneously to patients by qualified personnel who are not 
involved with conducting safety or efficacy evaluations using a disposable 25-gauge needle in 


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan GA39688
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.
Study drug will be administered subcutaneously every 2 or 4 weeks.  Because the solution is 
slightly viscous, the injection may take 510 seconds to administer. The dose (mg) and dosing 
frequency will be determined by serum total IgE level (IU/mL) (measured before the start of 
treatment) and body weight (kg) at Day -35.  Assignment of the study drug dose will be 
determined by using the study drugdosing table.  Doses of 150 mg are divided among more 
than one injection site to limit injections to no more than 150 mg per site.  The reconstituted vial 
is to be used for single-dose administration only.
Comparator
The placebo will be administered according to the same dose, route, and dosing regimen as 
omalizumab, shown above.
Non-Investigational Medicinal Products
In this study, mometasone furoate monohydrate nasal spray is considered a non-IMP and is 
used as background therapy only.
Statistical Methods
Primary Analysis
The analysis of data from the 24-week treatment period may be performed after all patients 
have either completed the Week 24 visit or discontinued from the treatment period prematurely, 
and all data from the treatment period are in the database and have been cleaned and verified.  
Patients who discontinue early will not be replaced.
The analysis of complete data from the study, including data from the safety follow-up period 
will be performed when all patients have either discontinued the study early or completed the 
safety follow-up period, all data from the study are in the database, and the database is cleaned 
and locked.
Determination of Sample Size
A total of approximately 120 patients will be enrolled in this study.  Patients will be randomly 
allocated in a 1:1 ratio to receive treatment with omalizumab or placebo, in addition to intranasal 
steroids.  
The sample size of 120 patients will provide at least 85% power to independently detect both a 
0.56-point difference between treatment groups in change from baseline at Week 24 in the 
average daily NCS and a 1.50-point difference between treatment groups in change from 
baseline at Week 24 in NPS.  






Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan GA39688
Appendix 2 Schedule of Assessments (cont.)
eDiaryelectronic diary; EQ-5D-5LEuroQol 5-Dimension 5-Level Questionnaire; HBcAbhepatitis B core antibody; HBsAghepatitis B surface 
antigen; HCVhepatitis C virus; IWRSinteractive web-based response system; NCSnasal blockage/congestion score; NPSnasal polyp 
score; PKpharmacokinetic; Q2W every 2 weeks; RBRRoche Biosample Repository; SNOT-22Sino-Nasal Outcome Test-22; SFUsafety 
follow-up; Term.termination; UPSIT University of Pennsylvania Smell Identification Test; UVunplanned visit; W week.
Notes:  Cells shaded in gray pertain to patients on Q2W dosing schedule only.
a
Patients requiring omalizumab dosing every 2 weeks, based on IgE levels and weight as in dosing table (see Appendix 5), will return to clinic 
every 2 weeks for study drug administration between baseline and Week 22.  Vital signs (blood pressure and pulse rate) should be assessed 
prior to all study drug administration, including administration at Weeks 2, 6, 10, 14, 18, and 22 in patients receiving study drug every 2 weeks.
b
4-week safety follow-up period for patients unless they enroll at Week 24 into another available sponsor-permitted study of omalizumab in 
nasal polyps.
c
Baseline/Day 1 visit should be targeted for 7 days after the Day -7 visit but may occur as late as 14 days after the Day -7 visit.  
d
The 1st screening visit at Day -35 is defined as Visit 1 (V1) and the 2nd screening visit at Day -7 is defined as Visit 2 (V2).  Thereafter, 
because some patients will require visits every 2 weeks and other patients every 4 weeks (depending on frequency of study drug administration), 
all remaining visits are referenced by their timing in relationship to baseline (e.g., Week 0 [W0], Week 2 [W2], Week 4 [W4]).
e
Patients will remain on mometasone intranasally throughout the study as specified in Section 4.3.3.  At each visit the investigator must ensure 
that the patient has the necessary doses up to the next visit.
f
Patients will be instructed to complete the questions in their eDiary in the morning, within approximately 1 hour of awakening.  NCS (1-week 
recall) at Day -35 used for inclusion criteria will be collected via the EDC system.
g
Video endoscopy will be read centrally.
h
If initial video endoscopy done during visit is of insufficient quality to allow for assessment of nasal polyps score, patient should return to clinic 
within 10 working days to repeat video endoscopy.
i
AQLQ assessed only in patients with asthma
j
For women of childbearing potential
k
PK samples should be obtained prior to study drug administration.  Residual PK samples will be stored and may be used for further PK 
analysis and/or ADA analysis.  See Section 4.5.8 for further details.
l
Dosing of omalizumab should be based on IgE and weight levels from Day -35, and patients must meet criteria for dosing based on dosing 
table in Appendix 5 using the IgE value from Day -35.  Exceptions to the specific timing of IgE measurement may be made for cases in which 
there are problems with sample processing (e.g., sample destroyed in shipment requiring repeat phlebotomy).  
m Total IgE and free IgE samples need to be drawn before study drug administration.  Residual samples will be stored and may be used for 
specific IgE testing.  See Section 4.5.8 for further details.


Omalizumab(IGE025)—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan GA39688
Appendix 2 Schedule of Assessments (cont.)
n
Hematology, including:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells)
o
Chemistry panel (serum or plasma), including:  sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, 
albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH
p
Coagulation:  INR, aPTT, PT
q
Viral serology:  HIV, HBsAg, total HBcAb, HCV antibody.  Viral serology will not be assessed if prohibited by local regulations or ethics 
committees. 
r
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria)
s
Stool ova and parasite examination should be performed on Day -7 in patients with an eosinophil count 2 times the upper limit of normal on 
Day -35 and risk factors for parasitic disease, as per Section 4.5.8.  Stool ova and parasite examination will be performed by a local laboratory.
t
Optional DNA collection for donation to RBR.  These samples will only be collected from patients who give specific consent for his or her 
samples to be stored for optional exploratory research.