Clinical trial NCT04740931
Conditions: Macular Edema Central Retinal Vein Occlusion Hemiretinal Vein Occlusion
Keywords: CRVO HRVO
Sponsor: Hoffmann-La Roche
Start date: 2021-03-02; Completion date: 2023-07-12
Enrollment: 729 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, multicenter, randomized, double-masked, active comparator-controlled, parallel-group study evaluating the efficacy, safety, and pharmacokinetics of faricimab administered by intravitreal (IVT) injection at 4-week intervals until Week 24, followed by a double-masked period of study without active control to evaluate faricimab administered according to a personalized treatment interval (PTI) dosing regimen in patients with macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO).

Detailed description:

Arms: arm 1: In Part 1 (Day 1 through Week 24), participants randomly assigned to Arm A will receive faricimab 6 milligrams (mg) by IVT injection once every 4 weeks (Q4W) from Day 1 through Week 20 (a total of 6 injections). In Part 2 (from Week 24 to Week 72), participants will receive faricimab 6 mg by IVT injection according to a personalized treatment interval (PTI) dosing regimen. To preserve masking for Part 2, a sham procedure will be administered during study visits at which no faricimab treatment is administered (according to the PTI dosing regimen). arm 2: In Part 1 (Day 1 through Week 24), participants randomly assigned to Arm B will receive aflibercept 2 milligrams (mg) by IVT injection once every 4 weeks (Q4W) from Day 1 through Week 20 (a total of 6 injections). In Part 2 (from Week 24 to Week 72), participants will receive faricimab 6 mg by IVT injection according to a personalized treatment interval (PTI) dosing regimen. To preserve masking for Part 2, a sham procedure will be administered during study visits at which no faricimab treatment is administered (according to the PTI dosing regimen).
Interventions: intervention 1: Faricimab intervention 2: Aflibercept intervention 3: Sham Procedure
Intervention descriptions: intervention 1: Faricimab will be administered by intravitreal (IVT) injection as specified in each treatment arm. intervention 2: Aflibercept 2 mg will be administered by IVT injection once every 4 weeks (Q4W) from Day 1 through Week 20 (a total of 6 injections). intervention 3: The sham is a procedure that mimics an IVT injection, but involves the blunt end of an empty syringe (without a needle) being pressed against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase III, Multicenter, Randomized, Double-Masked, Active 
Comparator-Controlled Study to Evaluate the Efficacy and Safety of 
Faricimab in Patients With Macular Edema Secondary to Central 
Retinal or Hemiretinal Vein Occlusion 
NCT Number: 
NCT04740931 
Document Date: 
Protocol Version 2: 17-November-2020 


PROTOCOL AMENDMENT 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.
Faricimab—F. Hoffmann-La Roche Ltd
Protocol GR41986, Version 2
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE COMPARATOR-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF FARICIMAB IN 
PATIENTS WITH MACULAR EDEMA SECONDARY 
TO CENTRAL RETINAL OR HEMIRETINAL VEIN 
OCCLUSION
PROTOCOL NUMBER:
GR41986
STUDY NAME:
COMINO
VERSION NUMBER:
2
EUDRACT NUMBER:
2020-000441-13
IND NUMBER:
119225
NCT NUMBER:
To be determined 
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
, M.B.B.S., M.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
17-Nov-2020 03:42:01
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Faricimab—F. Hoffmann-La Roche Ltd
2/Protocol GR41986, Version 2
PROTOCOL HISTORY
Protocol
Version
Date Final
1
3 April 2020


Faricimab—F. Hoffmann-La Roche Ltd
3/Protocol GR41986, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol GR41986 has been amended primarily to increase the patient sample size and 
to correct the best-corrected visual acuity (BCVA) stratification error.  Changes to the 
protocol, along with a rationale for each change, are summarized below: 

Language has been added to allow the Sponsor to propose exploratory substudies 
associated with protocol GR41986 (Section 2.6).

Due to extenuating circumstances, such as the COVID-19 pandemic, patients may 
not have the ability to complete certain trial activities, therefore, in order to ensure 
adequate power for the primary endpoint, the sample size has been increased to 
mitigate the loss of patients, loss of data, and the potential impact of protocol 
deviations affecting efficacy analyses (Sections 3.1.1, 3.1.1.1, 4.1, 6, 6.1, 9.5).

To correct the BCVA stratification error (Sections 3.1.1.1, 4.2.1, 6.5).

It has been clarified that missed mandatory pharmacokinetic, pharmacodynamic, or 
anti-drug antibody samples may be obtained at the next scheduled visit the patient 
attends (Section 3.1.2 and Appendix 1).

Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.3).

Administration of the National Eye Institute 25-Item Visual Functioning 
Questionnaire (NEI VFQ-25) was clarified (Section 4.5.8.1).

The Medical Monitors and Emergency Medical Contacts have been updated 
(Section 5.4.1).

Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1).

The faricimab-pooled safety population has been clarified (Section 6.2.5).

The immunogenicity analysis population has been clarified (Section 6.2.7).

The name of a Roche policy on data sharing has been corrected (Section 9.6).

Pages have been updated and added to the NEI VFQ-25 (Appendix 10). 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Faricimab—F. Hoffmann-La Roche Ltd
4/Protocol GR41986, Version 2
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Retinal Vein Occlusion ................................. 24
1.2
Background on Faricimab...................................................... 25
1.3
Study Rationale and Benefit-Risk Assessment...................... 26
1.3.1
Benefits.................................................................................. 27
1.3.2
Risks...................................................................................... 28
1.3.3
Conclusions........................................................................... 28
2.
OBJECTIVES AND ENDPOINTS ............................................................... 29
2.1
Efficacy Objectives ................................................................ 29
2.1.1
Primary Efficacy Objective..................................................... 29
2.1.2
Secondary Efficacy Objectives .............................................. 29
2.1.3
Exploratory Efficacy Objective............................................... 30
2.2
Safety Objective .................................................................... 31
2.3
Pharmacokinetic Objectives .................................................. 31
2.4
Immunogenicity Objectives.................................................... 32
2.5
Exploratory Biomarker Objective ........................................... 32
2.6
Exploratory Substudy ............................................................ 32
3.
STUDY DESIGN......................................................................................... 33
3.1
Description of the Study......................................................... 33
3.1.1
Overview of Study Design ..................................................... 33
3.1.1.1
Screening .............................................................................. 34
3.1.1.2
Re-Screening......................................................................... 35
3.1.1.3
Randomization and Visit Schedule........................................ 36
3.1.2
Compliance with Study Visits, Handling of Missed 
Visits, and Timely Reporting.................................................. 37
3.1.2.1
Timely Forwarding of OCT Images to the Central 
Reading Center or Reporting of Missed OCT 
Images................................................................................... 37


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5/Protocol GR41986, Version 2
3.1.2.2
IxRS Reporting of Visual Acuity Score, 
Study Treatment Interruption, and Missed Study 
Treatment Visits..................................................................... 38
3.1.3
Treatment Schedule for Part 1 (Q4W Dosing)....................... 38
3.1.4
Treatment Schedule for Part 2 (PTI Regimen) ...................... 38
3.1.4.1
Faricimab Interval Determination........................................... 39
3.1.4.2
Missed Faricimab Dosing Visits Starting from 
Week 20 ................................................................................ 40
3.1.4.3
Faricimab Interruption at Faricimab Dosing Visits 
Starting from Week 20........................................................... 41
3.1.4.4
Missing CST Value at Faricimab Dosing Visits 
Starting from Week 20........................................................... 41
3.1.4.5
Missing BCVA Value at Faricimab Dosing Visits 
Starting from Week 20........................................................... 41
3.1.5
China Enrollment Plan........................................................... 41
3.1.6
Independent Data Monitoring Committee .............................. 41
3.2
End of Study and Length of Study......................................... 42
3.3
Rationale for Study Design.................................................... 42
3.3.1
Rationale for Faricimab Dose ................................................ 43
3.3.2
Rationale for Faricimab Schedule.......................................... 44
3.3.3
Rationale for Aflibercept Dose and Schedule ........................ 45
3.3.4
Rationale for Control Group................................................... 45
3.3.5
Rationale for Biomarker Assessments................................... 45
4.
MATERIALS AND METHODS .................................................................... 46
4.1
Patients.................................................................................. 46
4.1.1
Inclusion Criteria.................................................................... 46
4.1.1.1
General Inclusion Criteria ...................................................... 46
4.1.1.2
Ocular Inclusion Criteria for Study Eye.................................. 47
4.1.2
Exclusion Criteria................................................................... 47
4.1.2.1
General Exclusion Criteria..................................................... 47
4.1.2.2
Ocular Exclusion Criteria for Study Eye................................. 48
4.1.2.3
Ocular Exclusion Criteria for Fellow (Non-Study) 
Eye ........................................................................................ 49
4.1.2.4
Ocular Exclusion Criteria for Both Eyes................................. 50
4.2
Method of Treatment Assignment and masking .................... 50


Faricimab—F. Hoffmann-La Roche Ltd
6/Protocol GR41986, Version 2
4.2.1
Treatment Assignment........................................................... 50
4.2.2
Masking ................................................................................. 50
4.2.2.1
Masked Roles........................................................................ 51
4.2.2.2
Unmasked Roles ................................................................... 51
4.2.2.3
Site Delegation Log ............................................................... 53
4.2.2.4
Role Switching....................................................................... 53
4.2.2.5
Study Backup Staff ................................................................ 53
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel ............................................................ 53
4.2.2.7
Patient Masking..................................................................... 54
4.2.2.8
Single-Patient Emergency Unmasking .................................. 54
4.2.2.9
Single-Patient Non-Emergency Unmasking........................... 54
4.2.2.10
Single-Patient Unmasking for Health Authority 
Reporting Requirements........................................................ 54
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 55
4.3.1
Study Treatment Formulation and Packaging........................ 55
4.3.1.1
Faricimab............................................................................... 55
4.3.1.2
Aflibercept (Active Comparator)............................................. 55
4.3.1.3
Sham ..................................................................................... 55
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 55
4.3.2.1
Faricimab............................................................................... 55
4.3.2.2
Aflibercept (Active Comparator)............................................. 56
4.3.2.3
Sham Procedure.................................................................... 56
4.3.3
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 56
4.3.4
Continued Access to Faricimab............................................. 57
4.4
Concomitant Therapy ............................................................ 58
4.4.1
Permitted Therapy................................................................. 58
4.4.2
Prohibited Therapy ................................................................ 59
4.5
Study Assessments ............................................................... 60
4.5.1
Informed Consent Forms and Screening Log........................ 60
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 60


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7/Protocol GR41986, Version 2
4.5.3
Physical Examinations........................................................... 60
4.5.4
Vital Signs.............................................................................. 61
4.5.5
Ocular Assessments.............................................................. 61
4.5.6
Concurrent Ocular Procedures.............................................. 62
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 62
4.5.8
Clinical Outcome Assessments ............................................. 64
4.5.8.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 64
4.5.8.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 65
4.5.9
Optional Aqueous Humor and Plasma Samples 
(Patients at Participating Sites).............................................. 65
4.5.10
Optional Unscheduled Collection of Vitreous 
Humor and Plasma Sample................................................... 66
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 67
4.5.11.1
Overview of the Research Biosample Repository.................. 67
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 67
4.5.11.3
Sample Collection.................................................................. 67
4.5.11.4
Confidentiality........................................................................ 68
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 69
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 69
4.5.11.7
Monitoring and Oversight....................................................... 69
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 70
4.6.1
Study Treatment Discontinuation........................................... 70
4.6.2
Patient Discontinuation from the Study.................................. 70
4.6.3
Study Discontinuation............................................................ 71
4.6.4
Site Discontinuation............................................................... 71
5.
ASSESSMENT OF SAFETY....................................................................... 71
5.1
Safety Plan ............................................................................ 71
5.1.1
Safety Assessments .............................................................. 71


Faricimab—F. Hoffmann-La Roche Ltd
8/Protocol GR41986, Version 2
5.1.2
Risks Associated with Faricimab ........................................... 72
5.1.3
Risks Associated with Aflibercept (Comparator).................... 73
5.1.4
Management of Patients Who Experience 
Adverse Events ..................................................................... 73
5.1.4.1
Dose Modification.................................................................. 73
5.1.4.2
Treatment Interruption:  Dose Interruption and 
Treatment Discontinuation Criteria ........................................ 73
5.2
Safety Parameters and Definitions ........................................ 75
5.2.1
Adverse Events ..................................................................... 75
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 76
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 76
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 77
5.3.1
Adverse Event Reporting Period ........................................... 77
5.3.2
Eliciting Adverse Event Information....................................... 78
5.3.3
Assessment of Severity of Adverse Events ........................... 78
5.3.4
Assessment of Causality of Adverse Events ......................... 78
5.3.5
Procedures for Recording Adverse Events............................ 79
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 80
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 80
5.3.5.3
Persistent or Recurrent Adverse Events................................ 81
5.3.5.4
Abnormal Laboratory Values ................................................. 81
5.3.5.5
Abnormal Vital Sign Values ................................................... 82
5.3.5.6
Abnormal Liver Function Tests.............................................. 82
5.3.5.7
Deaths ................................................................................... 83
5.3.5.8
Preexisting Medical Conditions.............................................. 83
5.3.5.9
Lack of Efficacy or Worsening of Macular Edema 
Due to Central Retinal Vein Occlusion in the 
Study Eye .............................................................................. 83
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 84
5.3.5.11
Cases of Medication Error and Associated 
Adverse Events ..................................................................... 84
5.3.5.12
Patient-Reported Outcome Data ........................................... 85


Faricimab—F. Hoffmann-La Roche Ltd
9/Protocol GR41986, Version 2
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 85
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 86
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 87
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 87
5.4.2.2
Events That Occur after Study Drug Initiation........................ 87
5.4.3
Reporting Requirements for Pregnancies.............................. 87
5.4.3.1
Pregnancies in Female Patients............................................ 87
5.4.3.2
Abortions ............................................................................... 88
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 88
5.5
Follow-Up of Patients after Adverse Events .......................... 88
5.5.1
Investigator Follow-Up........................................................... 88
5.5.2
Sponsor Follow-Up ................................................................ 89
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 89
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 89
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 90
6.1
Determination of Sample Size ............................................... 90
6.2
Analysis Populations ............................................................. 91
6.2.1
Intent-to-Treat Population...................................................... 91
6.2.2
Per-Protocol Population......................................................... 91
6.2.3
Safety-Evaluable Population.................................................. 91
6.2.4
Part 2 Efficacy Population...................................................... 92
6.2.5
Faricimab-Pooled Safety Population ..................................... 92
6.2.6
Pharmacokinetic-Evaluable Population ................................. 92
6.2.7
Immunogenicity Analysis Population ..................................... 92
6.3
Summaries of Conduct of Study............................................ 92
6.4
Summaries of Treatment Group Comparability ..................... 92
6.5
Efficacy Analyses .................................................................. 93
6.5.1
Primary Efficacy Endpoint...................................................... 93


Faricimab—F. Hoffmann-La Roche Ltd
10/Protocol GR41986, Version 2
6.5.2
Secondary Efficacy Endpoints............................................... 95
6.5.3
Exploratory Efficacy Endpoints.............................................. 96
6.6
Safety Analyses..................................................................... 96
6.7
Pharmacokinetic Analyses..................................................... 96
6.8
Pharmacodynamic Analyses ................................................. 97
6.9
Immunogenicity Analyses...................................................... 97
6.10
Biomarker Analyses............................................................... 98
6.11
China Subpopulation Analyses.............................................. 98
7.
DATA COLLECTION AND MANAGEMENT ............................................... 98
7.1
Data Quality Assurance......................................................... 98
7.2
Electronic Case Report Forms............................................... 99
7.3
Source Data Documentation.................................................. 99
7.4
Use of Computerized Systems .............................................. 99
7.5
Retention of Records........................................................... 100
8.
ETHICAL CONSIDERATIONS.................................................................. 100
8.1
Compliance with Laws and Regulations .............................. 100
8.2
Informed Consent................................................................ 100
8.3
Institutional Review Board or Ethics Committee.................. 102
8.4
Confidentiality...................................................................... 102
8.5
Financial Disclosure ............................................................ 103
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 103
9.1
Study Documentation .......................................................... 103
9.2
Protocol Deviations.............................................................. 103
9.3
Management of Study Quality ............................................. 103
9.4
Site Inspections ................................................................... 104
9.5
Administrative Structure....................................................... 104
9.6
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 104
9.7
Protocol Amendments ......................................................... 105
10. REFERENCES ......................................................................................... 106


Faricimab—F. Hoffmann-La Roche Ltd
11/Protocol GR41986, Version 2
LIST OF TABLES
Table 1
Dose Interruption and Treatment Discontinuation Criteria .......... 74
Table 2
Adverse Event Severity Grading Scale ....................................... 78
Table 3
Causal Attribution Guidance ....................................................... 79
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 34
Figure 2
Algorithm for IxRS-Determined Faricimab Personalized 
Treatment Interval Dosing Intervals ............................................ 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities............................................................... 110
Appendix 2
Unscheduled Safety Assessment Visit..................................... 122
Appendix 3
Study Treatment Preparation................................................... 123
Appendix 4
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cell.............................................................. 124
Appendix 5
Refraction and Best-Corrected Visual Acuity Testing .............. 125
Appendix 6
Color Fundus Photography ...................................................... 126
Appendix 7
Fundus Fluorescein Angiography ............................................ 127
Appendix 8
Spectral-Domain Optical Coherence Tomography................... 128
Appendix 9
Biological Sample Collection and Shipping Instructions........... 129
Appendix 10
National Eye Institute 25-Item Visual Functioning 
Questionnaire............................................................................ 131


Faricimab—F. Hoffmann-La Roche Ltd
12/Protocol GR41986, Version 2
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE COMPARATOR-
CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF FARICIMAB IN 
PATIENTS WITH MACULAR EDEMA SECONDARY 
TO CENTRAL RETINAL OR HEMIRETINAL VEIN
OCCLUSION
PROTOCOL NUMBER:
GR41986
STUDY NAME:
COMINO
VERSION NUMBER:
2
EUDRACT NUMBER:
2020-000441-13
IND NUMBER:
119225
NCT NUMBER:
To be determined 
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
, M.B.B.S., M.S.
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.


Faricimab—F. Hoffmann-La Roche Ltd
13/Protocol GR41986, Version 2
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATOR-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF FARICIMAB IN PATIENTS WITH 
MACULAR EDEMA SECONDARY TO CENTRAL RETINAL OR 
HEMIRETINAL VEIN OCCLUSION
PROTOCOL NUMBER:
GR41986
STUDY NAME:
COMINO
VERSION NUMBER:
2
EUDRACT NUMBER:
2020-000441-13
IND NUMBER:
119225
NCT NUMBER:
To be determined 
TEST PRODUCT:
Faricimab (RO6867461)
PHASE:
III
INDICATION:
Macular edema secondary to central retinal or hemiretinal vein 
occlusion
SPONSOR:
F. Hoffmann-La Roche Ltd
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab compared with 
aflibercept in patients with macular edema due to central retinal vein occlusion (CRVO) or 
hemiretinal vein occlusion (HRVO) up to the primary endpoint at Week 24.  Efficacy, safety, and 
pharmacokinetics of faricimab administered according to the personalized treatment interval 
(PTI) dosing regimen (i.e., from every 4 weeks [Q4W] to every 16 weeks [Q16W]) will be 
assessed during the study period from Weeks 24 to 72.  Specific objectives and corresponding 
endpoints for the study are outlined below.
EFFICACY OBJECTIVES
For efficacy endpoint evaluation, best-corrected visual acuity (BCVA) will be assessed on the 
Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting test 
distance of 4 meters.
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of faricimab 6 mg 
intravitreal (IVT) Q4W compared with aflibercept 2 mg IVT Q4W on the basis of the following 
endpoint:

Change from baseline in BCVA at Week 24
Secondary Efficacy Objectives
The secondary efficacy objective for Part 1 of this study (i.e., through Week 24) is to evaluate 
the efficacy of faricimab compared with aflibercept on the basis of the following endpoints:

Change from baseline in BCVA at specified timepoints through Week 24

Proportion of patients gaining 15 letters in BCVA from baseline at Week 24


Faricimab—F. Hoffmann-La Roche Ltd
14/Protocol GR41986, Version 2

Proportion of patients gaining 15, 10, 5, or 0 letters in BCVA from baseline at 
specified timepoints through Week 24

Proportion of patients avoiding a loss of 15, 105, or 0 letters in BCVA from baseline 
at specified timepoints through Week 24

Proportion of patients achieving 84 letters (20/20 Snellen equivalent) in BCVA at specified 
timepoints through Week 24

Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints through Week 24

Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints through Week 24

Change from baseline in central subfield thickness (CST) at specified timepoints through 
Week 24

Change from baseline in National Eye Institute 25-Item Visual Functioning Questionnaire
(NEI VFQ-25) composite score at specified timepoints through Week 24
The secondary efficacy objective for Part 2 of this study (i.e., Week 24 through Week 72) is to 
evaluate the efficacy of faricimab administered according to the PTI dosing regimen on the 
basis of the following endpoints:

Change from baseline in BCVA at specified timepoints from Week 24 through Week 72

Proportion of patients gaining 15 letters in BCVA from baseline at Week 72

Proportion of patients gaining 15, 10, 5, or 0 letters in BCVA from baseline at 
specified timepoints from Week 24 through Week 72

Proportion of patients avoiding a loss of 15, 105, or 0 letters in BCVA from baseline 
at specified timepoints from Week 24 through Week 72

Proportion of patients achieving 84 letters (20/20 Snellen equivalent) in BCVA at specified 
timepoints from Week 24 through Week 72

Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints from Week 24 through Week 72

Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints from Week 24 through Week 72

Change from Week 24 in BCVA at specified timepoints through Week 72

Proportion of patients avoiding a loss of 15, 105, or 0 letters in BCVA from Week 24 
through Week 72

Proportion of patients on a Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or Q16W 
treatment interval at Week 72

Number of study drug injections received from Week 24 through Week 72

Change from baseline in CST at specified timepoints from Week 24 through Week 72

Change from baseline in NEI VFQ-25 composite score at specified timepoints from Week 
24 through Week 72
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of faricimab on the 
basis of the following endpoints:

Proportion of patients with absence of retinal ischemia on fundus fluorescein angiography 
(FFA) and on optical coherence tomography angiography (OCT-A) (optional) over time (at 
specified timepoints)

Change from baseline in area of retinal ischemia on FFA and on OCT-A (optional) over time

Proportion of patients with vascular leakage on FFA and on OCT-A (optional) over time

Change from baseline in area of vascular leakage on FFA, and on OCT-A (optional) over 
time


Faricimab—F. Hoffmann-La Roche Ltd
15/Protocol GR41986, Version 2

Change from baseline in foveal avascular zone and other exploratory outputs defined in the 
Statistical Analysis Plan (SAP) on OCT-A (optional) over time

Proportion of patients with absence of retinal neovascularization over time (per investigator 
assessment)

Proportion of patients with absence of vitreal, preretinal, or subretinal hemorrhage over time 
(per investigator assessment)

Proportion of patients with absence of anterior segment (iris and anterior chamber angle) 
neovascularization over time

Proportion of patients requiring panretinal photocoagulation at any time during the study

Proportion of patients with absence of macular edema, defined as CST of 325 m for 
Spectralis spectral-domain optical coherence tomography (SD-OCT), or 315 m for Cirrus 
SD-OCT or Topcon SD-OCT, over time

Proportion of patients with absence of intraretinal fluid over time

Proportion of patients with absence of subretinal fluid over time

Proportion of patients with absence of both intraretinal fluid and subretinal fluid over time

Proportion of patients with absence of intraretinal cysts over time

Change from baseline in NEI VFQ-25 near activitiessubscale score and distance 
activitiessubscale scores over time
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of faricimab on the 
basis of the following endpoints:

Incidence and severity of ocular adverse events, with severity determined according to 
Adverse Event Severity Grading Scale

Incidence and severity of non-ocular adverse events, with severity determined according to 
Adverse Event Severity Grading Scale
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objective for this study is to characterize the faricimab PK profile on 
the basis of the following endpoint:

Plasma concentration of faricimab over time
The exploratory PK objective for this study is to explore the concentrationeffect relationship for 
visual acuity and other endpoints (e.g., anatomic measures) on the basis of the following 
endpoint:

Concentration of faricimab and the change in BCVA or other endpoints (e.g., anatomical 
markers) over time
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the antibody immune response to 
faricimab on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints


Faricimab—F. Hoffmann-La Roche Ltd
16/Protocol GR41986, Version 2
EXPLORATORY BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to faricimab (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of faricimab activity (i.e., 
pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Relationship between biomarkers in plasma (listed in Section 4.5.7) and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints

Relationship between baseline anatomic measures and the change in BCVA or other 
endpoints (e.g., the frequency of faricimab administration) over time

Relationship between anatomic measures and visual acuity
EXPLORATORY SUBSTUDY
At selected sites, the Sponsor may propose exploratory substudies associated with the Study 
GR41986 protocol.  Each substudy will be documented in a separate substudy protocol and 
will have a separate associated Informed Consent Form.
STUDY DESIGN
DESCRIPTION OF STUDY
This is a Phase III, multicenter, randomized, double-masked, active comparatorcontrolled, 
parallel-group study evaluating the efficacy, safety, and pharmacokinetics of 
faricimab administered by IVT injection at 4-week intervals until Week 24, followed by a 
double-masked period of study without active control to evaluate faricimab administered 
according to a PTI dosing regimen in patients with macular edema due to CRVO or HRVO.
This study is comprised of two parts: Part 1 (Day 1 through Week 24) will compare faricimab 
Q4W versus aflibercept (active comparator) Q4W; Part 2 (Weeks 2472) will evaluate faricimab 
administered at masked treatment intervals of Q4W to Q16W based on PTI dosing criteria.
The study will consist of a screening period of up to 28 days (Days 28 to 1) and an 
approximately 68-week treatment period (Parts 1 and 2), followed by the final study visit at 
Week 72.  All patients will complete scheduled study visits Q4W for the entire study duration 
(72 weeks).  To preserve the masking of faricimab treatment intervals for Week 24 through 
Week 68, a sham procedure will be administered during study visits at which (according to the 
PTI dosing regimen) no faricimab treatment is administered.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the eye 
with the worse BCVA, as assessed at screening, will be selected as the study eye, unless the 
investigator deems the other eye to be more appropriate for treatment in the study. 
There will be a minimum of two investigators per site to fulfill the masking requirements of the 
study.  At least one investigator will be designated as the assessor physician who will be 
masked to each patient’s treatment assignment and who will evaluate ocular assessments.  At 
least one other investigator will be unmasked and will perform study treatments. 
Patient recruitment is expected to take longer in China; therefore, a specific China enrollment 
plan may be established.  After the global enrollment phase of the study has been completed, 
additional patients may be enrolled in a China extension to ensure a total enrollment that is 
sufficient to support registration in China.  The China extension may include current residents of 
mainland China, Hong Kong, or Taiwan enrolled at National Medical Products Administration 
(NMPA)-recognized sites.  All Chinese patients enrolled in the global enrollment phase of the 
study will be included in the primary analysis of the study.  Data from patients enrolled during 
the China extension will not be included in the primary analyses.
NUMBER OF PATIENTS
Approximately 750 patients with macular edema due to CRVO or HRVO will be enrolled during 
the global enrollment phase of this study.


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TARGET POPULATION
Inclusion Criteria
General Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 3 months after the final dose of study 
treatment.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For patients enrolled in the extended China enrollment phase at NMPA-recognized sites:  
current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
Ocular Inclusion Criteria for Study Eye
Patients must also meet the following ocular criteria for study entry:

Foveal center–involved macular edema due to CRVO or HRVO diagnosed no longer than 
4 months prior to the screening visit and confirmed by central reading center (CRC) based 
on SD-OCT (or SS-OCT) images
CRVO or HRVO is defined by retinal hemorrhages, telangiectatic capillary bed, dilated 
venous system or other biomicroscopic evidence of retinal vein occlusion (RVO; 
neovascularization, vitreous hemorrhages) in the entire retina (CRVO) or two 
quadrants of the retina (HRVO)

BCVA of 73 to 19 letters, inclusive (20/40 to 20/400 approximate Snellen equivalent), as 
assessed on the ETDRS visual acuity chart at a starting test distance of 4 meters (see the 
BCVA manual for additional details) on Day 1

CST 325 m, as measured on Spectralis SD-OCT, or 315 m, as measured on Cirrus 
SD-OCT or Topcon SD-OCT at screening (SS-OCT acceptable after confirmation with CRC)

Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis


Faricimab—F. Hoffmann-La Roche Ltd
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Exclusion Criteria
General Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Any major illness or major surgical procedure within 1 month before screening

Active cancer within the 12 months prior to Day 1 except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with 
a Gleason score of 6 and a stable prostate-specific antigen for 12 months

Requirement for continuous use of any medications and treatments indicated in 
Section 4.4.2 (Prohibited Therapy)

Systemic treatment for suspected or active systemic infection on Day 1
Ongoing use of prophylactic antibiotic therapy may be acceptable if approved after 
discussion with the Medical Monitor.

Any systemic corticosteroid use (e.g., oral or injectable) within 1 month of the screening visit

Uncontrolled blood pressure, defined as systolic blood pressure 180 mmHg and/or 
diastolic blood pressure 110 mmHg while a patient is at rest on Day 1
If a patient’s initial reading exceeds these values, a second reading may be taken later 
on the same day or on another day during the screening period.  If the patient’s blood 
pressure is controlled by antihypertensive medication, the patient should be taking the 
same medication continuously for at least 30 days prior to Day 1.

Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to Day 1

History of other disease, metabolic dysfunction, physical examination finding, or historical or 
current clinical laboratory findings giving reasonable suspicion of a condition that 
contraindicates the use of the investigational drug or that might affect interpretation of the 
results of the study or renders the patient at high risk for treatment complications in the 
opinion of the investigator

Pregnant or breastfeeding, or intending to become pregnant during the study
Women of childbearing potential must have a negative urine pregnancy test result 
within 28 days prior to initiation of study drug.  If the urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.

History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the faricimab or aflibercept injections, study- related 
procedure preparations (including fluorescein), dilating drops, or any of the anesthetic and 
antimicrobial preparations used during the study

Participation in an investigational trial that involves treatment with any drug or device (with 
the exception of vitamins and minerals) within 3 months prior to Day 1
Ocular Exclusion Criteria for Study Eye
Patients who meet any of the following ocular exclusion criteria for the study eye will be 
excluded from study entry:

History of previous episodes of macular edema due to RVO or persistent macular edema 
due to RVO diagnosed more than 4 months before screening

Increase of 10 letters in BCVA ETDRS score between screening and Day 1

Any current ocular condition which, in the opinion of the investigator, is currently causing or 
could be expected to contribute to irreversible vision loss due to a cause other than macular 
edema due to RVO in the study eye (e.g., ischemic maculopathy, Irvine-Gass 
syndrome, foveal atrophy, foveal fibrosis, pigment abnormalities, dense subfoveal hard 
exudates, or other non-retinal conditions)

Current visually significant vitreous hemorrhage on Day 1

History of retinal detachment or macular hole (Stage 3 or 4)

Tractional retinal detachment, vitreomacular traction, full thickness macular hole or 
epiretinal membrane involving the fovea or disrupting the macular architecture in the study 
eye, as evaluated by the CRC and described in the CRC manual


Faricimab—F. Hoffmann-La Roche Ltd
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
Diagnosis of diabetic retinopathy (DR) moderate non-proliferative or worse, proliferative DR, 
diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), 
geographic atrophy, myopic choroidal neovascularization as assessed by the investigator

Active rubeosis, angle neovascularization, neovascular glaucoma

Aphakia or implantation of anterior chamber intraocular lens

Any cataract surgery or treatment for complications of cataract surgery with steroids or YAG 
(yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1

Any other intraocular surgery (e.g., pars plana vitrectomy, scleral buckle, glaucoma surgery, 
corneal transplant, or radiotherapy)

Any prior or current treatment for macular edema due to RVO, including antivascular 
endothelial growth factor (VEGF) IVT for macular edema due to RVO

Macular laser (focal/grid) in the study eye at any time prior to Day 1

Panretinal photocoagulation in the study eye within 3 months prior to Day 1 or anticipated 
within 3 months of study start on Day 1

Any IVT treatment for any other retinal diseases that can lead to macular edema 
complication

Any prior or current treatment for macular edema; macular neovascularization, including 
DME and nAMD; and vitreomacular-interface abnormalities, including, but not restricted to, 
IVT treatment with anti-VEGF, steroids, tissue plasminogen activator, ocriplasmin, C3F8, air 
or periocular injection

Any prior intervention with verteporfin photodynamic therapy, diode laser, transpupillary 
thermotherapy, or vitreo-retinal surgery including sheathotomy

Any prior steroid implant use including dexamethasone intravitreal implant (Ozurdex) and 
fluocinolone acetonide intravitreal implant (Iluvien)

Prior periocular pharmacological or IVT treatment (including anti-VEGF medication) for 
other retinal diseases
Ocular Exclusion Criteria for Fellow (Non-Study) Eye
Patients who meet the following ocular exclusion criterion for the fellow (non-study) eye at both 
screening and Day 1 will be excluded from study entry:

Non-functioning fellow eye, defined as either one of the following:
–
BCVA 20/320 or worse
–
No physical presence of fellow eye (i.e., monocular)
Ocular Exclusion Criteria for Both Eyes
Patients who meet any of the following ocular exclusion criteria for both eyes will be excluded 
from study entry:

Prior IVT administration of faricimab in either eye

History of idiopathic or autoimmune-associated uveitis in either eye

Active periocular, ocular or intraocular inflammation or infection (including suspected) in 
either eye on Day 1
END OF STUDY
The study consists of two enrollment phases:  the global enrollment phase, during which 
patients are recruited globally; and an optional China extension phase, during which additional 
patients may be recruited in China to support registration in China.
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
including patients from the optional China extension.  The end of the study is expected to occur 
approximately 72 weeks after the last patient is randomized.
The Sponsor may decide to terminate the study at any time.


Faricimab—F. Hoffmann-La Roche Ltd
20/Protocol GR41986, Version 2
LENGTH OF STUDY
The total length of the study (excluding the China extension) from screening of the first patient 
to the LPLV for patients from the global enrollment phase is expected to be approximately 
34 months.
INVESTIGATIONAL MEDICINAL PRODUCTS
TEST PRODUCT (INVESTIGATIONAL DRUG)
In Part 1 of the study, patients randomly assigned to Arm A will receive faricimab 6 mg IVT 
Q4W from Day 1 through Week 20, for a total of 6 injections.
In Part 2 of the study, patients randomly assigned to both Arms A and B will receive 
faricimab 6 mg IVT administered according to a PTI dosing regimen in intervals between 
Q4W and Q16W.  At faricimab dosing visits, treatment intervals will be maintained or adjusted 
(i.e., increased by 4 weeks or decreased by 4, 8, or 12 weeks), based on CST and BCVA 
values.  Patients will therefore receive between 3 and 12 injections during the period from 
Week 24 through Week 68.
COMPARATOR
In Part 1 of the study, patients randomly assigned to Arm B will receive aflibercept 2 mg IVT 
Q4W from Day 1 through Week 20, for a total of 6 injections.
SHAM PROCEDURE
During Part 2 of the study, to preserve the masking of faricimab treatment intervals, the sham 
procedure will be administered to patients in both Arms A and B during study visits at which 
(according to the PTI dosing regimen) no faricimab treatment is administered.  The sham vial is 
empty and will remain empty throughout the sham treatment.  The sham is a procedure that 
mimics an IVT injection and involves the blunt end of an empty syringe (without a needle) being 
pressed against the anesthetized eye.
STATISTICAL METHODS
PRIMARY ANALYSIS
The primary and secondary efficacy analyses will be based on the intent-to-treat (ITT)
population, unless otherwise specified, with patients grouped according to the treatment 
assigned at randomization.  Additional analysis based on the per-protocol population will also 
be conducted for the primary endpoint.
The primary comparison will be between the active comparator (aflibercept Q4W) and faricimab 
Q4W at Week 24.  The following hypothesis will be tested:

Non-inferiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT
population (at a 1-sided 0.025 significance level)

Superiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population (at a 2-sided 0.05 significance level)
The primary analysis will be performed using the mixed-effect model with repeated measures 
(MMRM) based on all available data up to Week 24.  All observed measurements will be 
included in the analysis regardless whether or not a patient has an intercurrent event.  Missing 
data will be implicitly imputed by the MMRM model, assuming a missing at random mechanism.
The MMRM model will include the change from baseline at Weeks 424 as the response 
variable and will include the categorical covariates of treatment group, visit, visit-by-treatment 
group interaction, the continuous baseline value for the response variable (in this case, baseline 
BCVA), as well as randomization stratification factors as fixed effects.  The MMRM model will 
assume an unstructured covariance structure.  If there are convergence problems with the 
model, a heterogeneous compound symmetry or an AR(1) covariance structure may be fitted.
DETERMINATION OF SAMPLE SIZE 
Determination of sample size is based on patients enrolled in the global enrollment phase.  The 
global enrollment phase will enroll approximately 750 patients.  Patients will be randomized in a 
1:1 ratio to receive treatment with faricimab (Arm A) or aflibercept (Arm B).


Faricimab—F. Hoffmann-La Roche Ltd
21/Protocol GR41986, Version 2
A sample size of approximately 375 patients in each arm will provide 90% power to show 
non-inferiority of faricimab to aflibercept in the change in BCVA at Week 24 in the ITT
population, using a non-inferiority margin of 4 letters, and under the following assumptions:

No difference in the mean change from baseline in BCVA between the two treatment arms

SD of 13 letters for the change from baseline in BCVA at Week 24

Two-sample t-tests

2.5% one-sided type I error rate

10% dropout rate
Furthermore, a sample size of approximately 375 patients per arm will provide greater than 
80% power to show a 3.5-letter superiority of faricimab over aflibercept in the ITT population, 
under the same SD, test, and dropout assumptions above, and a two-sided type I error rate of 
5%.
INTERIM ANALYSES
There are no prospectively planned interim efficacy or futility analyses.


Faricimab—F. Hoffmann-La Roche Ltd
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
BCVA
best-corrected visual acuity
BRVO
branch retinal vein occlusion
CFP
color fundus photograph
CNV
choroidal neovascularization
CRC
central reading center
CRVO
central retinal vein occlusion
CST
central subfield thickness
DME
diabetic macular edema
DR
diabetic retinopathy
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FFA
fundus fluorescein angiography
HIPAA
Health Insurance Portability and Accountability Act
HRVO
hemiretinal vein occlusion
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee 
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent-to-treat (population)
IVT
intravitreal
IxRS
interactive web-based response system
LPLV
last patient, last visit
MMRM
mixed model for repeated measures
nAMD
neovascular age-related macular degeneration
NEI VFQ-25
National Eye Institute 25-Item Visual Functioning 
Questionnaire 
NIMP
non-investigational medicinal product
NMPA
(China) National Medical Products Administration
OCT
optical coherence tomography


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Abbreviation
Definition
OCT-A
optical coherence tomographyangiography
PD
pharmacodynamic
PK
pharmacokinetic
PRO
patient-reported outcome
PTI
personalized treatment interval
Q4W
every 4 weeks
Q8W
every 8 weeks
Q12W
every 12 weeks
Q16W
every 16 weeks
RBR
Research Biosample Repository
RVO
retinal vein occlusion
SAP
Statistical Analysis Plan
SD
standard deviation
SD-OCT
spectral-domain optical coherence tomography
SmPC
Summary of Product Characteristics
SS-OCT
swept-source optical coherence tomography
Tie2
TEK receptor tyrosine kinase-2
ULN
upper limit of normal
USPI
U.S. Package Insert
UWF
ultrawide field
VA
visual acuity
VEGF (-A)
vascular endothelial growth factor (A)
WES
whole exome sequencing
WGS
whole genome sequencing


Faricimab—F. Hoffmann-La Roche Ltd
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1.
BACKGROUND
1.1
BACKGROUND ON RETINAL VEIN OCCLUSION
Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders and 
is associated with varying degrees of visual loss (Hayreh and Zimmerman 1994).  RVO 
has been reported as the second leading cause of blindness for patients with retinal 
vascular disease, following diabetic retinopathy (DR) (Cugati et al. 2006; Klein et al. 
2008; Rogers et al. 2010; Yasuda et al. 2010).  The main types of RVO include branch 
retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal 
vein occlusion (CRVO). 
The most common presenting complaint of RVO is an abrupt, painless decrease of 
central vision due to macular edema.  Less frequently, patients may present with a 
history of transient vision loss, lasting a few seconds to minutes, with complete recovery 
of vision.  These symptoms may recur over several days to weeks, followed by a 
permanent decrease in vision.  Metamorphopsia and visual field defects have also been 
described (Achiron et al. 2015; Manabe et al. 2017).
The pathogenesis of macular edema in these patients starts with an increase in 
intraluminal pressure due to vascular obstruction, which causes areas of reduced 
perfusion and ischemia.  Ischemia leads to up-regulation and secretion of vascular 
endothelial growth factor (VEGF) (Boyd et al. 2002; Noma et al. 2006) and 
angiopoietin-2 (Ang-2), both well-known proangiogenic and vessel hyperpermeability 
cytokines with Ang-2 contributing additional pro-inflammatory and vessel destabilization 
properties (Maisonpierre at al. 1997; Hackett et al 2000; Fiedler et al 2006).  Patients 
with RVO were found to have the highest vitreous levels of both Ang-2 and VEGF 
among all retinal vascular diseases (Aiello et al 1994; Regula et al. 2016).  Increased 
levels of Ang-2 and VEGF in retinal tissue result in pathological changes in the retina,
and in many patients also leads to macular edema that is accompanied with a decrease 
in vision.  A hallmark of RVO is the characteristic pattern of retinal hemorrhages, 
tortuous and dilated retinal veins across the affected area of retina (one quadrant in 
BRVO, two quadrants in HRVO and the entire retina in CRVO).  In more severe cases, 
patients can develop retinal ischemia with subsequent retinal neovascularization, 
hemorrhages, neovascularization in the anterior segment leading to rubeosis or 
neovascular glaucoma, and some patients may develop optic disc edema.
Although macular edema due to RVO and diabetic macular edema (DME) have different 
origins, they share a common pathophysiology.  Both are characterized by a thickening 
of the macula due to fluid accumulation consequent to breakdown of the blood-retinal
barrier and a pathological increase of retinal vessel permeability, which can lead to 
irreversible vision loss in both diseases.


Faricimab—F. Hoffmann-La Roche Ltd
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Anti-VEGF pharmacotherapy is the current mainstay of treatment in macular edema due 
to RVO and has demonstrated efficacy across several pivotal, randomized clinical 
studies, although macular laser and intravitreal (IVT) steroidsespecially steroid 
implantsare also used in some cases.  Despite anti-VEGF being the most effective 
therapy for macular edema due to RVO, data from anti-VEGF clinical trials showed that 
many patients do not achieve optimal best-corrected visual acuity (BCVA) and 
anatomical outcomes, and many require frequent long-term injections to maintain the 
gains achieved during initial intensive treatment.  Moreover, real-world data analyses 
suggested that many patients with RVO do not achieve the gains reached in clinical 
trials due to suboptimal injection frequency (Vaz-Pereira et al. 2017; Wecker et al. 2017; 
Jumper et al. 2018; LUMINOUS and OCEAN unpublished data).  The data suggest that 
many patients with macular edema due to BRVO and the majority of patients with 
macular edema due to CRVO require close monitoring and treatment for longer periods
of time and that more durable and efficacious treatment options are needed (Bhisitkul et 
al. 2012; Scott et al. 2019).
1.2
BACKGROUND ON FARICIMAB
Faricimab is a humanized full-length bispecific IgG1 monoclonal antibody that selectively 
binds to all isoforms of VEGF-A (hereafter referred to as "VEGF") and Ang-2, key factors 
involved in mediating the pathophysiology of macular edema due to RVO.  The Ang-2
and VEGF-binding variable regions of faricimab bind to Ang-2 and VEGF independently 
and simultaneously with high affinity.  The Fc portion of faricimab was engineered for 
ophthalmic use through inactivation of the effector function (FcR) and elimination of 
binding to the neonatal receptor (FcRn), which has the potential to reduce systemic 
exposure following IVT injection.
Nonclinical studies have shown that Ang-2 and VEGF act in concert to regulate the 
vasculature and to increase retinal endothelial cell permeability in vitro.  Simultaneous 
inhibition of Ang-2 and VEGF with the bispecific monoclonal antibody faricimab led to a 
greater reduction in the leakiness and severity of choroidal neovascularization (CNV)
lesions in a laser-induced CNV model in non-human primates compared with the molar 
equivalent of antiVEGF (ranibizumab) or antiAng-2 alone.  Earlier experiments using a 
mouse model of spontaneous CNV showed that dual inhibition of Ang-2 and VEGF 
consistently outperformed monotherapeutic inhibition of either target alone in terms of 
reduction in vascular growth, leakage, edema, leukocyte infiltration, and photoreceptor 
loss (Regula et al. 2016).
In addition, aqueous and vitreous concentrations of both Ang-2 and VEGF were shown 
to be upregulated in patients with neovascular age-related macular degeneration
(nAMD), DR, and RVO (Tong et al 2006; Penn et al. 2008; Kinnunen et al. 2009; 
Tuuminen and Loukovaara 2014; Regula et al. 2016; Ng et al. 2017).  Therefore, 
simultaneous neutralization of both targets, Ang-2 and VEGF, may further normalize the 
pathological ocular vasculature compared with anti-VEGF therapy alone.  Data from the 


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completed Phase II studies in DME and nAMD (see below) also support the hypothesis 
that targeting Ang-2 has the potential to extend the durability of effect beyond anti-VEGF 
therapy alone in diseases affecting the retinal vasculature.
Faricimab has been studied for the treatment of nAMD and DME in two Phase I studies 
(BP28936 in nAMD and JP39844 in nAMD and DME) and in three Phase II studies 
(BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 
[BOULEVARD] for DME).  Four global Phase III studies are ongoing:  GR40349 
(YOSEMITE) and GR40398 (RHINE) in DME and GR40306 (TENAYA) and GR40844 
(LUCERNE) in nAMD.
Based on the mechanism of action of faricimab, data from nonclinical and clinical trials, 
and the pathophysiology of macular edema due to RVO, it is hypothesized that faricimab 
may lead to stabilization of the pathological ocular vasculature and to improved visual 
and anatomical outcomes in RVO compared with anti-VEGF monotherapies.
Refer to the Faricimab (RO6867461) Investigator’s Brochure for details on nonclinical 
and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Over the past decade, the use of anti-VEGF therapies (for example, ranibizumab 
[Lucentis®] and aflibercept [Eylea®]) in macular edema due to RVO has greatly improved 
visual outcomes and prognosis for patients.  Despite this, some patients still do not 
achieve sufficient vision gains to enable reading or driving.  Data from the clinical trials 
with anti-VEGF agents in RVO and analyses of RVO outcomes in the real world suggest 
an unmet need for 1) treatments that would more fully address the underlying disease 
pathology by targeting molecular pathways beyond VEGF and deliver better efficacy, 
and 2) more durable treatments that would address the current requirement for frequent 
and often long-term administration to maintain vision gains (Wecker et al. 2016; Spooner 
et al. 2019).  Addressing both potentially better efficacy through novel multi-targeting 
molecules and the real-world issue of suboptimal dosing with more durable treatment 
options would have a positive impact for patients, caregivers, and the entire health care 
system.
Therefore, clinical evaluation of therapies with additional mechanisms of action is 
warranted to further improve upon the clinical benefit of currently approved anti-VEGF 
therapies.  In addition, many patients require frequent IVT injections for prolonged 
periods of time to maintain their vision, placing a significant burden on patients, 
caregivers, and healthcare providers.  Real-world outcomes do not mirror the optimal 
outcomes observed in clinical trials, which also underscores the clear clinical need for 
therapies with a more sustained effect, which would require less frequent office visits 
and offer dosing intervals tailored to individual need, while still providing visual acuity 
outcomes comparable to those observed in clinical trials.


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The objective of the current Phase III study is to address the existing unmet need of 
improved efficacy and extended durability of treatment, both of which would represent an 
important advance for patients with macular edema due to CRVO or HRVO.
1.3.1
Benefits
The elevated levels of both Ang-2 and VEGF in vitreous samples from patients with 
macular edema due to RVO are among the highest in retinal vascular diseases (Aiello 
et al. 1994; Regula et al. 2016).  The effect of Ang-2 and VEGF inhibition in the 
nonclinical models of angiogenesis and inflammation (Regula et al. 2016) and the data 
from Phase I and Phase II faricimab studies in patients with nAMD and DME provide the 
evidence of efficacy on pathological pathways that are common to all three retinal 
vascular diseases: nAMD, DME/DR, and macular edema due to RVO (Phase I study 
BP28936 in nAMD; Phase II studies AVENUE in nAMD, STAIRWAY in nAMD, and 
BOULEVARD in DME).
Data from the Phase II BOULEVARD study is reported here due to parallels in 
pathophysiology between DME and macular edema due to RVO.  While the trigger for 
macular edema in diabetic and RVO patients is different, the downstream 
pathophysiology of hypoxia-driven macular edema with subsequent vision loss is similar 
and driven by the same proangiogenic, pro-inflammatory, vessel destabilization and 
vessel permeability factors, including Ang-2, VEGF, and interleukin-6 (IL-6).
The BOULEVARD study provided preliminary evidence of a positive benefitrisk profile 
for the use of 6-mg IVT injections of faricimab for patients with DME and supported 
further evaluation of faricimab in the Phase III DME studies.  The study met its primary 
efficacy endpoint, demonstrating statistically significant improvement in the mean 
change from baseline in BCVA at Week 24 in patients naive to anti-VEGF treatment who 
were treated with 6 mg faricimab compared with 0.3 mg ranibizumab.
The outcomes in the off-treatment study observation period provided evidence of 
prolonged duration of effect with faricimab compared with anti-VEGF monotherapy.  
Assessment of time to disease reactivation up to 16 weeks after the last dose showed 
an improvement in the duration of the effect of faricimab over ranibizumab, as measured 
by the time to loss of 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters 
because of DME and an increase 50 m in central subfield thickness (CST), in the 
treatment-naive patient population in a dose-dependent manner.  This improvement in 
the duration of effect of faricimab over ranibizumab was also seen in the previously 
treated group and the overall patient group.
Based on the totality of this nonclinical and clinical evidence, it is anticipated that the 
well-established anti-VEGF mechanism of action combined with anti-Ang-2 targeting in 
the bispecific faricimab molecule could lead to improved efficacy over anti-VEGF 
standard of care in patients with macular edema due to RVO.  Additionally, this study will 
investigate a less frequent treatment administration schedule tailored to individual need 


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(up to every 16 weeks) that could provide BCVA outcomes comparable to those of more 
frequently administered anti-VEGF monotherapy (e.g., every 4 to 8 weeks). Together,
these would represent an important and meaningful advance relative to currently 
available therapies.
1.3.2
Risks
Nonclinical toxicology studies did not reveal any adverse effects that require specific 
warnings and precautions that are different from those applicable to any anti-VEGF 
agents currently used in clinical practice for the treatment of RVO.
In Phase I and II clinical studies in nAMD and DME, more than 400 patients have been 
exposed to at least one dose of faricimab.  More than 1600 patients have been exposed 
to faricimab in ongoing Phase III studies in the same indications.  No new or unexpected 
safety signals have been observed to date.
In the Phase I study (BP28936), faricimab was well tolerated up to the highest dose 
tested of 6 mg in previously treated patients with nAMD (Chakravarthy et al. 2017).  No 
dose-limiting events or unexpected ocular adverse events were observed, and no 
non-ocular study drugrelated serious adverse events or severe adverse events were 
reported. 
The Phase II studies in nAMD (AVENUE and STAIRWAY) and DME (BOULEVARD) 
demonstrated that faricimab has an acceptable tolerability and safety profile, with no 
new or unexpected safety signals.  The ocular and non-ocular safety findings for 
faricimab were generally consistent with the safety profile of approved intravitreally 
administered anti-VEGF products in patients with nAMD or DME.  The safety profile of 
faricimab in patients with macular edema due to RVO is anticipated to be comparable to 
that in nAMD and DME. 
Refer to the Faricimab (RO6867461) Investigator's Brochure for details on safety results 
from nonclinical and clinical Phase I and Phase II studies.
1.3.3
Conclusions
The available data from nonclinical studies and available Phase I and II efficacy and 
safety data in nAMD and DME support the positive benefitrisk assessment for the 
initiation of this Phase III study to establish the efficacy, safety, pharmacokinetics, and 
personalized treatment interval (PTI) dosing of faricimab administered every 4 weeks 
(Q4W) until Week 24 and in the intervals from Q4W up to every 16 weeks (Q16W) 
thereafter in patients with macular edema due to RVO.


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab
compared with aflibercept in patients with macular edema due to CRVO or HRVO (as 
defined in Section 4.1.1.2) up to the primary endpoint at Week 24.  Efficacy, safety, and 
pharmacokinetics of faricimab administered according to the PTI dosing regimen 
(i.e., from Q4W to Q16W) will be assessed during the study period from Week 24 to 
Week 72.  Specific objectives and corresponding endpoints for the study are outlined 
below.
In this protocol, "study drug" refers to faricimab or aflibercept and "study treatment" 
refers to faricimab, aflibercept, or the sham procedure (see Section 4.3.1 for further 
details).
2.1
EFFICACY OBJECTIVES
For efficacy endpoint evaluation, BCVA will be assessed on the ETDRS visual acuity 
chart at a starting test distance of 4 meters (see Section 4.5.5).
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of faricimab 6 mg 
IVT Q4W compared with aflibercept 2 mg IVT Q4W on the basis of the following 
endpoint:

Change from baseline in BCVA at Week 24
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objective for Part 1 of this study (i.e., through Week 24) is to 
evaluate the efficacy of faricimab compared with aflibercept on the basis of the following 
endpoints:

Change from baseline in BCVA at specified timepoints through Week 24

Proportion of patients gaining 15 letters in BCVA from baseline at Week 24

Proportion of patients gaining 15, 10, 5, or 0 letters in BCVA from baseline at 
specified timepoints through Week 24

Proportion of patients avoiding a loss of 15, 105, or 0 letters in BCVA from 
baseline at specified timepoints through Week 24

Proportion of patients achieving 84 letters (20/20 Snellen equivalent) in BCVA at 
specified timepoints through Week 24

Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints through Week 24


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
Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints through Week 24

Change from baseline in CST at specified timepoints through Week 24

Change from baseline in National Eye Institute 25-Item Visual Functioning 
Questionnaire (NEI VFQ-25) composite score at specified timepoints through 
Week 24
The secondary efficacy objective for Part 2 of this study (i.e., Week 24 through Week 72) 
is to evaluate the efficacy of faricimab administered according to the PTI dosing regimen 
on the basis of the following endpoints:

Change from baseline in BCVA at specified timepoints from Week 24 through 
Week 72

Proportion of patients gaining 15 letters in BCVA from baseline at Week 72

Proportion of patients gaining 15, 10, 5, or 0 letters in BCVA from baseline at 
specified timepoints from Week 24 through Week 72

Proportion of patients avoiding a loss of 15, 105, or 0 letters in BCVA from 
baseline at specified timepoints from Week 24 through Week 72

Proportion of patients achieving 84 letters (20/20 Snellen equivalent) in BCVA at 
specified timepoints from Week 24 through Week 72

Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints from Week 24 through Week 72

Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints from Week 24 through Week 72

Change from Week 24 in BCVA at specified timepoints through Week 72

Proportion of patients avoiding a loss of 15, 105, or 0 letters in BCVA from 
Week 24 through Week 72

Proportion of patients on a Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or 
Q16W treatment interval at Week 72

Number of study drug injections received from Week 24 through Week 72

Change from baseline in CST at specified timepoints from Week 24 through 
Week 72

Change from baseline in NEI VFQ-25 composite score at specified timepoints from 
Week 24 through Week 72
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of faricimab on 
the basis of the following endpoints:

Proportion of patients with absence of retinal ischemia on fundus fluorescein 
angiography (FFA) (as specified in Section 4.5.5) and on optical coherence 
tomography angiography (OCT-A) (optional) over time (at specified timepoints)


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
Change from baseline in area of retinal ischemia on FFA and on OCT-A (optional) 
over time

Proportion of patients with vascular leakage on FFA and on OCT-A (optional) over 
time

Change from baseline in area of vascular leakage on FFA, and on OCT-A (optional) 
over time

Change from baseline in foveal avascular zone and other exploratory outputs 
defined in the Statistical Analysis Plan (SAP) on OCT-A (optional) over time

Proportion of patients with absence of retinal neovascularization over time (per 
investigator assessment) 

Proportion of patients with absence of vitreal, preretinal, or subretinal hemorrhage 
over time (per investigator assessment)

Proportion of patients with absence of anterior segment (iris and anterior chamber 
angle) neovascularization over time

Proportion of patients requiring panretinal photocoagulation at any time during the 
study

Proportion of patients with absence of macular edema, defined as CST of 325 m 
for Spectralis SD-OCT, or 315 m for Cirrus SD-OCT or Topcon SD-OCT, over 
time

Proportion of patients with absence of intraretinal fluid over time

Proportion of patients with absence of subretinal fluid over time

Proportion of patients with absence of both intraretinal fluid and subretinal fluid over 
time

Proportion of patients with absence of intraretinal cysts over time

Change from baseline in NEI VFQ-25 near activitiessubscale score and distance 
activitiessubscale scores over time
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of faricimab on 
the basis of the following endpoints:

Incidence and severity of ocular adverse events, with severity determined according 
to Adverse Event Severity Grading Scale (see Table 2)

Incidence and severity of non-ocular adverse events, with severity determined 
according to Adverse Event Severity Grading Scale (see Table 2)
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objective for this study is to characterize the faricimab PK 
profile on the basis of the following endpoint:

Plasma concentration of faricimab over time


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The exploratory PK objective for this study is to explore the concentrationeffect 
relationship for visual acuity and other endpoints (e.g., anatomic measures) on the basis 
of the following endpoint:

Concentration of faricimab and the change in BCVA or other endpoints 
(e.g., anatomical markers) over time
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the antibody immune 
response to faricimab on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
2.5
EXPLORATORY BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to faricimab (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of faricimab activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints:

Relationship between biomarkers in plasma (listed in Section 4.5.7) and efficacy, 
safety, PK, immunogenicity, or other biomarker endpoints

Relationship between baseline anatomic measures and the change in BCVA or 
other endpoints (e.g., the frequency of faricimab administration) over time

Relationship between anatomic measures and visual acuity
2.6
EXPLORATORY SUBSTUDY
At selected sites, the Sponsor may propose exploratory substudies associated with the 
Study GR41986 protocol. Each substudy will be documented in a separate substudy 
protocol and will have a separate associated Informed Consent Form. 


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, multicenter, randomized, double-masked, active 
comparatorcontrolled, parallel-group study evaluating the efficacy, safety, and 
pharmacokinetics of faricimab administered by IVT injection at 4-week intervals until 
Week 24, followed by a double-masked period of study without active control to evaluate 
faricimab administered according to a PTI dosing regimen in patients with macular 
edema due to CRVO or HRVO.
3.1.1
Overview of Study Design
This study is comprised of two parts: Part 1 (Day 1 through Week 24) will compare 
faricimab Q4W versus aflibercept (active comparator) Q4W; Part 2 (Weeks 2472) will 
evaluate faricimab administered at masked treatment intervals of Q4W to Q16W based 
on PTI dosing criteria.
In Part 1 (Q4W Dosing), approximately 750 patients will be randomized during the global 
enrollment phase of the study in a 1:1 ratio to one of two treatment arms, with treatment 
defined as follows:

Arm A (n375):  Patients randomly assigned to Arm A will receive faricimab 6 mg 
IVT Q4W from Day 1 through Week 20 (6 injections).

Arm B (comparator arm, n375):  Patients randomly assigned to Arm B will receive 
aflibercept 2 mg IVT Q4W from Day 1 through Week 20 (6 injections).
In Part 2 (PTI Regimen), patients in both Arms A and B will receive faricimab 6 mg IVT 
according to a PTI dosing regimen from Week 24 through Week 68 (see Section 3.1.4.1
for the PTI dosing criteria). 
All patients will complete scheduled study visits Q4W for the entire study duration 
(72 weeks).  To preserve the masking of faricimab treatment intervals for Week 24 
through Week 68, a sham procedure will be administered during study visits at which
(according to the PTI dosing regimen) no faricimab treatment is administered.
Figure 1 presents an overview of the study design.  A schedule of activities is provided in
Appendix 1.


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Figure 1
Study Schema
IVT intravitreal; PTI personalized treatment interval; Q4W every 4 weeks; W Week.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the 
eye with the worse BCVA, as assessed at screening, will be selected as the study eye, 
unless the investigator deems the other eye to be more appropriate for treatment in the 
study. 
There will be a minimum of two investigators per site to fulfill the masking requirements 
of the study.  At least one investigator will be designated as the assessor physician who 
will be masked to each patient’s treatment assignment and who will evaluate ocular 
assessments.  At least one other investigator will be unmasked and will perform study 
treatments (see Section 4.2.2 for additional details on masking).
The study will consist of a screening period of up to 28 days (Days 28 to 1) and an 
approximately 68-week treatment period, followed by the final study visit at Week 72.  
A unique screening number will be assigned to each screened patient through a 
web-based response system (IxRS).
3.1.1.1
Screening
Informed consent must be administered and signed by patients before any study-specific 
screening procedure is performed.  Each consented patient must satisfy the eligibility 
criteria as applicable at screening and/or the Day 1 visit (see Sections 4.1.1 and 4.1.2).


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Some patients may require an extended screening period (more than 28 days) as a 
result of repeated evaluation of images or other circumstances.  Upon agreement with 
the Medical Monitor, the screening period may be extended by up to 5 business days in 
such cases.
In some countries or regions, the screening and Day 1 (randomization) visits may occur 
as a combined visit if all assessments (with the exception of informed consent, which 
may be obtained earlier) are completed and evaluated within 2 business days.  Prior 
discussion with and approval from the central reading center (CRC) will be required, to 
allow evaluation of the images to be performed in an expedited manner.
During screening, a patient’s eligibility will be assessed, including a CRC review of color 
fundus photographs (CFP) and spectral-domain optical coherence tomography (SD-OCT) 
(or swept-source optical coherence tomography [SS-OCT]).  The diagnosis of macular 
edema due to RVO must be confirmed by the CRC.  Note that the investigator will 
determine unilateral versus bilateral disease status at screening.  For patients with 
bilateral RVO, CFP and SD-OCT images of fellow eye may be captured and stored at 
the CRC.  No ocular images of the fellow eye will be captured or stored at screening for 
patients with unilateral RVO.
When screening and Day 1 visits are completed as a combined visit, the assessments 
listed for both visits should be conducted only once (see Appendix 1).  Prior discussion 
with and approval from the CRC is required before this combined visit, to enable an 
expedited evaluation of CFP and SD-OCT (or SS-OCT) images for an objective, masked 
assessment of patient eligibility.
If the screening and Day 1 visits are not completed on the same day, but rather within 
2 business days, the following safety assessments must be repeated on the day of the 
patient’s randomization and first study treatment administration: urine pregnancy test (if 
appropriate), slitlamp examination, indirect ophthalmoscopy, and predose IOP 
measurements. These assessments should be recorded on the Day 1 electronic Case
Report Form (eCRF) and dated accordingly.
After screening and predose Day 1 assessments have been completed, eligible patients 
will have a randomization identification number assigned through the IxRS and will be 
randomized in a 1:1 ratio, with approximately 375 patients randomized to each of the 
two treatment arms.  Randomization will be stratified by baseline BCVA ETDRS letter 
score, as assessed on Day 1 (34 letters, 3554 letters, and 55 letters), and region 
(United States and Canada, Asia, and the rest of the world).
3.1.1.2
Re-Screening
Patients who do not meet the criteria for participation in this study (screen failure) may 
qualify for two re-screening opportunities within a 3-month period (for a total 
of three screenings per participant) at the investigator's discretion.  Patients are not 


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required to re-sign the consent form if they are re-screened within 30 days after 
previously signing the consent form. If more than 30 days have elapsed between 
signing the most recent consent form and the date of re-screen, then the consent form 
must be re-signed.  The investigator will record reasons for screen failure in the 
screening log (see Section 4.5.1).
At re-screening, a new screening number will be assigned to each patient through the 
IxRS and all screening visit assessments will be performed.  At the Day 1 visit, fundus 
FFA images do not have to be repeated, provided that the same eye is selected for the 
study eye at re-screening and acceptable FFA images were taken within 28 days prior to 
the new Day 1 visit (randomization) date.
3.1.1.3
Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization (i.e., at 
the Day 1 visit). 
If a site has an unexpected issue (e.g., the IxRS is not able to assign the study kit), a 
patient’s randomization and first study treatment may be administered within 2 business 
days of the Day 1 visit assessments, after consultation with the Medical Monitor.  The 
following assessments will be repeated on the day of randomization and study treatment:  
urine pregnancy test (if applicable), slitlamp examination, indirect ophthalmoscopy, 
predose IOP measurements (recorded on the Day 1 eCRF and dated accordingly), and 
any new concomitant medications.
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger-counting test, 
hand-motion and/or light-perception tests [if applicable], and postdose IOP 
measurement).  Afterward, all study patients will also have a safety assessment visit on 
Day 7 (3 days) evaluated by the masked investigator.  At subsequent scheduled visits, 
patients will have predose safety assessments evaluated by the masked investigator 
prior to receiving study treatment administered by the unmasked investigator. 
Study treatment administration and study-related assessments will occur Q4W (starting 
from Day 1), as outlined in the schedule of activities (see Appendix 1).  The sham 
procedure will be delivered to patients from Weeks 24 through 68, as applicable to 
maintain treatment interval masking (see Section 4.3.1.3).
Patients will be instructed to contact the study site at any time if they have health-related 
concerns.  If warranted, patients will be asked to return to the clinic as soon as possible 
for an unscheduled safety assessment visit (see Appendix 2).
All study visits will be scheduled 28 (7) days relative to the randomization date as 
registered in IxRS.  All assessments for a scheduled visit, including study treatment, are 


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to be performed on the same day, except those performed during the screening period.  
All assessments are to be performed prior to study treatment, unless otherwise specified.
Patients who are prematurely discontinued from study treatment but who agree to 
continue to participate in the study will be encouraged to undergo as many scheduled 
visits as possible, with emphasis on completing the Week 24 and Week 72 visits.  
Patients who discontinue from the study prior to completion will be asked to return for an 
early termination visit a minimum of 28 days after their final study treatment for 
monitoring of adverse events and early termination visit assessments (see Appendix 1).
Patients who complete study treatment (i.e., through the Week 68 visit) will return for the 
final study visit (Week 72) a minimum of 28 days after their final study treatment for 
monitoring of adverse events and final study visit assessments (see Appendix 1).
3.1.2
Compliance with Study Visits, Handling of Missed Visits, and 
Timely Reporting
Sites will report all missed study treatment visits and study treatment interruptions to the 
IxRS for all patients (Arms A and B) to preserve masking.   
Study treatment visits cannot occur earlier than 21 days after the previous study 
treatment visit.  Missed study treatments will not be made up.
After the Day 1 visit, if a patient misses a study visit when ocular CFP and FFA images 
are to be obtained (see Appendix 1) or these images are not taken at the scheduled visit 
(e.g., equipment is broken), they must be obtained at the next scheduled visit the patient 
attends.  Missed mandatory PK, PD, or ADA samples may be obtained at the next 
scheduled visit the patient attends.
If a patient misses more than two consecutive study treatment visits within any 24-week 
treatment period, the investigator and the Medical Monitor may consider discontinuing 
the patient from study treatment.
3.1.2.1
Timely Forwarding of OCT Images to the Central Reading 
Center or Reporting of Missed OCT Images
Starting at the Day 1 visit, the following must occur:

Forward OCT images obtained at each study treatment visit to the CRC immediately 
so they can be evaluated for CST value and the data transferred by the CRC to 
IxRS prior to the patient’s next study visit.

If the OCT image was missed due to a missed visit or not taken, notify the CRC
immediately so they can inform IxRS that the expected data will not be available.


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3.1.2.2
IxRS Reporting of Visual Acuity Score, Study Treatment 
Interruption, and Missed Study Treatment Visits
Sites must enter the following information in IxRS at the time the study treatment kit 
assignment is requested:

Patient visual acuity score from the current study treatment visit (final score as 
calculated on the Visual Acuity Worksheet) 

Study treatment interruption information (if applicable) so that the correct study 
treatment (study drug or sham) is assigned by the system for a future study 
treatment visit

Missed study treatment visits
3.1.3
Treatment Schedule for Part 1 (Q4W Dosing)
In Part 1 of the study, patients will receive treatment as follows:

Patients randomly assigned to Arm A will receive faricimab Q4W from Day 1 
through Week 20

Patients randomly assigned to Arm B will receive aflibercept Q4W from Day 1 
through Week 20
3.1.4
Treatment Schedule for Part 2 (PTI Regimen)
In Part 2 of the study, all patients will visit the clinic Q4W from Week 24 through 
Week 68 and receive either sham treatment or faricimab 6 mg IVT, depending on their 
PTI dosing regimen.  Faricimab PTI decisions will be automatically calculated by the 
IxRS based on the PTI criteria described in this section.  Faricimab dosing visits are 
defined as those visits when the patient receives faricimab 6 mg IVT per IxRS 
assignment.
Starting at Week 24, patients will receive faricimab at a frequency of Q4W until CST 
meets the predefined reference CST threshold (325 m for Spectralis SD-OCT or 
315 m for Cirrus SD-OCT and Topcon SD-OCT), as determined by the CRC.  The 
reference CST (as defined in Figure 2) is used by the IxRS at faricimab dosing visits to 
determine the faricimab dosing interval.  After a patient’s initial reference CST is 
established, the patient is eligible to have the faricimab dosing interval increased in 
4-week increments by the IxRS if the CST value is stable (i.e., has not increased or 
decreased by 10%) with no associated loss of vision of 10 letters with respect to 
reference BCVA (as defined in Figure 2).
The maximum and minimum treatment intervals that may be assigned will be Q16W
and Q4W, respectively.  Patients whose dosing interval had been previously extended 
and who experience disease worsening that triggers interval reduction will not be 
allowed to extend the interval again, with the exception of patients whose dosing
intervals were reduced to Q4W; their interval may be extended again but only to an 
interval that is 4 weeks less than their original maximum extension.  For example, if a 
patient’s interval is reduced from Q12W to Q8W, this patient’s interval will not be 


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extended beyond Q8W for the remainder of the treatment period.  If a patient’s interval is 
reduced from Q16W to Q4W, this patient’s interval can be extended up to Q12W, but 
cannot be extended back to Q16W.
3.1.4.1
Faricimab Interval Determination
The algorithm used by the IxRS for interval decision-making, which is based on the 
relative change of the CST and BCVA at faricimab dosing visits compared with the 
reference CST and reference BCVA, is outlined below and in Figure 2.  The faricimab 
dosing interval will be extended, maintained, or reduced as follows.

Interval extended by 4 weeks
–
If the CST value is increased or decreased by 10% without an associated 
10-letter BCVA decrease

Interval maintained if any of the following criteria are met:
–
If the CST value is decreased by 10%
–
If the CST value is decreased 10% with an associated 10-letter BCVA 
decrease
–
If the CST value is increased between 10% and 20% without an associated 
5-letter BCVA decrease

Interval reduced by 4 weeks if any of the following criteria are met:
–
If the CST value is increased between 10% and 20% with an associated 
5-to 10-letter BCVA decrease
–
If the CST value is increased by 20% without an associated 10-letter BCVA 
decrease
–
If the CST value is increased by 10% with an associated BCVA decrease of 
10-letters

Interval reduced to Q4W
–
If the CST value is increased by 10% with an associated 10-letter BCVA 
decrease


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Figure 2
Algorithm for IxRS-Determined Faricimab Personalized 
Treatment Interval Dosing Intervals
BCVA best-corrected visual acuity; CST central subfield thickness; IxRS interactive 
web-based response system; Q4W every 4 weeks.
a Initial reference CST CST value when the initial CST threshold criteria are met, but no earlier 
than Week 20.  Reference CST is adjusted if CST decreases by 10% from the previous 
reference CST for two consecutive faricimab dosing visits and the values obtained are 
within 30 m. The CST value obtained at the latter visit will serve as the new reference CST, 
starting immediately at that visit.
b Reference BCVAmean of the three best BCVA scores obtained at any prior dosing visit.
3.1.4.2
Missed Faricimab Dosing Visits Starting from Week 20
If a patient misses a faricimab dosing visit, the IxRS will assign the patient to receive 
faricimab dosing at the next scheduled study visit the patient attends.  A decision 
regarding the subsequent faricimab dosing interval will be made by IxRS based on CST 
and BCVA assessments completed at the visit when faricimab is administered, and any 
changes in the faricimab dosing interval will be based from the last assigned interval 
prior to the missed faricimab dosing visit.
For example, if a patient was on a Q12W drug dosing interval prior to missing the 
faricimab dosing visit, the IxRS decision to maintain, extend, or reduce the dosing 
interval will be made on the basis of the previously assigned drug interval (Q12W), along 
with CST and BCVA data obtained at the visit when the patient receives faricimab.  If the 
data indicate that the patient should maintain the Q12W interval, the patient will receive 
faricimab 12 weeks after that visit.


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If the Week 20 visit is missed, the patient (regardless of Part 1 treatment arm assigned)
will receive a faricimab dose at Week 24.  At this point, if the patient meets CST and 
BCVA extension criteria, the patient’s faricimab dosing interval will be extended to Q8W 
by the IxRS, skipping the dose at Week 28.
3.1.4.3
Faricimab Interruption at Faricimab Dosing Visits Starting from 
Week 20
If a patient's dosing has to be interrupted at a faricimab dosing visit (e.g., because of an 
adverse event), the IxRS will assign the patient to receive faricimab at the earliest 
subsequent study visit when the patient is permitted to resume faricimab dosing.  The 
IxRS will be used to determine the next faricimab dosing based on a Q8W interval 
unless the patient was treated on a Q4W interval prior to dose interruption.  In that case, 
the patient will be evaluated on the basis of the Q4W interval.
3.1.4.4
Missing CST Value at Faricimab Dosing Visits Starting from 
Week 20
If a patient attends a faricimab dosing visit, but the CST value is not available for any 
reason (e.g., OCT machine is not available or is inoperative), the IxRS will assign the 
patient to receive faricimab at that visit.  Generally, the IxRS will maintain the previous 
drug dosing interval.  However, in the event of a concurrent 10-letter decrease relative 
to the reference BCVA at that faricimab dosing visit, the IxRS will reduce the faricimab 
dosing interval by 4 weeks.
3.1.4.5
Missing BCVA Value at Faricimab Dosing Visits Starting from 
Week 20
If a patient attends a faricimab dosing visit, but the BCVA value is not available for any 
reason, the IxRS will assign the patient to receive faricimab at that visit.  The IxRS will 
base the faricimab dosing interval determination on CST value only.
3.1.5
China Enrollment Plan
Patient recruitment is expected to take longer in China; therefore, a specific China 
enrollment plan may be established.  After the global enrollment phase of the study has 
been completed, additional patients may be enrolled in a China extension to ensure a 
total enrollment that is sufficient to support registration in China.  The China extension 
may include current residents of mainland China, Hong Kong, or Taiwan enrolled at 
National Medical Products Administration (NMPA)-recognized sites.  All Chinese 
patients enrolled in the global enrollment phase of the study will be included in the 
primary analysis of the study.  Data from patients enrolled during the China extension 
will not be included in the primary analyses (see Section 6.11 for details).
3.1.6
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study 
conduct on an ongoing basis.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities.


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The iDMC will meet approximately every 6 months (frequency may be adjusted if 
required) to evaluate unmasked ocular and systemic (non-ocular) safety events with an 
emphasis on the evaluation of the rate of ocular inflammation, increased IOP, 
endophthalmitis, arterial thromboembolic events, and clinically significant decreases in 
BCVA and rates of neovascularization, which will be prepared for the committee by an 
independent Data Coordinating Center (iDCC).  The iDMC may recommend stopping the 
study early for safety reasons. There are no prospectively planned interim efficacy or 
futility analyses.
After reviewing the data, the iDMC will provide a recommendation to the Sponsor as 
described in the iDMC Charter.  Final decisions will rest with the Sponsor.
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
3.2
END OF STUDY AND LENGTH OF STUDY
The study consists of two enrollment phases:  the global enrollment phase, during which 
patients are recruited globally; and an optional China extension phase, during which 
additional patients may be recruited in China to support registration in China.
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
including patients from the optional China extension.  The end of the study is expected 
to occur approximately 72 weeks after the last patient is randomized.
The total length of the study (excluding the China extension) from screening of the first 
patient to the LPLV for patients from the global enrollment phase is expected to be 
approximately 34 months.
The Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
A multicenter, double-masked, randomized, comparator-controlled design trial for Part 1 
was selected to minimize the bias in the evaluation of faricimab as a treatment for 
patients with CRVO or HRVO.  Part 2 of the study is designed to assess the efficacy and 
safety of faricimab PTI dosing. 
To ensure the safety of all patients during the study, several safety assessments have 
been included (e.g., regular ophthalmic monitoring and imaging assessments, adverse 
event monitoring [ocular and systemic], and laboratory safety tests) (see Section 4.5 and
Appendix 1 for a description of study assessments).


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3.3.1
Rationale for Faricimab Dose
The 6-mg dose of faricimab will be administered to patients in Arm A of Part 1 and to all 
patients in Part 2 of the study, as outlined in Section 3.1.1.
The 6-mg dose of faricimab selected for this study is based on data from nonclinical 
in vivo and toxicology models and clinical outcomes from Phase I and Phase II studies, 
and is supported by clinical PK and PD assessments. 
The first-in-human study (BP28936) evaluated the safety and tolerability of single and 
multiple administration of faricimab to 24 patients with nAMD, at doses ranging from 
0.5 mg to 6 mg.  The selection of these doses was based on nonclinical findings and 
absolute IVT doses administered in toxicology studies.  The 6-mg dose of faricimab was 
the highest feasible dose of faricimab, and single and multiple doses of up to 6 mg were 
well tolerated. 
In the Phase II studies (BOULEVARD in DME and AVENUE and STAIRWAY in nAMD), 
the ocular and non-ocular safety findings in patients receiving faricimab 1.5-mg and 
6-mg doses were consistent with the safety profile of anti-VEGF products licensed for 
nAMD and DME with no new or unexpected events.
The data from BOULEVARD suggest a dose-related benefit favoring the 6-mg dose of 
faricimab relative to the 1.5-mg dose, as measured by both the efficacy outcomes and 
duration of effect.  Based on these results, the 6-mg dose of faricimab was chosen for 
further clinical development in Phase III studies in patients with DME.
While the underlying disease etiologies are different (e.g., diabetes in DME versus a 
vascular occlusion in RVO), the downstream pathophysiology of hypoxia-driven macular 
edema with subsequent vision loss is similar.  DME and macular edema due to RVO are 
both characterized by a thickening of the macula due to fluid accumulation consequent 
to breakdown in the blood-retinal barrier and pathological increase of retinal vessel 
permeability, which can lead to irreversible vision loss.  Both Ang-2 and VEGF were 
increased in aqueous and vitreous samples from patients with diabetic eye disease or 
RVO (Adamis et al. 1994; Aiello et al 1994; Funatsu et al. 2002; Regula et al. 2016). 
Considering the similar pathophysiology of macular edema and vision loss in patients 
with DME and macular edema due to RVO and based on the data from BOULEVARD, 
the 6-mg dose of faricimab has been chosen for clinical development in Phase III studies 
in patients with macular edema due to RVO.
Refer to the Faricimab (RO6867461) Investigator's Brochure for details about efficacy 
and safety results from nonclinical and clinical studies of faricimab.


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3.3.2
Rationale for Faricimab Schedule
In this proposed Phase III study, patients in Arm A of Part 1 of the study will receive the 
6-mg faricimab dose Q4W up to Week 20 for a total of 6 injections, as outlined in 
Section 3.1.1.
The initial six faricimab IVT Q4W doses are proposed for this study provide the 
opportunity for maximum efficacy against an active comparator (aflibercept) dosed Q4W.  
This dosing regimen is also consistent with the dosing studied in all the pivotal anti-
VEGF trials and is consistent with global recommended dosing posologies (e.g., in the 
United States, the European Union, and Japan) for Eylea (aflibercept) and Lucentis
(ranibizumab) RVO product labeling (Eylea E.U. Summary of Product Characteristics 
(SmPC), Eylea and Lucentis U.S. Package Inserts (USPI), Eylea Japan local prescribing 
information).
In Part 2 of the study, all patients will receive faricimab (from Week 24 through Week 68) 
according to the PTI dosing regimen (intervals ranging from Q4W to Q16W) as outlined 
in Section 3.1.1.  A range of faricimab dosing intervals will be evaluated, as PTI dosing 
better reflects real-world clinical practice, allowing patients to receive injections 
individually tailored to maximize vision while minimizing treatment burden.  
Observational studies of anti-VEGF treatment patterns in patients with RVO 
demonstrated that visual gains and maintenance of these gains in the real world are 
worse than outcomes achieved in randomized controlled clinical trials.  This is because 
frequent office monitoring of all patients is often not feasible in the real world, and 
patients have lower numbers of visits and injections than they need overall.  There is an 
unmet need for more durable treatments and a personalized treatment approach in 
patients with RVO.  Extended treatment intervals are supported by PK/PD data and 
clinical data in DME.
As described in Section 1.1, while the upstream etiologies are different between DME 
and macular edema due to RVO, the downstream hypoxia-driven pathways leading to 
macular edema with subsequent vision loss are similar.  Faricimab has a potential for 
increased durability in RVO based on the dual mechanism of action, with inhibition of 
both Ang-2 and VEGF.  The PK and PD assessments of aqueous humor samples from a 
subset of patients in BOULEVARD show high suppression of Ang-2 and VEGF for 
8 weeks with faricimab 6 mg, thus supporting the potential for a Q8W dosing regimen.  
Additionally, the PK/PD model characterizing the aqueous humor free-VEGF time course 
shows a substantial proportion of patients with prolonged aqueous humor free-VEGF 
suppression for whom a Q12W or Q16W regimen could be sufficient to maintain efficacy.  
Furthermore, increased durability compared to anti-VEGF monotherapy was shown 
during the observational phase of the BOULEVARD.  On the basis of these data, after 
achieving the maximum gains from monthly dosing in RVO, extended dosing of intervals 
up to 16 weeks will be explored.


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Therefore, Part 2 of this Phase III study in RVO will investigate PTI dosing with faricimab 
to demonstrate that vision achieved with monthly dosing (i.e., in Part 1) can be 
maintained with PTI dosing.  It is expected that the PTI regimen will help extend the 
treatment interval (to a maximum of Q16W) in patients with inactive disease, while giving 
those with demonstrable disease activity the opportunity to be treated as frequently as 
Q4W if required.
3.3.3
Rationale for Aflibercept Dose and Schedule
The 2-mg dose of aflibercept will be administered Q4W through Week 20 in patients in 
Arm B of Part 1, as outlined in Section 3.1.1.  The aflibercept dose and schedule used in 
this study are consistent with global recommended dosing posologies (e.g., in the United 
States, the European Union, and Japan) for Eylea (aflibercept) RVO product labeling 
(Eylea E.U. SmPC, Eylea USPI, Eylea Japan local prescribing information).
3.3.4
Rationale for Control Group
Part 1 of this study (up to the primary endpoint at Week 24) is an interventional study to 
evaluate the efficacy of faricimab compared with standard-of-care anti-VEGF 
monotherapy for patients with CRVO or HRVO.
Anti-VEGF therapy is a well-established standard of care in patients with RVO, and 
studies with an inactive comparator (i.e., sham procedure) or macular laser treatment 
alone are no longer ethically acceptable alternatives given the improvements in visual 
and anatomical outcomes associated with anti-VEGF treatment.
Aflibercept is an approved anti-VEGF treatment for patients with RVO and has 
demonstrated improvement in BCVA in the target population in controlled, randomized 
clinical studies (Eylea E.U. SmPC, Eylea USPI, and Eylea Japan local prescribing 
information).  Eylea is a globally approved anti-VEGF therapy.  The most restrictive 
approved aflibercept dosing regimen on label (USPI) is monthly, facilitating a 
comparison with monthly faricimab (up to the primary endpoint at Week 24).
In Part 2 of this study, all patients will receive a PTI dosing regimen with faricimab and 
there will not be a comparator control.
3.3.5
Rationale for Biomarker Assessments
The concentration of free Ang-2 and free VEGF will be measured in plasma to assess 
the systemic target suppression following intravitreal faricimab injection.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 750 patients with macular edema due to CRVO or HRVO will be enrolled 
during the global enrollment phase of this study.
After completion of the global enrollment phase, additional patients may be enrolled at 
NMPA-recognized Chinese sites in a China extension to ensure a total enrollment that is 
sufficient to support registration in China.
4.1.1
Inclusion Criteria
4.1.1.1
General Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 3 months after the final 
dose of study treatment.  Women must refrain from donating eggs during this 
same period.
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.


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
For patients enrolled in the extended China enrollment phase at NMPA-recognized 
sites:  current resident of mainland China, Hong Kong, or Taiwan, and of Chinese 
ancestry
4.1.1.2
Ocular Inclusion Criteria for Study Eye
Patients must also meet the following ocular criteria for study entry:

Foveal center–involved macular edema due to CRVO or HRVO, diagnosed no 
longer than 4 months prior to the screening visit and confirmed by CRC based on 
SD-OCT (or SS-OCT) images
CRVO or HRVO is defined by retinal hemorrhages, telangiectatic capillary bed, 
dilated venous system or other biomicroscopic evidence of retinal vein 
occlusion (RVO; neovascularization, vitreous hemorrhages) in the entire retina 
(CRVO) or two quadrants of the retina (HRVO)

BCVA of 73 to 19 letters, inclusive (20/40 to 20/400 approximate Snellen equivalent), 
as assessed on the ETDRS visual acuity chart at a starting test distance of 4 meters 
(see the BCVA manual for additional details) on Day 1

CST 325 m, as measured on Spectralis SD-OCT, or 315 m, as measured on 
Cirrus SD-OCT or Topcon SD-OCT at screening (SS-OCT acceptable after 
confirmation with CRC)

Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition 
of good quality retinal images to confirm diagnosis
4.1.2
Exclusion Criteria
4.1.2.1
General Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Any major illness or major surgical procedure within 1 month before screening

Active cancer within the 12 months prior to Day 1 except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer 
with a Gleason score of 6 and a stable prostate-specific antigen for 12 months

Requirement for continuous use of any medications and treatments indicated in
Section 4.4.2 (Prohibited Therapy)

Systemic treatment for suspected or active systemic infection on Day 1
Ongoing use of prophylactic antibiotic therapy may be acceptable if approved 
after discussion with the Medical Monitor.

Any systemic corticosteroid use (e.g., oral or injectable) within 1 month of the 
screening visit


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
Uncontrolled blood pressure, defined as systolic blood pressure 180 mmHg and/or 
diastolic blood pressure 110 mmHg while a patient is at rest on Day 1
If a patient’s initial reading exceeds these values, a second reading may be 
taken later on the same day or on another day during the screening period.  If 
the patient’s blood pressure is controlled by antihypertensive medication, the 
patient should be taking the same medication continuously for at least 30 days 
prior to Day 1.

Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to 
Day 1

History of other disease, metabolic dysfunction, physical examination finding, or 
historical or current clinical laboratory findings giving reasonable suspicion of a 
condition that contraindicates the use of the investigational drug or that might affect 
interpretation of the results of the study or renders the patient at high risk for 
treatment complications in the opinion of the investigator

Pregnant or breastfeeding, or intending to become pregnant during the study
Women of childbearing potential must have a negative urine pregnancy test 
result within 28 days prior to initiation of study drug.  If the urine pregnancy test 
is positive, it must be confirmed by a serum pregnancy test.

History of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the faricimab or aflibercept injections, 
study- related procedure preparations (including fluorescein), dilating drops, or any 
of the anesthetic and antimicrobial preparations used during the study

Participation in an investigational trial that involves treatment with any drug or 
device (with the exception of vitamins and minerals) within 3 months prior to Day 1
4.1.2.2
Ocular Exclusion Criteria for Study Eye
Patients who meet any of the following ocular exclusion criteria for the study eye will be 
excluded from study entry:

History of previous episodes of macular edema due to RVO or persistent macular 
edema due to RVO diagnosed more than 4 months before screening

Increase of 10 letters in BCVA ETDRS score between screening and Day 1

Any current ocular condition which, in the opinion of the investigator, is currently 
causing or could be expected to contribute to irreversible vision loss due to a cause 
other than macular edema due to RVO in the study eye (e.g., ischemic 
maculopathy, Irvine-Gass syndrome, foveal atrophy, foveal fibrosis, pigment 
abnormalities, dense subfoveal hard exudates, or other non-retinal conditions)

Current visually significant vitreous hemorrhage on Day 1

History of retinal detachment or macular hole (Stage 3 or 4)

Tractional retinal detachment, vitreomacular traction, full thickness macular hole or
epiretinal membrane involving the fovea or disrupting the macular architecture in the 
study eye, as evaluated by the CRC and described in the CRC manual


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
Diagnosis of DR moderate non-proliferative or worse, proliferative DR, DME, nAMD, 
geographic atrophy, myopic choroidal neovascularization as assessed by the 
investigator

Active rubeosis, angle neovascularization, neovascular glaucoma

Aphakia or implantation of anterior chamber intraocular lens

Any cataract surgery or treatment for complications of cataract surgery with steroids 
or YAG (yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1

Any other intraocular surgery (e.g., pars plana vitrectomy, scleral buckle, glaucoma 
surgery, corneal transplant, or radiotherapy)

Any prior or current treatment for macular edema due to RVO, including anti-VEGF 
IVT for macular edema due to RVO

Macular laser (focal/grid) in the study eye at any time prior to Day 1

Panretinal photocoagulation in the study eye within 3 months prior to Day 1 or 
anticipated within 3 months of study start on Day 1

Any IVT treatment for any other retinal diseases that can lead to macular edema 
complication

Any prior or current treatment for macular edema; macular neovascularization, 
including DME and nAMD; and vitreomacular-interface abnormalities, including, but 
not restricted to, IVT treatment with anti-VEGF, steroids, tissue plasminogen 
activator, ocriplasmin, C3F8, air or periocular injection

Any prior intervention with verteporfin photodynamic therapy, diode laser, 
transpupillary thermotherapy, or vitreo-retinal surgery including sheathotomy

Any prior steroid implant use including dexamethasone intravitreal implant 
(Ozurdex) and fluocinolone acetonide intravitreal implant (Iluvien)

Prior periocular pharmacological or IVT treatment (including anti-VEGF medication) 
for other retinal diseases
4.1.2.3
Ocular Exclusion Criteria for Fellow (Non-Study) Eye
Patients who meet the following ocular exclusion criterion for the fellow (non-study) eye 
at both screening and Day 1 will be excluded from study entry:

Non-functioning fellow eye, defined as either one of the following: 
–
BCVA 20/320 or worse
–
No physical presence of fellow eye (i.e., monocular)


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4.1.2.4
Ocular Exclusion Criteria for Both Eyes
Patients who meet any of the following ocular exclusion criteria for both eyes will be 
excluded from study entry:

Prior IVT administration of faricimab in either eye

History of idiopathic or autoimmune-associated uveitis in either eye

Active periocular, ocular or intraocular inflammation or infection (including suspected) 
in either eye on Day 1
4.2
METHOD OF TREATMENT ASSIGNMENT AND MASKING
4.2.1
Treatment Assignment
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the IxRS.  A patient must satisfy all eligibility criteria 
(see Sections 4.1.1 and 4.1.2) prior to randomization through the IxRS.  As part of the 
screening process, the CRC will evaluate CFPs and SD-OCT images to provide an 
objective, masked assessment of patient eligibility.  After all patient eligibility 
requirements are confirmed, site personnel will contact the IxRS at the Day 1 visit for 
assignment of a patient identification number (a separate number from the screening 
number).
Patients will be randomized in a 1:1 ratio to one of two study treatment arms (faricimab 
Q4W or aflibercept Q4W).  After randomization and at each study treatment visit 
(i.e., including Day 1), the IxRS will assign the appropriate study treatment kit to be used.  
Patients will be randomized on the same day study treatment is to be initiated (i.e., the 
Day 1 visit).
Randomization will be stratified by the following baseline factors (Day 1):

Baseline BCVA ETDRS letter score (34 letters, 3554 letters, and 55 letters)

Region (United States and Canada, Asia, and the rest of the world)
A stratified permuted-block randomization scheme will be used to obtain approximately a 
1:1 ratio among the treatment groups overall and within each of the above strata. 
4.2.2
Masking
This is a double-masked study, and only site staff members in unmasked roles, as 
specified in Section 4.2.2.2, are unmasked in both Part 1 and Part 2.  There must be a 
minimum of two investigators per site to fulfill the masking requirements of this study and 
both investigators are required to be present at each scheduled study visit.


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4.2.2.1
Masked Roles
Principal Investigator
The Principal Investigator will be a retina specialist (or the equivalent in ex-U.S. 
countries) and must be in a masked role to oversee conduct of the whole trial.  The 
Principal Investigator must be masked to patients’ treatment assignment and may
assume any other masked role for which he or she qualifies, except for BCVA examiner 
tasks.
Assessor Physician/Masked Investigator
At least one investigator who is a retina specialist (or the equivalent in ex-U.S. countries) 
will be designated as the assessor physician/masked investigator.  The investigator(s) 
will be masked to patient treatment assignments and will evaluate all predose
assessments, as well as all assessments performed at screening, Day 7, and at the final 
or early termination visit.  The assessor physician/masked investigator will also evaluate 
the causality of all adverse events reported by the treatment administrator/unmasked 
investigator.  If qualified, this role can take on any other masked role tasks except tasks 
performed by the BCVA examiner.
Photographer(s) and OCT Technician(s)
If qualified, the photographers and OCT technicians can share any other masked role 
tasks except tasks performed by the BCVA examiner. 
Study Coordinator(s)
If qualified, the study coordinator(s) can share any other masked role tasks except tasks 
performed by the BCVA examiner. 
BCVA Examiner
The BCVA examiner will be masked to both the assigned treatment arm and designation 
of the study eye.  The BCVA examiner may have access only to a patient’s refraction 
data from previous visits.   Patients’ medical charts and visual acuity scores from 
patients' previous visits are not accessible to the BCVA examiner.  The BCVA examiner 
is not allowed to perform any other task involving direct patient care.
4.2.2.2
Unmasked Roles
Treatment Administrator/Unmasked Investigator
At least one investigator will be designated as the treatment administrator and will be 
unmasked to the patients’ treatment assignment.  The treatment 
administrator/unmasked investigator will be a retina specialist (or the equivalent in ex-
U.S. countries).  In addition, ophthalmologists who have completed a minimum of 2 full 
years of ophthalmology residency (or equivalent in ex-U.S. countries) may be permitted 
to perform the role of the treatment administrator/unmasked investigator following 
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The treatment administrator/unmasked investigator(s) performing the study treatment 
administration (faricimab, aflibercept, or sham) will also perform the postdose
administration safety assessments (finger-counting, hand-motion and/or light-perception 
tests [if applicable] and postdose IOP measurement) and will treat adverse events that 
occur during or shortly after the study treatment administration.  Cases of medication 
error, along with any associated adverse events, should be reported as described in
Section 5.3.5.11.  The person in this role, however, will not evaluate the causality of 
adverse events, which is the responsibility of the assessor physician/masked 
investigator(s).  The treatment administrator/unmasked investigator will also perform 
postdose IOP measurements, as well as optional aqueous humor and vitreous humor 
sample collection.
In addition, the qualifying treatment administrator/unmasked investigator can assist with 
and perform the screening and Day 1 visit assessments.  The treatment 
administrator/unmasked investigator must not be involved in any other aspect of the 
study and must preserve masking of treatment assignment.
Phlebotomist
The phlebotomist’s tasks can be performed by any qualified individual in masked or 
unmasked role, except for BCVA examiner.
Unmasked Assistants and Pharmacist
If desired, sites may have designated qualified unmasked assistants who can, for 
example, assemble study treatment supplies, prepare sterile field, prepare the patient’s 
study eye for treatment, discard all injection materials (i.e., syringes and needles) 
immediately following study treatment, and place vials in the kit box.  The qualified 
unmasked assistants can be assigned to measure postdose IOP.  If the site uses a 
pharmacy, the unmasked role is also assigned to the pharmacist who can take on 
IMP/NIMP-related tasks as applicable per the site delegation log.  In addition, qualifying 
unmasked assistants can assist with and perform the screening and Day 1 visit 
assessments.
Number of Unmasked Personnel per Site
Every effort must be made to limit the number of unmasked study personnel to ensure 
the integrity of this masked study.  There should be no more than six unmasked 
personnel (e.g., treatment administering physician[s] and assisting technician[s] if 
applicable) at an investigative site at one time.  In certain circumstances, the total 
number of unmasked personnel might be increased after discussion with and approval 
by the Medical Monitor.  If the site is using a pharmacist, this person may be in an 
unmasked role in addition to the unmasked staff at the site.
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4.2.2.3
Site Delegation Log
All roles for each study staff member should be clearly documented in the site delegation 
log.  The site delegation log must be signed by the Principal Investigator.
4.2.2.4
Role Switching
Once personnel assigned to the designated unmasked role start performing that role, 
they cannot switch to a masked role during the study.  Switching from a masked role to 
an unmasked role may be possible and must be documented in the site delegation log.
4.2.2.5
Study Backup Staff
Sites are strongly advised to have backup staff for key study roles.  In case of an 
emergency (e.g., an unscheduled safety visit), patients should be seen preferably by the 
assessor physician/masked investigator.  If the assessor physician/masked investigator
is unavailable, any clinic physician present, including the physician in the treatment 
administrator/unmasked investigator role, should attend to the patient.
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel
CRC personnel, study vendors, the Sponsor, and its agents will also be masked to 
treatment assignment, with the exception of individuals who require access to patient 
treatment assignments to fulfill their job roles during a clinical trial.  These roles include 
the clinical supply chain managers, sample handling staff, operational assay group 
personnel, IxRS service provider, drug accountability clinical research associates, the 
images coordinator, iDCC and iDMC members, and an internal unmasking statistician 
(this person is from the Sponsor's unmasking group and will follow the Sponsor's 
standard operation procedures to audit the implementation of the randomization scheme 
and the dosing interval assignment by the IxRS vendor periodically during the conduct of 
the study; this person will not be involved in other study-related activities).
To maintain the masked design of the study, blood samples, optional aqueous humor 
samples, and optional vitreous humor samples obtained at the timepoints specified in 
the schedule of activities (see Appendix 1) will be obtained from consenting patients in 
any treatment arm.  The laboratories responsible for performing sample analyses will be 
unmasked to patients' treatment assignment to identify appropriate samples to be 
analyzed.  Unmasking for analysis of the relevant biosamples during the conduct of the 
study will be performed by personnel outside of the study team and according to the 
Sponsor’s internal standard procedures to ensure the integrity of the data.  The number 
of Roche representative(s) and delegates who are unmasked will be kept to the 
minimum required to address the objective of the biosample analysis.
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the masking of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 


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and ADA assays will be unmasked to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the comparator 
arm will not be analyzed for faricimab PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Baseline immunogenicity samples will be analyzed 
for all patients.  Postbaseline immunogenicity samples from patients assigned to the 
comparator arm will not be analyzed for ADAs except by request.
4.2.2.7
Patient Masking
Patients will be masked to treatment assignment during the study and until study 
closeout, or until the Sponsor indicates that the study can be unmasked.
4.2.2.8
Single-Patient Emergency Unmasking
If unmasking is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the masked investigator will be able to break the treatment code 
by contacting the IxRS.  The masked investigator is not required to contact the Medical 
Monitor prior to breaking the treatment code; however, the treatment code should not be 
broken except in emergency situations.
4.2.2.9
Single-Patient Non-Emergency Unmasking
If the masked investigator wishes to know the identity of the study drug for any reason 
other than a medical emergency, he or she should contact the Medical Monitor directly.  
The masked investigator should document and provide an explanation for any non-
emergency unmasking.  If the Medical Monitor agrees to patient unmasking, the masked 
investigator will be able to break the treatment code by contacting the IxRS.
4.2.2.10
Single-Patient Unmasking for Health Authority 
Reporting Requirements
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the masked investigator or Sponsor to be 
related to study drug.  The patient may continue to receive treatment, and the masked 
investigator, patient, and Sponsor personnel, with the exception of the Drug Safety 
representative and personnel who must have access to patient treatment assignments to 
fulfill their roles (as defined above), will remain masked to treatment assignment.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is faricimab.
Aflibercept is being used as an active comparator in this study in Part 1; therefore, 
aflibercept is also considered an IMP for this study when administered to the study eye.
The sham is a procedure that mimics an IVT injection to preserve the study masking and
involves the blunt end of an empty syringe, without a needle, being pressed against an 
anaesthetized eye.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Faricimab
Faricimab will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.  For information on the faricimab formulation, see the pharmacy 
manual.
4.3.1.2
Aflibercept (Active Comparator)
Aflibercept will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.  For information on the aflibercept formulation, see the pharmacy 
manual.
4.3.1.3
Sham
The sham vial is empty and will remain empty throughout the sham treatment.  The 
sham is a procedure that mimics an IVT injection and involves the blunt end of an empty 
syringe (without a needle) being pressed against the anesthetized eye.
For information on the formulation of the sham vial, see the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration eCRF.  Cases of medication error, along with any associated 
adverse events, should be reported as described in Section 5.3.5.11.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.4 and Table 1.
4.3.2.1
Faricimab
In Part 1 of the study, patients randomly assigned to Arm A will receive faricimab 6 mg 
IVT Q4W from Day 1 through Week 20, for a total of 6 injections.


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In Part 2 of the study, patients randomly assigned to both Arms A and B will receive 
faricimab 6 mg IVT administered according to a PTI dosing regimen in intervals between 
Q4W and Q16W (see the study treatment schema in Figure 1).  At faricimab dosing 
visits, treatment intervals will be maintained or adjusted (i.e., increased by 4 weeks or 
decreased by 4, 8, or 12 weeks), based on CST and BCVA values (see Section 3.1.4.1).  
Patients will therefore receive between 3 and 12 injections during the period from Week 
24 through Week 68.
All faricimab administrations will be performed at the site.  See Appendix 3 for study 
treatment preparation.  Refer to the faricimab pharmacy manual for detailed instructions 
on drug preparation, storage, administration, and predose and postdose procedures.
4.3.2.2
Aflibercept (Active Comparator)
In Part 1 of the study, patients randomly assigned to Arm B will receive aflibercept 2 mg 
IVT Q4W from Day 1 through Week 20, for a total of 6 injections.
All aflibercept administrations will be performed at the site.  See Appendix 3 for study 
treatment preparation.  Refer to the aflibercept pharmacy manual for detailed 
instructions on drug preparation, storage, administration, and predose and postdose
procedures.
4.3.2.3
Sham Procedure
Both treatment Arms A and B will maintain Q4W study visits for the 72-week study 
duration.  To preserve the masking of faricimab treatment intervals for Week 24 
through Week 68, the sham procedure will be administered during study visits at which
(according to the PTI dosing regimen) no faricimab treatment is administered 
(see Figure 1).
See Appendix 3 for study treatment preparation.  Refer to the pharmacy manual for 
detailed instructions on sham preparation, storage, administration, and predose and 
postdose procedures.
4.3.3
Investigational Medicinal Product Handling and Accountability
All IMPs required for completion of this study (faricimab and aflibercept) will be provided 
by the Sponsor.  The study site (i.e., investigator or other authorized personnel [e.g., 
pharmacist]) is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and disposition or return of unused IMP, 
thus enabling reconciliation of all IMP received, and for ensuring that patients are 
provided with doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
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been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and 
authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and/or the Faricimab Investigator's Brochure or 
aflibercept local prescribing information for information on IMP handling, including 
preparation and storage, and accountability.
4.3.4
Continued Access to Faricimab
The Sponsor will offer continued access to Roche IMP (faricimab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (faricimab) after completing the study if all
of the following conditions are met:

The patient has a sight-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (faricimab) after completing the study 
if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)


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
The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for CRVO or HRVO

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
CRVO or HRVO

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter preparations or procedures other than protocol-specified procedural medications 
(e.g., dilating drops or fluorescein dyes, proparacaine, or antimicrobials [if applicable]) 
used by a patient within 7 days prior to the Day 1 visit and through the conclusion of the 
patient’s study participation or early termination visit.
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF, except for anti-VEGF therapy in the fellow eye that will 
be recorded on a separate eCRF.  Concomitant ocular procedures performed on either 
eye during the study should be recorded in the Concurrent Ocular Procedures Log on 
the eCRF.
4.4.1
Permitted Therapy
Patients who use maintenance therapies should continue their use.  Of note, the 
following are common therapies that are permitted:

Treatment for onset of ocular hypertension or glaucoma in the study eye during a 
patient’s study participation, as clinically indicated

Treatment of onset of cataract or posterior capsular opacification in either eye 
during a patient’s study participation, as clinically indicated
Dose interruption criteria (see Table 1) may apply with cataract surgery

Short-term use of topical ocular corticosteroids after cataract surgery, 
yttrium-aluminum garnet capsulotomy, peripheral iridotomy, argon/selective laser 
trabeculoplasty, or ocular allergic conditions in study eye or fellow eye

Complete, sector, or local panretinal photocoagulation in the study eye or fellow eye 
may be allowed if needed for the treatment of ischemic RVO or new peripheral 
neovascularization after discussion with the Medical Monitor
These conditions will be recorded as serious adverse events.  The patient 
should remain on study treatment and continue unchanged on the 
IxRS-assigned interval.


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
Vitrectomy may be performed at the discretion of the masked investigator in the 
event that study eye develops sight-threatening vitreous hemorrhage or retinal 
detachment
These conditions will be recorded as serious adverse events and will be 
recorded as a concomitant procedure.  Study treatment should be interrupted 
and may restart based on the patient’s status after consultation with the Medical 
Monitor.  The patient should remain in the study and complete all study visits as 
planned.

Fellow (nonstudy) eye may be treated with anti-VEGF therapy licensed for ocular 
use, if diagnosed with an ocular condition for which the selected anti-VEGF therapy 
is approved by the country regulatory agency and at the discretion of the masked 
investigator
Consult with the region-specific anti-VEGF prescribing information for the 
recommended dose and frequency of treatment.  The Sponsor will cover the 
cost of approved licensed ocular anti-VEGF therapy in accordance with local 
regulations.  Note:  bevacizumab (Avastin) is not licensed for ophthalmic use 
in any country; therefore, it is prohibited from use.
If (per the masked investigator's judgment) treatment with anti-VEGF is to be 
given to the fellow (nonstudy) eye at the same visit as the study eye treatment, 
all study eye assessments (including study eye study treatment administration) 
must be completed first.  If there are no safety concerns, the site may proceed 
with the fellow eye treatment administered by the unmasked physician to 
preserve masking.  Individual trays and sterile preparation must be separately 
prepared for each eye treatment.
If the fellow eye anti-VEGF treatment is performed outside of the study visit, a 
qualified investigator, in either masked or unmasked role, can administer the 
treatment.
At the discretion of the investigator, patients may continue to receive medications and 
standard treatments administered for other conditions.
4.4.2
Prohibited Therapy
The following medications and treatments are prohibited from use during a patient’s 
study treatment participation.  Patients may be discontinued from study treatment and/or 
the study to receive these therapies:

Systemic anti-VEGF therapy

Systemic drugs known to cause macular edema (fingolimod, tamoxifen)

IVT anti-VEGF agents (other than study-assigned aflibercept or faricimab) in study 
eye

IVT, periocular (subtenon), steroid implants (i.e., Ozurdex, Iluvien), or chronic 
topical ocular corticosteroids in study eye

Treatment with verteporfin (Visudyne) in study eye


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
Administration of micropulse and focal or grid laser in study eye

Other experimental therapies (except those comprising vitamins and minerals)
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient, and should be 
performed by site staff as outlined in Section 4.2.2.
All assessments (including the study treatment administration) for a scheduled visit are 
to be performed on the same day, except those performed during the screening period.
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, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinically significant diseases, chronic and ongoing conditions 
(e.g., trauma, cardiovascular, cerebrovascular, and ophthalmic), surgeries, cancer 
history (including prior cancer therapies and procedures), reproductive status, and 
smoking history, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to initiation of 
study treatment (Day 1 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.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because of the potential contribution of this variable to differences in 
observed pharmacokinetics, pharmacodynamics, toxicity, and/or response to treatment 
in retinal microvascular diseases (Zhang and Lai 2018).
4.5.3
Physical Examinations
A targeted physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat.  In addition, a 
patient’s height and weight will be recorded.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.


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New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
4.5.5
Ocular Assessments
Ocular assessments will be performed for both eyes, unless otherwise indicated, at 
specified timepoints according to the schedule of activities in Appendix 1.  Assessments 
include:

Refraction and BCVA assessed on ETDRS visual acuity chart at a starting test 
distance of 4 meters (perform prior to dilating eyes; see Appendix 5)

Predose IOP measurement of both eyes (perform prior to dilating eyes)

Slitlamp examination (for grading scales for anterior and vitreous cells, 
see Appendix 4)

Dilated binocular indirect high-magnification ophthalmoscopy

Finger-counting test followed by hand-motion and light-perception tests (when 
necessary) performed within approximately 15 minutes of study treatment in the 
study eye only

Postdose IOP measurement only in the study eye taken 30 (15) minutes after 
study treatment administration
If there are no safety concerns after 30 (15) minutes following study treatment 
administration, the patient will be permitted to leave the clinic.  If the IOP value 
is of concern to the treatment administrator/unmasked investigator, the patient 
will remain in the clinic and will be managed in accordance with the treatment 
administrator/unmasked investigator’s clinical judgment.  The adverse event will 
be recorded on the Adverse Event eCRF as applicable. 

The method of IOP measurement used for a patient must remain consistent 
throughout the study
Ocular Imaging
The CRC(s) will provide sites with the CRC manual and training materials for specified 
study ocular images.  Before any study images are obtained, site personnel, test 
images, systems and software (where applicable) will be certified and validated by the 
CRC(s) as specified in the CRC manual.  All ocular images results will be obtained by 
trained site personnel at the study sites and forwarded to the CRC(s) for independent 
analysis and/or storage (see Appendix 6, Appendix 7, and Appendix 8. 


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After randomization, if a patient misses a study visit when CFP or FFA ocular images are 
scheduled (see Appendix 1) or the images are not taken at the scheduled visit (e.g., due 
to broken equipment), they should be obtained at the next scheduled visit the patient 
attends.
Ocular images include the following:

FFA of study eye
Detailed guidance on the required equipment and image capture is described in 
the CRC manual. Same field of capture must be used consistently throughout 
the trial participation (if applicable, perform after blood samples are obtained).

CFP of study eye
Detailed guidance on the required equipment and image capture is described in 
the CRC manual.  Same field of capture must be used consistently throughout 
the trial participation.

SD-OCT or SS-OCT images of study eye
Certain SS-OCT machines may be acceptable; consult the CRC. 

Optional OCT-A of study eye at sites with OCT-A capabilities (provided sites 
approve optional sampling)
For patients diagnosed at screening with bilateral RVO, CFP and OCT images will also 
be captured of the fellow eye and stored at the CRC.
Additional details on obtaining these images are included in the CRC manual.
4.5.6
Concurrent Ocular Procedures
Any ocular procedures performed on either eye during the study (from Day 1, postdose) 
will be recorded on the Concurrent Ocular Procedures Log in the eCRF.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
At the scheduled visit, specimens should be obtained prior to study treatment and blood 
samples must be obtained prior to FFA assessments (if applicable).  Fasting is not 
required prior to specimen collection.  Laboratory supply kits will be provided to the sites 
by the central laboratory.  See Appendix 1 for sample collection timepoints and 
Appendix 9 for biological sample collection and shipping instructions.
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes [absolute], 
lymphocytes, and other cells)

Serum chemistry panel:  bicarbonate or total carbon dioxide (if considered standard 
of care for the region), sodium, potassium, chloride, glucose, BUN, creatinine, total 


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protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, and 
urate

Urinalysis:  pH, specific gravity, glucose, protein, ketones, blood, bilirubin, 
urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, 
other than glucose and ketones, are abnormal)

Coagulation:  aPTT and PT

Pregnancy test
All women of childbearing potential will have a urine pregnancy test at screening 
and prior to each study treatment.  If a urine test is positive, it must be confirmed 
by a serum pregnancy test.

Plasma samples for faricimab immunogenicity analysis

Plasma samples for faricimab PK analysis

Plasma samples for exploratory research on biomarkers
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions:

Plasma samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.

Plasma samples collected for biomarker research will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.

Optional aqueous humor and vitreous humor samples and optional plasma samples 
(if aqueous humor or vitreous humor sample is collected) collected for biomarker 
research will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.


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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 Sponsor policy on study data publication.
4.5.8
Clinical Outcome Assessments
Patient-reported outcome (PRO) instruments will be completed to assess the treatment 
benefit of faricimab.  In addition, PRO instruments will enable the capture of each 
patient's direct experience with faricimab.
PRO data will be collected through use of the NEI VFQ-25 (see Appendix 10).
4.5.8.1
Data Collection Methods for Clinical Outcome Assessments
PRO instruments will be interviewer-administered by the masked site staff (except for 
the BCVA examiner) at the clinic or over the telephone at specified timepoints during the 
study (see schedule of activities in Appendix 1).  At the clinic, instruments will be 
administered before the patient receives any information on disease status, prior to the 
performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified.
PRO instruments, translated into the local language as appropriate, will be provided by 
the Sponsor in pre-printed booklets to enable the instrument to be administered at each 
specified timepoint.  The booklets will be labeled with the timepoint of administration.
PRO instruments should be administered as outlined below:

Patients' health status should not be discussed prior to administration of the 
instruments.

Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 1015 minutes.

When onsite at the clinic, site staff should administer the instruments in a quiet 
area with minimal distractions and disruptions.

Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers.

Site staff should read questions verbatim and not attempt to interpret or explain 
questions.

Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments.


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4.5.8.2
Description of thoClinical Outcome Assessment Instruments
National Eye Institute Visual Function Questionnaire25
The NEI VFQ-25 captures a patient’s perception of vision-related functioning and 
vision-related quality of life.  The core measure includes 25 items that comprise 
11 vision-related subscales and 1 item on general health.  In this study, an additional six 
appendix items will be included for the Near Activities and Distance Activities subscales.  
The composite score and subscale scores range from 0 to 100, with higher scores 
indicating better vision-related functioning.  Subscale scores include general vision, 
ocular pain, near activities, distance activities, social functioning, mental health, role 
difficulties, dependency, driving, color vision, and peripheral vision.
4.5.9
Optional Aqueous Humor and Plasma Samples (Patients at 
Participating Sites)
Collection and submission of optional aqueous humor and plasma samples is contingent 
upon review and approval by the site, each site's IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for sampling, this 
section of the protocol (Section 4.5.9) will not be applicable at that site.
For patients who consent to provide aqueous humor sampling, the aqueous humor 
sample should be collected from the study eye just prior to study treatment (it is 
acceptable to collect the sample after FFA assessment) by a qualified treatment 
administrator/unmasked investigator, using an aseptic procedure and sterile field and 
according to local guidelines (see Appendix 9 and the central laboratory manual for 
aqueous humor sample collection, storage, and transfer). 
All efforts should be made to obtain a baseline aqueous humor sample on Day 1 
(predose).  The schedule of activities (see Appendix 1) provides guidance on 
recommended visits at which aqueous humor samples should be obtained.  Patients 
who are prematurely discontinued from study treatment but who agree to continue to 
participate in the study should discontinue collection of optional aqueous humor samples 
and any associated optional plasma samples.  However, (unscheduled) sampling may 
be performed at other or additional planned visits at the discretion of the investigator and 
in agreement with the participating patient.
Aqueous humor may reflect changes in the retina better than blood, given their close 
proximity and contiguity to the retina.  Aqueous humor samples have previously been 
demonstrated to be instrumental in improving our understanding of the relationships 
between ocular pharmacokinetics, VEGF suppression, and duration of clinical efficacy 
(Muether et al. 2012, 2013, 2014; Fauser et al. 2014; Fauser and Muether 2016; 
Hutton-Smith et al. 2017).  Therefore, to increase our understanding of the ocular 
pharmacokinetics and pharmacodynamics of faricimab and the relationship to dosing 
interval, optional aqueous humor samples will be obtained at different timepoints.
Aqueous humor will be analyzed for faricimab or aflibercept concentrations as well as 


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free Ang-2 and free VEGF-A concentrations.  Data from these analyses will be used to 
develop better predictive models for determining optimal PTIs by means of longitudinal 
target engagement assessments in these surrogate specimens and to support selection 
of a dosing regimen for future clinical trials.
Remaining samples will be analyzed for additional biomarkers, including those involved 
in angiogenesis (which may include, but are not limited to, angiopoietin 1 [Ang-1], 
soluble TEK receptor tyrosine kinase-2 [Tie2], soluble VEGF receptors, and 
platelet-derived growth factor) and inflammation (which may include, but are not limited 
to, IL-6, intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion protein 1 
(VCAM1), E-selectin, and P-selectin) to identify new therapeutic targets, better 
understand variability in patient responses to faricimab, and to support patient selection 
and/or stratification in future clinical trials.
Optional PK and PD plasma samples will be collected according to Appendix 1 for 
measurement of systemic faricimab or aflibercept concentration, free Ang-2, and free 
VEGF-A (see the Covance manual for PK/PD samples collection, storage, and transfer).
Faricimab, aflibercept, free Ang-2, and free VEGF-A will be quantified in plasma using 
validated immunoassay methods.  ADAs against faricimab will be detected in plasma 
using a validated bridging ELISA.  Based on results of the batch-wise analysis of plasma 
PD samples, it may be decided not to analyze all samples if no further information gain 
will be expected.
Samples may be used for exploratory biomarker research as described in Section 4.5.11.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.7 for details on duration of sample storage, use
of samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses).
4.5.10
Optional Unscheduled Collection of Vitreous Humor and 
Plasma Sample
Vitrectomy may be performed at the discretion of the masked investigator in the event 
that study eye develops sight-threatening vitreous hemorrhage or retinal detachment 
(see Section 4.4.1).  If the surgery is deemed medically necessary and the patient gives 
specific consent, a vitreous sample may be obtained from the study eye (see Appendix 9
for further details).  Associated PK plasma samples will be collected to measure 
faricimab or aflibercept concentration.  See the laboratory manual for vitreous and PK 
sample collection, storage, and transfer.
Vitreous humor samples will be analyzed primarily for faricimab or aflibercept 
concentrations.  The remaining samples may be analyzed for free Ang-2 and free VEGF 
concentrations, as well as additional biomarkers as noted in Section 4.5.9.


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Samples may be used for exploratory biomarker research as described in Section 4.5.11.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.7 for details on duration of sample storage, use 
of samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses.
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 biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples 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.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

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, storage, and analysis of RBR samples 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.
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 on biomarkers related to faricimab, diseases, or 
drug safety:

Blood sample collected at Day 1 visit

Leftover aqueous humor, vitreous, and plasma samples and any derivatives thereof 
(e.g., DNA, RNA, proteins, peptides)


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The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), 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 or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples 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
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples 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 samples, 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.
Data generated from RBR samples 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.


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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 consent 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 samples.  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 
samples 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 samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.11.7
Monitoring and Oversight
RBR samples 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 samples 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, IRB/EC review, 


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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 determination that treatment discontinuation is in the best 
interest of the patient
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced and will not be allowed to restart study treatment.  However, these patients 
should be strongly encouraged to continue their study participation and undergo as 
many scheduled visits as possible, with emphasis on the Week 24 and Week 72 visits.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues in the study

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
In order to avoid loss to follow-up, the investigator should ask the patient at study start 
for information on a relative or friend who can be contacted in case the patient cannot be 
reached.  However, patients will not be followed for any reason after consent has been 
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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.
Patients who discontinue from the study early should return for an early termination visit 
after a minimum of 28 days have elapsed following the last study treatment
(see Appendix 1).
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
5.1
SAFETY PLAN
Faricimab is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with faricimab in completed and 
ongoing studies.  Please refer to the Faricimab (RO6867461) Investigator's Brochure for 
a complete summary of safety information.
5.1.1
Safety Assessments
The schedule of safety assessments to be performed during the study is provided in
Appendix 1.  After the first study treatment on Day 1, all patients will return for a safety 
assessment visit on Day 7 (3 days).  Patients will be instructed to contact the site at 
any time if they have any health-related concerns.  If warranted, patients will be asked to 


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return to the clinic as soon as possible for an unscheduled safety assessment visit 
(see Appendix 2).
At sites where the masked investigator’s decision is for patients to self-administer 
predose and postdose antimicrobials, patients will also be asked whether they have 
self-administered predose and/or postdose antimicrobials. 
A finger-counting test will be conducted for each patient within 15 minutes postdose by 
the treatment administrator/unmasked investigator; hand-motion and light-perception 
tests will be performed when necessary. 
Following the study treatment, IOP will be measured in the study eye only at 
30 (15) minutes by qualified personnel assigned to the unmasked role.  If there are no 
safety concerns after 30 (15) minutes following study treatment, the patient will be 
permitted to leave the clinic.  If the IOP value is of concern to the treatment 
administrator/unmasked investigator, the patient will remain in the clinic and will be 
managed in accordance with the treatment administrator/unmasked investigator’s clinical 
judgment.  The adverse event will be recorded on the Adverse Event eCRF as 
applicable. 
If an anti-VEGF injection is administered to the non-study (fellow) eye at the same visit 
as the study eye study treatment (faricimab, aflibercept, or sham), the study eye 
treatment must be performed first (see Section 4.4.1 for additional details). 
An iDMC will monitor safety and study conduct on an ongoing basis (see Section 3.1.6
for additional details).
Patients who are discontinued from the study prior to completion (Week 72) will be 
asked to return for early termination visit assessments after a minimum of 28 days have 
elapsed following the last study treatment (see Appendix 1).  The visit will include 
assessment of all adverse events (serious and non-serious; ocular and non-ocular).  
Serious adverse events will be reported in compliance with GCP guidelines.
Treatment interruption and/or treatment discontinuation for adverse events will be 
determined using the criteria in Table 1.
5.1.2
Risks Associated with Faricimab
To date, no identified risks for faricimab have been observed.
Based on experience with aflibercept and other anti-VEGF therapies, potential risks of
faricimab include intraocular inflammation, the IVT injection-related risks of infectious 
endophthalmitis, retinal detachment and/or tear, iatrogenic traumatic cataracts, and 
increased IOP, as well as the potential non-ocular risk of arterial thromboembolic events.  
An independent Clinical Events Coding Committee will be established to adjudicate 


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thromboembolic events (myocardial infarcts, strokes, and vascular deaths) reported 
during the study.
Please see the Faricimab (RO6867461) Investigator's Brochure for more details on the 
risks of faricimab.
5.1.3
Risks Associated with Aflibercept (Comparator)
Important risks associated with aflibercept IVT injections are conjunctival hemorrhage, 
eye pain, reduced vision, endophthalmitis, intraocular inflammation, increased 
intraocular pressure, rhegmatogenous retinal detachment, retinal tear, and iatrogenic 
traumatic cataract.  Important potential risks associated with aflibercept treatment 
include arterial thromboembolic events and immunogenicity.
For full detail on risks associated with aflibercept, please see the Eylea (aflibercept) E.U.
Summary of Product Characteristics.
5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Dose Modification
No dose modifications for faricimab or aflibercept are allowed in this study.
5.1.4.2
Treatment Interruption:  Dose Interruption and Treatment 
Discontinuation Criteria
Study treatment interruption and/or patient discontinuation from the study treatment for 
adverse events will be determined using the criteria listed in Table 1.  If any of these 
criteria are met, treatment will be interrupted (or discontinued, if applicable) and will not 
be resumed earlier than the next scheduled study visit.  The reason for study treatment 
interruption/discontinuation should be recorded on the appropriate eCRF and, if 
applicable, on the Adverse Event eCRF.


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Table 1
Dose Interruption and Treatment Discontinuation Criteria
Event 
Criteria
Intraocular inflammation

Interrupt study treatment if intraocular inflammation (iritis, 
iridocyclitis or vitritis) is 2in the study eye. 

Study treatment may be resumed subsequently as determined 
by the investigator. 
Cataract surgery in the 
study eye

Interrupt study treatment after cataract surgery in study eye. 

Study treatment may be resumed no earlier than 28 days after 
an uncomplicated cataract surgery and no evidence of 
post-operational inflammation at that time.  For cataract 
surgery with complications, study treatment may be permitted 
as determined by Medical Monitor and investigator.  
BCVA decrease

Interrupt study treatment if there is a study treatmentrelated 
decrease in BCVA of 30 letters in the study eye compared 
with the last assessment of BCVA prior to the most recent 
treatment. 

Study treatment may be permitted subsequently, as 
determined by the investigator.
Elevated IOP

Interrupt study treatment if predose IOP in the study eye is 
30 mmHg. 

Treatment may be permitted when IOP has been lowered 
to 30 mmHg, either spontaneously or by treatment, as 
determined by the investigator.
Rhegmatogenous retinal 
break

Interrupt study treatment if a retinal break is present in the 
study eye. 

Study treatment may be resumed no earlier than 28 days after 
successful laser retinopexy, as determined by the investigator.
Rhegmatogenous retinal 
detachment or 
macular hole

Interrupt study treatment if rhegmatogenous retinal 
detachment or Stage 3 or 4 macular hole occurs in the study 
eye.

Study treatment may be subsequently permitted after 
discussion with Medical Monitor.  
Active or suspected 
infection

Interrupt study treatment if active or suspected ocular or 
periocular infections are present (e.g., infectious conjunctivitis, 
infectious keratitis, infectious scleritis, or endophthalmitis) in 
either eye.

Treatment can also be interrupted in cases where patient 
currently receives treatment for active systemic infection, per 
investigator's judgment.

Treatment can be restarted after the event resolves, per 
investigator judgment.
BCVA best-corrected visual acuity; IOP intraocular pressure


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Table 1
Dose Interruption and Treatment Discontinuation Criteria (cont.)
Vitrectomy

Interrupt study treatment if vitrectomy is performed in study 
eye to treat sight-threatening vitreous hemorrhage or retinal 
detachment.  Study treatment may restart based on the 
patient’s status after consultation with the Medical Monitor.
On-study prohibited 
medications

Refer to Section 4.4.2 for additional reasons for potential study 
treatment discontinuation.
BCVA best-corrected visual acuity; IOP intraocular pressure.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject who has been 
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 it is considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 for more 
information)

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., screening invasive 
procedures such as biopsies)


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5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity 
of an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)


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
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.

Sight-threatening adverse events:  an adverse event is considered to be 
sight-threatening and should be reported expeditiously if it meets one or more of the 
following criteria:
–
It causes a decrease of 30 letters in visual acuity score (compared with the 
last assessment of visual acuity prior to the most recent assessment) lasting 
more than 1 hour.
–
It requires surgical or medical intervention (i.e., conventional surgery, 
vitrectomy, vitreous tap, or biopsy with IVT injection of anti-infective treatments, 
or laser or retinal cryopexy with gas, or a medication) to prevent permanent loss 
of sight.
–
It is associated with severe intraocular inflammation (i.e., endophthalmitis, 
4anterior chamber cell/flare, or 4vitritis; see Section 5.3.5 and Appendix 4
for intraocular inflammation grading scales)
All of the above-listed sight-threatening adverse events should also be reported as 
serious adverse events, listing the underlying cause (if known) of the event as the 
primary event term
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
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).
For adverse events that occur during or shortly after study treatment, the unmasked 
investigator may assess the seriousness and severity of the event, but event causality 
will be assessed by the masked investigator.
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.


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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 final study visit 
at Week 72.  For patients who discontinue study treatment and withdraw prematurely 
from the study, all adverse events will be reported up to the early termination visit.  For 
patients who discontinue study treatment early (prior to Week 68 treatment) but continue 
to participate in the study, adverse events will be reported until their last study visit after 
the final dose of study drug.
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 2 provides guidance for assessing adverse event severity.
Table 2
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  Note that only the masked investigator will assess adverse event causality.


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The following guidance should be taken into consideration; see also Table 3:

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 3
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.
For the purposes of reporting events of infection and inflammation, the following are 
examples of terms and definitions to be used:

Iritis:  the presence of inflammatory cells in the anterior chamber
The presence of aqueous flare alone will not constitute iritis but should be 
documented as an anterior chamber flare for adverse event reporting purposes.


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
Iridocyclitis:  the presence of inflammatory cells in both the aqueous and vitreous

Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells
Active inflammation in the vitreous should be clinically differentiated from 
cellular debris from prior episodes of inflammation, hemorrhage, or other 
causes.

Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause
If possible, a sample for culture should be taken prior to initiating antibiotic 
treatment for presumed endophthalmitis.  Results of bacterial or fungal cultures, 
treatment given, and final ophthalmologic outcome should also be provided in 
the details section of the Adverse Event eCRF.
Note:  Trace benign, aqueous pigmented cells visible on slitlamp examination that are 
caused by dilation and are not RBCs or WBCs or the result of any ocular disorder should 
not be recorded as an adverse event.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.


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
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 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.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

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.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice


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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 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).
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.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Macular Edema Due to 
Central Retinal Vein Occlusion in the Study Eye
Medical occurrences or symptoms of deterioration that are anticipated as part of central 
retinal vein occlusion (study eye) 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 
central retinal vein occlusion on the Adverse Event eCRF, it is important to convey 
the concept that the condition has changed by including applicable descriptors 
(e.g., "accelerated worsening central retinal vein occlusion").  The expedited reporting 
requirements for associated sight-threatening events (listed in Section 5.2.3) will apply.


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5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Cases of Medication Error and Associated Adverse Events
Medication error, including an error intercepted prior to administration and accidental
overdose (hereafter collectively referred to as "special situations"), are defined as follows:

Medication error:  accidental deviation in the administration of a drug
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with the masked study treatment, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF in masked manner as described below (see eCRF Completion Guidelines for 
additional details):

For medication error, enter “Medication Error” on the Adverse Event eCRF as the 
primary event term and check the “Medication error” box

For intercepted medication error enter “Intercepted Medication Error” on the 
Adverse Event eCRF as the primary event term and check the “Medication error” 
box.


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Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 
(see Section 5.2.2) or qualifies as an adverse event of special interest (see 
Section 5.2.3), 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).  Adverse events associated 
with special situations should be recorded as described below for each situation:

Enter the adverse event caused by the medication error as primary adverse event 
term.  Check the "Medication error" box.
As an example, a special situation that resulted in a headache would require two entries 
on the Adverse Event eCRF, one entry to report the medication error and one entry to 
report the headache.  The "Medication error" box would need to be checked for both 
entries.
5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Medical Monitors and Emergency Medical Contacts
Contact Information for Western Hemisphere  
Medical Monitor/Emergency Medical Contact:
, M.D., Ph.D. 
(primary)
Mobile Telephone No.:
Medical Monitor/Emergency Medical Contact:
, M.D., Ph.D. 
(secondary)
Mobile Telephone No.:
Medical Monitor/Emergency Medical Contact:
, M.D. 
(secondary)
Mobile Telephone No.:
Contact Information for Europe
Medical Monitor/Emergency Medical Contact:
, M.B.B.S., M.S. (primary)
Mobile Telephone No.:
Medical Monitor/Emergency Medical Contact:  
, M.B., Ch.B.
(secondary)
Mobile Telephone No.:
Contact Information for Asia Pacific 
Medical Monitor/Emergency Medical Contact:     
, M.D., Ph.D. (primary)
Mobile Telephone No.:                                        
Medical Monitor/Emergency Medical Contact:     
, M.D., Ph.D. (secondary)
Mobile Telephone No.:                                         
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.


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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the final study visit at Week 72.  For patients who 
discontinue study treatment and withdraw prematurely from the study, adverse events 
will be reported up to the early termination visit.  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 after Week 72 visit or the 
early termination visit 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 through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 3 months after the final dose of study drug.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 


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events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available. 
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
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.


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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 in 
Section 5.3.1), if the event is believed to be related to prior study drug treatment.  These 
events should be reported through use of the Adverse Event eCRF.  However, if the 
EDC system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the paper Clinical 
Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the 
fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below:
Drug
Document
Faricimab
Faricimab (RO6867461) Investigator's Brochure
Aflibercept
Aflibercept (Eylea) E.U. Summary of Product 
Characteristics
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.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Approximately 750 patients will be randomized in the global enrollment phase of the 
study.  Additional patients may be enrolled in the China extension to ensure a total 
enrollment sufficient to support registration in China.
The primary analysis of this study will include patients enrolled during the global 
enrollment phase; data from patients enrolled during the China extension will not be 
included.
The primary analysis will be performed when all patients from the global enrollment 
phase have either completed the study through Week 24 or have discontinued from the 
study prior to Week 24, whichever comes later (i.e., timing is defined as the primary 
analysis after the LPLV), and all data collected prior to the primary LPLV in the global 
enrollment phase are in the database and have been cleaned and verified.
Results of the primary analysis, summarized by treatment group, may be reported to the 
public before completion of the study.  However, patients, masked study site personnel, 
and CRC personnel will remain masked to individual treatment assignment until the 
study is completed, the database is locked, and the study analyses are final.
The final analysis will be performed when all patients from the global enrollment phase 
have either completed the study through Week 72 or have discontinued early from the 
study, all data from the global enrollment phase are in the database, and the database is 
locked.
Unless otherwise specified, the analyses described in this section are based on patients 
enrolled during the global enrollment phase (excluding the China extension).  Details of 
the planned analyses, including any additional analyses needed to support 
country-specific or regional marketing applications, will be provided in the SAP.
6.1
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on patients enrolled in the global enrollment 
phase.  The global enrollment phase will enroll approximately 750 patients.
Patients will be randomized in a 1:1 ratio to receive treatment with faricimab (Arm A) or 
aflibercept (Arm B) (refer to Section 3.1.1 for details on dosing regimens).  The primary 
comparison will be between the active comparator (aflibercept Q4W) and the faricimab 
Q4W arm at Week 24.


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A sample size of approximately 375 patients in each arm will provide 90% power to 
show non-inferiority of faricimab to aflibercept in the change in BCVA at Week 24 in the 
intent-to-treat (ITT) population, using a non-inferiority margin of 4 letters, and under the 
following assumptions:

No difference in the mean change from baseline in BCVA between the two 
treatment arms

SD of 13 letters for the change from baseline in BCVA at Week 24

Two-sample t-tests

2.5% one-sided type I error rate

10% dropout rate
Furthermore, a sample size of approximately 375 patients per arm will provide greater 
than 80% power to show a 3.5-letter superiority of faricimab over aflibercept in the ITT 
population, under the same SD, test, and dropout assumptions above, and a two-sided 
type I error rate of 5%.
Additional patients may be randomized during the China extension to support 
registration in China.
6.2
ANALYSIS POPULATIONS
The analysis populations described in this section are based on patients enrolled during 
the global enrollment phase and will not include the China extension unless otherwise 
specified.
6.2.1
Intent-to-Treat Population
The ITT population will consist of all patients who are randomized in the study.  For 
analyses based on this patient population, patients will be grouped according to the 
treatment assigned at randomization.
6.2.2
Per-Protocol Population
The per-protocol population is defined as all patients randomized in the study who 
receive at least one dose of study treatment and who do not have a major protocol 
violation that impacts the efficacy evaluation.  For analyses based on this patient 
population, patients will be grouped according to the treatment assigned at 
randomization.
6.2.3
Safety-Evaluable Population
The safety-evaluable population will consist of all patients who receive at least one 
injection of active study drug (faricimab or aflibercept) in the study eye.  For analyses 
based on this patient population, patients will be grouped according to the actual 
treatment received up to Week 20.  If by error a patient receives a combination of 


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different active study drugs (faricimab and aflibercept) in the study eye, the patient’s 
treatment group will be as randomized.
6.2.4
Part 2 Efficacy Population
The Part 2 efficacy population will consist of all patients from the ITT population who 
receive at least one injection of faricimab in Part 2 of the study.  For analyses based on 
this patient population, data will be summarized overall as well as by treatment group 
assigned in Part 1.
6.2.5
Faricimab-Pooled Safety Population
The faricimab-pooled safety population will consist of all patients from the 
safety-evaluable population who receive at least one injection of faricimab in the study 
eye (i.e., Arm B patients treated with aflibercept who have not received faricimab will 
be excluded from the faricimab-pooled safety population). ADA will only be assessed in 
the faricimab-pooled safety population.  
6.2.6
Pharmacokinetic-Evaluable Population
The PK analyses will include safety-evaluable patients with at least one plasma sample, 
and if sufficient dosing information (dose and dosing time) is available, with patients 
grouped according to treatment received (as defined in Section 6.2.3).
6.2.7
Immunogenicity Analysis Population
The immunogenicity analysis population will consist of all patients randomized to 
faricimab with at least one plasma sample for ADA assessment. Patients will be 
grouped according to treatment received or, if no treatment is received prior to study 
discontinuation, according to treatment assigned at randomization.
6.3
SUMMARIES OF CONDUCT OF STUDY
Summaries of conduct of study will be based on the ITT population.
The number of patients randomized will be tabulated by country, site, and treatment arm.  
Patient disposition (the number of patients randomized, treated, and completing through 
the primary endpoint timing, as well as the end of study) will be tabulated by treatment 
arm.  Premature study drug discontinuation and study discontinuation, as well as 
reasons for discontinuations, will be summarized.  Eligibility criteria exceptions and other 
major protocol deviations will be summarized by treatment arm.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics such as age, sex, race/ethnicity and region, 
and baseline disease characteristics (such as baseline BCVA, ocular assessments, and 
medical history) will be summarized by treatment as assigned for the ITT population 
using means, SDs, medians, and ranges for continuous variables, and counts and 
proportions for categorical variables, as appropriate.


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Exposure to study drug (number of study drug administrations and duration of treatment) 
will be summarized by treatment arm for the safety-evaluable population.
6.5
EFFICACY ANALYSES
The primary and secondary efficacy analyses will be based on the ITT population, 
unless otherwise specified, with patients grouped according to the treatment assigned at 
randomization.  Additional analysis based on the per-protocol population will also be 
conducted for the primary endpoint.
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by 
baseline BCVA ETDRS letter score, as assessed on Day 1 (34 letters, 3554 letters,
and 55 letters), and region (United States and Canada, Asia, and the rest of the world).  
The stratification factor as recorded in IxRS will be used.
Continuous outcomes will be analyzed using a mixed model for repeated measures 
(MMRM).  Binary secondary endpoints will be analyzed using stratified estimation for 
binomial proportions.  Additional details are provided in Sections 6.5.1 and 6.5.2.
In addition to p-values for statistical tests, the estimates and CIs will be provided for the 
mean (for continuous variables) or proportion (for binary variables) for each treatment 
arm and for the difference in means or proportions between the active comparator arm 
(aflibercept Q4W) and the faricimab Q4W arm.  All CIs will be two-sided and at the 95% 
level.
6.5.1
Primary Efficacy Endpoint
The primary estimand for the study is defined as follows:

Population:  Adult patients with macular edema due to CRVO or HRVO, as defined 
by the inclusion and exclusion criteria (Sections 4.1.1 and 4.1.2)

Variable: Change from baseline in BCVA at Week 24
BCVA is assessed on the ETDRS visual acuity chart at a starting test distance 
of 4 meters

Intercurrent events, regardless whether or not a patient has one of the following 
intercurrent events prior to Week 24
–
Receives any prohibited systemic treatment or prohibited therapy in the study 
eye (Section 4.4.2)
–
Discontinues study treatment due to adverse events
–
Discontinues study treatment due to lack of efficacy

Population-level summary:  Difference in adjusted mean between the aflibercept 
Q4W arm and the faricimab Q4W arm


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The primary comparison will be between the active comparator (aflibercept Q4W) and 
faricimab Q4W at Week 24.  The following hypothesis will be tested:

Non-inferiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the 
ITT population (at a 1-sided 0.025 significance level)

Superiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population (at a 2-sided 0.05 significance level)
The non-inferiority test will be conducted with a non-inferiority margin of 4 letters at a 
0.025 one-sided significance level.  The null hypothesis (H0: faricimabaflibercept 4 letters) 
and the alternative hypothesis (Ha: faricimabaflibercept 4 letters) will be tested, for which 
faricimab and aflibercept are the expected change from baseline in BCVA at Week 24 for the 
faricimab Q4W arm and the active comparator (aflibercept Q4W) arm, respectively.
If the lower bound of a two-sided 95% CI for the difference of two treatments is greater 
than 4 letters (the NI margin), then the test is considered positive and IVT 6 mg 
faricimab administered Q4W is considered non-inferior to IVT 2 mg aflibercept 
administered Q4W.  Superiority will be tested only if the non-inferiority test is positive.
The primary analysis will be performed using the mixed-effect model with repeated 
measures (MMRM) based on all available data up to Week 24.  All observed 
measurements will be included in the analysis regardless whether or not a patient has 
an intercurrent event.  Missing data will be implicitly imputed by the MMRM model, 
assuming a missing at random mechanism.
The MMRM model will include the change from baseline at Weeks 424 as the response 
variable and will include the categorical covariates of treatment group, visit, visit-by-
treatment group interaction, the continuous baseline value for the response variable (in 
this case, baseline BCVA), as well as randomization stratification factors as fixed effects.  
The MMRM model will assume an unstructured covariance structure.  If there are 
convergence problems with the model, a heterogeneous compound symmetry or an 
AR(1) covariance structure may be fitted.
A per-protocol analysis is planned as a sensitivity analysis for the primary endpoint. The 
following supplementary analyses will be performed:

Trimmed mean analysis using an analysis of covariance (ANCOVA) model with 
adjustment for covariates. The estimand assumes patients have the worst outcome 
after the following intercurrent events prior to Week 24:
–
Receives any prohibited systemic treatment or prohibited therapy in the study 
eye (Section 4.4.2)
–
Discontinues study treatment due to adverse events
–
Discontinues study treatment due to lack of efficacy

Analyses using different handling rules for intercurrent event.  Intercurrent events 
prior to Week 24 are handled as follows:


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–
Had any prohibited systemic treatment or prohibited therapy in the study eye 
(Section 4.4.2) not been made available
–
Regardless whether a patient discontinues study treatment due to adverse 
events
–
Regardless whether a patient discontinues study treatment due to lack of 
efficacy as per investigator’s clinical judgment
Two analyses will be performed using the same analysis method as the primary 
endpoint with the exception of data handling methods for intercurrent events and 
missing data:
–
Method 1: Assessments after prohibited treatments will be imputed using the 
last observation prior to such intercurrent event.  Other missing data will be 
imputed using the last observation carried forward method.
–
Method 2: Assessments after prohibited treatment will be excluded.  All missing 
data will be implicitly imputed by the MMRM model, assuming a missing at 
random mechanism.
Additional details about the planned analyses will be provided in the SAP.
6.5.2
Secondary Efficacy Endpoints
For all secondary endpoints measured on a continuous scale up to Week 24, estimates 
of each treatment group and difference between the two treatment groups will be 
provided with 95% CI, using the same analyses methods and data handling rules for 
intercurrent events and missing data as described in Section 6.5.1 for the primary 
endpoint.
For binary secondary endpoints up to Week 24, the proportion of patients in each 
treatment group and the overall difference in proportions between treatment groups will 
be estimated using the weighted average of the observed proportions and the 
differences in observed proportions over the strata defined by randomization factors 
using the Cochran-Mantel-Haenszel weights (Cochran 1954; Mantel and Haenszel 
1959).  CIs of the proportion of patients in each treatment group and the overall 
difference in proportions between treatment groups will be calculated using the normal 
approximation to the weighted proportions (Mehrota and Railkar 2000).
No formal statistical comparisons will be made between the patients randomized to 
faricimab (Arm A) or aflibercept (Arm B) at the beginning of the study after the Week 24 
primary analysis.  Maintenance of visual acuity outcomes will be assessed based on 
descriptive statistics of BCVA change from baseline and change from Week 24 (after the 
initial monthly doses for each arm).  Changes in visual acuity will be assessed based on 
both continuous and categorical measures of BCVA.  Descriptive statistics will be 
summarized separately for patients randomly assigned to faricimab (Arm A) and 
aflibercept (Arm B) at the beginning of the study, as well as for pooled patients from the 
two arms.


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Additional details regarding the plan for the secondary endpoint analyses will be 
provided in the SAP.
6.5.3
Exploratory Efficacy Endpoints
Details regarding analysis of the exploratory efficacy endpoints will be provided in the 
SAP.
6.6
SAFETY ANALYSES
Safety data will be summarized for the safety-evaluable population up to Week 24 and 
for the faricimab-pooled safety population.
Safety will be assessed through descriptive summaries of ocular and non-ocular adverse 
events, deaths, and ocular assessments (e.g., IOP).  Clinically significant laboratory 
abnormalities and clinically significant vital sign abnormalities will be reported as adverse 
events and evaluated as part of the adverse event assessments.
At the time of the primary analysis, safety summaries will be summarized based on the 
complete Week 24 data in the safety-evaluable population. In addition, summaries for 
ongoing safety data (after Week 24 and up to a single specified clinical cutoff date) in the 
faricimab-pooled safety population will be summarized.  At the time of the final analysis, 
safety summaries will be produced based on cumulative Week 72 data in the faricimab-
pooled safety population.
Verbatim descriptions of treatment-emergent adverse events will be mapped to MedDRA 
thesaurus terms, and the incidence and severity will be summarized by treatment arm.  
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.  Adverse 
events will be tabulated by System Organ Class and Preferred Term.  In addition, 
summaries will be generated for serious adverse events, deaths, adverse events leading 
to discontinuation of study drug, adverse events of special interest, and adverse events 
judged to be related to study treatment.  Non-ocular and ocular adverse events will be 
summarized.  For ocular adverse events, events in the study eye and fellow eye will be 
summarized separately.
Results of the ocular assessments will be summarized by eye (study vs. fellow) using 
descriptive summaries.  In addition, changes from baseline in predose IOP 
measurements and changes between predose and postdose IOP measurements will 
also be summarized.
Additional details regarding the safety analysis plan will be provided in the SAP.
6.7
PHARMACOKINETIC ANALYSES
PK analyses will be performed in the PK-evaluable population.


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A non-linear mixed-effects modeling approach (using NONMEMsoftware [Beal and 
Sheiner 1998]) will be used to analyze the concentrationtime data for faricimab.  
Population and individual primary PK parameters (i.e., clearances and volumes) will be 
estimated.  The plasma data collected in this study may be pooled with aqueous humor 
drug concentrations and with data collected in previous studies as appropriate.  A 
covariate modeling approach emphasizing parameter estimation will be implemented for 
the covariate model development.  Potential covariate-parameter relationships will be
identified based on mechanistic plausibility and exploratory graphics.  Inferences about 
covariate effects and their clinical relevance will be based on the resulting parameter 
estimates and measures of estimation precision (asymptotic standard errors).  PK 
parameters, such as area under the concentrationtime curve and maximum 
concentration, will be derived from the individual post-hoc predictions.  Additional PK 
analyses will be conducted as appropriate.
The result of this analysis will be reported in a separate document from the Clinical 
Study Report.
6.8
PHARMACODYNAMIC ANALYSES
PD analyses will be based on the safety-evaluable population.  PD biomarkers and the 
change from baseline values (absolute or percent change as appropriate) will be 
summarized by treatment arm and timepoint.
The data collected from this study may be pooled with data from previous studies.  The 
effect of exposure or dosing information on BCVA, aqueous humor free VEGF-A, and 
free Ang-2 will be explored using a longitudinal model approach.  The influence of 
various baseline covariates on model parameters will be investigated.  The PK-PD or 
dose-PD relationship will be characterized.  Additional details about the PK and PD 
analyses will be provided in the Modeling Analysis Plan.  The results will be reported in a 
separate document from the Clinical Study Report.
6.9
IMMUNOGENICITY ANALYSES
Humoral immunogenicity analyses will be based on the immunogenicity analysis 
population.
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining the postbaseline incidence, 
patients are considered to be ADA-positive if they are ADA-negative or have missing 
data at baseline but who develop an ADA response following study drug exposure, or if 
they are ADA-positive at baseline and the titer of one or more postdose samples is 
greater than the titer of the baseline sample by a scientifically reasonable margin (details 
to be provided in the SAP).  Patients are considered to be ADA-negative if they are 
ADA-negative or have missing data at baseline and all postbaseline samples are 


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negative, or if they are ADA-positive at baseline but do not have any postbaseline
samples with a titer that is greater than the titer of the baseline sample by a scientifically 
reasonable margin such as 4-fold.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported using descriptive statistics.
6.10
BIOMARKER ANALYSES
Biomarker analyses will be based on the safety-evaluable population.
Analyses will be performed, as deemed appropriate, to identify biomarkers that are 
predictive of response to faricimab, are associated with progression to a more severe 
disease state, are associated with susceptibility to developing adverse events, can 
provide evidence of faricimab activity, or can increase the knowledge and understanding 
of disease biology and drug safety.  Prognostic biomarker analyses will include all 
patients for which biomarker assessments were made during randomization ("baseline").  
Baseline values will be used to evaluate prognostic biomarkers in the context of efficacy, 
PK, safety, and/or immunogenicity endpoints.  Results will be summarized descriptively. 
6.11
CHINA SUBPOPULATION ANALYSES
The China subpopulation will include all patients enrolled at NMPA-recognized sites 
(i.e., during both the global enrollment phase and the extended China enrollment phase).  
Details regarding the China subpopulation analysis will be provided in the SAP.
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.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and CRC reports 
and images 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.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.


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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 that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
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 7.5.
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.
7.4
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 


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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.
7.5
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 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
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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 
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.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
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.


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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 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.
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 Sponsor policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 


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participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/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.
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
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 


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from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 200 sites globally will participate to enroll approximately 750 patients.  
Enrollment will occur through IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5. 
An iDMC will be employed to monitor and evaluate patient safety throughout the study. 
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
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.


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


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10.
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the vitreous of eyes with proliferative diabetic retinopathy. Am J 
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Bhisitkul RB, Campochiaro PA, Shapiro H, et al. Predictive value in retinal vein 
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Boyd SR, Zachary I, Chakravarthy U, et al. Correlation of Increased Vascular Endothelial 
Growth Factor With Neovascularization and Permeability in Ischemic Central Vein 
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growth factor/antiangiopoietin 2 bispecific antibody RG7716 for neovascular 
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Fauser S, Schwabecker V, Muether PS. Suppression of intraocular vascular endothelial 
growth factor during aflibercept treatment of age-related macular degeneration. 
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to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 
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factor and interleukin-6 in the aqueous humor of diabetics with macular edema. 
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Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with 
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Appendix 1
Schedule of Activities
Table 1
Screening through Week 24 (Part 1) and Early Termination
Visit Window (days)
Screening a
Visit Day
Visit Week
ET
Visit c
1a
7b
4
8
12
16
20
24
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Main informed consent d
x
Optional aqueous, vitreous and plasma 
sample informed consent
x d
x d
Optional collection and/or storage of 
samples for RBR informed consent
x d
x d
Review of inclusion and exclusion criteria
x
x
Demographics (age, sex, and self-reported 
race/ethnicity)
x
Medical and surgical history including 
tobacco history e
x
Physical examination f 
x
x
Body weight and height
x
Vital signs g 
x
x
x
NEI VFQ-25 h
x
x
x
Refraction and BCVA i
x
x
x
x
x
x
x
x
x
x
Predose IOP j
x
x
x
x
x
x
x
x
x
x
Pregnancy test k
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
SD-OCT l or SS-OCT (if applicable)
x
x
x
x
x
x
x
x
x
x
Optional OCT-A l, m
x
x
x
x
x
x
x
x
x


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Appendix 1
Schedule of Activities (cont.)
Table 1
Screening through Week 24 (Part 1) and Early Termination 
Visit Window (days)
Screening a
Visit Day
Visit Week
ET
Visit c
1a
7b
4
8
12
16
20
24
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
FFA l 
(x)
x
x
x
CFP l
x
x
x
Hematology n, o
x
x
Chemistry n, o
x
x
Coagulation n, o
x
x
Urinalysis n, o
x
Mandatory plasma PK sample n
x
x
x
x
Mandatory plasma PD sample n
x
x
x
Mandatory plasma ADA sample n
x
x
x
x
Optional aqueous humor sample for 
biomarkers p
x
x
x
x
x
Optional PK plasma sample (if aqueous humor 
sample is collected) n, p
x
Optional PD plasma sample (if aqueous 
humor sample is collected) n, p
x
x
Optional vitreous humor sample for 
biomarkers q
Collected if vitrectomy is necessary
Optional PK plasma sample (if vitreous humor 
sample is collected) n, q
Collect plasma PK sample if vitreous humor sample is collected
Optional blood sample for RBR n, r
x


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Appendix 1
Schedule of Activities (cont.)
Table 1
Screening through Week 24 (Part 1) and Early Termination 
Visit Window (days)
Screening a
Visit Day
Visit Week
ET
Visit c
1a
7b
4
8
12
16
20
24
–28 to 1
NA
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(28)
Administration of study treatment
x
x
x
x
x
x
x
Finger-counting test s
x
x
x
x
x
x
x
Postdose IOP t
x
x
x
x
x
x
x
Adverse events u
x
x
x
x
x
x
x
x
x
x
Concomitant medications v
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures w
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; Ang-2angiopoietin-2; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; CRCcentral reading center; 
eCRFelectronic Case Report Form; ETearly termination; FFAfundus fluorescein angiography; IOPintraocular pressure; IxRSinteractive web-based response 
system; NEI VFQ-25National Eye Institute 25-Item Visual Functioning Questionnaire; OCT-Aoptical coherence tomographyangiography; PDpharmacodynamic; 
PKpharmacokinetic; RBRResearch Biosample Repository; SD-OCTspectral-domain optical coherence tomography; SS-OCTswept-source optical coherence 
tomography; UWFultrawide field; VAvisual acuity; VEGF-Avascular endothelial growth factorA.


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Appendix 1
Schedule of Activities (cont.)
Table 1:
Screening through Week 24 (Part 1) and Early Termination
Notes:  All ocular assessments are to be performed on both eyes unless stated otherwise.  All assessments are to be performed on the same day, 
except during screening.  All study visits will be scheduled 28 (7) days relative to the randomization date as registered in IxRS. 
There must be a minimum of 21 days between study treatment visits occurring from Day 1 through to Week 68.  The final study visit at Week 72 
should not occur earlier than 28 days after the final study treatment.  All assessments should be performed prior to dosing, unless otherwise 
specified. Fellow eye anti-VEGF treatment approved by the country regulatory agency for ocular use may be covered by the Sponsor only as long 
as the patient remains in the study (for details, refer to Section 4.4.1).  The fellow eye anti-VEGF treatments after the ET visit or the final study visit
(Week 72) will not be covered by the Sponsor.
a The screening and Day 1 (randomization) visits may occur as a combined visit if all assessments are completed and evaluated within 2 business 
days.  When screening and randomization are combined and performed in 1 day, assessments listed for both visits should be conducted only 
once.  If the combined visit is conducted within 2 business days, then the following safety assessments will be repeated on the day of patient’s 
randomization and study treatment administration:  urine pregnancy test (if applicable), slitlamp examination, indirect ophthalmoscopy, and 
predose IOP measurements (recorded on the Day 1 eCRF and dated accordingly).  Verify that the patient has not started any prohibited 
medication.
b The Day 7 visit should take place 7 days after the Day 1 visit (e.g., if the Day 1 visit takes place on a Wednesday, the Day 7 visit would take 
place on the following Wednesday).
c Patients who discontinue from the study early (prior to the final study visit at Week 72) but have not withdrawn consent should return for an early 
termination visit after a minimum of 28 days have elapsed following their final study treatment.
d Informed consent must be administered and documented before any study-specific screening procedure is performed and may be obtained no 
more than 28 days before initiation of study treatment at the Day 1 visit.  The Informed Consent Forms for optional aqueous humor, vitreous 
humor, and plasma samples, as well as the Informed Consent Form for optional collection and/or storage of samples for RBR can be signed 
either at the screening or Day 1 visit prior to sample collection.
e Medical history, including clinically significant diseases, chronic and ongoing conditions (e.g., trauma, cardiovascular, cerebrovascular, and 
ophthalmic), surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, smoking history will be recorded at 
baseline.
f
A targeted physical examination should include an evaluation of the head, ears, nose and throat.  If any abnormalities are noted during the study, 
the patient may be referred to another doctor.
g Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure.  Vital signs will be taken 
while the patient is in a seated position after resting for 5 minutes.


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Appendix 1
Schedule of Activities (cont.)
Table 1:
Screening through Week 24 (Part 1) and Early Termination
h To be administered by the masked site staff (except for the BCVA examiner) 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.
i
Perform the assessments prior to dilating the eyes.  Both refraction and BCVA will be assessed at every study visit for both eyes, however, only 
study eye refraction from the Day 1, Week 24 and Week 68 visits will be entered on the refraction-specific eCRF.  The BCVA assessment data 
for both eyes will be entered on the BCVA-specific eCRF for every study visit.  The study eye BCVA score at each study treatment visit must be 
entered in IxRS during the same visit so that the correct study treatment can be assigned for future visits. Prior to entering the study eye BCVA 
score in IxRS, the study coordinator must recalculate the BCVA score using the BCVA worksheet to verify accurate study eye BCVA score.
j
The same method should be used throughout the study period.  Perform measurements prior to dilating the eyes.  At screening and on Day 7, 
IOP should be performed, although study treatment will not be given.
k All women of childbearing potential (including those who had had a tubal ligation) will have a urine pregnancy test performed at screening and 
prior to each study treatment at subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  If 
positive, study treatment should not be administered.  Perform urine pregnancy test before FFA (if applicable).
l
The CRC will review SD-OCT (certain SS-OCT equipment may be acceptable; consult CRC) and CFP images obtained at screening for 
determination of patient eligibility.  The investigator will determine unilateral versus bilateral disease status at screening.  For patients with 
bilateral RVO, screening CFP and SD-OCT images of fellow eye may be captured and stored at the CRC.  No ocular images of the fellow eye 
will be captured or stored at screening for patients with unilateral RVO.  At all subsequent visits, imaging will be performed in the study eye only, 
except for patients diagnosed at screening with bilateral RVO.  For these patients, at subsequent visits CFP and SD-OCT images may also be 
captured in the fellow eye and stored at the CRC.  Outputs from all types of imaging assessments will be sent to the relevant CRC.  See the 
CRC manual for details on the required equipment and image-capture guidance for FFA and CFP.  The baseline CFP must be completed at 
screening and sent to the CRC together with the OCT image.  The baseline FFA may be obtained either at screening or the Day 1 visit, but it is 
recommended to obtain it at the Day 1 visit.  The FFA images should be obtained after laboratory samples have been collected.  Note:  After 
randomization, if a patient misses a study visit when CFP or FFA ocular images are scheduled or these images are not taken at the scheduled 
visit (e.g., equipment is broken), they must be obtained at the next scheduled visit the patient attends.  Please remember to forward OCT images 
to the CRC immediately after the visit as they need to be evaluated and data submitted to IxRS by the CRC before the next study visit.  If the 
OCT image was missed due to a missed visit or not taken, then notify the CRC immediately so they can inform IxRS that the expected data will 
not be available.
m Optional OCT-A in study eye to be conducted at sites with OCT-A capability and provided sites approve optional OCT-A sampling.
n Obtain prior to FFA (if applicable) and prior to study treatment. Missed mandatory PK, PD, or ADA samples may be obtained at the next 
scheduled visit the patient attends.


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Appendix 1
Schedule of Activities (cont.)
Table 1:
Screening through Week 24 (Part 1) and Early Termination
o Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes [absolute], lymphocytes, and other cells).  Serum chemistry panel includes bicarbonate or total carbon dioxide (if considered standard 
of care for the region), sodium, potassium, chloride, glucose, BUN, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, 
ALP, ALT, AST, and urate.  Coagulation includes aPTT and PT. Urinalysis includes pH, specific gravity, glucose, protein, ketones, blood, 
bilirubin, urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, other than glucose and ketones, are abnormal). If 
screening and Day 1 visits are combined, historical laboratory data obtained within 2 months of Day 1 may be used at the Principal Investigator’s 
discretion; samples must still be collected for submission to the central laboratory.
p If a patient consents to collection of optional aqueous humor sample, collect the sample from the study eye at indicated timepoints prior to study 
treatment administration.  It is permissible to collect aqueous humor sample after FFA was performed at applicable visits.  Associated optional 
PK and PD plasma samples should be collected at scheduled visits only from patients consenting to optional aqueous humor sampling.  Not 
applicable for a site that has not been granted approval by a site's Institutional Review Board or Ethics Committee. 
q If a vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  Associated PK plasma 
sample should also be collected.
r
Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.  If the optional RBR sample is not obtained at the assigned visit (Day 1), the sample may be 
collected at any subsequent study visit when a blood draw is being performed for other purposes as specified (e.g., PK and ADA sampling, 
and/or hematology or chemistry).
s The finger-counting test should be conducted by the treatment administrator/unmasked investigator within approximately 15 minutes following 
study treatment administration for the study eye only.
t
Postdose IOP measurement to be conducted in the study eye only at 30 (15) minutes by qualified personnel assigned to the unmasked role.  If 
there are no safety concerns after 30 (15) minutes following the study treatment, the patient will be permitted to leave the clinic.  If the IOP 
value is of concern to the investigator, the patient will remain in the clinic and will be managed in accordance with the investigator’s clinical 
judgment.  The adverse event will be recorded on the Adverse Event eCRF as applicable. The same method of measuring IOP should be used 
throughout the study.


Faricimab—F. Hoffmann-La Roche Ltd
116/Protocol GR41986, Version 2
Appendix 1
Schedule of Activities (cont.)
Table 1:
Screening through Week 24 (Part 1) and Early Termination
u After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug (Day 1), all adverse events will be reported until the final study visit, or if applicable, 
until the early termination visit.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse events
that are believed to be related to prior study treatment (see Section 5.6).  The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until 
a final outcome can be reported.  
v Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient from 7 days prior to initiation of study treatment (Day 1) until the final 
study visit or early termination visit.
w Record all concurrent ocular procedures performed on the study or non-study eye between the Day 1 visit after study treatment and the final 
study visit or early termination visit.  


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117/Protocol GR41986, Version 2
Appendix 1
Schedule of Activities (cont.)
Table 2
Week 28 through Week 72 (Part 2) and Early Termination
Visit Window (days)
Visit Week
ET
Visit b
28
32
36
40
44
48
52
56
60
64
68
72
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35) a
(28)
Physical examination c
x
x
Vital signs d
x
x
NEI VFQ-25 e
x
x
x
Refraction and BCVA f
x
x
x
x
x
x
x
x
x
x
x
x
x
Predose IOP g
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test h 
x
x
x
x
x
x
x
x
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT i or SS-OCT (if applicable)
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A i, j
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA i
x
x
x
CFP i
x
x
x
Hematology k, l
Chemistry k, l
Coagulation k, l
Urinalysis k, l
Mandatory plasma PK sample k
x
x
x
x
Mandatory plasma PD sample k
x
Mandatory plasma ADA sample k
x
x
x
x


Faricimab—F. Hoffmann-La Roche Ltd
118/Protocol GR41986, Version 2
Appendix 1
Schedule of Activities (cont.)
Table 2
Week 28 through Week 72 (Part 2) and Early Termination
Visit Window (days)
Visit Week
ET
Visit b
28
32
36
40
44
48
52
56
60
64
68
72
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
(28 and 
35) a
(28)
Optional aqueous humor sample for 
biomarkers m
x
x
x
x
x
Optional PK plasma sample (if aqueous 
humor sample is collected) k,m
x
x
Optional PD plasma sample (if aqueous 
humor sample is collected) k,m
x
x
x
x
Optional vitreous humor sample for 
biomarkers n
Can be collected if vitrectomy is necessary
Optional PK plasma sample (if vitreous 
humor sample is collected) k,n
Collect PK sample if vitreous humor sample is collected
Administration of study treatment
x
x
x
x
x
x
x
x
x
x
x
Finger-counting test o
x
x
x
x
x
x
x
x
x
x
x
Postdose IOP p
x
x
x
x
x
x
x
x
x
x
x
Adverse events q
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications r
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures s
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; Ang-2angiopoietin-2; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; CRCcentral reading center; 
eCRFelectronic Case Report Form; ETearly termination; FFAfundus fluorescein angiography; IOPintraocular pressure; IxRSinteractive web-based response 
system; NEI VFQ-25National Eye Institute 25-Item Visual Functioning Questionnaire; OCT-Aoptical coherence tomographyangiography; PDpharmacodynamic; 
PKpharmacokinetic; RBRResearch Biosample Repository; SD-OCTspectral-domain optical coherence tomography; SS-OCTswept-source optical coherence 
tomography; UWFultrawide field; VAvisual acuity; VEGF-Avascular endothelial growth factorA.


Faricimab—F. Hoffmann-La Roche Ltd
119/Protocol GR41986, Version 2
Appendix 1
Schedule of Activities (cont.)
Table 2
Week 28 through Week 72 (Part 2) and Early Termination
Notes:  All ocular assessments are to be performed on both eyes unless stated otherwise.  All assessments are to be performed on the same day.  
All study visits will be scheduled 28 (7) days relative to the randomization date as registered in IxRS.
There must be a minimum of 21 days between study treatment visits occurring from Day 1 through to Week 68.  All assessments should be 
performed prior to dosing, unless otherwise specified. Fellow eye anti-VEGF treatment approved by the country regulatory agency for ocular use 
may be covered by the Sponsor only as long as the patient remains in the study (for details, refer to Section 4.4.1).  The fellow eye anti-VEGF 
treatments after the ET visit or the final study visit (Week 72) will not be covered by the Sponsor.
a The Week 72 visit must occur 28 days and 35 days after the actual date of the Week 68 visit.
b Patients who discontinue from the study early (prior to the final study visit at Week 72) but have not withdrawn consent should return for an early 
termination visit after a minimum of 28 days have elapsed following their final study treatment.
c A targeted physical examination should include an evaluation of the head, ears, nose, and throat.  If any abnormalities are noted during the study, 
the patient may be referred to another doctor.
d Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure.  Vital signs will be taken 
while the patient is in a seated position after resting for 5 minutes.
e To be administered by the masked site staff (except for the BCVA examiner) 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.
f
Perform the assessments prior to dilating the eyes.  Both refraction and BCVA will be assessed at every study visit for both eyes; however, only 
study eye refraction from the Day 1, Week 24, and Week 68 visits will be entered on the refraction-specific eCRF.  The BCVA assessment data 
for both eyes will be entered on the BCVA-specific eCRF for every study visit.  The study eye BCVA score at each study treatment visit must be 
entered in IxRS so that the correct study treatment can be assigned for future visits.  Prior to entering the study eye BCVA score in IxRS, the 
study coordinator must recalculate the BCVA score using the BCVA worksheet to verify accurate study eye BCVA score.
g The same method should be used throughout the study period.  Perform measurements prior to dilating the eyes.  At Week 72 and early 
termination (if applicable) visits, IOP should be performed, although study treatment will not be given.
h All women of childbearing potential (including those who had had a tubal ligation) will have a urine pregnancy test performed at screening and 
prior to each study treatment at subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  If 
positive, study treatment should not be administered.  Perform urine pregnancy test before FFA (if applicable).


Faricimab—F. Hoffmann-La Roche Ltd
120/Protocol GR41986, Version 2
Appendix 1
Schedule of Activities (cont.)
Table 2
Week 28 through Week 72 (Part 2) and Early Termination
i
Imaging will be performed in the study eye only, except for patients diagnosed at screening with bilateral RVO.  For these patients, CFP and SD-
OCT images may also be captured in the fellow eye and stored at the CRC.  Outputs from all types of imaging assessments will be sent to the 
relevant CRC.  See the CRC manual for details on the required equipment and image-capture guidance for FFA and CFP.  Please remember to 
forward OCT images to the CRC immediately after the visit as they need to be evaluated and data submitted to the IxRS by the CRC before the 
next study visit.  If the OCT image was missed due to a missed visit or not taken, then notify the CRC immediately so they can inform IxRS that 
the expected data will not be available.
j
Optional OCT-A in study eye to be conducted at sites with OCT-A capability and provided sites approve optional sampling.
k Obtain prior to FFA (if applicable) and prior to study treatment. Missed mandatory PK, PD, or ADA samples may be obtained at the next 
scheduled visit the patient attends.
l
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes [absolute], lymphocytes, and other cells).  Serum chemistry panel includes bicarbonate or total carbon dioxide (if considered standard 
of care for the region), sodium, potassium, chloride, glucose, BUN, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, 
ALP, ALT, AST, and urate.  Coagulation includes aPTT and PT.  Urinalysis includes pH, specific gravity, glucose, protein, ketones, blood, 
bilirubin, urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, other than glucose and ketones, are abnormal).
m If a patient consents to collection of optional aqueous humor sample, collect the sample at indicated timepoints prior to study treatment 
administration.  It is permissible to collect aqueous humor sample after FFA was performed at applicable visits.  Associated optional PK and PD 
plasma samples should be collected at scheduled visits only from patients consenting to optional aqueous humor sampling.  Not applicable for a 
site that has not been granted approval by a site's Institutional Review Board or Ethics Committee.
n If a vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  Associated PK plasma 
sample should also be collected.
o The finger-counting test should be conducted by the treatment administrator/unmasked investigator within approximately 15 minutes of study 
treatment administration for the study eye only.
p Postdose IOP measurement to be conducted in the study eye only at 30 (15) minutes by qualified personnel assigned to the unmasked role.  If 
there are no safety concerns after 30 (15) minutes following the study treatment, the patient will be permitted to leave the clinic.  If the IOP 
value is of concern to the investigator, the patient will remain in the clinic and will be managed in accordance with the investigator’s clinical 
judgment.  The adverse event will be recorded on the Adverse Event eCRF as applicable. The same method of measuring IOP should be used 
throughout the study.


Faricimab—F. Hoffmann-La Roche Ltd
121/Protocol GR41986, Version 2
Appendix 1
Schedule of Activities (cont.)
Table 2
Week 28 through Week 72 (Part 2) and Early Termination
q After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug (Day 1), all adverse events will be reported until the final study visit, or if applicable, 
until the early termination visit.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse 
events that are believed to be related to prior study treatment (see Section 5.6).  The investigator should follow each adverse event until the 
event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient 
withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
r
Record any concomitant medications (i.e., any prescription medications or over-the-counter preparations other than protocol-specified 
procedural medications such as proparacaine, etc.) used by the patient from 7 days prior to initiation of study treatment (Day 1) until the final visit 
or early termination visit.
s Record all concurrent ocular procedures performed on the study or non-study eye between the Day 1 visit after study treatment and the final 
study visit or early termination visit.


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122/Protocol GR41986, Version 2
Appendix 2
Unscheduled Safety Assessment Visit
Assessments (at the discretion of the investigator) a
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature)
Best-corrected visual acuity (assessed at a 4-meter starting distance) b
Slitlamp examination
Dilated binocular indirect high-magnification ophthalmoscopy
Intraocular pressure c
Adverse events d
Concurrent ocular procedures
Concomitant medications
Hematology, serum chemistry panel, and coagulation e
Ocular imaging, as necessary
IOPintraocular pressure.
a Patients will be instructed to contact the investigator at any time if they have 
any health-related concerns.  If warranted, patients will be asked to return to 
the clinic as soon as possible for an unscheduled safety assessment visit.  
Assessments performed at unscheduled safety visits are at the discretion of 
the investigator.  It is recommended to perform ocular assessments on both 
eyes.
b Perform finger-counting test followed by hand-motion and light-perception 
tests when necessary.
c The method used for the IOP measurement for a patient must remain 
consistent throughout the study.
d Adverse event causality to be evaluated by the masked physician in the 
assessor role.
e Hematology includes WBC count, RBC count, hemoglobin, hematocrit, 
quantitative platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes [absolute], lymphocytes, and bands).  Serum 
chemistry panel includes bicarbonate or total carbon dioxide (if considered 
standard of care for the region), sodium, potassium, chloride, glucose, BUN, 
creatinine, total protein, albumin, phosphate, calcium, total and direct 
bilirubin, ALP, ALT, AST, and urate.  Coagulation includes aPTT and PT.


Faricimab—F. Hoffmann-La Roche Ltd
123/Protocol GR41986, Version 2
Appendix 3
Study Treatment Preparation
The pharmacist responsible for dispensing the study treatment, or designated unmasked 
site personnel, will prepare the correct study treatment (faricimab, aflibercept, or sham) 
as assigned through the interactive web-based response system (IxRS).
Detailed stepwise instructions for the preparation of faricimab, aflibercept, or sham for 
administration, and mandatory materials to be used will be specified by the Sponsor and 
are detailed in the pharmacy manual.
A specified filter needle must be used for each dose preparation of faricimab or 
aflibercept according to the instructions provided in the pharmacy manual.  All materials 
to prepare and administer study treatments will be provided or reimbursed by the 
Sponsor, and no other material than specified should be used.
Vials of faricimab drug product and vials of aflibercept (the active comparator) are for 
single-use only (one injection preparation per patient per eye).  Vials used for one 
patient must not be used for any other patient.  Partially used vials, remaining faricimab 
drug product or aflibercept vials, as well as administration material must not be reused.


Faricimab—F. Hoffmann-La Roche Ltd
124/Protocol GR41986, Version 2
Appendix 4
Grading Scale for Assessment of Anterior Chamber Flare
or Cells and Vitreous Cell
Anterior Chamber Flare
Grade
Description
0
None
1 
Faint
2 
Moderate (iris and lens details clear)
3 
Marked (iris and lens details hazy)
4 
Intense (fibrin or plastic aqueous)
Anterior Chamber Cells
Grade
Cells in Field a
0
1
0.5 
15
1 
615
2 
1625
3 
2650
4 
50
a Field size is a 1-mm slit beam.
Vitreous Cells
Grade
Number of Vitreous Cells
0
No cells
0.5 
110
1 
1120
2 
2130
3 
31100
4 
101 a
a  There is an error in the publication. This should read 101.
From:  The Standardization of Uveitis Nomenclature (SUN) Working Group criteria.
Reference:  Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis 
Foundation preferred practice patterns of uveitis management. Surv Ophthalmol 
2016;61:117.


Faricimab—F. Hoffmann-La Roche Ltd
125/Protocol GR41986, Version 2
Appendix 5
Refraction and Best-Corrected Visual Acuity Testing
SCOPE
Best-corrected visual acuity (BCVA) is assessed on the Early Treatment Diabetic 
Retinopathy Study (ETDRS) visual acuity chart, at a starting test distance of 4 meters.  
The refraction BCVA assessment must be conducted before pupil dilation.  The 
refraction and BCVA will be measured by trained and certified personnel at the study 
sites.  Both refraction and BCVA will be assessed at every study visit, however, only 
study eye refraction on Day 1, Week 24, and Week 68 visits will be entered on the 
refraction-specific electronic Case Report Form (eCRF).  The BCVA assessment data 
will be entered on the BCVA-specific eCRF for every study visit.  The visual acuity 
(VA) examiner must be masked to each patient’s study (treated) eye and treatment 
arm assignment.  VA will be measured at the intervals specified in the protocol 
(see Appendix 1).
EQUIPMENT
The following are needed to conduct the examination:

Examination lane of adequate dimensions to allow testing at required distances 
(4- and 1-meter lanes)

Standard chair with a firm back

Set of three Precision Visionor Lighthouse distance acuity charts as applicable 
per country and region (see the BCVA manual for details)

Retro-Illuminated box

Study frame

Study lens set

Note:  for additional details, see the BCVA specification manual.
TRAINING AND CERTIFICATION
A VA specifications document, procedure manual, and training materials will be provided 
to the investigational sites, and examiner certification will be obtained from a third party 
vendor.  The visual acuity examination room also must be certified before any visual 
acuity examinations are performed.
ETDRS Reference:  Kniestedt C, Stamper RL. Visual acuity and its measurement. 
Ophthalmol Clin North Am. 2003;16:155–70.


Faricimab—F. Hoffmann-La Roche Ltd
126/Protocol GR41986, Version 2
Appendix 6
Color Fundus Photography
SCOPE
Color fundus photographs will be obtained from study eye by trained personnel at the 
study sites.  Please see the central reading center (CRC) manual for details on the 
required equipment and image-capture guidance.
Fundus photography will be performed at baseline (screening) and at the intervals 
specified in the schedule of activities (see Appendix 1).  Analysis (if applicable) of fundus 
photographs will be performed by the same CRC that will evaluate fluorescein 
angiograms.
EQUIPMENT
See the CRC manual.
PROCEDURE
The CRC will provide a study manual and training materials.  The fundus photographer 
and photography equipment will be certified by the CRC before any study images are 
taken.  See the CRC manual for further details.


Faricimab—F. Hoffmann-La Roche Ltd
127/Protocol GR41986, Version 2
Appendix 7
Fundus Fluorescein Angiography
SCOPE
Fundus fluorescein angiography (FFA) will be obtained from study eye by trained 
personnel at the study sites.  Please see the central reading center (CRC) manual for 
details on the required equipment and image-capture guidance.  The photographs must 
be performed by trained personnel who are certified by the CRC and capable of
capturing the images at the precise correct times after the fluorescein injection as 
described in the CRC manual. 
The fundus fluorescein angiograms will be obtained at baseline (at screening or on 
Day 1) and at the intervals specified in the protocol (see Appendix 1).  Analysis (if 
applicable) of fundus fluorescein angiograms will be performed by the CRC.
EQUIPMENT
Digital angiograms must be used while conducting an angiographic evaluation for the 
study.
Film-based angiography is not acceptable.
UWF (Optos or Zeiss Clarus) is the preferred method for FFA capture.  The study sites 
without Optos or Zeiss Clarus equipment and certification must consult the CRC.  Please 
see the CRC manual for details on the required equipment and image-capture guidance.
DIGITAL IMAGING SYSTEMS AND CERTIFICATION
Digital imaging systems are required.  The system and software at the site will be 
certified by the CRC prior to obtaining any study angiograms.  This certification and 
validation process will ensure that the CRC will be able to correctly calculate the 
required measurements.
PROCEDURES
The CRC will provide a study manual and training materials.  Photographers, systems, 
and software will be certified prior to obtaining angiograms of patients.


Faricimab—F. Hoffmann-La Roche Ltd
128/Protocol GR41986, Version 2
Appendix 8
Spectral-Domain Optical Coherence Tomography
SCOPE
Spectral-domain optical coherence tomography (SD-OCT) will be performed at the 
study sites by trained personnel who are certified by the central reading center (CRC).  
SD-OCT imaging will be performed for each patient at the intervals specified in the 
protocol (see Appendix 1) and will be forwarded to the CRC.
Note:  The optional images will be collected at the sites with optical coherence 
tomographyangiography capabilities and forwarded to the CRC.
EQUIPMENT
Equipment utilized during this study is described in the CRC manual.  The ability to 
transfer images to electronically exportable digital files is required (i.e., no printed SD-
OCT images will be sent to the CRC).
Note:  Certain swept-source optical coherence tomography (SS-OCT) machines may be 
acceptable to use; consult the CRC for further details.
PROCEDURES AND CERTIFICATION
The CRC will provide the study manual and training materials.  SD-OCT operators, 
systems, and software will be certified prior to any evaluation of patients.


Faricimab—F. Hoffmann-La Roche Ltd
129/Protocol GR41986, Version 2
Appendix 9
Biological Sample Collection and Shipping Instructions
BIOLOGICAL SAMPLES
Biological samples for the assessment of faricimab concentrations (pharmacokinetics), 
pharmacodynamics, anti-faricimab antibodies, blood DNA sample, laboratory 
assessment (hematology, serum chemistry, coagulation, and urinalysis), and optional 
aqueous humor and vitreous samples will be obtained at the timepoints specified in the 
protocol (see Section 4.5.7 and Appendix 1).
Refer to the central laboratory manual for detailed sample collection, storage, and 
shipping instructions.  All necessary transfer tubes, Vacutainers, labels, shipping boxes, 
and forms will be provided by the central laboratory.
OPTIONAL ANTERIOR CHAMBER (AQUEOUS HUMOR) 
SAMPLE COLLECTION
The study eye optional aqueous humor paracentesis samples will be collected by the 
unmasked treating physician from patients who consent to the procedure and sample 
acquisition.  An aqueous humor sample will be collected before the patient’s study eye 
treatment at the visits as indicated in Appendix 1.  Please refer to the central laboratory 
manual for additional details regarding sample collection and shipping information.   
OPTIONAL UNSCHEDULED COLLECTION OF VITREOUS HUMOR 
SAMPLE COLLECTION
Vitrectomy may be performed at the discretion of the masked investigator in the event 
that study eye develops sight-threatening vitreous hemorrhage or retinal detachment 
(see Section 4.4.1).  If the surgery is deemed medically necessary and the patient gives 
specific consent, a vitreous sample may be obtained from the study eye.  Either masked 
or unmasked investigators can collect the sample.  Approximately 0.5 mL of undiluted 
vitreous humor should be collected using an aseptic procedure and sterile field and 
according to local guidelines and shipped as specified in the central laboratory manual.
A pharmacokinetic blood sample (for plasma preparation) should also be collected and 
shipped as specified in the central laboratory manual.
Vitreous humor samples will be analyzed primarily for faricimab or aflibercept 
concentrations.  The remaining samples may be analyzed for free angiopoitin-2 (Ang-2) 
and free vascular endothelial growth factor (VEGF) concentrations, and possibly other 
biomarkers.


Appendix 9: Biological Sample Collection and Shipping Instructions
Faricimab—F. Hoffmann-La Roche Ltd
130/Protocol GR41986, Version 2
BIOLOGICAL SAMPLES STORAGE DURATION
The hematology, serum chemistry, urinalysis, coagulation, serum, and urine pregnancy 
test samples will be destroyed after their analysis during the study.
Unless the patient gives specific Research Biosample Repository consent for his or her 
remaining samples to be stored for optional exploratory research (see Section 4.5.11), 
the rest of the biological samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed.


Faricimab—F. Hoffmann-La Roche Ltd
131/Protocol GR41986, Version 2
Appendix 10
National Eye Institute 25-Item Visual Functioning Questionnaire


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
132/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
133/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
134/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
135/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
136/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
137/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
138/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
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139/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
140/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
141/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
142/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
143/Protocol GR41986, Version 2


Appendix 10:National Eye Institute 25-Item Visual Functioning Questionnaire
Faricimab—F. Hoffmann-La Roche Ltd
144/Protocol GR41986, Version 2

SAP_001.pdf: 
Official Title: A Phase III, Multicenter, Randomized, Double-masked, Active Comparator 
Controlled Studies to Evaluate the Efficacy and Safety of Faricimab in 
Patients with Macular Edema Secondary To Branch Retinal Vein Occlusion 
and Macular Edema Secondary To Central Retinal or Hemiretinal Vein 
Occlusion 
NCT Number: 
NCT04740905 and NCT04740931 
Document Date: 
Statistical Analysis Plan (SAP) Version 1: 03 October 2022




 
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STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document Version 2, 26 October 2020. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
see electronic date stamp 
on the last page of this 
document 
Version 2, 3 April 2020 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 8 
1.1 
Objectives and Endpoints .......................................................... 9 
1.1.1 
Efficacy Objectives .................................................................... 9 
1.1.1.1 
Primary Efficacy Objective ......................................................... 9 
1.1.1.2 
Secondary Efficacy Objectives ................................................ 10 
1.1.1.3 
Exploratory Efficacy Objective ................................................. 11 
1.1.2 
Safety Objectives ..................................................................... 11 
1.1.3 
Pharmacokinetic Objectives..................................................... 11 
1.1.4 
Immunogenicity Objectives ...................................................... 12 
1.1.5 
Exploratory Biomarker Objectives ............................................ 12 
1.2 
Study Design ........................................................................... 12 
1.2.1 
Treatment Assignment and Masking ....................................... 17 
1.2.2 
Independent Review Facility .................................................... 18 
1.2.3 
Data Monitoring ....................................................................... 18 
2. 
STATISTICAL HYPOTHESES ...................................................... 19 
2.1 
Non-Inferiority Margin .............................................................. 19 
3. 
SAMPLE SIZE DETERMINATION ................................................ 20 
3.1 
Sample Size for the China Extension ...................................... 21 
4. 
ANALYSIS POPULATIONS/SETS ................................................ 22 
5. 
STATISTICAL ANALYSES ........................................................... 23 
5.1 
General ConsiderationS .......................................................... 23 
5.2 
Patient Disposition ................................................................... 24 
5.3 
Primary Endpoint(s) Analysis ................................................... 24 
5.3.1 
Definition of Primary Endpoints ................................................ 24 
5.3.2 
Main Analytical Approach for Primary Endpoint(s) ................... 25 
5.3.3 
Sensitivity Analyses for Primary Endpoint(s) ........................... 25 
5.3.4 
Supplementary Analyses for Primary Endpoint(s) ................... 26 
5.3.5 
Subgroup Analyses for Primary Endpoint(s) ............................ 28 
5.4 
Secondary EndpointS Analysis(ses) ........................................ 29 
5.4.1 
Secondary Endpoints ............................................................... 29 
5.4.1.1 
Continuous Secondary Endpoints ............................................ 34 


 
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5.4.1.2 
Binary Secondary Endpoints.................................................... 35 
5.5 
Exploratory Endpoint(s) Analysis ............................................. 37 
5.6 
Safety Analyses ....................................................................... 37 
5.6.1 
Extent of Exposure .................................................................. 37 
5.6.2 
Adverse Events ........................................................................ 38 
5.6.3 
Laboratory Data ....................................................................... 39 
5.6.4 
Vital Signs ................................................................................ 39 
5.6.5 
Ocular Assessments ................................................................ 39 
5.7 
Other Analyses ........................................................................ 40 
5.7.1 
Summaries of Conduct of Study .............................................. 40 
5.7.2 
Summaries of Treatment Group Comparability ........................ 40 
5.7.3 
Pharmacokinetic Analyses ....................................................... 40 
5.7.4 
Pharmacodynamic Analyses .................................................... 41 
5.7.5 
Immunogenicity Analyses ........................................................ 41 
5.7.6 
Biomarker Analyses ................................................................. 43 
5.7.7 
Analyses of China Subpopulation ............................................ 43 
5.8 
Analyses for COVID-19 ........................................................... 44 
5.8.1 
Study Conduct Analyses for COVID-19 ................................... 44 
5.8.2 
Efficacy Analyses for COVID-19 .............................................. 44 
5.8.3 
Safety Analyses for COVID-19 ................................................ 45 
5.9 
Interim Analyses ...................................................................... 46 
6. 
REFERENCES.............................................................................. 47 
 
 
LIST OF TABLES 
Table 1 
Additional Estimand Attributes and Analysis Methods for 
Continuous Secondary Endpoints ............................................... 30 
Table 2 
Additional Estimand Attributes and Analysis Methods for 
Binary Secondary Endpoints ....................................................... 32 
Table 3 
Roche COVID-19 SMQ (narrow) Preferred Terms for 
Confirmed Cases ........................................................................ 45 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 13 
Figure 2 
Algorithm for IxRS-Determined Faricimab Personalized 
Treatment Interval Dosing Intervals ............................................ 16 
 
 


 
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LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis for Study BALATON (GR41984) .................... 49 
Appendix 2 
Protocol Synopsis for Study COMINO (GR41986) ...................... 58 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
ADA 
anti-drug antibody 
AE 
adverse event 
Ang-2 
angiopoietin-2 
ANCOVA 
analysis of covariance 
APTC 
anti-Platelet Trialists’ Collaboration 
AESI 
adverse events of special interest 
BCVA 
best-corrected visual acuity 
BM 
Bruch's membrane 
BRVO 
branch retinal vein occlusion 
CFP 
color fundus photograph 
CI 
confidence interval 
CMH 
Cochran Mantel-Haenszel 
COVID-19 
coronavirus disease 2019 
CRC 
central reading center 
CRVO 
central retinal vein occlusion 
CSR 
clinical study report 
CST 
central subfield thickness 
DR 
diabetic retinopathy 
ETDRS 
early treatment diabetic retinopathy study 
FFA 
fundus fluorescein angiography 
HRVO 
hemiretinal vein occlusion 
iDMC 
independent Data Monitoring Committee 
IgG1 
immunoglobulin G1 
ILM 
internal limiting membrane 
IOI 
intraocular inflammation 
IOP 
intraocular pressure 
ITT 
intent to treat 
IVT 
intravitreal 
IxRS 
interactive Voice/Web Response System 
LOCF 
last observation carried forward 
LPLV 
last patient last visit 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
NEI VFQ-25 
National Eye Institute 25-Item Visual Functioning Questionnaire 


 
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NI 
non-inferiority 
OCT-A 
optical coherence tomography angiography 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PT 
preferred term 
PTI 
personalized treatment interval 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
Q12W 
every 12 weeks 
Q16W 
every 16 weeks 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SD 
standard deviation 
SD-OCT 
spectral-domain optical coherence tomography 
SS-OCT 
swept-source optical coherence tomography 
SMQs 
standardized MedDRA queries 
VEGF -A 
vascular endothelial growth factor A 
 
 
 


 
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1. 
INTRODUCTION 
Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders and 
is associated with varying degrees of visual loss (Hayreh et al. 1994).  RVO has been 
reported as the second leading cause of blindness for patients with retinal vascular 
disease, following diabetic retinopathy (DR) (Cugati et al. 2006; Klein et al. 2008; Rogers 
et al. 2010; Yasuda et al. 2010).  The main types of RVO include branch retinal vein 
occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion 
(CRVO).  Patients with RVO were found to have the highest vitreous levels of both 
angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) among all retinal 
vascular diseases (Aiello et al 1994; Regula et al. 2016).  Increased levels of Ang-2 and 
VEGF in retinal tissue result in pathological changes in the retina, and in many patients 
also leads to macular edema that is accompanied with a decrease in vision.  A hallmark 
of RVO is the characteristic pattern of retinal hemorrhages, tortuous and dilated retinal 
veins across the affected area of retina (one quadrant in BRVO, two quadrants in HRVO 
and the entire retina in CRVO). 
Despite anti-VEGF being the most effective therapy for macular edema due to RVO, 
data from anti-VEGF clinical trials showed that many patients do not achieve optimal 
best-corrected visual acuity (BCVA) and anatomical outcomes, and many require 
frequent long-term injections to maintain the gains achieved during initial intensive 
treatment.  Moreover, real-world data analyses suggested that outside of trials many 
patients with RVO do not achieve the gains reached in clinical trials due to suboptimal 
injection frequency (Vaz-Pereira et al. 2017; Wecker et al. 2017; Jumper et al. 2018; 
Callizo et al. 2019; Pearce et al. 2020).  The data suggest that many patients with 
macular edema due to BRVO and the majority of patients with macular edema due to 
CRVO require close monitoring and treatment for longer periods of time and that more 
durable and efficacious treatment options are needed (Bhisitkul et al. 2013; 
Scott et al. 2019). 
Faricimab is a humanized full-length bispecific immunoglobulin G1 (IgG1) monoclonal 
antibody that selectively binds to all isoforms of VEGF-A (hereafter referred to as 
"VEGF") and Ang-2, key factors involved in mediating the pathophysiology of macular 
edema due to RVO.  The Ang-2 and VEGF-binding variable regions of faricimab bind to 
Ang-2 and VEGF independently and simultaneously with high affinity.  Based on the 
mechanism of action of faricimab, data from nonclinical and clinical trials, and the 
pathophysiology of macular edema due to RVO, it is hypothesized that faricimab may 
lead to stabilization of the pathological ocular vasculature and to improved visual and 
anatomical outcomes in RVO compared with anti-VEGF monotherapies. 
The purpose of this document is to provide details of the planned analyses for Phase III 
Studies GR41984 (BALATON) for BRVO, and GR41986 (COMINO) for CRVO or HRVO.  


 
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The designs of these studies are identical with the exception of the inclusion/exclusion 
criteria, stratification factors and sample size.  In this Statistical Analysis Plan (SAP), 
study equally refers to BALATON or COMINO.  China Extension refers to China 
extension for COMINO.  Protocol collectively refers to protocols for both BALATON and 
COMINO, unless otherwise specified.  Study drug refers to faricimab or aflibercept, 
whereas study treatment refers to faricimab, aflibercept, or the sham procedure. 
The analysis plan and the endpoints specified in this document supersede the analysis 
plan described in the study protocols.  This document will address analysis for efficacy, 
safety, immunogenicity, biomarkers, pharmacokinetics (PK) and pharmacodynamics 
(PD).  Detailed specifications of tables, figures and listings are provided in separate 
documents.  
1.1 
OBJECTIVES AND ENDPOINTS 
BALATON and COMINO are comprised of two parts: Part 1 (Day 1 through Week 24) 
and Part 2 (Weeks 24-72).  See Section 1.2 for details on the study design. 
Part 1 of the trial will compare faricimab 6 mg intravitreal (IVT) every 4 weeks (Q4W) 
with aflibercept 2 mg IVT Q4W (active comparator) through Week 24 in adult patients 
with macular edema due to BRVO (for BALATON), CRVO or HRVO (for COMINO).  The 
primary trial objective is to evaluate the efficacy of faricimab 6 mg IVT Q4W compared 
with aflibercept 2 mg IVT Q4W on the basis of the change from baseline in BCVA at 
Week 24.  
Part 2 of the trial will evaluate faricimab 6 mg IVT Q4W administered at masked 
treatment intervals of Q4W to every 16 weeks (Q16W) based on personalized treatment 
interval (PTI) dosing criteria.  Patients in both Arms A and B will receive faricimab 6 mg 
IVT according to a PTI dosing regimen from Week 24 through Week 68.  See 
Section 1.2 for details of PTI dosing criteria. 
Secondary and exploratory endpoints over time include assessments at each study visit 
with the exception of endpoints on fundus fluorescein angiography (FFA), color fundus 
photographs (CFP) and National Eye Institute 25-Item Visual Functioning Questionnaire 
(NEI VFQ-25), which are assessed at Week 24, Week 48 and Week 72.  
Endpoints evaluating proportions of patients meeting certain criteria over time refers to 
meeting the criteria at each time point, and summarized across timepoints. 
1.1.1 
Efficacy Objectives 
1.1.1.1 
Primary Efficacy Objective 
The primary efficacy objective for Part 1 of the study is to evaluate the efficacy of 
faricimab 6 mg IVT Q4W compared with aflibercept 2 mg IVT Q4W on the basis of the 
following endpoint: Change from baseline in BCVA at Week 24. 


 
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1.1.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objective for Part 1 of this study (i.e., through Week 24) is to 
evaluate the efficacy of faricimab 6 mg Q4W compared with aflibercept 2 mg Q4W 
based on additional endpoints.  The secondary efficacy objective for Part 2 of this study 
(i.e., Week 24 through Week 72) is to evaluate the efficacy of faricimab administered 
according to the PTI dosing regimen.  The secondary endpoints (for both Part 1 and 
Part 2) are listed below. 
Endpoints at both primary analysis (through Week 24) and the final analysis: 
 
Change from baseline in BCVA over time 
 
Proportion of patients gaining  15,  10,  5, or  0 letters in BCVA from baseline 
over time 
 
Proportion of patients avoiding a loss of  15,  10or  5, letters in BCVA from 
baseline over time 
 
Proportion of patients achieving  84 letters (20/20 Snellen equivalent) in BCVA 
over time 
 
Proportion of patients with BCVA Snellen equivalent of 20/40 or better 
(BCVA  69 letters) over time 
 
Proportion of patients with BCVA Snellen equivalent of 20/200 or worse 
(BCVA  38 letters) over time 
 
Change from baseline in central subfield thickness (CST) over time  
– 
CST is defined as the distance between internal limiting membrane (ILM) and 
Bruch’s Membrane (BM), as measured in m as assessed by CRC. 
 
Change from baseline in NEI VFQ-25 composite score over time 
 
Proportion of patients with absence of macular edema, defined as CST of 
 325 mover time 
– 
CST for Cirrus spectral-domain optical coherence tomography (SD-OCT) or 
Topcon SD-OCT were standardized to Spectralis SD-OCT by the central 
reading center. 
 
Proportion of patients with absence of intraretinal fluid over time 
– 
Intraretinal fluid is as measured in the central subfield (center 1 mm) 
 
Proportion of patients with absence of subretinal fluid over time 
– 
Subretinal fluid is as measured in the central subfield (center 1 mm) 
 
Proportion of patients with absence of both intraretinal fluid and subretinal fluid over 
time 
 
Endpoints  at the primary analysis: 
 
Proportion of patients gaining  15 letters in BCVA from baseline at Week 24 
 


 
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Endpoints at the final analysis: 
 
Change from baseline in BCVA averaged over Week 64, Week 68 and Week 72 
 
Proportion of patients on a Q4W, every 8 weeks (Q8W), every 12 weeks 
(Q12W), or Q16W treatment interval at Week 68 
– 
treatment intervals at Week 68 will be defined as the treatment interval 
decision followed at Week 68 
 
Endpoints assessed in reference to Week 24 at the final analysis: 
 
Change from Week 24 in BCVA over time 
 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from 
Week 24 over time 
 
1.1.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective is to evaluate the efficacy of faricimab based on 
additional endpoints.  The exploratory endpoints are listed below and will be assessed  
at the primary analysis (through Week 24) and the final analysis.  
 
Proportion of patients with absence of macular ischemic non perfusion (capillary 
loss) on FFA over time  
– 
Where ’absence’ is defined as an area of ischemic non perfusion within the 
macula of 0 to 0.1 mm2  
 
Change from baseline in the area of ischemic non perfusion within the macula on 
FFA over time  
 
Proportion of patients with absence of macular leakage on FFA over time 
– 
Where ‘absence’ is defined as an area of leakage within the macula of 0 mm2 
 
Change from baseline in vascular leakage area on FFA in the macula over time 
 
Proportion of patients requiring panretinal photocoagulation  
 
Change from baseline in NEI VFQ-25 near activities-subscale score and distance 
activitiessubscale scores over time 
 
1.1.2 
Safety Objectives 
The safety objective for this study is to evaluate the safety and tolerability of faricimab on 
the basis of the following endpoints: 
 
Incidence and severity of ocular adverse events, with severity determined according 
to Adverse Event (AE) Severity Grading Scale (as defined in Protocol Table 2) 
 
Incidence and severity of non-ocular adverse events, with severity determined 
according to AE Severity Grading Scale (as defined in Protocol Table 2) 
 
1.1.3 
Pharmacokinetic Objectives 
The PK objective for this study is to characterize the faricimab PK profile on the basis of 
the following endpoint:  Plasma concentration of faricimab over time. 


 
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The exploratory PK objective for this study is to explore the concentration--effect 
relationship for visual acuity and other endpoints (e.g., anatomic measures) on the basis 
of the following endpoint:  Concentration of faricimab and the change in BCVA or other 
endpoints (e.g., anatomical markers) over time. 
1.1.4 
Immunogenicity Objectives 
The immunogenicity objective for this study is to evaluate the antibody immune response 
to faricimab on the basis of the following endpoint:  Prevalence of anti-drug antibodies 
(ADAs) at baseline and incidence of ADAs during the study. 
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:  Relationship between ADA status and 
efficacy, safety, or PK endpoints. 
1.1.5 
Exploratory Biomarker Objectives 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to faricimab (i.e., predictive biomarkers), are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), 
are associated with susceptibility to developing adverse events or can lead to improved 
AE monitoring or investigation (i.e., safety biomarkers), can provide evidence of 
faricimab activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints: 
 
Relationship between biomarkers in plasma and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints 
 
Relationship between baseline anatomic measures and the change in BCVA or 
other endpoints (e.g., the frequency of faricimab administration) over time 
 
Relationship between anatomic measures and visual acuity 
 
1.2 
STUDY DESIGN 
The Protocol Synopsis for BALATON and COMINO are in Appendix 1 and Appendix 2, 
respectively. 
BALATON and COMINO are Phase III, multicenter, randomized, double-masked, active 
comparator-controlled, parallel-group studies evaluating the efficacy, safety, and 
pharmacokinetics of faricimab administered by IVT injection at 4-week intervals until 
Week 24, followed by a double-masked period of study without active control to evaluate 
faricimab administered according to a PTI dosing regimen in patients with macular 
edema due to BRVO (BALATON), and CRVO or HRVO (COMINO).  The study schema 
is shown in Figure 1.  
BALATON and COMINO are comprised of two parts:  Part 1 (Day 1 through Week 24) 
will compare faricimab Q4W versus aflibercept (active comparator) Q4W; Part 2 (Weeks 




 
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include all participants enrolled during the global enrollment phase (including participants 
enrolled in mainland China, Hong Kong, and Taiwan during that phase), and the China 
subpopulation will include all patients enrolled in mainland China, Taiwan and Hong 
Kong (during both the global enrollment phase and the extended China enrollment 
phase).  Separate analyses will be performed for the global population and the China 
subpopulation (see Section 5.7.7 for China subpopulation analyses). 
The primary analysis for the global population will be performed when all patients from 
the global enrollment phase have either completed the study through Week 24 or have 
discontinued from the study prior to Week 24, whichever comes later (i.e., timing is 
defined as the primary analysis last patient last visit [LPLV]), and all data collected prior 
to the primary LPLV in the global enrollment phase are in the database, and cleaning 
and verification of critical variables have been completed.  At the time of the primary 
analysis, the study will be ongoing.  Results of the primary analysis, summarized by 
treatment group, may be reported to the public before completion of the study.  
However, patients, masked study site personnel, and central reading center (CRC) 
personnel will remain masked to individual treatment assignment until the global study 
clinical study report through Week 72 is completed.  
The final analysis for the global population will be performed when all patients from the 
global enrollment phase have either completed the study through Week 72 or have 
discontinued early from the study, whichever comes later, and all data from the global 
enrollment phase are in the database, and cleaning and verification of critical variables 
have been completed.  
Primary analysis for the China subpopulation of each study will be performed when all 
patients from China (i.e., during both the global enrollment phase and the China 
extension) within a specific study have either completed the study through Week 24 or 
have discontinued from the study prior to Week 24, whichever comes later, and all data 
collected are in the database, and cleaning and verification of critical variables have 
been completed. 
A final analysis for the China subpopulation of each study will be performed when all 
patients from China (i.e., during both the global enrollment phase and the China 
enrollment phase) within a specific study have either completed the study through 
Week 72 or have discontinued early from the study, whichever comes later, and all data 
are in the database, and cleaning and verification of critical variables have been 
completed.  
Faricimab Interval Determination for Part 2 (PTI Regimen) 
In Part 2 of the study, all patients will visit the clinic Q4W from Week 24 through 
Week 68 and receive either sham treatment or faricimab 6 mg IVT, depending on their 
PTI dosing regimen.  The first visit that a patient could receive sham treatment is 
Week 24.  Faricimab PTI decisions will be automatically calculated by the interactive 


 
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Voice/Web Response System (IxRS) based on the PTI criteria described in this section.  
Faricimab dosing visits are defined as those visits when the patient receives faricimab 
6 mg IVT per IxRS assignment. 
Starting at Week 24, if CST met the predefined reference CST threshold (<325 µm), as 
determined by the CRC, and there was no decrease in BCVA of   10 letters compared 
with the reference BCVA, the patient’s dosing interval was extended.  If CST was   325 
µm, the patient continued to receive faricimab Q4W until the reference CST threshold 
was met.  The reference CST, defined as the CST value at Week 20 or a later visit when 
the CST met the predefined reference CST threshold (<325 µm), was used by the IxRS 
at faricimab dosing visits to determine the faricimab dosing interval.  After a patient’s 
initial reference CST was established, the patient was eligible to have the faricimab 
dosing interval increased in 4-week increments by the IxRS if the CST value was stable 
(i.e., had not increased or decreased by >10%) with no associated loss of vision of   10 
letters with respect to reference BCVA (Figure 2).  Reference CST was adjusted if CST 
decreased by >10% from the previous reference CST for two consecutive faricimab 
dosing visits and the values obtained were within 30 µm.  The CST value obtained at the 
latter visit served as the new reference CST, starting immediately at that visit.  
Reference BCVA was defined as the mean of the three best BCVA scores obtained at 
any prior dosing visit. 
The maximum and minimum treatment intervals that could be assigned were Q16W and 
Q4W, respectively.  Patients who had previously had a dosing interval extension and 
who experienced disease worsening that triggered interval reduction were not allowed to 
extend the interval again (with the exception of patients who had dosing intervals 
reduced to Q4W); their interval could be extended again but only to an interval that was 
4 weeks less than their original maximum extension.  For example, if a patient’s interval 
was reduced from Q12W to Q8W, this patient’s interval could not be extended beyond 
Q8W for the remainder of the treatment period.  If a patient’s interval was reduced from 
Q16W to Q4W, this patient’s interval could be extended up to Q12W, but could not be 
extended back to Q16W. 




 
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– 
If the CST value is increased by  20% without an associated  10-letter BCVA 
decrease 
– 
If the CST value is increased by  10% with an associated BCVA decrease of 
 10-letters 
 
Interval reduced to Q4W 
– 
If the CST value is increased by  10% with an associated  10-letter BCVA 
decrease 
 
1.2.1 
Treatment Assignment and Masking 
Patients will be randomized in a 1:1 ratio to one of two study treatment arms (faricimab 
Q4W or aflibercept Q4W through Week 20).  After randomization and at each study 
treatment visit (i.e., including Day 1), the IxRS will assign the appropriate study 
treatment kit to be used. 
Randomization will be stratified by the following baseline factors (Day 1): 
BALATON (BRVO): 
 
Baseline BCVA Early Treatment Diabetic Retinopathy Study (ETDRS) letter score 
(≥ 55 letters vs. ≤ 54 letters) 
 
Region (United States and Canada, Asia, and the rest of the world) 
 
COMINO (C/HRVO): 
 
Baseline BCVA ETDRS letter score (≤ 34 letters, 35-54 letters, and ≥ 55 letters) 
 
Region (United States and Canada, Asia, and the rest of the world) 
 
A stratified permuted-block randomization scheme will be used to obtain approximately a 
1:1 ratio among the treatment groups overall and within each of the above strata.  For 
analyses, the stratification factors as recorded in IxRS will be used. 
The randomization method implemented in the China extension study will be the same 
as that implemented in the global population. 
Statistics Collaborative, Inc. (StatCollab), as an independent Data Coordinating Center 
(iDCC), conducted randomization audits of the randomization and kit allocation data 
provided by Signant Health (IxRS vendor).  Two randomization audits were performed 
(first review in July 2021 and second review in February 2022).  No major randomization 
issues were found.  For all audit findings, appropriate corrective and preventive actions 
were undertaken.  The corresponding report will be provided by the iDCC at study end, 
the report will be filled to the electronic Trial Master File. 
This is a double-masked study, and only site staff members in unmasked roles, as 
specified in Section 4.2.2.2 of the protocol, are unmasked in both Part 1 and Part 2.  
There must be a minimum of two investigators per site to fulfill the masking requirements 


 
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of this study and both investigators are required to be present at each scheduled study 
visit. 
To preserve the masking of faricimab treatment intervals for Week 24 through Week 68, 
a sham procedure will be administered during study visits at which (according to the PTI 
dosing regimen) no faricimab treatment is administered. 
1.2.2 
Independent Review Facility 
Ocular Imaging 
All ocular images are obtained by trained site personnel at the study sites and forwarded 
to CRCs, for independent analysis and storage.  As part of the screening process, the 
CRCs evaluate CFPs and SD-OCT (or swept-source optical coherence tomography 
[SS-OCT]) images to provide an objective assessment of patient eligibility.  The 
diagnosis of macular edema due to RVO must be confirmed by the CRC.  During the 
study treatment period, the CRCs provide a masked evaluation of all ocular images 
including CFP, FFA, SD-OCT or SS-OCT, and optional coherence tomography 
angiography (OCT-A).  The data resulting from this masked review of ocular images are 
forwarded to the Sponsor and additionally, the SD-OCT CST values are forwarded to the 
IxRS for treatment interval determination. 
Anti-Platelet Triallists’ Collaboration (APTC) 
APTC events that are identified during the study are externally adjudicated on an 
ongoing basis.  A dossier of available information on each case of interest is provided to 
the external expert adjudicators for their review and assessment. 
1.2.3 
Data Monitoring 
An independent Data Monitoring Committee (iDMC) monitors safety and study conduct 
on an ongoing basis and the iDMC’s responsibility of monitoring ends after the primary 
analysis.  Members of the iDMC are external to the Sponsor and follow a charter that 
outlines the iDMC's roles and responsibilities.  The iDMC meets approximately every 
6 months (frequency adjustable as required) to evaluate unmasked ocular and 
non‑ocular safety events.  After reviewing the data, the iDMC provides a 
recommendation to the Sponsor as described in the iDMC Charter.  Final decisions rest 
with the Sponsor.  Any outcome of these data reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of their respective 
Institutional Review Boards/Ethics Committees (IRBs/ECs). 
A nominal type I error penalty of 0.0001 (two-sided) will be taken for each time the iDMC 
reviews unmasked data prior to the formal analysis of the primary efficacy endpoint.  At 
the time of the primary analysis, it is estimated that three safety interim data reviews will 
have been conducted by the iDMC; therefore, efficacy analyses would be performed with 
a family-wise significance level of 0.0497.  The actual adjustment will depend on the 
actual number of iDMC interim safety reviews.  This type I error adjustment is not 
expected to impact sample size or power. 


 
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2. 
STATISTICAL HYPOTHESES 
The primary efficacy endpoint is the change from baseline in BCVA at Week 24.  The 
following hypothesis will be tested: 
 
Non-inferiority (NI) of faricimab Q4W compared with aflibercept Q4W at Week 24 in 
the intent to treat (ITT) population as defined in Section 4 (at a one-sided 0.02485 
significance level) 
 
Superiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population (at a two-sided 0.0497 significance level) 
 
The hypotheses on the primary endpoint will be tested in the order shown above, 
proceeding sequentially starting from the non-inferiority test and only testing the 
superiority after achieving statistical significance on the non-inferiority test.  There is no 
impact on the type I error rate for the superiority test following the NI test, therefore a 
claim of superiority after NI can be made without multiplicity adjustment (Ke et al. 2012). 
The null and alternative hypotheses for NI test are as follows: 
 
The null hypothesis (H0) is: faricimabaflibercept  4 letters  
 
The alternative hypothesis (Ha) is: faricimabaflibercept  4 letters  
 
where faricimab and aflibercept are the expected change from baseline in BCVA at Week 24 
for the faricimab Q4W arm and the active comparator (aflibercept Q4W) arm, 
respectively. 
If the lower bound of a two-sided 95.03% confidence interval (CI) for the difference of 
two treatments is greater than 4 letters (the NI margin), the test is considered positive 
and IVT 6 mg faricimab administered Q4W is considered non-inferior to IVT 2 mg 
aflibercept administered Q4W.  
The null and alternative hypotheses for superiority test are as follows: 
 
The null hypothesis (H0) is: faricimabaflibercept   letters 
 
The alternative hypothesis (Ha) is: faricimabaflibercept ≠  letters  
 
where faricimab and aflibercept are the expected change from baseline in BCVA at Week 24 
for the faricimab Q4W arm and the active comparator (aflibercept Q4W) arm, 
respectively. 
If the lower bound of a two-sided 95.03% CI for the difference of two treatments is 
greater than 0 letters, the test is considered positive and IVT 6 mg faricimab 
administered Q4W is considered superior to IVT 2 mg aflibercept administered Q4W.  
2.1 
NON-INFERIORITY MARGIN  
Noninferiority hypothesis testing for the primary endpoint of the change from baseline in 
BCVA at Week 24 (Month 6) will be performed using a 4letter NI margin for both BRVO 


 
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and CRVO (includes HRVO cases) studies.  The NI margin is selected based upon the 
aflibercept pivotal trials in BRVO and CRVO.  The pathological states are part of the 
spectrum of the same disease caused by obstruction in central, hemi‑central, or branch 
retinal vein, with CRVO presenting as the most severe form.  While there is only one 
BRVO study of aflibercept versus control available, there are multiple CRVO studies of 
aflibercept versus sham available.  The NI margin rationale is therefore built upon the 
past BRVO and CRVO study results.  
The VIBRANT study (Campochiaro et al. 2015) in BRVO randomized 183 patients in a 
1:1 ratio to 2 mg IVT aflibercept or laser control.  At Week 24 (Month 6), patients 
receiving aflibercept Q4W gained on average 17 letters from baseline compared to 6.9 
letters in the control arm, with a 95% CI for the difference between treatments of [7.1, 
14.0] letters. 
The COPERNICUS (Boyer et al. 2012) and GALILEO (Holz et al. 2013) studies in CRVO 
randomized 189 and 177 patients respectively in a 3:2 ratio to 2 mg IVT aflibercept or 
sham procedure.  At Month 6 in the COPERNICUS study, patients receiving aflibercept 
Q4W gained on average 17.3 letters from baseline compared to a loss of 4 letters in the 
control arm, for a 95% CI for the difference between treatments of [17.3, 26.1].  The 
corresponding results for the GALILEO study were a gain on average of 18 letters for 
aflibercept versus 3.3 letters from the control arm, with a 95% CI for the difference 
between treatments of [10.7, 18.7]. 
The NI margin of 4 letters for the mean change from baseline in BCVA at Week 24 is 
chosen based on the statistical rationale of preserving approximately 50% of the benefit 
compared with sham control as estimated by the lower limit of a 95% CI.  Based on the 
aflibercept pivotal trials described, the proposed NI margin of 4 letters preserves 
between 44% (calculated as [(7.14)/7.1]43.7%) and 77% (calculated as 
[(17.34)/17.3]76.9%) of the least estimated benefit of aflibercept relative to control. 
This NI boundary is also supported from a clinical perspective and is in alignment with 
the general considerations highlighted in Section 2 of the European guidance document 
(EMA 2005).  The NI margin should be small enough to allow a conclusion that the new 
treatment is not inferior to the active control to an unacceptable extent on the basis of a 
combination of clinical judgment and statistical reasoning.  From a clinical perspective, a 
loss of 5 letters (one ETDRS line) between treatments would be considered clinically 
relevant, and therefore a NI margin of 4 letters provides assurance that there would be 
no important loss of efficacy if the new treatment is used instead of the reference 
product. 
3. 
SAMPLE SIZE DETERMINATION 
Determination of sample size is based on patients enrolled in the global enrollment 
phase.  The global enrollment phase will enroll approximately 570 patients for BALATON 


 
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and 750 patients for COMINO.  Patients will be randomized in a 1:1 ratio to receive 
treatment with faricimab (Arm A) or aflibercept (Arm B).  The primary comparison will be 
between the active comparator (aflibercept Q4W) and the faricimab Q4W arm at 
Week 24. 
A sample size of approximately 285 patients for BALATON and 375 patients for 
COMINO in each arm will provide  90% power to show NI of faricimab to aflibercept in 
the change in BCVA at Week 24 in the ITT population, using a NI margin of 4 letters, 
and under the following assumptions: 
 
No difference in the mean change from baseline in BCVA between the two 
treatment arms 
 
Standard deviation (SD) of 13 letters for BALATON and 15 letters for COMINO for 
the change from baseline in BCVA at Week 24 
 
Two-sample t-tests 
 
2.5% one-sided type I error rate 
 
10% dropout rate 
 
Furthermore, a sample size of approximately 285 patients for BALATON and 
375 patients for COMINO per arm will provide greater than 80% power to show a 
3.5‑letter superiority of faricimab over aflibercept, under the same SD, test, and dropout 
assumptions above, and a two-sided type I error rate of 5%. 
The enrollment ended after 553 and 730 patients were enrolled in BALATON and 
COMINO, respectively.  The planned sample size aimed to also provide adequate power 
for the Per Protocol analysis accounting for potential impact of coronavirus disease-19 
(COVID-19); however, as the COVID-19 impact was less than originally anticipated, the 
Sponsor decided to stop recruitment with an under-recruitment of about 3%.  The final 
sample size provided > 90% power for the NI assessment and > 80% power for the 
superiority test. 
3.1 
SAMPLE SIZE FOR THE CHINA EXTENSION 
After the global enrollment phase has been completed, additional patients may be 
enrolled in a China extension to ensure a total enrollment that is sufficient to support 
registration in the People’s Republic of China.  It is anticipated that approximately 
62 patients will be enrolled (including patients who have already enrolled during the 
global enrollment phase) for BALATON, and approximately 82 patients will be enrolled 
(including patients who have already enrolled during the global enrollment phase) for 
COMINO.  The data from China patients enrolled during the global enrollment phase of 
the study will be included in the primary analysis of the study.  Data from patients 
enrolled during the China extension will not be included in the primary analyses but will 
be included in the China subpopulation analysis. 


 
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4. 
ANALYSIS POPULATIONS/SETS 
The analysis populations presented in this section are based on patients enrolled during 
the global enrollment phase of the study and will not include the China extension, unless 
otherwise specified.  The analysis plans for the China extensions are presented in 
Section 5.7.7. 
The following populations are defined: 
Population 
Definition 
ITT 
All patients who are randomized in the study.  For analyses based 
on this patient population, patients will be grouped according to the 
treatment assigned at randomization. 
Note: Subjects who were wrongly randomized to one study 
(BALATON or COMINO), discontinued without treatment, and then 
randomized to the other study (COMINO or BALATON respectively) 
are included in the latter study only. 
Per-Protocol 
All patients randomized in the study who receive at least one dose 
of study treatment and who do not have a major protocol violation 
that impacts the efficacy evaluation.  Patients will be grouped 
according to actual treatment received through Week 20.  If by 
error, a patient receives a combination of different active study 
drugs (faricimab and aflibercept) in the study eye, the patient’s 
treatment group will be as randomized. 
Prior to study unmasking, protocol deviations will be reviewed and 
a determination of the definition of the population for per protocol 
analysis will be made. 
Safety-Evaluable 
All patients who receive at least one injection of active study drug 
(faricimab or aflibercept) in the study eye.  Patients will be grouped 
according to actual treatment received through Week 20.  If by error 
a patient receives a combination of different active study drugs 
(faricimab and aflibercept) in the study eye, the patient’s treatment 
group will be as randomized. 
Pharmacokinetic-
Evaluable 
Safety-evaluable patients with at least one plasma sample, and if 
sufficient dosing information (dose and dosing time) is available.  
Patients will be grouped according to actual treatment received (as 
defined for Safety-Evaluable population) 
Faricimab 
Pharmacokinetic-
Evaluable 
Pharmacokinetic-Evaluable patients from faricimab treatment group 
(as defined for Pharmacokinetic-Evaluable population) 
Immunogenicity Analysis 
The immunogenicity prevalence set will consist of all patients 
randomized to or who received faricimab with at least one 
determinant anti-drug antibody (ADA against faricimab) 
assessment.  Patients will be grouped according to actual treatment 
received as described for the Safety-Evaluable population or if no 
treatment is received prior to study discontinuation, according to 
treatment assigned.  The immunogenicity incidence set will consist 
of all patients who received faricimab with at least one determinant 
ADA assessment after the initiation of faricimab treatment.  Patients 
will be grouped according to actual treatment received as described 
for the Safety-Evaluable population. 


 
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5. 
STATISTICAL ANALYSES 
Unless otherwise specified, the analyses described in this section are based on patients 
enrolled during the global enrollment phase (excluding the China extension).  Details of 
the planned analyses, including any additional analyses needed to support China 
marketing applications, will be provided in Section 5.7.7.  
The analyses timing for primary and final analyses are provided in Section 1.2.  
5.1 
GENERAL CONSIDERATIONS 
Efficacy analyses will be based on the ITT population and grouped according to the 
treatment assigned at randomization unless otherwise specified.  A supplementary 
analysis based on the per-protocol population will also be conducted for the primary 
endpoint.  At the primary analysis, efficacy analysis will be based on data through 
Week 24 (efficacy endpoints at Week 24 are measured before the Week 24 injection and 
will be included in the comparative analysis).  
Unless otherwise noted, analyses of efficacy outcome measures will be stratified by the 
following stratification factors, as recorded in IxRS:  
 
Baseline BCVA ETDRS letter score, as assessed on Day 1 (≥ 55 letters vs. ≤ 54 
letters for BALATON; and ≤ 34 letters, 3554 letters, and ≥ 55 letters for COMINO)  
 
Region (United States and Canada, Asia, and the rest of the world).  
 
Continuous outcomes will be analyzed using a mixed model for repeated measures 
(MMRM) unless otherwise specified.  Binary secondary endpoints will be analyzed using 
stratified estimation for binomial proportions.  Nominal superiority p-values will be 
provided for secondary and exploratory endpoints where applicable for reference 
purposes.  The estimates and CIs will be provided for the mean (for continuous 
variables) or proportion (for binary variables) for each treatment arm and for the 
difference in means or proportions between the aflibercept Q4W arm and the faricimab 
Q4W arm (where applicable).  All CIs will be two-sided and at the 95.03% level. 
Invalid BCVA (BCVA values that are confirmed to be inaccurate, due to the BCVA test 
being performed incorrectly) will be excluded from the analyses.  Non-standard BCVA 
data (such as assessed by ETDRS BCVA testing with prior visit refraction, BCVA test 
performed by unmasked certified ETDRS BCVA assessor, or by uncertified experienced 
ETDRS BCVA assessor) will be included in the analyses. 
Central Subfield Thickness is assessed by the CRCs and standardized to Spectralis 
SD-OCT (distance measured between ILM and BM).  Analysis will be based on the 
same type of read over time within patient.  When available, algorithmic reads with a 
predefined centerpoint (as opposed to manual reads) of CST values will be used for 
analysis.  


 
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All safety analyses will be performed in the safety-evaluable population unless otherwise 
specified.  At the primary analysis, safety analysis will be based on data before the 
Week 24 visit date, with the exception of assessments measured at Week 24 but before 
the administration of the Week 24 injection such as labs, vital signs (where applicable) 
and ocular assessments in Section 5.6.5, where data through Week 24 will be used. 
Baseline for non-safety analyses is defined as the last available measurement obtained 
on or prior to randomization.  Baseline for safety analyses is defined as the last available 
measurement prior to first exposure to study drug.  Patients with missing baseline 
assessments will not be imputed.  Data collected in scheduled and unscheduled visits 
will be mapped to visits that appear in the schedule of assessments per the protocol 
using the actual study day of assessment.  If there are multiple values in the same visit 
window, the value closest to the target study day will be used in the analysis. 
Due to extended exportation timelines of PD, PK, and ADA samples from mainland 
China, a small percentage of data from these samples may not be included in the 
primary analysis.  All PD, PK, and ADA data will be included in the final analysis. 
5.2 
PATIENT DISPOSITION 
The number of patients randomized will be tabulated by country, site, and treatment arm.  
At the primary and final analysis, patient disposition (the number of patients randomized, 
treated, and completing through the primary endpoint timing, as well as overall through 
the end of study) will be tabulated by treatment arm in the ITT population.  Premature 
study drug discontinuation and study discontinuation, as well as reasons for 
discontinuations, will be summarized.  
5.3 
PRIMARY ENDPOINT(S) ANALYSIS 
5.3.1 
Definition of Primary Endpoints 
The primary efficacy endpoint is the change from baseline in BCVA at Week 24.  BCVA 
is assessed on the ETDRS visual acuity chart at a starting test distance of 4 meters.  
The primary estimand is defined as follows: 
 
Population: Adult patients with macular edema due to BRVO (for BALATON), CRVO 
or HRVO (for COMINO), as defined by the inclusion and exclusion criteria (ITT 
population) 
 
Variable: Change from baseline in BCVA at Week 24 
 
Treatments (as randomized): 
– 
Experimental: Faricimab 6 mg IVT Q4W  
– 
Control: Aflibercept 2 mg IVT Q4W 
 
Intercurrent events prior to Week 24: 
– 
Discontinuation of study treatment due to AEs or lack of efficacy  


 
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– 
Use of any prohibited systemic treatment or prohibited therapy in the Study eye 
(Section 4.4.2 of Protocol)  
 
Handling of intercurrent events: 
– 
A treatment policy strategy will be applied to all intercurrent events.  
 
5.3.2 
Main Analytical Approach for Primary Endpoint(s) 
The rationale of using ITT population and treatment policy strategy for the primary 
estimand is to provide a picture of a treatment effect foreseen in clinical practice when 
treatment (including use of prohibited therapies) is administered.  Additional analysis 
applying hypothetical strategy to all intercurrent events, applying hypothetical strategy to 
COVID-19 related intercurrent events and treatment policy strategy to non-COVID-19 
related intercurrent events, and analysis on the per-protocol population will also be 
provided (details see Section 5.3.4). 
The main analysis for the primary endpoint will be performed using a MMRM.  The 
model will include the change from baseline at Weeks 4-24 as the response variable and 
will include the categorical covariates of treatment group, visit, visit-by-treatment group 
interaction, baseline BCVA (continuous), as well as randomization stratification factors 
as fixed effects.  The MMRM model will assume an unstructured covariance structure.  If 
there are convergence problems with the model, then a heterogeneous compound 
symmetry or an autoregressive (AR) (1) covariance structure may be fitted.  
Missing data will be implicitly imputed by the MMRM model assuming missing at random 
(MAR).  Additional analyses using different missing data handling approaches will be 
included as sensitivity analyses (Section 5.3.3).  The proportion of patients who receive 
prohibited therapy or who discontinue study drug due to lack of efficacy or adverse 
events is anticipated to be low. 
5.3.3 
Sensitivity Analyses for Primary Endpoint(s) 
The following sensitivity analysis using a different handling of missing data will be 
performed for the primary efficacy endpoint to evaluate the robustness of the main 
analysis of the primary endpoint finding: 
Multiple imputation:  
The population, intercurrent events, and handling of intercurrent events will be the same 
as in the main analysis, however missing primary endpoint BCVA data will be imputed 
via multiple imputation.  The analysis will be performed using an analysis of covariance 
(ANCOVA) model with adjustment for the following covariates:  treatment group, 
baseline BCVA (continuous), as well as randomization stratification factors.  The 
dependent variable in the ANCOVA model is the Week 24 assessment in change from 
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Missing BCVA data will be assumed to be missing not at random (MNAR).  Each arm 
will be imputed separately.  Imputation will only be performed for patients with missing 
BCVA data at Week 24.  
An approximate Bayesian bootstrap method will be used for imputation.  These patients 
will be assumed to have worse outcomes compared to the rest of the population and will 
be imputed from patients with non-missing BCVA data with the worst outcomes. 
Suppose there are n1 patients with an assessment from at Week 24 (i.e., patients with 
non-missing primary endpoint data), and n0 patients that are missing the Week 24 
assessment.  The imputation steps will be as follows: 
1. 
Among patients with an assessment at Week 24, identify 20% of the patients with 
the worst values for change in BCVA score from baseline at Week 24.  Call this Yobs.  
2. 
Draw n1 observations randomly with replacement from Yobs to create a new data set 
Yobs*. 
3. 
Draw n0 values randomly with replacement from Yobs* to obtain the missing values. 
 
The imputation will be implemented in statistical analysis system (SAS) using the three 
standard steps to generate inference from imputed data: imputation step, analysis step, 
and pooling step.  The number of imputations will be set to 100. 
1. 
The missing data will be filled in 100 times to generate 100 imputed datasets.  
2. 
Each of the 100 imputed datasets will be analyzed using the ANCOVA model. 
3. 
The results from the 100 imputed data sets will be combined for inference following 
the methodology developed by (Rubin 1987). 
 
The SAS codes for multiple imputation will be added to a separate table/listing/graph 
mockup document (Data Analysis Plan – Module 2) prior to the study unmasking; and 
will also be included in the Analysis Data Reviewer’s Guide. 
5.3.4 
Supplementary Analyses for Primary Endpoint(s) 
The following supplementary analyses will be performed for the primary efficacy 
endpoint to provide further understanding of the treatment effect. 
1. 
Per-protocol analysis: 
The per-protocol analysis will follow the same intercurrent events, handling of 
intercurrent events, analysis method and handling of missing data as the main analysis 
for the primary endpoint  (Section 5.3.2) with the exception that the analysis will be 
based on the per-protocol population (Section 4).  Patients with major protocol 
deviations that impact the efficacy evaluation will be excluded from the analysis. 
2. 
Analysis distinguishing COVID-19 and non-COVID-19 related intercurrent events.  
The estimand is defined as follows:  


 
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 
Population: Adult patients with macular edema due to BRVO (for BALATON), CRVO 
or HRVO (for COMINO), as defined by the inclusion and exclusion criteria (ITT 
population) 
 
Variable: Change from baseline in BCVA at Week 24 
 
Treatments (as randomzied): 
– 
Experimental: Faricimab 6 mg IVT Q4W  
– 
Control: Aflibercept 2 mg IVT Q4W 
 
Intercurrent events prior to Week 24: 
– 
Discontinuation of study treatment due to AEs or lack of efficacy not due to 
COVID-19 
– 
Use of any prohibited systemic treatment or prohibited therapy in the Study eye 
(Section 4.4.2 of Protocol) not due to COVID-19  
– 
Discontinuation of study treatment due to COVID-19 
– 
Use of any prohibited systemic treatment or prohibited therapy in the study eye 
due to COVID-19  
– 
Missed dose(s) with potentially major impact on efficacy due to COVID-19  
– 
COVID-19 death 
 
Handling of intercurrent events: 
– 
A treatment policy strategy will be applied to intercurrent events not related to 
COVID-19, where all observed values will be used regardless of the occurrence 
of the intercurrent event  
– 
A hypothetical strategy will be applied to intercurrent events related to 
COVID‑19, where all values will be censored after the intercurrent event 
 
Population-level summary: Difference in adjusted means between treatment groups 
 
All observed data will be included in the analysis regardless of whether or not a patient 
has experienced an intercurrent event unrelated to COVID-19; the treatment policy 
strategy is applied in a best attempt to approximate the effectiveness of the treatment 
under real world conditions (in the absence of COVID-19).  If a patient experiences an 
intercurrent event related to COVID-19, all values following the intercurrent event will be 
set to missing.  The rationale for applying the hypothetical strategy for COVID-19 related 
intercurrent events is to discard potentially confounding impacts of the pandemic, and 
estimate the treatment effect in the absence of COVID-19 assuming COVID-19 will not 
be present or will not have the same impact in the future.  
Data censored after intercurrent events following hypothetical strategy and missing data 
due to reasons other than intercurrent events will both be implicitly imputed by the 
MMRM model assuming MAR.  The rationale of MAR assumption for data censored 
after COVID-19 related intercurrent events following hypothetical strategy is based on 
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treatment group with similar covariates, had the patients not had such intercurrent 
events.  
3. 
Analysis using hypothetical strategy for all intercurrent events:  
The analysis method, population, and definition of intercurrent events will be the same 
as the main analysis (Section 5.3.2).  However, all intercurrent events will follow a 
hypothetical strategy, where all values will be censored after the occurrence of the 
intercurrent event, to estimate a treatment effect in the absence of intercurrent events.  
Data censored after intercurrent events following hypothetical strategy and missing data 
due to reasons other than intercurrent events will both be implicitly imputed by the 
MMRM model assuming MAR.  
5.3.5 
Subgroup Analyses for Primary Endpoint(s) 
The following subgroups will be analyzed with respect to the primary efficacy endpoint 
using the same method as specified above for the primary endpoint within each 
subgroup (except in the case of baseline BCVA and region subgroup where the baseline 
covariate consisting of the BCVA stratification factor and region stratification, 
respectively, will be removed from the model).  A forest plot will be presented to 
summarize the results.  The subgroup categories may be combined if there is not 
enough representation of a specific subpopulation.  
 
Baseline BCVA (based on stratification factors) 
– 
BALATON (BRVO): ≤ 54 letters and ≥ 55 letters 
– 
COMINO (C/HRVO): ≤ 34 letters, 35-54 letters, and ≥ 55 letters 
 
Baseline BCVA (low vision of ≤ 23 letters and ≥ 24 letters) 
– 
Analysis will be performed should a sufficient sample size be available to draw 
meaningful conclusions. 
 
Region (United States and Canada, Asia, and the rest of the world) 
 
Age (65 years and ≥65 years) 
 
Gender (female and male) 
 
Race (White, Asian, and other) 
 
Baseline RVO status (CRVO and HRVO) 
– 
Only applies to COMINO. 
 
At the final analysis, analyses in Section 5.3 will be performed for the endpoint of BCVA 
change from baseline averaged over Weeks 64, 68 and 72, with the exception that no 
comparisons between treatment groups will be made since all patients will receive 
faricimab during Part 2 of the study.  Differences between groups will not be assessed 
and nominal p-values will not be provided. 


 
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5.4 
SECONDARY ENDPOINTS ANALYSIS(SES) 
5.4.1 
Secondary Endpoints 
The following intercurrent events and handling of intercurrent events will be used for all 
secondary endpoints unless specified otherwise.  Note that the time period of 
intercurrent events may differ for different secondary endpoints, see details in Table 1 
and Table 2. 
 
Intercurrent events:  
– 
Discontinuation of study treatment due to AEs or lack of efficacy  
– 
Use of any prohibited systemic treatment or prohibited therapy in the Study eye 
(Section 4.4.2 of Protocol)  
 
Handling of intercurrent events (same as the main analysis for the primary 
endpoint): 
A treatment policy strategy will be applied to all intercurrent events. 
Table 1 and Table 2 provide additional attributes of the estimand and analysis methods 
for the continuous and binary secondary endpoints, respectively.  Details of the estimand 
and analysis methods will be provided in the subsequent sections.  
At the primary analysis, nominal superiority p-values will be included for secondary 
endpoints for reference purposes.  No formal superiority test will be performed for 
secondary endpoints.  At the final analysis, no comparisons between treatment groups 
will be made since all patients will receive faricimab during Part 2 of the study.  
Differences between groups will not be estimated and nominal p-values will not be 
provided.  
At the final analysis, secondary endpoints will be summarized over time from baseline to 
Week 72, and selected secondary endpoints will be summarized by the average over 
Weeks 64, 68 and 72 as appropriate.










 
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5.4.1.1 
Continuous Secondary Endpoints  
5.4.1.1.1 
Continuous secondary endpoints at the primary analysis 
Continuous secondary endpoints (Table 1) at the primary analysis will be analyzed using 
the same estimand and analysis methods for the main analysis of the primary endpoint 
(Section 5.3.1 and Section 5.3.2), with the exception that change from baseline in NEI 
VFQ-25 composite score will be analyzed using ANCOVA analysis. 
5.4.1.1.2 
Continuous secondary endpoints at the Final Analysis 
Continuous secondary endpoints (Table 1) at the final analysis will be analyzed using 
the same analysis methods for the main analysis of the primary endpoint (Section 5.3.2) 
with the exception that treatment difference will not be estimated and nominal p-values 
will not be provided, and the same intercurrent events and intercurrent events handling 
strategies described in Section 5.4.1 with the following additional attributes. 
 
Population: 
– 
Change from baseline in BCVA and CST, and NEI VFQ-25 endpoints (Table 1, 
Group 1 and Group 2): Adult patients with macular edema due to BRVO (for 
BALATON), CRVO or HRVO (for COMINO), as defined by the inclusion and 
exclusion criteria (ITT population) 
– 
Change from Week 24 in BCVA (Table 2, Group 3): Adult patients with macular 
edema due to BRVO (for BALATON), CRVO or HRVO (for COMINO), as 
defined by the inclusion and exclusion criteria (ITT population) with an 
evaluable Week 24 BCVA. 
 
Variable: Same as endpoint  
 
Treatments (as randomized): 
– 
Experimental: Faricimab PTI (Faricimab Q4W in Part 1)  
– 
Experimental: Faricimab PTI (Aflibercept Q4W in Part 1 crossover)  
 
Intercurrent events time period: 
– 
Change from baseline in BCVA and CST, and NEI VFQ-25 endpoints (Table 1 
Group 1 and Group 2): Intercurrent events measured throughout the study will 
be accounted for 
– 
Change from Week 24 in BCVA (Table 2 Group 3): Intercurrent events 
occurring prior to Week 24 will not be accounted for 
 
Population-level summary: Adjusted means of each treatment group and adjusted 
means for all patients after Week 24 
– 
Change from baseline in BCVA and CST, and NEI VFQ-25 endpoints (Table 1 
Group 1 and Group 2): Adjusted means of each treatment group 
– 
Change from Week 24 in BCVA (Table 2 Group 3): Adjusted means for all 
patients after Week 24 
 


 
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5.4.1.2 
Binary Secondary Endpoints  
5.4.1.2.1 
Binary Secondary Endpoints at Primary Analysis 
Binary secondary endpoints (Table 2, Group 1 and Group 2) at the primary analysis will 
be analyzed using the same population, treatments, intercurrent events and intercurrent 
handling strategies described in Section 5.4.1 and the following additional attributes: 
 
Variable: Same as endpoint 
 
Population-level summary: Difference in weighted proportions between treatment 
groups 
 
The proportion of patients in each treatment group and the overall difference in 
proportions between treatment groups will be estimated using the weighted average of 
the observed proportions and the differences in observed proportions over the strata 
defined by randomization stratification factor of baseline BCVA score and region (as 
defined in Section 1.2.1) using the Cochran Mantel-Haenszel (CMH) weights 
(Cochran 1954; Mantel and Haenszel 1959).  The endpoints on proportion of patients 
with BCVA Snellen equivalent of 20/200 (BCVA-ETDRS  38 letters) or worse over time 
will be estimated using a different baseline BCVA strata (BCVA  38 vs. BCVA  38 
letters).  Confidence intervals of the proportion of patients in each treatment group and 
the overall difference in proportions between treatment groups will be calculated using 
the normal approximation to the weighted proportions (Mehrotra and Railkar 2000).  No 
formal superiority tests will be performed.  Nominal superiority p-values will be included 
as appropriate, using a CMH test stratified by the same stratification factors.  If the 
response rate is low, an unstratified analysis may also be performed.   
All intercurrent events will be handled using a treatment policy strategy and all observed 
data will be used.  For CMH method,  missing data will be imputed using last observation 
carried forward (LOCF). 
In addition, a supplementary analysis will be performed for the following secondary 
endpoints at the primary analysis. 
 
Proportion of patients gaining  15 letters in BCVA from baseline at Week 24 
 
Proportion of patients avoiding a loss of  15 letters in BCVA from baseline at 
Week 24 
 
The above supplementary analyses will be analyzed using the same estimand, analysis 
method as the main analysis for binary secondary endpoints with the following 
differences: 
– 
Handling of intercurrent events:  A composite variable strategy will be applied 
where patients with any intercurrent event are assumed to be failures after the 
intercurrent event 


 
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– 
Missing data (without intercurrent events) handling rules:  If BCVA at Week 16, 
20 and 24 are all missing, patients will be assumed to be failures at  Week 24.  
Otherwise, missing data will be imputed using LOCF. 
 
5.4.1.2.2 
Binary Secondary Endpoints at Final Analysis 
Binary secondary endpoints (Table 2, Group 2, Group 3 and Group 4) at the final 
analysis will be analyzed using the same intercurrent events and intercurrent events 
handling strategies described in Section 5.4.1, unless otherwise specified, with the 
following additional attributes: 
 
Population: 
– 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA 
from Week 24 (Table 2, Group 3): Adult patients with macular edema due to 
BRVO (for BALATON), CRVO or HRVO (for COMINO), as defined by the 
inclusion and exclusion criteria (ITT population) with an evaluable Week 24 
BCVA 
– 
Proportions of patients on Q4W, Q8W, Q12W, or Q16W treatment interval and 
other binary endpoints (Table 2, Group 2 and Group 4): Adult patients with 
macular edema due to BRVO (for BALATON), CRVO or HRVO (for COMINO), 
as defined by the inclusion and exclusion criteria (ITT population) 
 
Variable: Same as endpoint  
 
Treatments (as randomized): 
– 
Experimental: Faricimab PTI (Faricimab Q4W in Part 1)  
– 
Experimental: Faricimab PTI (Aflibercet Q4W in Part 1 crossover)  
 
Intercurrent events time period: 
– 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA 
from Week 24 (Table 2, Group 3): Intercurrent events occurring prior to Week 
24 will not be accounted for  
– 
Proportions of patients on Q4W, Q8W, Q12W, or Q16W treatment interval and 
other binary endpoints (Table 2, Group 2 and Group 4): Intercurrent events 
measured throughout the study will be accounted for 
 
Population-level summary:  
– 
Binary BCVA endpoints in reference to baseline (Table 2, Group 2): Weighted 
proportions of each treatment group  
– 
Binary BCVA endpoint in reference to Week 24 (Table 2 Group 3): Weighted 
proportions for all patients after Week 24 
– 
Proportions of patients on Q4W, Q8W, Q12W, or Q16W treatment interval 
(Table 2, Group 4): Proportions of each treatment group and for all patients 
 
Binary endpoints (Table 2, Group 2 and Group 3) at the final analysis will be analyzed 
using the same analysis methods for the binary BCVA endpoints at the primary analysis 


 
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(Section 5.4.1.2.1) with the exception that the treatment differences will not be estimated 
and nominal p-values will not be provided after Week 24.  
Proportions of patients on Q4W, Q8W, Q12W, or Q16W treatment interval at Week 68 
(Table 2, Group 4) will be analyzed using descriptive statistics.  Percentage will be 
based on the patients who have not discontinued the study at Week 68. 
5.5 
EXPLORATORY ENDPOINT(S) ANALYSIS 
Exploratory endpoints will be summarized for the ITT population at the primary analysis 
and the final analysis (if applicable).  All observed data will be used and missing data will 
not be imputed.  For the final analysis, no comparisons between treatment groups will be 
made since all patients will receive faricimab during Part 2 of the study.  Differences 
between groups will not be assessed. 
The exploratory endpoints will be summarized using descriptive statistics by including 
the mean, SD, median, and range for continuous endpoints, and counts and 
percentages for categorical endpoints. 
5.6 
SAFETY ANALYSES 
Safety data will be summarized for the Safety-Evaluable population (see Section 4). 
Safety will be assessed through descriptive summary of ocular and non-ocular AEs, 
deaths, and ocular assessments.  Clinically significant laboratory abnormalities and 
clinically significant vital sign abnormalities will be reported as AEs and evaluated as part 
of the AE assessments.  
At the primary analysis, safety summaries will be performed based on data before the 
Week 24 visit in the safety-evaluable population by treatment group.  At the final 
analysis, safety summaries will be summarized by the following groups:  Faricimab Q4W 
before Week 24 visit, Aflibercept Q4W before Week 24 visit, Faricimab PTI (Faricimab 
Q4W in Part 1) on and after Week 24 visit, Faricimab PTI (Aflibercept Q4W in Part 1 
crossover) on and after the first dose of faricimab, all patients who received at least one 
dose of faricimab with safety data on and after the first dose of faricimab. 
Missing data for safety analyses will not be imputed. 
5.6.1 
Extent of Exposure 
At the primary analysis, exposure to study drug (number of study drug administrations 
and duration of treatment) will be summarized by treatment group for the study eye 
based on data before the Week 24 visit for the safety-evaluable population. 


 
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Duration of treatment is the time from first study drug (faricimab or aflibercept) to the 
earlier of:  
 
Date of treatment discontinuation before the Week 24 visit 
 
Date of last dose of study drug or last dose hold before the Week 24 visit 
 
At the final analysis, exposure to study drug (number of study drug administrations and 
duration of treatment) will be summarized by treatment group and by period for the study 
eye through Week 72 for the safety-evaluable population. 
Duration of treatment for Faricimab PTI (Faricimab Q4W in Part 1) and Faricimab PTI 
(Aflibercept Q4W in Part 1 crossover) from Week 24 onwards is the time from the first 
study treatment (faricimab or sham) on or after Week 24 to the earlier of:  
 
Date of treatment discontinuation  
 
Date of last dose of study drug or last dose hold prior to Week 72 
 
Duration of treatment for patients who received at least one dose of faricimab is the time 
from first dose of faricimab to the earlier of: 
 
Date of treatment discontinuation 
 
Date of last dose of study drug or last dose hold prior to Week 72 
 
5.6.2 
Adverse Events 
All verbatim AEs terms will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA), and the incidence and severity will be summarized by 
treatment arm. 
For safety analyses, unless otherwise specified, only treatment-emergent AEs will be 
included in the analyses.  A treatment-emergent AE is defined as any new AE reported 
or any worsening of an existing condition on or after the first dose of study drug 
(faricimab or aflibercept) for the Safety-Evaluable population.  Adverse events with 
missing onset date will be considered to be treatment emergent.  Adverse events with 
partially missing onset date will also be included as treatment emergent when the month 
(if it was recorded) and the year occur on or later than the month and year of the start 
date of the reporting period. 
Frequency tables, including patient incidence rates by treatment arm, will be provided for 
the events listed below.  In addition, graphical presentations will be included, as 
applicable.  For ocular AEs, events in the study eye and fellow eye will be summarized 
separately: 
 
Ocular AEs and serious adverse events (SAEs) 
 
Non-ocular AEs and SAEs  
 
Adverse events of special interest (AESI) defined as follows: 


 
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– 
Cases of potential drug-induced liver injury that include elevated alanine 
aminotransferase or aspartate aminotransferase in combination with either an 
elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.6 of Protocol) 
– 
Suspected transmission of an infectious agent by the study drug 
– 
Sight-threatening AEs (see Section 5.2.3 of Protocol for definitions) 
 
AEs leading to discontinuation of study treatment 
 
AEs leading to discontinuation from the study 
 
AEs leading to study treatment interruption 
 
Treatment related ocular AEs and SAEs as determined by the Investigator 
 
Non-Ocular Adverse Events of Arterial Thromboembolic Event (ATE) and 
Cerebrovascular Haemorrhagic Adverse Events 
 
Externally adjudicated APTC events 
 
Intraocular inflammation (IOI) 
 
Retinal vascular occlusive disease 
 
Deaths  
 
There is no standardized MedDRA queries (SMQ) that encompasses the medical 
concepts of IOI or retinal vascular occlusive disease.  These definitions will be assessed 
based on the masked review of clinical database preferred terms (PTs) before the 
primary analysis and final analysis, and with subsequent MedDRA version updates, to 
ensure no event terms are missed. 
5.6.3 
Laboratory Data 
Laboratory data will be collected at baseline and Week 24 only (Section 4.5.7 of 
Protocol).  Laboratory assessments will be summarized by treatment group and 
timepoint, using descriptive summaries. 
5.6.4 
Vital Signs 
Vital signs will be collected at screening, randomization, Week 72 or early termination 
visit.  These data can be used for interpretation of AEs, no general summary is planned. 
5.6.5 
Ocular Assessments 
Results of the following ocular assessments will be summarized by treatment group, by 
timepoint, by eye (Study vs. Fellow) using descriptive summaries and graphical 
presentations (as applicable): 
 
intraocular pressure (IOP) 
 
slitlamp examination 
 
indirect ophthalmoscopy 
 


 
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Changes from baseline in pre-dose IOP measurements and changes between pre-dose 
and post-dose IOP measurements will be summarized.  The presence of IOI and 
vitreous hemorrhage, as determined on slitlamp examination, will be tabulated by grade 
(according to grading scales for flares and cells in Appendix 4 of Protocol).  The 
presence of retinal break or detachment as determined from ophthalmoscopy will be 
tabulated. 
5.7 
OTHER ANALYSES 
5.7.1 
Summaries of Conduct of Study 
Conduct of study will be summarized for the ITT population at the primary analysis and 
the final analysis. 
Eligibility criteria deviations and other major protocol deviations will be summarized by 
treatment arm.  
Pre-treatment and concomitant systemic medications, ocular medications for the study 
eye, and ocular medications for the fellow eye will be summarized separately by 
treatment group. 
5.7.2 
Summaries of Treatment Group Comparability 
Treatment group comparability will be summarized for the ITT population at the primary 
analysis and will not be summarized at the final analysis.  Demographic and baseline 
characteristics such as age, sex, race/ethnicity and region, and baseline disease 
characteristics (such as baseline BCVA, ocular assessments, and medical history) will 
be summarized using means, SDs, medians, and ranges for continuous variables, and 
counts and proportions for categorical variables, as appropriate. 
5.7.3 
Pharmacokinetic Analyses 
At the primary analysis, PK summaries will be based on the faricimab PK-evaluable 
population (see Section 4) using data from Day 1 up to Week 24 by treatment group.  At 
the final analysis, PK summaries will be based on the PK-evaluable population (see 
Section 4) using data from Day 1 up to Week 72 by treatment group. 
Summaries of individual plasma and aqueous humor faricimab (RO6867461) 
concentrations will be provided by treatment arm with summary statistics.  Mean 
faricimab (RO6867461) plasma and aqueous humor concentration versus time data will 
be plotted. 
In addition, a population PK analysis will be performed including co-variate analysis and 
assessment of potential effect of ADA on the kinetics of faricimab.  Details of the 
population PK analyses will be described in a Modeling and Simulation Analysis Plan.  


 
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The result of the population PK analyses will be reported in a document separate from 
the Clinical Study Report (CSR) and may include data from the China extensions. 
5.7.4 
Pharmacodynamic Analyses 
PD analyses will be based on the Safety-Evaluable population (see Section 4). 
At the primary analysis, PD summaries will be based on data from Day 1 up to Week 24 
by treatment group.  At the final analysis, PD summaries will be based on data from Day 
1 up to Week 72 by treatment group. 
PD biomarker analyses will be focused primarily on, but not limited to, the change in 
Ang-2 and VEGF.  Graphical displays and summaries of the absolute values or change 
from baseline (or as appropriate, percent change from baseline) will be provided.  The 
data collected from this study may be pooled with data from previous studies and the 
results of such analyses will be reported in a document separate from the CSR.  The 
effect of exposure or dosing information on BCVA, CST, aqueous humor free VEGF-A 
and Ang-2 may be explored using a longitudinal modeling approach if appropriate.  The 
influence of various baseline covariates on model parameters may be investigated.  The 
PK-PD or dose-PD relationship will be characterized as appropriate and results will be 
reported in a document separate from the CSR. 
5.7.5 
Immunogenicity Analyses 
Immunogenicity analyses will be based on the Immunogenicity-Analysis population (see 
Section 4). 
At the primary analysis, ADA summaries will be based on data through Week 24 for 
patients in the Faricimab Q4W arm in Part 1.  At the final analysis, ADA summaries will 
be based on data from Day 1 to week 72 for patients in the Faricimab Q4W arm in Part 1 
followed by Faricimab PTI in Part 2.  For patients in the Aflibercept Q4W arm in Part 1 
followed by Faricimab PTI in Part 2, ADA summaries will be based on data on Day 1, 
and from Week 24 to Week 72. 
The following properties of each sample will be listed by patient: ADA status (from the 
confirmatory assay): ADA positive (yes) or ADA negative (no) and titer value for the ADA 
positive sample. 
The ADA status at baseline will be summarized using the Immunogenicity prevalence 
set and summarized according to treatment received.  For patients in the Aflibercept 
Q4W arm in Part 1 followed by Faricimab PTI in Part 2, ADA status at Week 24 will also 
be summarized using the Immunogenicity prevalence set. 
The ADA status will be listed by patient using the Immunogenicity incidence set and 
summarized according to actual treatment received.  For the immunogenicity incidence 
set, baseline for patients in the Faricimab Q4W arm refers to study Day 1 and baseline 


 
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for patients in the Aflibercept Q4W arm in Part 1 followed by Faricimab PTI in Part 2 
refers to Week 24. 
 
Treatment-boosted ADA-positive: number and percent of patients with at least one 
treatment-boosted ADA-positive sample.  The numerator is the number of patients 
with an ADA-positive sample at baseline and with post-baseline samples with a titer 
that is equal or greater than 4-fold baseline titer.  The denominator is the total 
number of patients in the immunogenicity incidence set summarized according to 
treatment received.  
 
Treatment-induced ADA-positive: number and percent of patients with at least one 
treatment-induced ADA-positive sample.  The numerator is the number of patients 
with an ADA-negative or missing sample at baseline and any post-baseline positive 
sample.  The denominator is the total number of patients in the immunogenicity 
incidence set.  Among the treatment –induced ADA‑positive, the number of patients 
with transient (ADA‑positive result detected (a) at only one post-baseline sampling 
time point (excluding last timepoint) OR (b) at 2 or more timepoints during treatment 
where the first and last ADA‑positive samples are separated by a period of 
 16 weeks, irrespective of any negative samples in between) and persistent 
(ADA‑positive result detected (a) at the last post-baseline sampling time point, OR 
(b) at 2 or more time points during treatment where the first and last ADA‑positive 
samples are separated by a period of  16 weeks, irrespective of any negative 
samples in between) will be listed. 
 
Treatment-unaffected ADA-positive patient: number and percent of patients with an 
ADA-positive baseline sample (level of pre-existing ADAs) that does not change 
following drug administration.  The numerator is the number of patients with 
ADA‑positive sample and with all post-baseline titers lower than 4-fold the 
ADA‑positive baseline titer.  The denominator is the total number of patients in the 
immunogenicity incidence set. 
 
ADA-negative: number and percent of patients without positive ADA during the 
study period or if they are ADA‑positive at baseline but without positive ADA post 
baseline (numerator).  The denominator is the total number of patients in the 
immunogenicity incidence set. 
 
ADA incidence (i.e., ADA-positive in %): number and percent of patients with at 
least one treatment-induced or treatment-boosted ADA-positive sample.  The 
numerator is the number of patients positive for boosted or induced ADA.  The 
denominator is the total number of patients in the immunogenicity incidence set. 
 
Of note, ADA-positive is defined as treatment-boosted ADA-positive, treatment-induced 
ADA-positive or treatment-unaffected ADA-positive (see definition above). 
The following summaries, both overall and by time point (including baseline) will be 
provided using the Immunogenicity prevalence set: 
 
ADA prevalence: number and percent of patients with at least one ADA-positive 
sample at any timepoint (including baseline).  The numerator is the number of 


 
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ADA‑positive patients at each timepoint and overall timepoints.  The denominator is 
the total number of evaluable patients in the study at corresponding timepoints.  
 
The relationship between ADA status and safety and efficacy will be analyzed and 
reported using descriptive statistics. 
5.7.6 
Biomarker Analyses 
Biomarker analyses will be based on the Safety-Evaluable population (see Section 4). 
Baseline values will be used to evaluate predictive biomarkers in the context of efficacy, 
PK, safety, and/or immunogenicity endpoints.  In addition, whole genome sequencing 
data will be analyzed in the context of this study and may be explored in aggregate with 
data from other studies to increase researcher's understanding of disease pathobiology 
and faricimab treatment response, and guide the development of new therapeutic 
approaches.  The results from these analyses will be reported in a document separate 
from the CSR.  
Details of the biomarker analyses will be described in a separate Analysis Plan. 
5.7.7 
Analyses of China Subpopulation 
Separate analyses will be performed for each China subpopulation, where data from all 
patients enrolled in mainland China, Hong Kong, or Taiwan for each study (i.e., during 
both the global enrollment phase and China extension) will be summarized individually 
for each study.  
Analyses described in this section will include data from the China subpopulation as 
defined in Section 1.2. 
The analysis populations will be equally defined as per Section 4 but will be based only 
on patients who enroll in mainland China, Hong Kong, or Taiwan.  Analyses of study 
conduct will be performed as described in Section 5.7.1.  Summaries of demographics, 
stratification factors, disease history, baseline disease characteristics, and patient 
treatment history will be produced as described in Section 5.7.2.  Primary and key 
efficacy endpoints for the China subpopulation will be summarized using descriptive 
statistics.  Similarly, key PK, ADA and safety data for the China subpopulation will also 
be summarized. 
No formal statistical testing of the comparison between faricimab and the active 
comparator aflibercept is planned for the China subpopulation and the clinical data will 
be descriptively summarized.  The China subpopulation results will be interpreted in the 
context of results from the global enrollment phase.  Thus, the consideration of whether 
the China subpopulation data is consistent with the results from the global population will 
be based on the totality of the data, including the direction of efficacy and safety profiles. 


 
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5.8 
ANALYSES FOR COVID-19  
Based on the first reports of COVID-19 infection globally, the Sponsor determined that 
the window for all analyses of COVID-19 associated events would start from 
1 December 2019.  
The impact of COVID-19 will be assessed for study conduct, efficacy analyses and 
safety events. 
5.8.1 
Study Conduct Analyses for COVID-19 
In order to assess the impact of COVID-19 on study conduct, the following metrics will 
be recorded: 
 
BCVA not performed per protocol (non-standard BCVA) due to COVID-19 or related 
precautions 
 
Major protocol deviations due to COVID-19, including, but not limited to:  
– 
Missed visits reported as due to COVID-19 or related precautions on or prior to 
Week 24 
– 
Missed injections reported as due to COVID-19 or related precautions on or 
prior to Week 20 
– 
Use of prohibited therapies due to COVID-19 
 
Discontinuations from treatment and/or study due to COVID-19, which includes: 
– 
Indirect COVID-19 pandemic-related aspects (e.g., patients leaving the study 
due to fear of going to the site during the pandemic) as collected on the 
disposition or study drug early discontinuation electronic Case Report Form 
(eCRF), and 
– 
Direct COVID-19 pandemic-related aspects (Safety events related to COVID-19 
as specified in Section 5.8.3). 
 
5.8.2 
Efficacy Analyses for COVID-19 
A supplementary analysis for the primary endpoint applying a hypothetical strategy for 
COVID-19 related intercurrent events, where all values will be censored after such 
intercurrent events, will be performed.  A supplementary analysis on the per-protocol 
population will also be conducted to help assess pandemic related impacts 
(Section 5.3.4).  
For data integrity of efficacy analyses, the following will be summarized by treatment arm 
at the primary and final analysis: 
 
Discontinuation of study treatment due to COVID-19 
 
Use of prohibited therapy due to COVID-19 
 
Missed doses with a potentially major impact on efficacy due to COVID-19  
 
Death due to COVID-19 


 
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5.8.3 
Safety Analyses for COVID-19 
Following the MedDRA 24.0 release, a COVID-19 SMQ (narrow) is available.  This SMQ 
includes terms relevant to COVID-19 infection.  Patients with AEs from this COVID-19 
SMQ (narrow) will be considered to have a confirmed or suspected COVID-19 infection. 
For the patients identified from the search as having confirmed or suspected COVID-19 
infection, outputs to evaluate safety events will be produced as follows: 
 
Summary table and listing of confirmed and suspected COVID-19 AEs 
 
In addition to presenting the suspected/confirmed COVID-19 infections, the Sponsor 
developed a broad search strategy for AEs associated with COVID-19 infection to further 
evaluate the confirmed events of COVID-19 and reported AEs that could be considered 
complications of the disease.  This search strategy includes both the AEs of a confirmed 
or suspected COVID-19 infection and any AEs considered associated with COVID-19.  
The Sponsor identified associated AEs as those reported ≤7 days before and ≤30 days 
after any reported AE suggesting a confirmed COVID-19 infection (PTs listed in 
Table 3). 
Table 3 
Roche COVID-19 SMQ (narrow) Preferred Terms for Confirmed 
Cases 
Congenital COVID-19 
Coronavirus Infection  
Coronavirus Test Positive  
COVID-19  
COVID -19 Pneumonia 
COVID-19 Treatment 
Multisystem Inflammatory Syndrome in Children 
Post-acute COVID-19 Syndrome 
SARS-CoV-2 RNA Decreased 
SARS-CoV-2 RNA Fluctuation 
SARS-CoV-2 RNA Increased 
SARsS-Cov-2 Test Positive 
SARS-CoV-2 sepsis 
SARS-CoV-2 viraemia 
Vaccine Derived SARS-CoV-2 Infection 
COVID-19  coronavirus disease 2019; SARS-CoV-2  severe acute respiratory syndrome 
coronavirus 2. 
  
For the patients identified from the search as having COVID-19 associated AEs, outputs 
to evaluate these safety events will be produced as follows: 
 
Summary table and listing of COVID-19 Associated Events: including all of the 
above confirmed/suspected COVID-19 infections plus, for those patients with 


 
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confirmed COVID-19 infection or positive polymerase chain reaction test flag, any 
other AEs occurring within ≤ 7 days before and ≤ 30 days after start date of all the 
confirmed COVID-19 events in Table 3. 
 
In addition, the following outputs will be produced: 
 
Listing of Adverse Events associated with COVID-19 Leading to Study Treatment 
Discontinuation 
 
Listing of Adverse Events associated with COVID-19 Leading to Study 
Discontinuation 
 
Listing of adverse Events associated with COVID-19 Resulting in Death 
 
5.9 
INTERIM ANALYSES  
No interim efficacy or futility analyses are planned or conducted.  The iDMC reviewed 
interim safety analyses approximately every 6 months, 3 interim safety analyses before 
the primary analysis are expected. 
 
 


 
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6. 
REFERENCES 
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patients with diabetic retinopathy and other retinal disorders. New England Journal 
of Medicine. 1994 Dec 1;331(22):1480-7. 
Bhisitkul RB, Campochiaro PA, Shapiro H, et al. Predictive value in retinal vein 
occlusions of early versus late or incomplete ranibizumab response defined by 
optical coherence tomography. Ophthalmology. 2013 May 1;120(5):1057-63. 
Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for 
macular edema secondary to central retinal vein occlusion: six-month results of the 
phase 3 COPERNICUS study. Ophthalmology. 2012 May 1;119(5):1024-32. 
Callizo J, Ziemssen F, Bertelmann T, et al. Real-world data: ranibizumab treatment for 
retinal vein occlusion in the OCEAN study. Clinical Ophthalmology (Auckland, NZ). 
2019;13:2167. 
Campochiaro PA, Clark WL, Boyer DS, et al. Intravitreal aflibercept for macular edema 
following branch retinal vein occlusion: the 24-week results of the VIBRANT study. 
Ophthalmology. 2015 Mar 1;122(3):538-44. 
Cochran WG. Some methods for strengthening the common χ 2 tests. Biometrics. 1954 
Dec 1;10(4):417-51. 
Cugati S, Wang JJ, Rochtchina E, et al. Ten-year incidence of retinal vein occlusion in 
an older population: the Blue Mountains Eye Study. Archives of ophthalmology. 
2006 May 1;124(5):726-32. 
GUIDELINE ON THE CHOICE OF THE NON-INFERIORITY MARGIN. European 
Medicines Agency Pre-authorisation Evaluation of Medicines for Human Use 
London, 27 July 2005 Doc. Ref. EMEA/CPMP/EWP/2158/99  
Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein 
occlusion and their recurrence and demographic characteristics. American journal 
of ophthalmology. 1994 Apr 1;117(4):429-41. 
Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to 
central retinal vein occlusion: 6-month results of the phase III GALILEO study. 
British Journal of Ophthalmology. 2013 Mar 1;97(3):278-84. 
Jumper JM, Dugel PU, Chen S, et al. Anti-VEGF treatment of macular edema 
associated with retinal vein occlusion: patterns of use and effectiveness in clinical 
practice (ECHO study report 2). Clinical Ophthalmology (Auckland, NZ). 
2018;12:621. 
Ke C, Ding B, Jiang Q, Snapinn SM. The issue of multiplicity in noninferiority studies. 
Clinical Trials. 2012 Dec;9(6):730-5. 


 
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Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic 
Retinopathy XXII: the twenty-five-year progression of retinopathy in persons with 
type 1 diabetes. Ophthalmology. 2008 Nov 1;115(11):1859-68. 
 Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective 
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48. 
Mehrotra DV and Railkar R. Minimum risk weights for comparing treatments in stratified 
binomial trials. Statistics in medicine. 2000 Mar 30;19(6):811-25. 
Pearce I, Clemens A, Brent MH, et al. Real-world outcomes with ranibizumab in branch 
retinal vein occlusion: The prospective, global, LUMINOUS study. PloS one. 2020 
Jun 18;15(6):e0234739. 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharmaceutical 
statistics. 2017 Jan;16(1):20-8. 
Regula JT, von Leithner PL, Foxton R, et al. Targeting key angiogenic pathways with a 
bispecific CrossMAb optimized for neovascular eye diseases. EMBO molecular 
medicine. 2016 Nov; 8(11): 1265–88.. 
 Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: 
pooled data from population studies from the United States, Europe, Asia, and 
Australia. Ophthalmology. 2010 Feb 1;117(2):313-9. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons; 1987. 
SAS Institute Inc. 2018. SAS/STAT® 15.1 User’s Guide. Cary, NC: SAS Institute Inc. 
Scott IU, Oden NL, VanVeldhuisen PC, et al. Month 24 Outcomes After Treatment 
Initiation With Anti–Vascular Endothelial Growth Factor Therapy for Macular 
Edema Due to Central Retinal or Hemiretinal Vein Occlusion: SCORE2 Report 10: 
A Secondary Analysis of the SCORE2 Randomized Clinical Trial. JAMA 
ophthalmology. 2019 Dec 1;137(12):1389-98. 
 Vaz-Pereira S, Marques IP, Matias J, et al. Real-world outcomes of anti-VEGF 
treatment for retinal vein occlusion in Portugal. European journal of ophthalmology. 
2017 Nov 8;27(6):756-61. 
Wecker T, Ehlken C, Bühler A, et al. Five-year visual acuity outcomes and injection 
patterns in patients with pro-re-nata treatments for AMD, DME, RVO and myopic 
CNV. British Journal of Ophthalmology. 2017 Mar 1;101(3):353-9. 
Yasuda M, Kiyohara Y, Arakawa S, et al. Prevalence and systemic risk factors for retinal 
vein occlusion in a general Japanese population: the Hisayama study. 
Investigative ophthalmology & visual science. 2010 Jun 1;51(6):3205-9. 


 
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Appendix 1 Protocol Synopsis for Study BALATON (GR41984) 
 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATOR-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF FARICIMAB IN PATIENTS WITH 
MACULAR EDEMA SECONDARY TO BRANCH RETINAL VEIN 
OCCLUSION 
PROTOCOL NUMBER: 
GR41984 
STUDY NAME 
BALATON 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2020-000440-63 
IND NUMBER: 
119225 
NCT NUMBER: 
To be determined  
TEST PRODUCT: 
Faricimab (RO6867461) 
PHASE: 
III 
INDICATION: 
Macular edema secondary to branch retinal vein occlusion 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab compared with 
aflibercept in patients with macular edema due to branch retinal vein occlusion (BRVO) up to 
the primary endpoint at Week 24.  Efficacy, safety, and pharmacokinetics of faricimab 
administered according to the personalized treatment interval (PTI) dosing regimen (i.e., from 
every 4 weeks [Q4W] to every 16 weeks [Q16W]) will be assessed during the study period from 
Weeks 24 to 72.  Specific objectives and corresponding endpoints for the study are outlined 
below. 
EFFICACY OBJECTIVES 
For efficacy endpoint evaluation, best-corrected visual acuity (BCVA) will be assessed on the 
Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting test 
distance of 4 meters. 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective for this study is to evaluate the efficacy of faricimab 6 mg 
intravitreal (IVT) Q4W compared with aflibercept 2 mg IVT Q4W on the basis of the following 
endpoint: 
 
Change from baseline in BCVA at Week 24 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objective for Part 1 of this study (i.e., through Week 24) is to evaluate 
the efficacy of faricimab compared with aflibercept on the basis of the following endpoints: 
 
Change from baseline in BCVA at specified timepoints through Week 24 
 
Proportion of patients gaining  15 letters in BCVA from baseline at Week 24 
 
Proportion of patients gaining  15,  10,  5, or  0 letters in BCVA from baseline at 
specified timepoints through Week 24 


 
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 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from baseline 
at specified timepoints through Week 24 
 
Proportion of patients achieving  84 letters (20/20 Snellen equivalent) in BCVA at specified 
timepoints through Week 24 
 
Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints through Week 24 
 
Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints through Week 24 
 
Change from baseline in central subfield thickness (CST) at specified timepoints through 
Week 24 
 
Change from baseline in National Eye Institute 25Item Visual Functioning Questionnaire 
(NEI VFQ-25) composite score at specified timepoints through Week 24 
The secondary efficacy objective for Part 2 of this study (i.e., Week 24 through Week 72) is to 
evaluate the efficacy of faricimab administered according to the PTI dosing regimen on the 
basis of the following endpoints: 
 
Change from baseline in BCVA at specified timepoints from Week 24 through Week 72 
 
Proportion of patients gaining  15 letters in BCVA from baseline at Week 72 
 
Proportion of patients gaining  15,  10,  5, or  0 letters in BCVA from baseline at 
specified timepoints from Week 24 through Week 72 
 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from baseline 
at specified timepoints from Week 24 through Week 72 
 
Proportion of patients achieving  84 letters (20/20 Snellen equivalent) in BCVA at specified 
timepoints from Week 24 through Week 72 
 
Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints from Week 24 through Week 72 
 
Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints from Week 24 through Week 72 
 
Change from Week 24 in BCVA at specified timepoints through Week 72 
 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from Week 24 
through Week 72 
 
Proportion of patients on a Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or Q16W 
treatment interval at Week 72 
 
Number of study drug injections received from Week 24 through Week 72 
 
Change from baseline in CST at specified timepoints from Week 24 through Week 72 
 
Change from baseline in NEI VFQ-25 composite score at specified timepoints from Week 
24 through Week 72 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective for this study is to evaluate the efficacy of faricimab on the 
basis of the following endpoints: 
 
Proportion of patients with absence of retinal ischemia on fundus fluorescein angiography 
(FFA) and on optical coherence tomography angiography (OCT-A) (optional) over time (at 
specified timepoints) 
 
Change from baseline in area of retinal ischemia on FFA and on OCT-A (optional) over time 
 
Proportion of patients with vascular leakage on FFA and on OCT-A (optional) over time 
 
Change from baseline in area of vascular leakage on FFA, and on OCT-A (optional) over 
time 
 
Change from baseline in foveal avascular zone and other exploratory outputs defined in the 
Statistical Analysis Plan (SAP) on OCT-A (optional) over time 


 
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 
Proportion of patients with absence of retinal neovascularization over time (per investigator 
assessment) 
 
Proportion of patients with absence of vitreal, preretinal, or subretinal hemorrhage over time 
(per investigator assessment) 
 
Proportion of patients with absence of anterior segment (iris and anterior chamber angle) 
neovascularization over time 
 
Proportion of patients requiring panretinal photocoagulation at any time during the study 
 
Proportion of patients with absence of macular edema, defined as CST of  325 m for 
Spectralis spectral-domain optical coherence tomography (SD-OCT), or  315 m for Cirrus 
SD-OCT or Topcon SD-OCT, over time 
 
Proportion of patients with absence of intraretinal fluid over time 
 
Proportion of patients with absence of subretinal fluid over time 
 
Proportion of patients with absence of both intraretinal fluid and subretinal fluid over time 
 
Proportion of patients with absence of intraretinal cysts over time 
 
Change from baseline in NEI VFQ-25 near activitiessubscale score and distance 
activitiessubscale scores over time 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of faricimab on the 
basis of the following endpoints: 
 
Incidence and severity of ocular adverse events, with severity determined according to 
Adverse Event Severity Grading Scale 
 
Incidence and severity of non-ocular adverse events, with severity determined according to 
Adverse Event Severity Grading Scale 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective for this study is to characterize the faricimab PK profile on 
the basis of the following endpoint: 
 
Plasma concentration of faricimab over time 
The exploratory PK objective for this study is to explore the concentrationeffect relationship for 
visual acuity and other endpoints (e.g., anatomic measures) on the basis of the following 
endpoint: 
 
Concentration of faricimab and the change in BCVA or other endpoints (e.g., anatomical 
markers) over time 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the antibody immune response to 
faricimab on the basis of the following endpoint: 
 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study 
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
EXPLORATORY BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to faricimab (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of faricimab activity (i.e., 
pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints: 
 
Relationship between biomarkers in plasma (listed in Section 4.5.7) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 


 
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 
Relationship between baseline anatomic measures and the change in BCVA or other 
endpoints (e.g., the frequency of faricimab administration) over time 
 
Relationship between anatomic measures and visual acuity 
EXPLORATORY SUBSTUDY 
At selected sites, the Sponsor may propose exploratory substudies associated with the Study 
GR41984 protocol.  Each substudy will be documented in a separate substudy protocol and 
will have a separate associated Informed Consent Form. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a Phase III, multicenter, randomized, double-masked, active comparatorcontrolled, 
parallel-group study evaluating the efficacy, safety, and pharmacokinetics of 
faricimab administered by IVT injection at 4-week intervals until Week 24, followed by a 
double-masked period of study without active control to evaluate faricimab administered 
according to a PTI dosing regimen in patients with macular edema due to BRVO. 
This study is comprised of two parts:  Part 1 (Day 1 through Week 24) will compare faricimab 
Q4W versus aflibercept (active comparator) Q4W; Part 2 (Weeks 2472) will evaluate faricimab 
administered at masked treatment intervals of Q4W to Q16W based on PTI dosing criteria. 
The study will consist of a screening period of up to 28 days (Days 28 to 1) and an 
approximately 68-week treatment period (Parts 1 and 2), followed by the final study visit at 
Week 72.  All patients will complete scheduled study visits Q4W for the entire study duration 
(72 weeks).  To preserve the masking of faricimab treatment intervals for Week 24 through 
Week 68, a sham procedure will be administered during study visits at which (according to the 
PTI dosing regimen) no faricimab treatment is administered. 
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the eye 
with the worse BCVA, as assessed at screening, will be selected as the study eye, unless the 
investigator deems the other eye to be more appropriate for treatment in the study.  
There will be a minimum of two investigators per site to fulfill the masking requirements of the 
study.  At least one investigator will be designated as the assessor physician who will be 
masked to each patient’s treatment assignment and who will evaluate ocular assessments.  At 
least one other investigator will be unmasked and will perform study treatments.  
Patient recruitment is expected to take longer in China; therefore, a specific China enrollment 
plan may be established.  After the global enrollment phase of the study has been completed, 
additional patients may be enrolled in a China extension to ensure a total enrollment that is 
sufficient to support registration in China.  The China extension may include current residents of 
mainland China, Hong Kong, or Taiwan enrolled at National Medical Products Administration 
(NMPA)-recognized sites.  All Chinese patients enrolled in the global enrollment phase of the 
study will be included in the primary analysis of the study.  Data from patients enrolled during 
the China extension will not be included in the primary analyses. 
NUMBER OF PATIENTS 
Approximately 570 patients with macular edema due to BRVO will be enrolled during the global 
enrollment phase of this study. 
TARGET POPULATION 
INCLUSION CRITERIA 
General Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below: 


 
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Women must remain abstinent or use contraceptive methods with a failure rate of  1% 
per year during the treatment period and for 3 months after the final dose of study 
treatment.  Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
For patients enrolled in the extended China enrollment phase at NMPA-recognized sites:  
current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry 
Ocular Inclusion Criteria for Study Eye 
Patients must also meet the following ocular criteria for study entry: 
 
Foveal center–involved macular edema due to BRVO diagnosed no longer than 4 months 
prior to the screening visit and confirmed by central reading center (CRC) based on SDOCT 
(or SS-OCT) images 
BRVO is defined by retinal hemorrhages, telangiectatic capillary bed, dilated venous 
system or other biomicroscopic evidence of retinal vein occlusion (RVO; 
neovascularization, vitreous hemorrhages) in one quadrant or less of the retina drained 
by the affected vein 
 
BCVA of 73 to 19 letters, inclusive (20/40 to 20/400 approximate Snellen equivalent), as 
assessed on the ETDRS visual acuity chart at a starting test distance of 4 meters (see the 
BCVA manual for additional details) on Day 1 
 
CST 325 m, as measured on Spectralis SD-OCT, or 315 m, as measured on Cirrus 
SD-OCT or Topcon SD-OCT at screening (SS-OCT acceptable after confirmation with 
CRC) 
 
Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis 
EXCLUSION CRITERIA 
General Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Any major illness or major surgical procedure within 1 month before screening 
 
Active cancer within the 12 months prior to Day 1 except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with 
a Gleason score of  6 and a stable prostate-specific antigen for  12 months 
 
Requirement for continuous use of any medications and treatments indicated in 
Section 4.4.2 (Prohibited Therapy) 
 
Systemic treatment for suspected or active systemic infection on Day 1 
Ongoing use of prophylactic antibiotic therapy may be acceptable if approved after 
discussion with the Medical Monitor. 
 
Any systemic corticosteroid use (e.g., oral or injectable) within 1 month of the screening visit 


 
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 
Uncontrolled blood pressure, defined as systolic blood pressure  180 mmHg and/or 
diastolic blood pressure  110 mmHg while a patient is at rest on Day 1 
If a patient’s initial reading exceeds these values, a second reading may be taken later 
on the same day or on another day during the screening period.  If the patient’s blood 
pressure is controlled by antihypertensive medication, the patient should be taking the 
same medication continuously for at least 30 days prior to Day 1. 
 
Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to Day 1 
 
History of other disease, metabolic dysfunction, physical examination finding, or historical or 
current clinical laboratory findings giving reasonable suspicion of a condition that 
contraindicates the use of the investigational drug or that might affect interpretation of the 
results of the study or renders the patient at high risk for treatment complications in the 
opinion of the investigator 
 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative urine pregnancy test result 
within 28 days prior to initiation of study drug.  If the urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the faricimab or aflibercept injections, study- related 
procedure preparations (including fluorescein), dilating drops, or any of the anesthetic and 
antimicrobial preparations used during the study 
 
Participation in an investigational trial that involves treatment with any drug or device (with 
the exception of vitamins and minerals) within 3 months prior to Day 1 
Ocular Exclusion Criteria for Study Eye 
Patients who meet any of the following ocular exclusion criteria for the study eye will be 
excluded from study entry: 
 
History of previous episodes of macular edema due to RVO or persistent macular edema 
due to RVO diagnosed more than 4 months before screening 
 
Increase of  10 letters in BCVA ETDRS score between screening and Day 1 
 
Any current ocular condition which, in the opinion of the investigator, is currently causing or 
could be expected to contribute to irreversible vision loss due to a cause other than macular 
edema due to RVO in the study eye (e.g., ischemic maculopathy, Irvine-Gass 
syndrome, foveal atrophy, foveal fibrosis, pigment abnormalities, dense subfoveal hard 
exudates, or other non-retinal conditions) 
 
Current visually significant vitreous hemorrhage on Day 1 
 
History of retinal detachment or macular hole (Stage 3 or 4) 
 
Tractional retinal detachment, vitreomacular traction, full thickness macular hole or 
epiretinal membrane involving the fovea or disrupting the macular architecture in the study 
eye, as evaluated by the CRC and described in the CRC manual 
 
Diagnosis of diabetic retinopathy (DR) moderate non-proliferative or worse, proliferative DR, 
diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), 
geographic atrophy, myopic choroidal neovascularization as assessed by the investigator 
 
Active rubeosis, angle neovascularization, neovascular glaucoma 
 
Aphakia or implantation of anterior chamber intraocular lens 
 
Any cataract surgery or treatment for complications of cataract surgery with steroids or YAG 
(yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1 
 
Any other intraocular surgery (e.g., pars plana vitrectomy, scleral buckle, glaucoma surgery, 
corneal transplant, or radiotherapy) 
 
Any prior or current treatment for macular edema due to RVO, including antivascular 
endothelial growth factor (VEGF) IVT for macular edema due to RVO 
 
Macular laser (focal/grid) in the study eye at any time prior to Day 1 


 
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 
Panretinal photocoagulation in the study eye within 3 months prior to Day 1 or anticipated 
within 3 months of study start on Day 1 
 
Any IVT treatment for any other retinal diseases that can lead to macular edema 
complication 
 
Any prior or current treatment for macular edema; macular neovascularization, including 
DME and nAMD; and vitreomacular-interface abnormalities, including, but not restricted to, 
IVT treatment with anti-VEGF, steroids, tissue plasminogen activator, ocriplasmin, C3F8, air 
or periocular injection 
 
Any prior intervention with verteporfin photodynamic therapy, diode laser, transpupillary 
thermotherapy, or vitreo-retinal surgery including sheathotomy 
 
Any prior steroid implant use including dexamethasone intravitreal implant (Ozurdex) and 
fluocinolone acetonide intravitreal implant (Iluvien) 
 
Prior periocular pharmacological or IVT treatment (including anti-VEGF medication) for 
other retinal diseases 
Ocular Exclusion Criteria for Fellow (Non-Study) Eye 
Patients who meet the following ocular exclusion criterion for the fellow (non-study) eye at both 
screening and Day 1 will be excluded from study entry: 
 
Non-functioning fellow eye, defined as either one of the following: 
BCVA 20/320 or worse 
No physical presence of fellow eye (i.e., monocular) 
Ocular Exclusion Criteria for Both Eyes 
Patients who meet any of the following ocular exclusion criteria for both eyes will be excluded 
from study entry: 
 
Prior IVT administration of faricimab in either eye 
 
History of idiopathic or autoimmune-associated uveitis in either eye 
 
Active periocular, ocular or intraocular inflammation or infection (including suspected) in 
either eye on Day 1 
END OF STUDY 
The study consists of two enrollment phases:  the global enrollment phase, during which 
patients are recruited globally; and an optional China extension phase, during which additional 
patients may be recruited in China to support registration in China. 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
including patients from the optional China extension.  The end of the study is expected to occur 
approximately 72 weeks after the last patient is randomized. 
The Sponsor may decide to terminate the study at any time. 
LENGTH OF STUDY 
The total length of the study (excluding the China extension) from screening of the first patient 
to the LPLV for patients from the global enrollment phase is expected to be approximately 
34 months. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
In Part 1 of the study, patients randomly assigned to Arm A will receive faricimab 6 mg IVT 
Q4W from Day 1 through Week 20, for a total of 6 injections. 
In Part 2 of the study, patients randomly assigned to both Arms A and B will receive 
faricimab 6 mg IVT administered according to a PTI dosing regimen in intervals between 
Q4W and Q16W.  At faricimab dosing visits, treatment intervals will be maintained or adjusted 
(i.e., increased by 4 weeks or decreased by 4, 8, or 12 weeks), based on CST and BCVA 
values.  Patients will therefore receive between 3 and 12 injections during the period from 
Week 24 through Week 68. 


 
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COMPARATOR 
In Part 1 of the study, patients randomly assigned to Arm B will receive aflibercept 2 mg IVT 
Q4W from Day 1 through Week 20, for a total of 6 injections. 
SHAM PROCEDURE 
During Part 2 of the study, to preserve the masking of faricimab treatment intervals, the sham 
procedure will be administered to patients in both Arms A and B during study visits at which 
(according to the PTI dosing regimen) no faricimab treatment is administered.  The sham vial is 
empty and will remain empty throughout the sham treatment.  The sham is a procedure that 
mimics an IVT injection and involves the blunt end of an empty syringe (without a needle) being 
pressed against the anesthetized eye. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary and secondary efficacy analyses will be based on the intent-to-treat (ITT 
population) population, unless otherwise specified, with patients grouped according to the 
treatment assigned at randomization.  Additional analysis based on the per-protocol population 
will also be conducted for the primary endpoint. 
The primary comparison will be between the active comparator (aflibercept Q4W) and faricimab 
Q4W at Week 24.  The following hypothesis will be tested: 
 
Non-inferiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population population (at a 1-sided 0.025 significance level) 
 
Superiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population population (at a 2-sided 0.05 significance level) 
The primary analysis will be performed using the mixed-effect model with repeated measures 
(MMRM) based on all available data up to Week 24.  All observed measurements will be 
included in the analysis regardless whether or not a patient has an intercurrent event.  Missing 
data will be implicitly imputed by the MMRM model, assuming a missing at random mechanism.  
The MMRM model will include the change from baseline at Weeks 424 as the response 
variable and will include the categorical covariates of treatment group, visit, visit-by-treatment 
group interaction, the continuous baseline value for the response variable (in this case, baseline 
BCVA), as well as randomization stratification factors as fixed effects.  The MMRM model will 
assume an unstructured covariance structure.  If there are convergence problems with the 
model, a heterogeneous compound symmetry or an AR(1) covariance structure may be fITT 
populationed. 
DETERMINATION OF SAMPLE SIZE  
Determination of sample size is based on patients enrolled in the global enrollment phase.  The 
global enrollment phase will enroll approximately 570 patients.  Patients will be randomized in a 
1:1 ratio to receive treatment with faricimab (Arm A) or aflibercept (Arm B). 
A sample size of approximately 285 patients in each arm will provide  90% power to show 
non-inferiority of faricimab to aflibercept in the change in BCVA at Week 24 in the ITT 
population population, using a non-inferiority margin of 4 letters, and under the following 
assumptions: 
 
No difference in the mean change from baseline in BCVA between the two treatment arms 
 
SD of 13 letters for the change from baseline in BCVA at Week 24 
 
Two-sample t-tests 
 
2.5% one-sided type I error rate 
 
10% dropout rate 
 
Furthermore, a sample size of approximately 285 patients per arm will provide greater than 
80% power to show a 3.5-letter superiority of faricimab over aflibercept in the ITT population 
population, under the same SD, test, and dropout assumptions above, and a two-sided type I 
error rate of 5%. 


 
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INTERIM ANALYSES 
There are no prospectively planned interim efficacy or futility analyses. 
 
 


 
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Appendix 2 Protocol Synopsis for Study COMINO (GR41986) 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATOR-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF FARICIMAB IN PATIENTS WITH 
MACULAR EDEMA SECONDARY TO CENTRAL RETINAL OR 
HEMIRETINAL VEIN OCCLUSION 
PROTOCOL NUMBER: 
GR41986 
STUDY NAME: 
COMINO 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2020-000441-13 
IND NUMBER: 
119225 
NCT NUMBER: 
To be determined  
TEST PRODUCT: 
Faricimab (RO6867461) 
PHASE: 
III 
INDICATION: 
Macular edema secondary to central retinal or hemiretinal vein 
occlusion 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of faricimab compared with 
aflibercept in patients with macular edema due to central retinal vein occlusion (CRVO) or 
hemiretinal vein occlusion (HRVO) up to the primary endpoint at Week 24.  Efficacy, safety, and 
pharmacokinetics of faricimab administered according to the personalized treatment interval 
(PTI) dosing regimen (i.e., from every 4 weeks [Q4W] to every 16 weeks [Q16W]) will be 
assessed during the study period from Weeks 24 to 72.  Specific objectives and corresponding 
endpoints for the study are outlined below. 
EFFICACY OBJECTIVES 
For efficacy endpoint evaluation, best-corrected visual acuity (BCVA) will be assessed on the 
Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart at a starting test 
distance of 4 meters. 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of faricimab 6 mg 
intravitreal (IVT) Q4W compared with aflibercept 2 mg IVT Q4W on the basis of the following 
endpoint: 
 
Change from baseline in BCVA at Week 24 
Secondary Efficacy Objectives 
The secondary efficacy objective for Part 1 of this study (i.e., through Week 24) is to evaluate 
the efficacy of faricimab compared with aflibercept on the basis of the following endpoints: 
 
Change from baseline in BCVA at specified timepoints through Week 24 
 
Proportion of patients gaining  15 letters in BCVA from baseline at Week 24 


 
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 
Proportion of patients gaining  15,  10,  5, or  0 letters in BCVA from baseline at 
specified timepoints through Week 24 
 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from baseline 
at specified timepoints through Week 24 
 
Proportion of patients achieving  84 letters (20/20 Snellen equivalent) in BCVA at specified 
timepoints through Week 24 
 
Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints through Week 24 
 
Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints through Week 24 
 
Change from baseline in central subfield thickness (CST) at specified timepoints through 
Week 24 
 
Change from baseline in National Eye Institute 25Item Visual Functioning Questionnaire 
(NEI VFQ-25) composite score at specified timepoints through Week 24 
The secondary efficacy objective for Part 2 of this study (i.e., Week 24 through Week 72) is to 
evaluate the efficacy of faricimab administered according to the PTI dosing regimen on the 
basis of the following endpoints: 
 
Change from baseline in BCVA at specified timepoints from Week 24 through Week 72 
 
Proportion of patients gaining  15 letters in BCVA from baseline at Week 72 
 
Proportion of patients gaining  15,  10,  5, or  0 letters in BCVA from baseline at 
specified timepoints from Week 24 through Week 72 
 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from baseline 
at specified timepoints from Week 24 through Week 72 
 
Proportion of patients achieving  84 letters (20/20 Snellen equivalent) in BCVA at specified 
timepoints from Week 24 through Week 72 
 
Proportion of patients with BCVA Snellen equivalent of 20/40 or better at specified 
timepoints from Week 24 through Week 72 
 
Proportion of patients with BCVA Snellen equivalent of 20/200 or worse at specified 
timepoints from Week 24 through Week 72 
 
Change from Week 24 in BCVA at specified timepoints through Week 72 
 
Proportion of patients avoiding a loss of  15,  10  5, or  0 letters in BCVA from Week 24 
through Week 72 
 
Proportion of patients on a Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W), or Q16W 
treatment interval at Week 72 
 
Number of study drug injections received from Week 24 through Week 72 
 
Change from baseline in CST at specified timepoints from Week 24 through Week 72 
 
Change from baseline in NEI VFQ-25 composite score at specified timepoints from Week 
24 through Week 72 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective for this study is to evaluate the efficacy of faricimab on the 
basis of the following endpoints: 
 
Proportion of patients with absence of retinal ischemia on fundus fluorescein angiography 
(FFA) and on optical coherence tomography angiography (OCT-A) (optional) over time (at 
specified timepoints) 
 
Change from baseline in area of retinal ischemia on FFA and on OCT-A (optional) over time 
 
Proportion of patients with vascular leakage on FFA and on OCT-A (optional) over time 
 
Change from baseline in area of vascular leakage on FFA, and on OCT-A (optional) over 
time 


 
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 
Change from baseline in foveal avascular zone and other exploratory outputs defined in the 
Statistical Analysis Plan (SAP) on OCT-A (optional) over time 
 
Proportion of patients with absence of retinal neovascularization over time (per investigator 
assessment) 
 
Proportion of patients with absence of vitreal, preretinal, or subretinal hemorrhage over time 
(per investigator assessment) 
 
Proportion of patients with absence of anterior segment (iris and anterior chamber angle) 
neovascularization over time 
 
Proportion of patients requiring panretinal photocoagulation at any time during the study 
 
Proportion of patients with absence of macular edema, defined as CST of  325 m for 
Spectralis spectral-domain optical coherence tomography (SD-OCT), or  315 m for Cirrus 
SD-OCT or Topcon SD-OCT, over time 
 
Proportion of patients with absence of intraretinal fluid over time 
 
Proportion of patients with absence of subretinal fluid over time 
 
Proportion of patients with absence of both intraretinal fluid and subretinal fluid over time 
 
Proportion of patients with absence of intraretinal cysts over time 
 
Change from baseline in NEI VFQ-25 near activitiessubscale score and distance 
activitiessubscale scores over time 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of faricimab on the 
basis of the following endpoints: 
 
Incidence and severity of ocular adverse events, with severity determined according to 
Adverse Event Severity Grading Scale 
 
Incidence and severity of non-ocular adverse events, with severity determined according to 
Adverse Event Severity Grading Scale 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective for this study is to characterize the faricimab PK profile on 
the basis of the following endpoint: 
 
Plasma concentration of faricimab over time 
The exploratory PK objective for this study is to explore the concentrationeffect relationship for 
visual acuity and other endpoints (e.g., anatomic measures) on the basis of the following 
endpoint: 
 
Concentration of faricimab and the change in BCVA or other endpoints (e.g., anatomical 
markers) over time 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the antibody immune response to 
faricimab on the basis of the following endpoint: 
 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the 
study 
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
EXPLORATORY BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to faricimab (i.e., predictive biomarkers), are associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of faricimab activity (i.e., 
pharmacodynamic [PD] biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints: 


 
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 
Relationship between biomarkers in plasma (listed in Section 4.5.7) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 
 
Relationship between baseline anatomic measures and the change in BCVA or other 
endpoints (e.g., the frequency of faricimab administration) over time 
 
Relationship between anatomic measures and visual acuity 
EXPLORATORY SUBSTUDY 
At selected sites, the Sponsor may propose exploratory substudies associated with the Study 
GR41986 protocol.  Each substudy will be documented in a separate substudy protocol and will 
have a separate associated Informed Consent Form. 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a Phase III, multicenter, randomized, double-masked, active comparatorcontrolled, 
parallel-group study evaluating the efficacy, safety, and pharmacokinetics of 
faricimab administered by IVT injection at 4-week intervals until Week 24, followed by a 
double-masked period of study without active control to evaluate faricimab administered 
according to a PTI dosing regimen in patients with macular edema due to CRVO or HRVO. 
This study is comprised of two parts:  Part 1 (Day 1 through Week 24) will compare faricimab 
Q4W versus aflibercept (active comparator) Q4W; Part 2 (Weeks 2472) will evaluate faricimab 
administered at masked treatment intervals of Q4W to Q16W based on PTI dosing criteria. 
The study will consist of a screening period of up to 28 days (Days 28 to 1) and an 
approximately 68-week treatment period (Parts 1 and 2), followed by the final study visit at 
Week 72.  All patients will complete scheduled study visits Q4W for the entire study duration 
(72 weeks).  To preserve the masking of faricimab treatment intervals for Week 24 through 
Week 68, a sham procedure will be administered during study visits at which (according to the 
PTI dosing regimen) no faricimab treatment is administered. 
Only one eye will be assigned as the study eye.  If both eyes are considered eligible, the eye 
with the worse BCVA, as assessed at screening, will be selected as the study eye, unless the 
investigator deems the other eye to be more appropriate for treatment in the study.  
There will be a minimum of two investigators per site to fulfill the masking requirements of the 
study.  At least one investigator will be designated as the assessor physician who will be 
masked to each patient’s treatment assignment and who will evaluate ocular assessments.  At 
least one other investigator will be unmasked and will perform study treatments.  
Patient recruitment is expected to take longer in China; therefore, a specific China enrollment 
plan may be established.  After the global enrollment phase of the study has been completed, 
additional patients may be enrolled in a China extension to ensure a total enrollment that is 
sufficient to support registration in China.  The China extension may include current residents of 
mainland China, Hong Kong, or Taiwan enrolled at National Medical Products Administration 
(NMPA)-recognized sites.  All Chinese patients enrolled in the global enrollment phase of the 
study will be included in the primary analysis of the study.  Data from patients enrolled during 
the China extension will not be included in the primary analyses. 
NUMBER OF PATIENTS 
Approximately 750 patients with macular edema due to CRVO or HRVO will be enrolled during 
the global enrollment phase of this study. 
TARGET POPULATION 
INCLUSION CRITERIA 
General Inclusion Criteria 
 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol 


 
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 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of  1% 
per year during the treatment period and for 3 months after the final dose of study 
treatment.  Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
For patients enrolled in the extended China enrollment phase at NMPA-recognized sites:  
current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry 
Ocular Inclusion Criteria for Study Eye 
 
Patients must also meet the following ocular criteria for study entry: 
 
Foveal center–involved macular edema due to CRVO or HRVO diagnosed no longer than 
4 months prior to the screening visit and confirmed by central reading center (CRC) based 
on SD-OCT (or SS-OCT) images 
CRVO or HRVO is defined by retinal hemorrhages, telangiectatic capillary bed, dilated 
venous system or other biomicroscopic evidence of retinal vein occlusion (RVO; 
neovascularization, vitreous hemorrhages) in the entire retina (CRVO) or two 
quadrants of the retina (HRVO) 
 
BCVA of 73 to 19 letters, inclusive (20/40 to 20/400 approximate Snellen equivalent), as 
assessed on the ETDRS visual acuity chart at a starting test distance of 4 meters (see the 
BCVA manual for additional details) on Day 1 
 
CST 325 m, as measured on Spectralis SD-OCT, or 315 m, as measured on Cirrus 
SD-OCT or Topcon SD-OCT at screening (SS-OCT acceptable after confirmation with 
CRC) 
 
Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis 
EXCLUSION CRITERIA 
General Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Any major illness or major surgical procedure within 1 month before screening 
 
Active cancer within the 12 months prior to Day 1 except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with 
a Gleason score of  6 and a stable prostate-specific antigen for  12 months 
 
Requirement for continuous use of any medications and treatments indicated in 
Section 4.4.2 (Prohibited Therapy) 
 
Systemic treatment for suspected or active systemic infection on Day 1 


 
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Ongoing use of prophylactic antibiotic therapy may be acceptable if approved after 
discussion with the Medical Monitor. 
 
Any systemic corticosteroid use (e.g., oral or injectable) within 1 month of the screening visit 
 
Uncontrolled blood pressure, defined as systolic blood pressure  180 mmHg and/or 
diastolic blood pressure  110 mmHg while a patient is at rest on Day 1 
If a patient’s initial reading exceeds these values, a second reading may be taken later 
on the same day or on another day during the screening period.  If the patient’s blood 
pressure is controlled by antihypertensive medication, the patient should be taking the 
same medication continuously for at least 30 days prior to Day 1. 
 
Stroke (cerebral vascular accident) or myocardial infarction within 6 months prior to Day 1 
 
History of other disease, metabolic dysfunction, physical examination finding, or historical or 
current clinical laboratory findings giving reasonable suspicion of a condition that 
contraindicates the use of the investigational drug or that might affect interpretation of the 
results of the study or renders the patient at high risk for treatment complications in the 
opinion of the investigator 
 
Pregnant or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative urine pregnancy test result 
within 28 days prior to initiation of study drug.  If the urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the faricimab or aflibercept injections, study- related 
procedure preparations (including fluorescein), dilating drops, or any of the anesthetic and 
antimicrobial preparations used during the study 
 
Participation in an investigational trial that involves treatment with any drug or device (with 
the exception of vitamins and minerals) within 3 months prior to Day 1 
Ocular Exclusion Criteria for Study Eye 
Patients who meet any of the following ocular exclusion criteria for the study eye will be 
excluded from study entry: 
 
History of previous episodes of macular edema due to RVO or persistent macular edema 
due to RVO diagnosed more than 4 months before screening 
 
Increase of  10 letters in BCVA ETDRS score between screening and Day 1 
 
Any current ocular condition which, in the opinion of the investigator, is currently causing or 
could be expected to contribute to irreversible vision loss due to a cause other than macular 
edema due to RVO in the study eye (e.g., ischemic maculopathy, Irvine-Gass 
syndrome, foveal atrophy, foveal fibrosis, pigment abnormalities, dense subfoveal hard 
exudates, or other non-retinal conditions) 
 
Current visually significant vitreous hemorrhage on Day 1 
 
History of retinal detachment or macular hole (Stage 3 or 4) 
 
Tractional retinal detachment, vitreomacular traction, full thickness macular hole or 
epiretinal membrane involving the fovea or disrupting the macular architecture in the study 
eye, as evaluated by the CRC and described in the CRC manual 
 
Diagnosis of diabetic retinopathy (DR) moderate non-proliferative or worse, proliferative DR, 
diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), 
geographic atrophy, myopic choroidal neovascularization as assessed by the investigator 
 
Active rubeosis, angle neovascularization, neovascular glaucoma 
 
Aphakia or implantation of anterior chamber intraocular lens 
 
Any cataract surgery or treatment for complications of cataract surgery with steroids or YAG 
(yttrium-aluminum-garnet) laser capsulotomy within 3 months prior to Day 1 
 
Any other intraocular surgery (e.g., pars plana vitrectomy, scleral buckle, glaucoma surgery, 
corneal transplant, or radiotherapy) 


 
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 
Any prior or current treatment for macular edema due to RVO, including antivascular 
endothelial growth factor (VEGF) IVT for macular edema due to RVO 
 
Macular laser (focal/grid) in the study eye at any time prior to Day 1 
 
Panretinal photocoagulation in the study eye within 3 months prior to Day 1 or anticipated 
within 3 months of study start on Day 1 
 
Any IVT treatment for any other retinal diseases that can lead to macular edema 
complication 
 
Any prior or current treatment for macular edema; macular neovascularization, including 
DME and nAMD; and vitreomacular-interface abnormalities, including, but not restricted to, 
IVT treatment with anti-VEGF, steroids, tissue plasminogen activator, ocriplasmin, C3F8, air 
or periocular injection 
 
Any prior intervention with verteporfin photodynamic therapy, diode laser, transpupillary 
thermotherapy, or vitreo-retinal surgery including sheathotomy 
 
Any prior steroid implant use including dexamethasone intravitreal implant (Ozurdex) and 
fluocinolone acetonide intravitreal implant (Iluvien) 
 
Prior periocular pharmacological or IVT treatment (including anti-VEGF medication) for 
other retinal diseases 
Ocular Exclusion Criteria for Fellow (Non-Study) Eye 
Patients who meet the following ocular exclusion criterion for the fellow (non-study) eye at both 
screening and Day 1 will be excluded from study entry: 
 
Non-functioning fellow eye, defined as either one of the following: 
BCVA 20/320 or worse 
No physical presence of fellow eye (i.e., monocular) 
Ocular Exclusion Criteria for Both Eyes 
Patients who meet any of the following ocular exclusion criteria for both eyes will be excluded 
from study entry: 
 
Prior IVT administration of faricimab in either eye 
 
History of idiopathic or autoimmune-associated uveitis in either eye 
 
Active periocular, ocular or intraocular inflammation or infection (including suspected) in 
either eye on Day 1 
END OF STUDY 
The study consists of two enrollment phases:  the global enrollment phase, during which 
patients are recruited globally; and an optional China extension phase, during which additional 
patients may be recruited in China to support registration in China. 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
including patients from the optional China extension.  The end of the study is expected to occur 
approximately 72 weeks after the last patient is randomized. 
The Sponsor may decide to terminate the study at any time. 
LENGTH OF STUDY 
The total length of the study (excluding the China extension) from screening of the first patient 
to the LPLV for patients from the global enrollment phase is expected to be approximately 
34 months. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
In Part 1 of the study, patients randomly assigned to Arm A will receive faricimab 6 mg IVT 
Q4W from Day 1 through Week 20, for a total of 6 injections. 
In Part 2 of the study, patients randomly assigned to both Arms A and B will receive 
faricimab 6 mg IVT administered according to a PTI dosing regimen in intervals between 
Q4W and Q16W.  At faricimab dosing visits, treatment intervals will be maintained or adjusted 


 
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(i.e., increased by 4 weeks or decreased by 4, 8, or 12 weeks), based on CST and BCVA 
values.  Patients will therefore receive between 3 and 12 injections during the period from 
Week 24 through Week 68. 
COMPARATOR 
In Part 1 of the study, patients randomly assigned to Arm B will receive aflibercept 2 mg IVT 
Q4W from Day 1 through Week 20, for a total of 6 injections. 
SHAM PROCEDURE 
During Part 2 of the study, to preserve the masking of faricimab treatment intervals, the sham 
procedure will be administered to patients in both Arms A and B during study visits at which 
(according to the PTI dosing regimen) no faricimab treatment is administered.  The sham vial is 
empty and will remain empty throughout the sham treatment.  The sham is a procedure that 
mimics an IVT injection and involves the blunt end of an empty syringe (without a needle) being 
pressed against the anesthetized eye. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary and secondary efficacy analyses will be based on the intent-to-treat (ITT 
population) population, unless otherwise specified, with patients grouped according to the 
treatment assigned at randomization.  Additional analysis based on the per-protocol population 
will also be conducted for the primary endpoint. 
The primary comparison will be between the active comparator (aflibercept Q4W) and faricimab 
Q4W at Week 24.  The following hypothesis will be tested: 
 
Non-inferiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population population (at a 1-sided 0.025 significance level) 
 
Superiority of faricimab Q4W compared with aflibercept Q4W at Week 24 in the ITT 
population population (at a 2-sided 0.05 significance level) 
The primary analysis will be performed using the mixed-effect model with repeated measures 
(MMRM) based on all available data up to Week 24.  All observed measurements will be 
included in the analysis regardless whether or not a patient has an intercurrent event.  Missing 
data will be implicitly imputed by the MMRM model, assuming a missing at random mechanism.  
The MMRM model will include the change from baseline at Weeks 424 as the response 
variable and will include the categorical covariates of treatment group, visit, visit-by-treatment 
group interaction, the continuous baseline value for the response variable (in this case, baseline 
BCVA), as well as randomization stratification factors as fixed effects.  The MMRM model will 
assume an unstructured covariance structure.  If there are convergence problems with the 
model, a heterogeneous compound symmetry or an AR(1) covariance structure may be fITT 
populationed. 
DETERMINATION OF SAMPLE SIZE  
Determination of sample size is based on patients enrolled in the global enrollment phase.  The 
global enrollment phase will enroll approximately 750 patients.  Patients will be randomized in a 
1:1 ratio to receive treatment with faricimab (Arm A) or aflibercept (Arm B). 
A sample size of approximately 375 patients in each arm will provide  90% power to show 
non-inferiority of faricimab to aflibercept in the change in BCVA at Week 24 in the ITT 
population population, using a non-inferiority margin of 4 letters, and under the following 
assumptions: 
 
No difference in the mean change from baseline in BCVA between the two treatment arms 
 
SD of 13 letters for the change from baseline in BCVA at Week 24 
 
Two-sample t-tests 
 
2.5% one-sided type I error rate 
 
10% dropout rate 
 


 
Faricimab —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GR41984 and GR41986, version 1 
66 
 
Furthermore, a sample size of approximately 375 patients per arm will provide greater than 
80% power to show a 3.5-letter superiority of faricimab over aflibercept in the ITT population 
population, under the same SD, test, and dropout assumptions above, and a two-sided type I 
error rate of 5%. 
INTERIM ANALYSES 
There are no prospectively planned interim efficacy or futility analyses. 


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