Conditions: Wet Macular Degeneration
Keywords: AMD nAMD neovascular age-related macular degeneration choroidal neovascularization secondary to age-related macular degeneration
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 671
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of faricimab administered at intervals as specified in the protocol, compared with aflibercept once every 8 weeks (Q8W), in participants with neovascular age-related macular degeneration (nAMD).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Faricimab intervention 2: Aflibercept intervention 3: Sham Procedure
Intervention descriptions: intervention 1: Faricimab will be administered by intravitreal injection into the study eye at intervals as specified in the study protocol. intervention 2: Aflibercept will be administered by intravitreal injection into the study eye once every 4 weeks for 3 consecutive months, followed by once every 8 weeks (Q8W). intervention 3: The sham is a procedure that mimics an intravitreal 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 document:
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 Neovascular Age-Related Macular 
Degeneration (TENAYA) 
NCT Number: 
NCT03823287 
Document Date: 
Protocol Version 3: 06-August-2019 


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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 GR40306, Version 3
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, ACTIVE 
COMPARATORCONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
FARICIMAB IN PATIENTS WITH NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION
(TENAYA)
PROTOCOL NUMBER:
GR40306
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-002152-32
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  20 November 2018
DATE AMENDED:
Version 2:  28 February 2019
Version 3:  See electronic date stamp below.
 
06-Aug-2019 18:44:20
Title
Approver's Name
Company Signatory
Date and Time (UTC)


 
Faricimab—F. Hoffmann-La Roche Ltd 
2/Protocol GR40844, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol GR40306 Version 2 has been amended for the following reasons: 
 
The primary Medical Monitor name has been updated to 
, M.D. 
(protocol cover page, acceptance form, Section 5.4.1). 
 
The criteria for the extension of the drug-dosing interval during the personalized 
treatment interval (PTI) phase has been changed from a qualitative assessment of 
the presence of fluid to a quantitative assessment of central subfield thickness (CST) 
stability (Section 3.1.1.5, Table 2). 
 
The study-eye inclusion criteria have been amended to include patients with 
extrafoveal choroidal neovascular membranes (CNV) with a subfoveal component, 
secondary to neovascular age-related macular degeneration (nAMD; Section 4.1.1.2) 
 
To ensure appropriate patient representation, the Sponsor may elect to cap the 
recruitment of patients in certain baseline BCVA strata.  If implemented, details of 
the cap will be described in the Statistical Analysis Plan (Section 4.1, 
Section 4.1.1.2, Section 6.1).  
 
Reporting of medication errors and associated adverse event in Section 5.4.4 has 
been updated and moved to Section 5.3.5.12.  Medication errors will no longer be 
reported expeditiously (within 24 hours), unless they cause a serious adverse event 
or adverse event of special interest (Section 5.3.5.12).  
 
 
In addition, the following clarifications have been made: 
 
Section 3.1.1.1:  This section, Screening, has been updated to improve readability 
and to clarify the process for combined screening and Day 1 visits. 
 
Section 3.1.2:  Clarification on handling missed visits has been added. 
 
 
Section 4.4.2:  Clarification of the permitted therapies for fellow eye anti-VEGF 
treatment has been made. 
 
Section 4.2.2.2:  Clarification of the minimum experience required for a non-retinal 
specialist to be approved as an unmasked treatment administrator has been made; 
it also clarifies that the unmasked physician assistant may prepare the eye for IVT 
administration. 
 
Section 4.1.2.3:  Clarification was added that the study ocular-exclusion criteria for 
the fellow eye pertains to both the screening and Day 1 visits. 


 
Faricimab—F. Hoffmann-La Roche Ltd 
3/Protocol GR40844, Version 3 
 
Section 4.5.7:  Clarification has been made that leftover samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed. 
 
Section 4.5.7.1:  The section has been modified to improve content flow and 
readability. 
 
As applicable throughout the protocol, the term "free" was added before VEGF-A 
and Ang-2 to more accurately describe what the assays are measuring and to be 
consistent with the other sections of the protocol.  
 
Section 4.5.9.6:  Language has been added to clarify that, after withdrawal of 
consent for participation in the Research Biosample Repository (RBR), remaining 
RBR samples will be destroyed or will no longer be linked to the patient.  Details 
regarding instruction for patient withdrawal of consent to the testing of his or her 
RBR samples after closure of the site has been added. 
 
Appendix 1, Schedule of Activities (SoA):  Clarification was added in the footnotes of 
the SoA that, if taken sequentially, indocyanine green angiography (ICGA) should 
be performed after all other imaging has been performed, but that if the site’s 
standard of practice is to perform ICGA in parallel with fundus fluorescein 
angiography (FFA), this is also acceptable. 
 
Section 4.5.5:  The section has been updated to advise sites that ultra-wide field 
photography is not permitted. 




Faricimab—F. Hoffmann-La Roche Ltd
5/Protocol GR40306, Version 3
3.1.5
Independent Data Monitoring Committee .............................. 46
3.2
End of Study and Length of Study......................................... 46
3.3
Rationale for Study Design.................................................... 47
3.3.1
Rationale for Faricimab Dose ................................................ 47
3.3.2
Rationale for Faricimab Schedule.......................................... 48
3.3.3
Rationale for Aflibercept Dose and Schedule ........................ 49
3.3.4
Rationale for Biomarker Assessments................................... 49
3.3.5
Rationale for Optional Aqueous Humor Samples .................. 50
3.3.6
Rationale for Control Group................................................... 50
4.
MATERIALS AND METHODS .................................................................... 50
4.1
Patients.................................................................................. 50
4.1.1
Inclusion Criteria.................................................................... 51
4.1.1.1
General Inclusion Criteria ...................................................... 51
4.1.1.2
Ocular Inclusion Criteria for Study Eye.................................. 52
4.1.2
Exclusion Criteria................................................................... 52
4.1.2.1
General Exclusion Criteria..................................................... 52
4.1.2.2
Ocular Exclusion Criteria for Study Eye................................. 53
4.1.2.3
Ocular Exclusion Criteria for Fellow 
(NonStudy) Eye ................................................................... 54
4.1.2.4
Exclusion Criteria for Both Eyes ............................................ 54
4.2
Method of Treatment Assignment and Masking .................... 54
4.2.1
Treatment Assignment........................................................... 54
4.2.2
Masking ................................................................................. 55
4.2.2.1
Masked Roles........................................................................ 55
4.2.2.2
Unmasked Roles ................................................................... 56
4.2.2.3
Delegation Log ...................................................................... 57
4.2.2.4
Role Switching....................................................................... 57
4.2.2.5
Study Backup Staff ................................................................ 57
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel ............................................................ 57
4.2.2.7
Patient Masking..................................................................... 58
4.2.3
Unmasking............................................................................. 58
4.2.3.1
Single-Patient Emergency Unmasking .................................. 58


Faricimab—F. Hoffmann-La Roche Ltd
6/Protocol GR40306, Version 3
4.2.3.2
Single-Patient Non-Emergency Unmasking........................... 58
4.2.3.3
Single-Patient Unmasking for Health Authority 
Reporting Requirements........................................................ 58
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 59
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 59
4.3.1.1
Faricimab, Aflibercept, and Sham.......................................... 59
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 60
4.3.2.1
Dosage .................................................................................. 60
4.3.2.2
Administration........................................................................ 61
4.3.2.3
Compliance............................................................................ 61
4.3.3
Investigational Medicinal Product Accountability ................... 61
4.3.4
Continued Access to Faricimab............................................. 62
4.4
Concomitant Therapy ............................................................ 62
4.4.1
Permitted Therapy................................................................. 63
4.4.2
Fellow (NonStudy) Eye Treatment with 
Anti-VEGF Therapy ............................................................... 63
4.4.3
Prohibited Therapy ................................................................ 64
4.5
Study Assessments ............................................................... 64
4.5.1
Informed Consent Forms and Screening Log........................ 64
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 65
4.5.3
Physical Examinations........................................................... 65
4.5.4
Vital Signs.............................................................................. 65
4.5.5
Ocular Assessments.............................................................. 66
4.5.6
Concurrent Ocular Procedures.............................................. 67
4.5.7
Laboratory, Biomarker, and Other 
Biological Samples ................................................................ 67
4.5.7.1
Optional Aqueous Humor and Optional Plasma 
Samples................................................................................. 68
4.5.7.2
Optional Unscheduled Collection of 
Vitreous Samples .................................................................. 69
4.5.8
Patient-Reported Outcomes .................................................. 69


Faricimab—F. Hoffmann-La Roche Ltd
7/Protocol GR40306, Version 3
4.5.9
Optional Samples for Research Biosample 
Repository ............................................................................. 70
4.5.9.1
Overview of the Research Biosample Repository.................. 70
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 70
4.5.9.3
Sample Collection.................................................................. 71
4.5.9.4
Confidentiality........................................................................ 71
4.5.9.5
Consent to Participate in the Research 
Biosample Repository............................................................ 72
4.5.9.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 72
4.5.9.7
Monitoring and Oversight....................................................... 73
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 73
4.6.1
Study Treatment Discontinuation........................................... 73
4.6.2
Patient Discontinuation from Study........................................ 73
4.6.3
Study Discontinuation............................................................ 74
4.6.4
Site Discontinuation............................................................... 74
5.
ASSESSMENT OF SAFETY....................................................................... 75
5.1
Safety Plan ............................................................................ 75
5.1.1
Safety Assessments .............................................................. 75
5.1.2
Risks Associated with Faricimab ........................................... 76
5.1.3
Risks Associated with the Comparator Aflibercept ................ 76
5.1.4
Management of Patients Who Experience 
Adverse Events ..................................................................... 76
5.1.4.1
Treatment Interruption: Dose Interruption and 
Treatment Discontinuation Criteria ........................................ 76
5.2
Safety Parameters and Definitions ........................................ 78
5.2.1
Adverse Events ..................................................................... 78
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 78
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 79
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 80
5.3.1
Adverse Event Reporting Period ........................................... 80


Faricimab—F. Hoffmann-La Roche Ltd
8/Protocol GR40306, Version 3
5.3.2
Eliciting Adverse Event Information....................................... 81
5.3.3
Assessment of Severity of Adverse Events ........................... 81
5.3.4
Assessment of Causality of Adverse Events ......................... 81
5.3.5
Procedures for Recording Adverse Events............................ 82
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 83
5.3.5.2
Adverse Events That Are Secondary to 
Other Events.......................................................................... 83
5.3.5.3
Persistent or Recurrent Adverse Events................................ 83
5.3.5.4
Abnormal Laboratory Values ................................................. 84
5.3.5.5
Abnormal Vital Sign Values ................................................... 84
5.3.5.6
Abnormal Liver Function Tests.............................................. 85
5.3.5.7
Deaths ................................................................................... 85
5.3.5.8
Preexisting Medical Conditions.............................................. 86
5.3.5.9
Worsening of Neovascular Age-Related Macular 
Degeneration in the Study Eye.............................................. 86
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 86
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 87
5.3.5.12
Reporting Requirements for Cases of Medication 
Error and Associated Adverse Events ................................... 87
5.3.5.13
Patient-Reported Outcome Data ........................................... 88
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 88
5.4.1
Emergency Medical Contacts................................................ 88
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 89
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 89
5.4.2.2
Events That Occur after Study Drug Initiation........................ 89
5.4.3
Reporting Requirements for Pregnancies.............................. 90
5.4.3.1
Pregnancies in Female Patients............................................ 90
5.4.3.2
Abortions ............................................................................... 90
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 90
5.5
Follow-Up of Patients after Adverse Events .......................... 91
5.5.1
Investigator Follow-Up........................................................... 91
5.5.2
Sponsor Follow-Up ................................................................ 91


Faricimab—F. Hoffmann-La Roche Ltd
9/Protocol GR40306, Version 3
5.6
Adverse Events That Occur after the 
Adverse Event Reporting Period ........................................... 91
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 91
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 92
6.1
Determination of Sample Size ............................................... 93
6.2
Analysis Populations ............................................................. 93
6.2.1
Intent-to-Treat Population...................................................... 94
6.2.2
Per-Protocol Population......................................................... 94
6.2.3
Safety-Evaluable Population.................................................. 94
6.2.4
Pharmacokinetic-Evaluable Population ................................. 94
6.2.5
Immunogenicity-Analysis Population..................................... 94
6.3
Summaries of Conduct of Study............................................ 94
6.4
Summaries of Treatment Group Comparability ..................... 94
6.5
Efficacy Analyses .................................................................. 95
6.5.1
Primary Efficacy Endpoint...................................................... 95
6.5.2
Secondary Efficacy Endpoints............................................... 97
6.5.3
Exploratory Efficacy Endpoints.............................................. 97
6.6
Safety Analyses..................................................................... 97
6.7
Pharmacokinetic Analyses..................................................... 98
6.8
Pharmacodynamic Analyses ................................................. 98
6.9
Immunogenicity Analyses...................................................... 99
6.10
Biomarker Analyses............................................................... 99
99
7.
DATA COLLECTION AND MANAGEMENT ............................................. 100
7.1
Data Quality Assurance....................................................... 100
7.2
Electronic Case Report Forms............................................. 100
7.3
Source Data Documentation................................................ 100
7.4
Use of Computerized Systems ............................................ 101
7.5
Retention of Records........................................................... 101
8.
ETHICAL CONSIDERATIONS.................................................................. 102
8.1
Compliance with Laws and Regulations .............................. 102


Faricimab—F. Hoffmann-La Roche Ltd
10/Protocol GR40306, Version 3
8.2
Informed Consent................................................................ 102
8.3
Institutional Review Board or Ethics Committee.................. 103
8.4
Confidentiality...................................................................... 103
8.5
Financial Disclosure ............................................................ 104
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 104
9.1
Study Documentation .......................................................... 104
9.2
Protocol Deviations.............................................................. 105
9.3
Site Inspections ................................................................... 105
9.4
Administrative Structure....................................................... 105
9.5
Dissemination of Data and Protection of 
Trade Secrets...................................................................... 105
9.6
Protocol Amendments ......................................................... 106
10. REFERENCES ......................................................................................... 107
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 35
Table 2
Personalized Treatment Interval Algorithm ................................. 43
Table 3
Dose Interruption and Treatment Discontinuation Criteria .......... 77
Table 4
Adverse Event Severity Grading Scale ....................................... 81
Table 5
Causal Attribution Guidance ....................................................... 82
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 39


Faricimab—F. Hoffmann-La Roche Ltd
11/Protocol GR40306, Version 3
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 111
Appendix 2
Unscheduled Safety Assessment Visit...................................... 121
Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells............................................................ 122
Appendix 4
Best-Corrected Visual Acuity Testing........................................ 124
Appendix 5
Low-Luminance Best-Corrected Visual Acuity Testing ............. 125
Appendix 6
Color Fundus Photography ....................................................... 126
Appendix 7
Fundus Fluorescein Angiography and Optional Indocyanine 
Green 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 Function Questionnaire .. 131


Faricimab—F. Hoffmann-La Roche Ltd
12/Protocol GR40306, Version 3
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 NEOVASCULAR 
AGE-RELATED MACULAR DEGENERATION
(TENAYA)
PROTOCOL NUMBER:
GR40306
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-002152-32
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local monitor.


Faricimab—F. Hoffmann-La Roche Ltd
13/Protocol GR40306, Version 3
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 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
(TENAYA)
PROTOCOL NUMBER:
GR40306
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-002152-32
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
PHASE:
Phase III
INDICATION:
Neovascular age-related macular degeneration
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of the 6-mg dose 
of faricimab administered at up to 16-week intervals compared with aflibercept monotherapy 
every 8 weeks (Q8W) in patients with choroidal neovascularization (CNV) secondary to 
age-related macular generation (AMD), also known as neovascular AMD (nAMD).  Specific 
objectives and corresponding endpoints for the study are outlined in the following table.  
In this protocol, study drug refers to faricimab or aflibercept and study treatment refers to 
faricimab, aflibercept, or the sham procedure.


Faricimab—F. Hoffmann-La Roche Ltd
14/Protocol GR40306, Version 3
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint

To evaluate the efficacy of IVT injections 
of the 6-mg dose of faricimab on BCVA 
outcomes compared with aflibercept 

Change from baseline in BCVA (as measured 
on the ETDRS chart at a starting distance of 
4 meters) based on an average at Weeks 40, 
44, and 48 
Secondary Efficacy Objectives
Corresponding Endpoints

To evaluate the efficacy of faricimab on 
additional BCVA outcomes 

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 loss of 15, 
105, or 0 letters in BCVA from baseline 
over time

Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time

Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time

Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time

To evaluate the frequency of study drug 
administration

Proportion of patients on a Q8W, Q12W, and 
Q16W treatment interval at Weeks 48, 60, 
and 112 

Number of study drug injections received 
through Weeks 48, 60, and 112 

To evaluate the efficacy of faricimab on 
anatomic outcome measures using OCT

Change from baseline in CST based on an 
average at Weeks 40, 44, and 48

Change from baseline in CST 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 
intraretinal and subretinal fluid over time

Proportion of patients with absence of 
intraretinal cysts over time

Proportion of patients with absence of pigment 
epithelial detachment over time 

To evaluate the efficacy of faricimab on 
anatomic outcome measures using FFA

Change from baseline in total area of CNV 
lesion at Week 48 and Week 112

Change from baseline in total area of CNV 
leakage at Week 48 and Week 112


Faricimab—F. Hoffmann-La Roche Ltd
15/Protocol GR40306, Version 3
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints

To evaluate the ocular and non-ocular 
safety and tolerability of faricimab

Incidence and severity of ocular adverse 
events

Incidence and severity of non-ocular 
adverse events
Exploratory Efficacy Objectives
Corresponding Endpoint

To evaluate the efficacy of faricimab on 
patient-reported vision-related functioning 
and quality of life using the NEI VFQ-25

Change from baseline in NEI VFQ-25 
composite score over time 
Pharmacokinetic Objectives
Corresponding Endpoints

To characterize the systemic 
pharmacokinetics of faricimab

Plasma concentration of faricimab over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response to 
faricimab

To evaluate potential effects of ADAs

Presence of ADAs during the study relative 
to the presence of ADAs at baseline

Relationship between ADA status and 
efficacy, safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints

To evaluate potential relationships 
between selected covariates and exposure 
to faricimab 

Relationship between selected covariates 
and plasma or aqueous humor (optional) 
concentration or PK parameters for 
faricimab

To evaluate the drug concentration 
(exposure)-effect relationship for free 
VEGF-A and free Ang-2 

To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of faricimab

Relationship between pharmacokinetics of 
faricimab and concentration of free VEGF-A 
and free Ang-2 in aqueous humor (optional), 
plasma, and/or vitreous (optional) over time

Aqueous humor (optional) and vitreous 
(optional) concentration of faricimab 
over time

To explore concentration-effect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers)

Pharmacokinetics of faricimab and the 
change in BCVA or other endpoints 
(e.g., anatomical markers) over time




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17/Protocol GR40306, Version 3
that visit and to continue with an every 12-week (Q12W) dosing regimen of faricimab.  
Patients receiving faricimab who do not have active disease according to the 
protocol-defined criteria at Week 20 and Week 24 will be treated with a Q16W dosing 
regimen of faricimab.  Patients will continue receiving faricimab on a fixed regimen every 8, 
12, or 16 weeks until Week 60 according to the disease activity assessments made at 
Weeks 20 and 24. 
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) onward, all 
patients in Arm A will be treated according to a personalized treatment interval (PTI) dosing 
regimen (up to Week 108). 

Arm B (comparator arm) (Q8W) (n320):  Patients randomized to Arm B will receive 2 mg 
of IVT aflibercept Q4W up to Week 8 (3 injections), followed by 2 mg of IVT aflibercept 
Q8W up to Week 108. 
Patients in both treatment arms will complete scheduled study visits Q4W for the entire study 
duration (112 weeks).  A sham procedure will be administered to patients in both treatment 
arms at study visits with no study treatment administration to maintain masking among 
treatment arms.
Only one eye will be assigned as the study eye.  If both eyes are considered eligible (per the 
inclusion and exclusion criteria), the eye with the worse best-corrected visual acuity (BCVA), as 
assessed at screening, will be selected as the study eye (unless based on medical reasons, 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. 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length and an 
approximately 108-week treatment period, followed by the final study visit at Week 112 (at least 
28 days after the last study treatment administration).  A unique screening number will be 
assigned to each screened patient through an interactive voice or web-based response system 
(IxRS).
Screening
Informed consent must be administered and signed by each patient 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.  
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 on the same day or within 2 business days.  
During screening, a patient’s eligibility will be assessed, including a central reading center 
review of color fundus photographs (CFPs), optical coherence tomography (OCT), and fundus 
fluorescein angiography (FFA), to ensure that CNV secondary to AMD meets the ocular criteria 
for the study.  
After screening and pre-treatment Day 1 assessments have been completed, eligible patients 
will have a randomization identification number assigned to them through the IxRS and will be 
randomized in a 1:1 ratio in order that approximately 320 patients are randomized to each of the 
two treatment arms.  Randomization will be stratified by baseline best-corrected visual acuity 
(BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score as assessed on 
Day 1 (74 letters, 7355 letters, and 54 letters), low-luminance deficit (LLD; 33 letters and 
33 letters), and region (United States and Canada, Asia, and the rest of the world).
Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which will be 
performed through the IxRS (i.e., at the Day 1 visit).  


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Note:  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 administration:  
urine pregnancy test (if appropriate), slitlamp examination, indirect ophthalmoscopy, and 
pre-treatment IOP measurements (recorded on the Day 1 eCRF and dated accordingly).
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger counting test and post-dose
IOP measurement).  Afterward, all study patients will have a safety assessment visit on 
Day 7 (3 days) evaluated by the masked investigator.  At subsequent scheduled visits, 
patients will have safety assessments evaluated by the masked investigator prior to receiving 
study treatment (for additional details about masking).  Study treatment administration and 
study-related assessments will occur Q4W (starting on Day 1), as outlined in the schedule of 
activities).  The sham procedure will be delivered to patients in all arms throughout the study as 
applicable.  
At Weeks 20 and 24, a protocol-defined assessment of disease activity performed for all 
patients in the study requires patients with active disease receiving faricimab (Arm A) to be 
treated with an 8 weekly or 12 weekly dosing regimen, respectively, until Week 60.  Patients 
receiving faricimab who do not have active disease according to the protocol-defined criteria will 
be treated with a 16 weekly dosing regimen until Week 60.
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) to Week 108, 
patients in Arm A will be treated according to a PTI dosing regimen (Q8W, Q12W, or Q16W).  
At study drug dosing visits treatment intervals may be maintained or adjusted (i.e., increased by 
4 weeks, or decreased by 4 or 8 weeks), based on OCT, BCVA, and clinical assessment.
Patients in Arm B will receive aflibercept Q4W up to Week 8, followed by Q8W up to Week 108. 
Patients will receive the assigned therapy up to and including Week 108 and return for a final 
visit at Week 112.  After the final visit, adverse events should be followed.  Assessments 
performed in case of an unscheduled safety visit(s) are at the discretion of the investigator.  
Patients who prematurely discontinue 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 40, 44, 48, 60, and 112 visits. 
Patients who wish to discontinue from the study prior to completion but have not withdrawn 
consent will be asked to return for an early termination visit after a minimum of 28 days have 
elapsed following their last study treatment for monitoring of adverse events and early 
termination visit assessments.
Weeks 20 and 24 Disease Activity Criteria
Determination of active disease at Weeks 20 and 24 will be made if any of the following criteria 
are met:

Increase 50 m in central subfield thickness (CST) compared with the average CST value
over the previous two scheduled visits (Weeks 12 and 16 for the Week 20 assessment and 
Weeks 16 and 20 for the Week 24 assessment)
Or

Increase 75 m in CST compared with the lowest CST value recorded at either of the 
previous two scheduled visits
Or

Decrease 5 letters in BCVA compared with average BCVA value over the previous two 
scheduled visits, owing to nAMD disease activity (as determined by the investigator)
Or

Decrease 10 letters in BCVA compared with the highest BCVA value recorded at either of 
the previous two scheduled visits, owing to nAMD disease activity (as determined by the 
investigator)
Or

Presence of new macular hemorrhage (as determined by the investigator), owing to nAMD 
activity


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Additional considerations at Week 24:  If there is significant nAMD disease activity at 
Week 24 that does not meet the criteria above, but which in the opinion of the investigator would 
otherwise warrant treatment, following Sponsor notification through the IxRS, patients 
randomized to Arm A will receive 6 mg of faricimab at Week 24 and will continue to receive 
repeated 12 weekly treatments.  Patients randomized to Arm A who meet the disease activity 
criteria at Week 20 will remain on their Q8W dosing schedule and will not receive treatment at
Week 24.  Patients randomized to Arm B will remain on their Q8W dosing schedule and will 
receive aflibercept at Week 24. 
Personalized Treatment Interval Disease Activity Criteria
Starting at Week 60, when all patients in Arm A are scheduled to receive faricimab, the study 
drug dosing interval for patients in Arm A will be extended, reduced, or maintained based on 
assessments made at study drug dosing visits.  Study drug dosing interval decisions during the 
PTI regimen phase for Arm A are automatically calculated by the IxRS based on the algorithm 
described in the following table.  The decision will be made based on data from visits at which 
patients received study drug.  Patients will receive a sham procedure at study visits when 
they are not receiving treatment with faricimab.
Personalized Treatment Interval Algorithm
Dosing Interval
Criteria
Interval extended by 4 weeks
(to a maximum of Q16W)
Stable CSTa compared with the average of the last 
2 study drug dosing visits, and no increase 50 m in 
CST (compared with the lowest on-study drug dosing 
visit measurement) and 
No decrease 5 letters in BCVA b compared with the 
average from the last two study drug dosing visits, and 
no decrease 10 letters in BCVA b compared with the 
highest on-study drug dosing visit measurement and 
No new macular hemorrhage c
Interval reduced (to a minimum 
Q8W)
If one of the criteria is met, the 
interval will be reduced by 
4 weeks.   If two or more criteria 
are met or one criterion includes 
new macular hemorrhage, the 
interval will be reduced to an 
8-week interval. d
Increase 50 m in CST compared with the average 
from the last two study drug dosing visits or 75 m 
compared with the lowest on-study drug dosing visit 
measurement or
Decrease 5 letters in BCVA b compared with average 
of last two study drug dosing visits or decrease 10 
letters in BCVA b compared with the highest on-study 
drug dosing visit measurement or
New macular hemorrhage c
Interval maintained
If extension or reduction criteria have not been met
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; nAMDneovascular 
age-related macular degeneration; Q8W every 8 weeks; Q16W every 16 weeks.
a Where stability is defined as a change of CST of less than 30 m.
b Change in BCVA should be attributable to nAMD disease activity (as determined by 
investigator).
c Refers to macular hemorrhage owing to nAMD activity (as determined by investigator).
d Patients whose treatment interval is reduced by 8 weeks from Q16W to Q8W will not be 
allowed to return to a Q16W interval during the study.


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Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study conduct on an 
ongoing basis throughout the study.  Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities.
The iDMC will meet approximately every 6 months (frequency adjustable as required) to 
evaluate unmasked ocular and non-ocular safety events, with emphasis on the evaluation of the 
rate of ocular inflammation, increased IOP, endophthalmitis, arterial thromboembolic events, 
and clinically significant decreases in BCVA, which will be prepared for the committee by an 
independent Data Coordinating Center.  The iDMC may recommend stopping the study early for 
safety reasons.
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.
Number of Patients
Approximately 640 patients will be enrolled at approximately 200 sites globally.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent  
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act authorization, and in other countries, as applicable according to 
national laws.

Age 50 years on Day 1

Ability to comply with the study protocol, in the investigator’s judgment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive measures that result in failure 
rate 1% per year during the treatment period and for at least 3 months after the final dose 
of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of acceptable contraceptive methods include bilateral tubal ligation, male 
sterilization; hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices; and copper intrauterine devices. 
Contraception methods that do not result in a failure rate of 1% per year such as male 
or female condom with or without spermicide; and cap, diaphragm, or sponge with 
spermicide are not acceptable.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception. 


 
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 
 
Ocular Inclusion Criteria for Study Eye 
Patients must meet the following ocular criteria for study entry: 
 
Treatment-naive CNV secondary to AMD (nAMD) 
 
Subfoveal CNV or juxtafoveal/extrafoveal CNV with a subfoveal component related to the 
CNV activity identified by FFA or OCT (where CNV activity is defined as showing 
evidence of subretinal fluid, subretinal hyper-reflective material, or leakage) 
 
CNV lesion of any type (i.e., predominantly classic, minimally classic, or occult [including 
polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) that exhibits all of 
the following characteristics: 
– 
A total lesion size (including blood, atrophy, fibrosis, and neovascularization) of 9 disc 
areas on FFA 
– 
A CNV component area of  50% of the total lesion size on FFA 
– 
Active CNV confirmed on FFA (evidence of leakage) 
– 
CNV exudation confirmed on OCT (presence of fluid) 
 
BCVA of 78 to 24 letters, inclusive (20/32 to 20/320 approximate Snellen equivalent), using 
the ETDRS protocol and assessed at the initial testing distance of 4 meters on Day 1 
 
Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
General Exclusion Criteria 
Patients who meet any of the following general exclusion 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 prohibited medications and treatments  
 
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 
 
Uncontrolled blood pressure, defined as systolic blood pressure  180 mmHg and/or 
diastolic blood pressure  100 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 
 
Pregnancy or breastfeeding, or intention 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 treatment.  If the urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 


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
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 by a patient 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:

CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, pathological 
myopia, angioid streaks, choroidal rupture, or uveitis 

Any history of macular pathology unrelated to AMD affecting vision or contributing to the 
presence of intraretinal or subretinal fluid  

Presence at screening of central serous chorioretinopathy 

Retinal pigment epithelial tear involving the macula on Day 1

On FFA/CFP: 
–
Subretinal hemorrhage of 50% of the total lesion area and/or that involves 
the fovea
–
Fibrosis or atrophy of 50% of the total lesion area and/or that involves the fovea

Any concurrent intraocular condition (e.g., amblyopia, aphakia, retinal detachment, cataract,
diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the 
opinion of the investigator, could either reduce the potential for visual improvement or 
require medical or surgical intervention during the study

Current vitreous hemorrhage on Day 1

Uncontrolled glaucoma 

Spherical equivalent of refractive error demonstrating more than 8 diopters of myopia 
For patients who have undergone prior refractive or cataract surgery, the preoperative 
refractive error should not have exceeded 8 diopters of myopia.

Any prior or concomitant treatment for CNV or vitreomacular-interface abnormalities, 
including, but not restricted to, IVT treatment (e.g., anti-vascular endothelial growth factor 
[VEGF], steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular 
pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic 
therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention

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, glaucoma surgery, corneal transplant, 
or radiotherapy)

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 exclusion criterion for the fellow eye (non-study eye) at both the   
screening and Day 1 visits will be excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of non-study eye (i.e., monocular)




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Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in BCVA averaged over Weeks 40, 
44, and 48.  The BCVA outcome measure is based on the ETDRS visual acuity chart assessed 
at a starting distance of 4 meters.
The primary comparison will be to test non-inferiority of faricimab compared with aflibercept in 
the intent-to-treat (ITT) population.  Additional analysis based on the per-protocol population will 
also be conducted.
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 averaged over Weeks 40, 44, and 48 
for the faricimab up to Q16W arm and the active comparator (aflibercept Q8W), respectively.  
The change from baseline averaged over Weeks 40, 44, and 48 will be compared between the 
faricimab up to Q16W arm and the aflibercept Q8W arm using a mixed model for repeated 
measures (MMRM).  The model will include the change from baseline at Weeks 448 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.  
Comparisons between the two treatment arms will be made using a composite contrast over 
Weeks 40, 44, and 48.  The MMRM model will assume an unstructured covariance structure.  
If there are convergence problems with the model, then a heterogeneous compound symmetry 
or an AR(1) covariance structure may be fitted.
Missing data will be implicitly imputed by the MMRM model, assuming a missing at random 
missing data mechanism (i.e., the probability that missing data are dependent on other 
observed variables but not on the missing data).  Data for patients who receive prohibited 
therapy will be censored at the timing of use of prohibited therapy.  Data for patients who 
discontinue from study drug and do not receive prohibited therapy after discontinuation of 
study drug will be included in the analysis.
Additional details about the planned analyses, as well as supplementary and sensitivity 
analyses using other imputation methods for missing data, analysis using the trimmed mean 
approach for patients who receive prohibited therapy or discontinue study drug due to lack of 
efficacy or adverse events, analyses of the per-protocol population, and subgroup analyses to 
assess the robustness of the primary endpoint results will be provided in the Statistical Analysis 
Plan.
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 640 patients. 
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 
Q8W) and the faricimab up to Q16W arm. 
A sample size of approximately 320 patients in each arm will provide greater than 90% power to 
show non-inferiority of faricimab to aflibercept in the change in BCVA averaged over Weeks 40, 
44, and 48 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 two treatment arms

Standard deviation (SD) of 14 letters for the change from baseline in BCVA averaged over 
Weeks 40, 44, and 48

Two-sample t-test

2.5% one-sided type I error rate

10% dropout rate


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To ensure appropriate patient representation, the Sponsor may elect to cap the recruitment of 
patients in certain baseline BCVA strata.  If implemented, details of the cap will be described 
in the Statistical Analysis Plan.
The sample size may be adjusted as appropriate based on a masked assessment of the pooled 
SD of the change in BCVA from baseline.  The assessment will be performed by the Sponsor at 
a specified timepoint prior to completing enrollment.  Details on the masked sample size 
re-estimation conducted, as well as actions and decisions taken regarding changes in sample 
size, will be documented in the Statistical Analysis Plan.  The Sponsor will remain masked.  
Other factors external to the study may also trigger a decision to modify the sample size. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AMD
age-related macular degeneration
Ang-2
angiopoietin-2 (protein)
Anti-VEGF
anti-vascular endothelial growth factor
BCVA
best-corrected visual acuity
CATT
Comparison of Age-Related Macular Degeneration Treatment 
Trials (Research Group)
CFP
color fundus photograph
CMH
Cochran-Mantel-Haenszel (test)
CNV
choroidal neovascularization
CRC
central reading center
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
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICGA
indocyanine green angiography
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee 
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent to treat
IVT
intravitreal
IxRS
interactive voice or web-based response system
LLD
low-luminance deficit
LPLV
last patient, last visit


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (cont.)
Abbreviation
Definition
MMRM
mixed model for repeated measures
nAMD
neovascular age-related macular degeneration
NEI VFQ-25
National Eye Institute Visual Function Questionnaire-25
OCT
optical coherence tomography
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
SD
standard deviation
SD-OCT
spectral-domain optical coherence tomography
SS-OCT
swept-source optical coherence tomography
Tie2
TEK receptor tyrosine kinase-2
ULN
upper limit of normal
UWP
ultra-wide photography
VA
visual acuity
VEGF (-A)
vascular endothelial growth factor (A)
WGS
whole genome sequencing


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON NEOVASCULAR AGE-RELATED 
MACULAR DEGENERATION 
Neovascular age-related macular degeneration (nAMD) (also known as choroidal 
neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet 
AMD) is a form of advanced AMD that causes rapid and severe visual loss and remains 
a leading cause of visual impairment in the elderly (Bourne et al. 2013; 
Wong et al. 2014).  Several biochemical and biological processes, such as angiogenesis, 
inflammation, and oxidative stress, are known to play a role in the pathogenesis of 
nAMD, which is characterized by the abnormal proliferation of choroidal capillaries that 
penetrate Bruch’s membrane and migrate to or through the retinal pigment epithelium.  
CNV leaks fluid, lipids, and blood into the outer retina causing severe, irreversible loss of 
central vision if left untreated.  
Prior to antivascular endothelial growth factor (anti-VEGF) agents, laser 
photocoagulation therapy and photodynamic therapy with verteporfin were the standard 
of care and were shown to stabilize vision.  Although such treatments remain a 
therapeutic option for selected patients, the treatment of nAMD has been markedly 
improved by the introduction of biological molecules that target an important factor in 
pathological angiogenesis, vascular endothelial growth factor (-A) (VEGF-A) 
(Brown et al. 2006; Rosenfeld et al. 2006; Heier et al. 2012).  The impressive benefit of 
anti-VEGF therapies and their ability to restore vision has been widely recognized since 
the first approval of Lucentis® (ranibizumab) in 2006 (American Academy of 
Ophthalmology 2015).  
A key challenge with currently available anti-VEGF treatments is the requirement for 
frequent and long-term administration to maintain vision gains (Heier et al. 2012; the 
Comparison of Age-Related Macular Degeneration Treatment Trials [CATT] Research 
Group 2016).  Real-world data suggest that many patients with nAMD do not receive 
treatment at the optimal frequency, and this under-treatment in clinical practice is 
associated with lower visual acuity (VA) gains compared with those observed in 
controlled clinical trials (Cohen et al. 2013; Finger et al. 2013; Holz et al. 2015; 
Rao et al. 2018).  Under-treatment of nAMD in clinical practice reflects the burden of 
frequent therapy on patients, caregivers, and the healthcare system (Gohil et al. 2015; 
Prenner et al. 2015; Varano et al. 2015; CATT Research Group et al. 2016; 
Vukicevic et al. 2016).  


 
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1.2 
BACKGROUND ON FARICIMAB 
Faricimab is a novel humanized bispecific IgG1 monoclonal antibody that selectively 
binds to VEGF-A and angiopoietin-2 (Ang-2).  The VEGF binding component binds to all 
isoforms of VEGF-A with high affinity, and the Ang-2 binding component binds to Ang-2, 
also with high affinity. 
VEGF-A is a signal protein produced by cells that stimulates angiogenesis.  Uncontrolled 
VEGF-A expression results in growth of new blood vessels (choroidal neovascular 
membranes), which fail to mature and show a number of abnormalities, including 
tortuosity and reduced number of pericytes.  These structural defects in the choroidal 
neovascular membranes can result in fragility, hyperpermeability, and a propensity for 
exudation and bleeding, all of which are key features of pathological neovascularization 
and can lead to photoreceptor damage and vision impairment.  VEGF has also been 
shown to have a direct effect on vessel hyperpermeability (Fantin et al. 2017), and 
hence in nAMD, suppression of VEGF reduces leakage from vessels, allowing for some 
normalization of structure and restoration of function. 
Ang-1 and Ang-2 are of key importance in the homeostasis of the vascular compartment, 
functioning as ligands of the TEK receptor tyrosine kinase-2 (Tie2) receptor tyrosine 
kinase that is expressed on endothelial cells (Davis et al. 1996; Maisonpierre et al. 1997; 
Fiedler et al. 2003).  Ang-1 is a Tie2 receptor agonist and acts as a homeostatic factor 
that stabilizes the mature vasculature by promoting recruitment of pericytes and smooth 
muscle cells to the vessel wall.  In contrast, Ang-2 is a context-dependent antagonist of 
Tie2 and acts as a vascular destabilization factor by blocking Ang-1dependent Tie2 
activation, which leads to dissociation of pericytes from existing vessels, thus increasing 
vessel plasticity, rendering vasculature amendable to endothelial barrier breakdown, and 
sprouting of new vessels (Yancopolous et al. 2000; Augustin et al. 2009).  Ang-2 levels 
can be upregulated by other pro-angiogenic factors, including VEGF-A, and were shown 
to be increased during angiogenic stress triggered by hypoxia or hyperglycemia 
(Bhadari et al. 2006; Fiedler et al. 2006; Benest et al. 2013).  Ang-2 may also cause 
angiogenesis and vascular endothelial destabilization in a Tie2-independent manner by 
means of 1-integrin activation (Kienast et al. 2015; Hakanpaa et al. 2015).  In addition, 
Ang-2 functions as a pro-inflammatory cytokine (Fiedler et al. 2006; Benest et al. 2013).  
Given that upregulation of Ang-2 is associated with the release of inflammatory 
cytokines, adhesion of leukocytes to endothelial cells, and migration of leukocytes into 
the retina, its inhibition may also have additional anti-inflammatory benefits 
(Fiedler et al. 2006; Benest et al. 2013).  
Nonclinical studies have shown that VEGF-A and Ang-2 act in concert to regulate the 
vasculature and to increase retinal endothelial cell permeability in vitro.  Simultaneous 
inhibition of VEGF-A and Ang-2 with the bispecific monoclonal antibody faricimab led to 
a greater reduction in the leakiness and severity of CNV lesions in a laser-induced CNV 
model in non-human primates compared with the molar equivalent of antiVEGF-A 


 
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(ranibizumab) or antiAng-2 alone.  Earlier experiments using a mouse model of 
spontaneous CNV showed that dual inhibition of VEGF-A and Ang-2 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 VEGF-A and Ang-2 were 
shown to be upregulated in patients with nAMD, diabetic retinopathy (DR), and retinal 
vein occlusion (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, VEGF-A and Ang-2, may further normalize the 
pathological ocular vasculature compared with anti-VEGF therapy alone.  Data from the 
completed Phase II studies (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 
nAMD.  
Faricimab has been studied for the treatment of nAMD and diabetic macular edema 
(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).  Two global Phase III studies in DME are 
ongoing (GR40349 [YOSEMITE] and GR40398 [RHINE]).  
Refer to the Faricimab (RO6867461) Investigator’s Brochure for details on nonclinical 
and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
As a result of the chronic, progressive nature of nAMD, frequent injections (e.g., monthly 
or bimonthly injections) of currently available therapies are usually required over 
extended periods.  In the pivotal ranibizumab nAMD studies ANCHOR and MARINA, 
eyes treated with 0.5 mg of ranibizumab every 4 weeks (Q4W) demonstrated a mean 
change from baseline in best-corrected visual acuity (BCVA) of  11.3 and  7.2 letters, 
respectively, at 12 months, and 10.7 and 6.6 letters, respectively, at 24 months 
(Rosenfeld et al. 2006; Brown et al. 2009).  
However, these findings contrast with data from the real world.  In routine clinical 
practice, frequent office visits place a significant burden on patients, caregivers, their 
treating physicians, and the healthcare system, and hence there are challenges with 
compliance with approved dosing recommendations.  Real-world data suggest many 
patients with nAMD are under-treated with current intravitreal (IVT) anti-VEGF therapies, 
leading to suboptimal outcomes in comparison with data from clinical trials.  For example, 
a retrospective, observational study conducted in Canada, France, Germany, Ireland, 
Italy, Netherlands, the United Kingdom, and Venezuela found that in 2,227 nAMD 
patients, the mean number of anti-VEGF injections received was 5.0 and 2.2 injections 
during the first and second years, respectively, with a mean change in VA score from 


 
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baseline of 2.4 and 0.6 letters after 1 and 2 years, respectively (Holz et al. 2015).  
Likewise, data from the American Academy of Ophthalmology Intelligent Research in 
Sight registry in the United States of nearly 14,000 patients with nAMD who were treated 
for at least 1 year with a single anti-VEGF agent showed that a mean of 6.1 injections 
were administered in the first year of treatment and that the mean change in logMAR 
(logarithm of the minimum angle of resolution) VA from baseline to Year 1 was  0.05 
(2.5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart) 
(Rao et al. 2018).   
This difference in outcomes between patients treated in the real-world setting and those 
treated in the controlled environment of a clinical trial demonstrates the clear clinical 
need for therapies with a more durable effect that would thus require less-frequent 
dosing that is tailored to individual need (e.g., every 2 to 4 months), while still being able 
to provide VA outcomes comparable to those observed in the pivotal clinical trials of 
licensed anti-VEGF monotherapies. 
1.3.1 
Benefits 
A Phase I, open-label, multicenter, single-ascending dose (0.5, 1.5, 3, or 6 mg) and 
multiple-ascending dose (3 or 6 mg) study (BP28936) designed to investigate the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of faricimab administered 
intravitreally to patients with nAMD has been completed (Chakravarthy et al. 2017).  
Patients recruited in the Phase I study had already received anti-VEGF treatment (3 or 
more IVT treatments within the preceding 6 months) with an insufficient response, 
defined as BCVA 20/40 and presence of fluid on optical coherence tomography (OCT).  
Although the primary focus of this study was the safety and tolerability of faricimab 
following a single dose and 3 sequential doses of faricimab, administered to patients 
4 weeks apart, there were signals of biological activity and vision gains in these 
hard-to-treat patients.  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. 
Study BP29647 (AVENUE) evaluated the safety, efficacy, and pharmacokinetics of 
1.5 mg and 6.0 mg of IVT faricimab Q4W or every 8 weeks (Q8W) administered to 
patients with nAMD who were treatment naive compared with 0.5 mg of ranibizumab 
Q4W.  Although the study did not meet its primary or key secondary endpoints for 
superiority in the change from baseline in BCVA or OCT in either the 1.5-mg faricimab 
Q4W or the 6-mg faricimab Q4W treatment arm compared with the 0.5-mg ranibizumab 
Q4W treatment arm at Week 36, it did show that the 6-mg faricimab Q8W treatment arm 
(after 4 initial Q4W doses) had similar BCVA results and central subfield thickness (CST) 
reductions compared with the 6-mg faricimab Q4W treatment arm and the 0.5-mg 
ranibizumab Q4W treatment arm.   
Study CR39521 (STAIRWAY) evaluated the safety, efficacy, and pharmacokinetics of 
6 mg of faricimab administered to patients by IVT injection at an extended dosing 


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interval (every 12 weeks [Q12W] and every 16 weeks [Q16W] administration) compared 
with 0.5 mg of ranibizumab Q4W in treatment-naive patients with nAMD.  The treatment 
regimens for the two faricimab treatment arms were identical up to Week 24, with both 
arms receiving 6 mg of faricimab Q4W for the first 4 injections, followed by a 12-week 
observation period.  At Week 24, a protocol-defined disease activity assessment was 
conducted for all patients.  Patients in the Q16W dosing arm with protocol-defined 
disease activity were treated with Q12W dosing for the remainder of the 52-week study.  
Patients randomized to the Q16W dosing arm who had no protocol-defined disease 
activity at Week 24 continued to receive Q16W dosing throughout the remainder of the
study.  In the combined 6-mg faricimab treatment arms (Q12W and Q16W), 36 of 
55 patients (65.5%) did not show disease activity according to the pre-specified criteria 
at Week 24, 12 weeks after their final initiation dose.  In the 6-mg faricimab Q16W 
treatment arm, 19 of 31 patients (61.3%) with no protocol-defined disease activity 
continued receiving the Q16W regimen, while the remaining 12 patients had their 
treatment regimen switched to Q12W dosing for the remainder of the study.  
Efficacy data demonstrated that patients in the 6-mg faricimab Q12W and Q16W arms
maintained the initial gains from baseline in BCVA through to the primary endpoint 
(Week 40) and study completion (Week 52), comparable to the 0.5-mg ranibizumab
Q4W arm.  Likewise, the proportions of patients gaining at least 3 lines of VA from 
baseline and maintaining VA (not losing 15 letters) at Week 52 are comparable across 
the 6-mg faricimab and 0.5-mg ranibizumab arms. VA outcome data are supported by 
anatomical outcomes; the reductions in CST from baseline observed in the 6-mg 
faricimab treatment arms (Q12W and Q16W) are comparable with those in the 0.5-mg
ranibizumab Q4W arm, as are the reductions in CNV lesion size on fundus fluorescein 
angiography (FFA). 
The combined evidence from the Phase II studies BP29647 and CR39521 indicates that 
6 mg of faricimab administered to patients with nAMD at various treatment intervals 
delivers similar efficacy compared with 0.5 mg of ranibizumab Q4W, but importantly, has 
the potential to be given at substantially less-frequent treatment intervals (up to Q16W).
As discussed in the scientific rationale (Section 2.2) of the Investigator’s Brochure, the 
proposed hypothesis is that simultaneous neutralization of both VEGF-A and Ang-2 may 
provide a more sustained anti-leakage effect, allowing for less-frequent dosing 
compared with anti-VEGF monotherapy in the treatment of nAMD.  A less-frequent 
treatment administration schedule tailored to individual need (e.g., every 2 to 4 months) 
that could provide VA outcomes comparable to those of more frequently administered 
anti-VEGF monotherapy (e.g., every 1 to 2 months) would represent an important and 
meaningful advance relative to currently available therapies.
Refer to the Faricimab (RO6867461) Investigator’s Brochure for additional details about
nonclinical and clinical Phase I and Phase II studies.


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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 nAMD.
In Phase I and II clinical studies, more than 400 patients have been exposed to at least 
one dose of faricimab. 
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 faricimab has an acceptable tolerability and safety profile, with no new or 
unexpected safety signals.  The ocular and non-ocular safety findings for faricimab
observed in the Phase II studies were generally consistent with the safety profile findings 
reported in patients with nAMD or DME who received intravitreally administered 
approved anti-VEGF products.  
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 combined evidence from the Phase II studies BP29647 and CR39521 indicates that 
the 6-mg dose of faricimab can be administered to patients with nAMD at various 
treatment intervals (Q4W, Q8W, Q12W, and Q16W) to deliver similar efficacy compared 
with 0.5 mg of ranibizumab Q4W, and importantly, has the potential to be given at 
substantially less-frequent treatment intervals (up to Q16W), while still achieving 
comparable visual (BCVA) and anatomic (OCT) outcomes. Based on the totality of 
evidence from the Phase I and Phase II studies, and taking into account evidence from 
the murine and non-human primate preclinical and toxicology models, it is anticipated 
that the additional antiAng-2 mechanism of action of the faricimab molecule will not 
negatively impact the safety profile compared with IVT anti-VEGF monotherapy, while
less-frequent dosing may offer a more favorable benefitrisk profile.
Taken together, data from nonclinical, Phase I and Phase II studies, as well as the clear 
unmet need for less-frequent dosing in nAMD, support the positive benefitrisk
assessment for the initiation of this Phase III study to assess the efficacy, safety, 
durability, and pharmacokinetics of faricimab administered up to Q16W to patients with 
nAMD. 


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of the 6-mg
dose of faricimab administered at up to 16-week intervals compared with aflibercept 
monotherapy Q8W in patients with CNV secondary to AMD, also known as nAMD.
Specific objectives and corresponding endpoints for the study are outlined in Table 1.  
An overview of the proposed statistical analyses is described in Section 6.
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 for further details).


 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of IVT injections 
of the 6-mg dose of faricimab on BCVA 
outcomes compared with aflibercept  
 Change from baseline in BCVA (as 
measured on the ETDRS chart at a 
starting distance of 4 meters) based on an 
average at Weeks 40, 44, and 48  
Secondary Efficacy Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of faricimab on 
additional BCVA outcomes  
 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 loss of  15, 
 10  5, or  0 letters in BCVA from 
baseline over time 
 Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time 
 Proportion of patients gaining  15 letters 
or achieving BCVA of  84 letters over  
time 
 Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time 
 To evaluate the frequency of study drug 
administration  
 Proportion of patients on a Q8W, Q12W, 
and Q16W treatment interval at Weeks 48, 
60, and 112  
 Number of study drug injections received 
through Weeks 48, 60, and 112  
 To evaluate the efficacy of faricimab on 
anatomic outcome measures using OCT 
 Change from baseline in CST based on an 
average at Weeks 40, 44, and 48 
 Change from baseline in CST 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 
intraretinal and subretinal fluid over time 
 Proportion of patients with absence of 
intraretinal cysts over time 
 Proportion of patients with absence of 
pigment epithelial detachment over time  
 To evaluate the efficacy of faricimab on 
anatomic outcome measures using FFA 
 Change from baseline in total area of CNV 
lesion at Week 48 and Week 112 
 Change from baseline in total area of 
leakage at Week 48 and Week 112 
 


 
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Table 1 
Objectives and Endpoints (cont.) 
Safety Objective 
Corresponding Endpoints 
 To evaluate the ocular and non-ocular 
safety and tolerability of faricimab 
 Incidence and severity of ocular adverse 
events 
 Incidence and severity of non-ocular 
adverse events 
Exploratory Efficacy Objectives 
Corresponding Endpoint 
 To evaluate the efficacy of faricimab on 
patient-reported vision-related functioning 
and quality of life using the NEI VFQ-25 
 Change from baseline in NEI VFQ-25 
composite score over time  
Pharmacokinetic Objectives 
Corresponding Endpoints 
 To characterize the systemic 
pharmacokinetics of faricimab 
 Plasma concentration of faricimab 
over time 
Immunogenicity Objectives 
Corresponding Endpoints 
 To evaluate the immune response to 
faricimab 
 To evaluate potential effects of ADAs 
 Presence of ADAs during the study 
relative to the presence of ADAs at 
baseline 
 Relationship between ADA status and 
efficacy, safety, or PK endpoints 
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives 
Corresponding Endpoints 
 To evaluate potential relationships 
between selected covariates and exposure 
to faricimab  
 Relationship between selected covariates 
and plasma or aqueous humor (optional) 
concentration or PK parameters for 
faricimab 
 To evaluate the drug concentration 
(exposure)-effect relationship for free 
VEGF-A and free Ang-2  
 To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of faricimab 
 Relationship between pharmacokinetics of 
faricimab and concentration of free 
VEGF-A and free Ang-2 in aqueous humor 
(optional), plasma, and/or vitreous 
(optional) over time 
 Aqueous humor (optional) and vitreous 
(optional) concentration of faricimab 
over time 
 To explore concentration-effect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers) 
 Pharmacokinetics of faricimab and the 
change in BCVA or other endpoints 
(e.g., anatomical markers) over time 




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active disease (for the criteria, refer to Section 3.1.1.4) to be treated at that visit and 
to continue with a Q8W dosing regimen of faricimab. A second protocol-defined 
assessment of disease activity at Week 24 requires patients in Arm A with active 
disease (excluding those with active disease at Week 20 and therefore receiving a 
Q8W dosing regimen of faricimab) to be treated at that visit and to continue with a 
Q12W dosing regimen of faricimab. Patients receiving faricimab who do not have 
active disease according to the protocol-defined criteria at Week 20 and Week 24 
will be treated with a Q16W dosing regimen of faricimab. Patients will continue 
receiving faricimab on a fixed regimen every 8, 12, or 16 weeks until Week 60 
according to the disease activity assessments made at Weeks 20 and 24.
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) 
onward, all patients in Arm A will be treated according to a personalized treatment 
interval (PTI) dosing regimen (see Table 2 for the PTI dosing criteria) up to 
Week 108. 

Arm B (comparator arm) (Q8W) (n320):  Patients randomized to Arm B will receive 
2 mg of IVT aflibercept Q4W up to Week 8 (3 injections), followed by 2 mg of IVT 
aflibercept Q8W up to Week 108.
Patients in both treatment arms will complete scheduled study visits Q4W for the entire 
study duration (112 weeks).  A sham procedure will be administered to patients in both 
treatment arms at study visits with no study treatment administration to maintain 
masking among treatment arms (see Section 4.3.1.1.3).
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
BCVAbest-corrected visual acuity; ETDRSEarly Treatment Diabetic Retinopathy Study; 
IVTintravitreal; PTIpersonalized treatment interval; Q8Wevery 8 weeks; Q12Wevery 
12 weeks; Q16Wevery 16 weeks; WWeek.
a At Weeks 20 and 24, patients will undergo a disease activity assessment. Patients with 
anatomic or functional signs of disease activity at these timepoints will receive Q8W or Q12W
dosing, respectively, rather than Q16W dosing.
b The primary endpoint is the change from baseline in BCVA (as assessed on the ETDRS chart 
at a starting distance of 4 meters) based on an average at Weeks 40, 44, and 48. 
c From Week 60 (when all patients in Arm A are scheduled to receive faricimab) onward, 
patients in Arm A will be treated according to a PTI dosing regimen (between Q8W and Q16W).
Only one eye will be assigned as the study eye.  If both eyes are considered eligible (per 
the inclusion and exclusion criteria), the eye with the worse BCVA, as assessed at 
screening, will be selected as the study eye (unless based on medical reasons, 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 masking details). 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length 
and an approximately 108-week treatment period, followed by the final study visit at 
Week 112 (at least 28 days after the last study treatment administration).  A unique 
Active Disease at Week 20
Arm B:
Aflibercept 
Q8W
Randomization
Screening
Study Treatment Administration
W4
W8
W12 W16
W20 W24
W28
W44
W36
W32
W40
Day 1
Final Visit
Day -28 to
Day -1
Arm A:
Faricimab  
up to Q16W
Primary Endpoint b
W48 W52
W56
Active Disease at Week 24
Disease Activity 
Assessments a
W68
W60
W64
W72 W76
W80
W88 
W84
W92 W96
W100 W104 W108 W112
6 mg of faricimab IVT
Sham procedure
2 mg of aflibercept IVT
6 mg of faricimab IVT or sham procedure according to PTI criteria
PTI Regimen for Arm A c


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screening number will be assigned to each screened patient through an interactive voice 
or web-based response system (IxRS).
3.1.1.1
Screening
Informed consent must be administered and signed by each patient 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).  
Note:  Some patients may require an extended screening period (more than 28 days) as 
a result of repeated evaluation of images or other issues.  Upon agreement with the 
Medical Monitor, the screening period may be extended by up to 5 business days in 
such cases.
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 on the same day or within 2 business days.  
During screening, a patient’s eligibility will be assessed, including a central reading 
center review of color fundus photographs (CFPs), OCT, and FFA, to ensure that CNV 
secondary to AMD meets the ocular criteria for the study.
When screening and Day 1 visits are completed as a combined visit, the assessments 
listed for both visits (see the schedule of activities in Appendix 1) should be conducted 
only once.  Prior discussion with, and approval from, the central reading center is 
required prior to this combined visit, so as to enable an expedited evaluation of CFP, 
OCT and FFA images to provide 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 study treatment administration:  urine pregnancy test (if 
appropriate), slitlamp examination, indirect ophthalmoscopy, and pre- treatment 
intraocular pressure (IOP) measurements (recorded on the Day 1 electronic Case 
Report Form [eCRF] and dated accordingly). 
After screening and pre-treatment Day 1 assessments have been completed, eligible 
patients will have a randomization identification number assigned to them through the 
IxRS and will be randomized in a 1:1 ratio in order that approximately 320 patients are 
randomized to each of the two treatment arms. Randomization will be stratified by 
baseline BCVA ETDRS letter score as assessed on Day 1 (74 letters, 7355 letters, 
and 54 letters), low-luminance deficit (LLD; 33 letters and 33 letters; adapted from 
Frenkel et al. 2016), and region (United States and Canada, Asia, and the rest of the 
world).


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3.1.1.2
Screen-Failed Patients
Patients who are not eligible for enrollment (screen failures) may be eligible for 
re-screening for up to an additional two times during the enrollment period of the study.
At re-screening, a new screening number will be assigned to each patient through the 
IxRS and all screening visit assessments will be performed.  Only 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 are received by the central reading center 
within 4 weeks before 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, which 
will be performed through the IxRS (i.e., at the Day 1 visit).  
Note:  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 administration:  urine pregnancy test (if appropriate), slitlamp 
examination, indirect ophthalmoscopy, and pre-treatment IOP measurements (recorded 
on the Day 1 eCRF and dated accordingly).
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger counting test and 
post-dose IOP measurement). Afterward, all study patients will have a safety 
assessment visit on Day 7 (3 days) evaluated by the masked investigator.  At 
subsequent scheduled visits, patients will have safety assessments evaluated by the 
masked investigator prior to receiving study treatment (for additional details about 
masking, see Section 4.2.2). Study treatment administration and study-related 
assessments will occur Q4W (starting on Day 1), as outlined in the schedule of activities 
(see Appendix 1).  The sham procedure will be delivered to patients in all arms 
throughout the study as applicable (see Section 4.3.1.1.3).  
At Weeks 20 and 24, a protocol-defined assessment of disease activity performed for all 
patients in the study requires patients with active disease (for the criteria, refer to 
Section 3.1.1.4) receiving faricimab (Arm A) to be treated with an 8 weekly or 12 weekly 
dosing regimen, respectively, until Week 60. Patients receiving faricimab who do not 
have active disease according to the protocol-defined criteria will be treated with a 
16 weekly dosing regimen until Week 60.
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) to 
Week 108, patients in Arm A will be treated according to a PTI dosing regimen (Q8W, 
Q12W, or Q16W). At study drug dosing visits, treatment intervals may be maintained or 
adjusted (i.e., increased by 4 weeks, or decreased by 4 or 8 weeks), based on OCT, 
BCVA, and clinical assessment (for the criteria, refer to Section 3.1.1.5). 


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Patients in Arm B will receive aflibercept Q4W up to Week 8, followed by Q8W up to 
Week 108. 
Patients will receive the assigned therapy up to and including Week 108 and return for a 
final visit at Week 112.  After the final visit, adverse events should be followed as 
outlined in Section 5.6.  Assessments performed in case of an unscheduled safety visit(s) 
(see Appendix 2) are at the discretion of the investigator.  
Patients who prematurely discontinue 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 40, 44, 48, 60, and 112 visits.
Patients who wish to discontinue from the study prior to completion but have not 
withdrawn consent will be asked to return for an early termination visit after a minimum 
of 28 days have elapsed following their last study treatment for monitoring of adverse 
events and early termination visit assessments (see Appendix 1).
3.1.1.4
Weeks 20 and 24 Disease Activity Criteria
Determination of active disease at Weeks 20 and 24 will be made if any of the following 
criteria are met:

Increase 50 m in CST compared with the average CST value over the previous 
two scheduled visits (Weeks 12 and 16 for the Week 20 assessment and Weeks 16 
and 20 for the Week 24 assessment)
Or

Increase 75 m in CST compared with the lowest CST value recorded at either of 
the previous two scheduled visits
Or

Decrease 5 letters in BCVA compared with average BCVA value over the previous 
two scheduled visits, owing to nAMD disease activity (as determined by the 
investigator)
Or

Decrease 10 letters in BCVA compared with the highest BCVA value recorded at 
either of the previous two scheduled visits, owing to nAMD disease activity (as 
determined by the investigator)
Or

Presence of new macular hemorrhage (as determined by the investigator), owing to 
nAMD activity
Additional considerations at Week 24:  If there is significant nAMD disease activity at 
Week 24 that does not meet the criteria above, but which in the opinion of the 
investigator would otherwise warrant treatment, following Sponsor notification through 
the IxRS, patients randomized to Arm A will receive 6 mg of faricimab at Week 24 and 


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will continue to receive repeated 12 weekly treatments.  Patients randomized to Arm A 
who meet the disease activity criteria at Week 20 will remain on their Q8W dosing 
schedule and will not receive treatment at Week 24.  Patients randomized to Arm B will 
remain on their Q8W dosing schedule and will receive aflibercept at Week 24. 
3.1.1.5
Personalized Treatment Interval Disease Activity Criteria
Starting at Week 60, when all patients in Arm A are scheduled to receive faricimab, the 
study drug dosing interval for patients in Arm A will be extended, reduced, or maintained 
based on assessments made at study drug dosing visits.  Study drug dosing interval 
decisions during the PTI regimen phase for Arm A are automatically calculated by the 
IxRS based on the algorithm described in Table 2.  The decision will be made based on 
data from visits at which patients received study drug. Patients will receive a sham 
procedure at study visits when they are not receiving treatment with faricimab.
Table 2
Personalized Treatment Interval Algorithm
Dosing Interval
Criteria
Interval extended by 4 weeks
(to a maximum of Q16W)
Stable CSTa compared with the average of the last  
2 study drug dosing visits, and no increase 50 m in
CST (compared with the lowest on-study drug dosing
visit measurement) and 
No decrease 5 letters in BCVA b compared with the 
average from the last two study drug dosing visits, and 
no decrease 10 letters in BCVA b compared with the 
highest on-study drug dosing visit measurement and 
No new macular hemorrhage c
Interval reduced (to a minimum
Q8W)
If one of the criteria is met, the 
interval will be reduced by 
4 weeks. If two or more criteria 
are met or one criterion includes 
new macular hemorrhage, the 
interval will be reduced to an 
8-week interval. d
Increase 50 m in CST compared with the average 
from the last two study drug dosing visits or 75 m 
compared with the lowest on-study drug dosing visit 
measurement or
Decrease 5 letters in BCVA b compared with average 
of last two study drug dosing visits or decrease 10 
letters in BCVA b compared with the highest on-study
drug dosing visit measurement or
New macular hemorrhage c
Interval maintained
If extension or reduction criteria have not been met
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; nAMDneovascular 
age-related macular degeneration; Q8W every 8 weeks; Q16W every 16 weeks.
a Where stability is defined as a change of CST of less than 30 m.
b Change in BCVA should be attributable to nAMD disease activity (as determined by 
investigator).
c Refers to macular hemorrhage owing to nAMD activity (as determined by investigator).
d Patients whose treatment interval is reduced by 8 weeks from Q16W to Q8W will not be 
allowed to return to a Q16W interval during the study.


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3.1.2
Compliance with Study Visits and Handling of Missed Visits
Sites will report missed study drug dosing visits and study drug dosing interruption visits 
to the IxRS for all patients (Arms A and B) to preserve masking.
In a masked manner (through the IxRS), missed faricimab and aflibercept administration 
(not sham) will be made up at the next visit that the patient attends.  The study drug 
dosing schedule will be reset at that visit. An exception is for patients in Arm A who 
miss their Week 12 dose.  These patients will not have their dose made up at Week 16, 
in order to maintain the validity of disease activity assessments at Weeks 20 and 24.
If more than one study visit is missed between Day 1 and Week 28, the investigator and 
Sponsor may consider discontinuing the patient from study drug.  Beyond Week 28, if a 
patient misses more than two study visits in any 24-week treatment period, the 
investigator and Sponsor may consider discontinuing the patient from study treatment.
Study drug dosing visits should not occur earlier than after a full 21 days have elapsed 
after the previous scheduled study treatment visit.  
After the Day 1 visit, if a patient misses a study visit when CFPs and FFA (and 
indocyanine green angiography [ICGA] performed at selected sites with ICGA 
capabilities) images are obtained, the images must be obtained at the next scheduled 
visit that the patient attends (see Appendix 1).  Other missed study assessments will not 
be made up.
3.1.2.1
Handling of Missed Visits up to Week 24 in Arm A
If a patient misses the Week 20 visit only, disease activity will be assessed at Week 24 
and, depending on disease activity, the patient will be eligible for Q8W dosing or Q16W 
dosing up to Week 60.
If a patient misses the Week 24 visit only, the disease activity assessment conducted at 
Week 20 will determine whether dosing is continued Q8W or Q12W thereafter up to 
Week 60.
If a patient misses one of the two visits prior to a disease activity assessment visit 
(Week 20 or Week 24), data will be used from the visit that the patient does attend for a 
disease activity assessment. If a patient misses both visits prior to a disease activity 
assessment visit (Week 20 or Week 24), or misses both the Week 20 and 24 disease 
activity assessment visits, the patient will be dosed Q8W up to Week 60. 
3.1.2.2
Additional Considerations for the PTI Regimen Phase in 
Arm A: IxRS Study Drug Dosing Interval Decision
Missed Study Drug Dosing Visit(s)
For the PTI regimen phase, a decision regarding the subsequent study drug dosing 
interval will be made by IxRS based on CST, BCVA, and clinical assessments 






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The total length of the study 
 from screening of the first 
patient to the end of the study is expected to be approximately 48 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 trial design was 
selected to minimize bias in the evaluation of faricimab as a treatment for patients with 
nAMD. 
To ensure the safety of all patients during the conduct of the study, several safety 
assessments have been included, for example, regular ophthalmological monitoring and 
imaging assessments, adverse event monitoring (of ocular and non-ocular events), and 
protocol-specified laboratory safety tests (see Section 4.5 and Appendix 1 for a 
description of study assessments).
3.3.1
Rationale for Faricimab Dose
The 6-mg dose of faricimab will be administered to patients as initiating and 
maintenance doses in treatment Arm A, as outlined in Section 3.1.1. 
In the Phase I study (BP28936), the 6-mg dose of faricimab was the highest feasible 
dose, and single and multiple doses of up to 6 mg were well tolerated.  In the Phase II
studies, the ocular and non-ocular safety findings for faricimab were consistent with the 
safety profiles of anti-VEGF products licensed for nAMD and no clinically meaningful 
imbalances in events were observed for patients receiving the 1.5-mg and 6-mg doses.  
 
The combined evidence from the Phase II studies BP29647 and CR39521 in nAMD 
indicates that the 6-mg faricimab dose delivers similar efficacy compared with monthly 
ranibizumab administration but importantly, has the potential to be given at substantially 
less-frequent treatment intervals (up to Q16W).
In Phase II, longer dosing intervals (Q8W, Q12W, and Q16W) were studied only with the 
6-mg dose. The duration of ocular VEGF and Ang-2 suppression is described by a 
pharmacokinetic/pharmacodynamic (PK/PD) model (Hutton-Smith et al. 2016).
The predicted longer duration of target suppression informed the choice to study the 
6-mg dose for evaluation of 8-week intervals in Phase II.
For Phase III, the 6-mg dose has been selected to maximize the potential for a durable 
treatment effect on the basis of this PK/PD model, given its similar efficacy and 
comparable safety profile to the 1.5-mg dose.
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
The dosing schedule in Year 1 of this proposed Phase III study is based primarily on 
clinical data from the Phase II study CR39521 and is designed to allow the assessment 
of efficacy of the 6-mg faricimab dose administered at intervals of up to 16 weeks, as 
outlined in Figure 1.
In Study CR39521, following 4 initial monthly doses, Q12W and Q16W intervals of 6 mg 
of faricimab were explored. In this study, similar BCVA gains were observed in all 
treatment arms; patients treated with both the Q12W and Q16W regimens maintained 
initial improvements in vision (mean change in BCVA from baseline at Week 16, 1 month 
after the last monthly dose) through to the primary endpoint (Week 40) and the end of 
study (Week 52). Reductions from baseline in CST and CNV leakage in both the Q12W 
and Q16W treatment arms during extended dosing were comparable with those with 
monthly ranibizumab administration.  
During the study, an assessment of disease activity according to protocol-defined criteria 
was conducted at Week 24 (12 weeks after 4 initial monthly doses). In the combined 
6-mg faricimab treatment arms (Q12W or Q16W), 66% of patients did not show disease 
activity according to the pre-specified disease activity criteria at Week 24, 12 weeks after 
their last dose. In the 6-mg faricimab Q16W treatment arm, 61% of patients with no 
protocol-defined disease activity continued on the Q16W regimen, while the remaining 
39% of patients had their dosing interval decreased to Q12W dosing at Week 24 for the 
remainder of the study. Patient discontinuation because of lack of efficacy or nAMD 
disease progression, as defined by investigator assessment, in the 6-mg faricimab 
treatment arms was low (1 of 55 patients had discontinued prior to Week 24 as did 2 of 
55 patients beyond Week 24). As discussed above, initial vision gains were maintained 
with both the Q12W and Q16W regimens. 
In addition, PK and PD assessment of aqueous humor samples from a subset of 
patients in the Phase II studies demonstrated high ocular suppression of VEGF and 
Ang-2 for 8 weeks or more with faricimab, supporting dosing regimens beyond Q8W.
In summary, data from Study CR39521 suggest that nAMD disease activity should be 
managed adequately with a faricimab Q12W or a Q16W regimen in the majority of 
patients with nAMD. The option for Q8W dosing (which was shown to be effective in 
Study BP29647) is included in the Phase III study design to help ensure that individual 
treatment needs are met by allowing dosing according to the most appropriate frequency, 
ranging between Q8W and Q16W.
In this proposed Phase III study, patients in Arm A will be administered the 6-mg 
faricimab dose Q4W up to Week 12 (4 injections), as outlined in Section 3.1.1. 
Disease activity assessments at Weeks 20 and 24 will require patients with anatomic or 
functional signs of disease activity to be treated with faricimab at Q8W or Q12W 


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treatment intervals, respectively. Patients receiving faricimab who do not have active 
disease at Week 20 and Week 24 will be treated with faricimab at Q16W intervals.
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) onward, 
patients in Arm A will be treated according to a PTI dosing regimen (between Q8W and 
Q16W).  Provision of a PTI approach for patients receiving faricimab after Week 60 
closely reflects current clinical practice in nAMD and provides patients with the 
opportunity to either extend, maintain, or reduce treatment frequency according to need, 
thus minimizing the administration of unnecessary IVT injections while maintaining gains 
in VA achieved during fixed dosing. 
Given the heterogeneity of disease activity in nAMD and the differences in treatment 
response across patients, the assessment of disease activity at multiple timepoints 
during the study, with the opportunity to move to a different treatment frequency aims to 
ensure that individual treatment needs are met.  The disease activity criteria at 
Weeks 20 and 24 are specified in Section 3.1.1.4 and are based on the assessment of 
disease activity at Week 24 in Study CR39521.  At Week 24, before patients can 
continue on the Q16W interval, the criteria allow the masked physician to make an 
assessment of whether there is significant nAMD disease activity that requires 
immediate treatment but does not meet the other specified disease activity criteria.  The 
PTI criteria are specified in Section 3.1.1, Table 2.  The disease activity assessment 
criteria are based on visual and anatomic criteria and aim to extend the treatment 
interval (to a maximum of every 16 weeks) in patients with inactive disease, while giving 
those with demonstrable disease activity the chance to have treatment intervals reduced 
to a minimum of every 8 weeks.  
3.3.3
Rationale for Aflibercept Dose and Schedule
The 2-mg aflibercept dose will be administered to patients in treatment Arm B, 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 nAMD product labeling for Eylea® (aflibercept) (see 
Section 3.3.6).
3.3.4
Rationale for Biomarker Assessments
Several biochemical and biological processes, such as angiogenesis, inflammation, and 
oxidative stress, are known to play a role in the pathogenesis of AMD (the CATT 
Research Group 2011; Turpcu et al. 2014).  Therefore, protein biomarkers of pathways 
involved in these processes may be analyzed to improve the understanding of the 
patients’ response to faricimab treatment. The molecular targets of faricimab (VEGF 
and Ang-2) will be measured in the systemic circulation and, if possible, in aqueous and 
vitreous humor. Other biomarkers of angiogenesis that may be measured include Ang-1,
VEGF receptor, Tie2, placental growth factor, basic fibroblast growth factor, and 


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platelet-derived growth factor. Furthermore, biomarkers of inflammation and oxidative 
stress may be measured in plasma and, if possible, in aqueous humor.
3.3.5
Rationale for Optional Aqueous Humor Samples
Aqueous humor may reflect changes in the retina better than blood, given its close 
proximity and contiguity to the retina. Single (Krohne et al. 2012) and multiple 
(Campochiaro et al. 2013) aqueous humor samplings have previously been instrumental 
in the understanding of the relationship 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. 2016) and were safely 
obtained from a total of 180 patients in faricimab clinical studies. Therefore, optional 
aqueous humor samples will be collected from consenting patients in regions where 
optional sampling is approved, with the aim to increase understanding of the ocular 
pharmacokinetics and pharmacodynamics of faricimab. Analyses derived from these 
samples will be used to develop better predictive models for determining optimal dosing 
intervals in different subgroups and to support selection of a dosing regimen for future 
clinical trials. Furthermore, additional biomarkers may be analyzed in aqueous humor 
samples to improve the understanding of patients’ response to faricimab treatment (see 
Section 3.3.4).  
3.3.6
Rationale for Control Group
This study is an interventional study to evaluate the efficacy of faricimab compared with 
a standard-of-care anti-VEGF monotherapy for patients with nAMD.  Anti-VEGF therapy 
is a well-established standard of care in patients with nAMD, 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 nAMD and has 
demonstrated improvement in BCVA in the target population in controlled, randomized 
clinical studies (Eylea® [aflibercept] U.S. Package Insert, Eylea® [aflibercept] E.U. 
Summary of Product Characteristics, and Eylea® [aflibercept] Japan Package Insert).  
Eylea® is a globally approved anti-VEGF therapy with a Q8W maintenance regimen, 
facilitating a comparison with the longer regimens of faricimab that are being 
investigated in Arm A. 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 640 patients with CNV secondary to AMD (also known as nAMD) will be 
randomized during the global enrollment phase of this study.  To ensure appropriate 
patient representation, the Sponsor may elect to cap the recruitment of patients in 
certain baseline BCVA strata.  If implemented, details of the cap will be described in the 
Statistical Analysis Plan. 


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The protocol allows enrollment of both men and women, provided the following entry 
criteria are met (see Sections 4.1.1 and 4.1.2).
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
4.1.1.1
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent  
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act (HIPAA) authorization, and in other countries, as applicable 
according to national laws.

Age 50 years on Day 1

Ability to comply with the study protocol, in the investigator’s judgment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive measures that result in 
failure rate 1% per year during the treatment period and for at least 3 months after 
the final dose of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). The definition of childbearing 
potential may be adapted for alignment with local guidelines or requirements.
Examples of acceptable contraceptive methods include bilateral tubal ligation, 
male sterilization; hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices; and copper intrauterine devices. 
Contraception methods that do not result in a failure rate of1% per year such 
as male or female condom with or without spermicide; and cap, diaphragm, or 
sponge with spermicide are not acceptable.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.

 


 
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4.1.1.2 
Ocular Inclusion Criteria for Study Eye 
Patients must meet the following ocular criteria for study entry: 
 
Treatment-naive CNV secondary to AMD (nAMD) 
 
Subfoveal CNV or juxtafoveal/extrafoveal CNV with a subfoveal component related 
to the CNV activity identified by FFA or OCT (where CNV activity is defined as 
showing evidence of subretinal fluid, subretinal hyper-reflective material, or leakage) 
 
CNV lesion of any type (i.e., predominantly classic, minimally classic, or occult 
[including polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) 
that exhibits all of the following characteristics: 
– 
A total lesion size (including blood, atrophy, fibrosis, and neovascularization) of 
9 disc areas on FFA 
– 
A CNV component area of  50% of the total lesion size on FFA 
– 
Active CNV confirmed on FFA (evidence of leakage) 
– 
CNV exudation confirmed on OCT (presence of fluid) 
 
BCVA of 78 to 24 letters, inclusive (20/32 to 20/320 approximate Snellen equivalent), 
using the ETDRS protocol and assessed at the initial testing distance of 4 meters 
(see the BCVA manual for additional details) on Day 1  
 
Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition 
of good quality retinal images to confirm diagnosis 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
4.1.2.1 
General Exclusion Criteria 
Patients who meet any of the following general exclusion 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 4.4.3, 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 
 
Uncontrolled blood pressure, defined as systolic blood pressure  180 mmHg and/or 
diastolic blood pressure  100 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 


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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

Pregnancy or breastfeeding, or intention 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 treatment.  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 by a patient 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:

CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, 
pathological myopia, angioid streaks, choroidal rupture, or uveitis 

Any history of macular pathology unrelated to AMD affecting vision or contributing to 
the presence of intraretinal or subretinal fluid

Presence at screening of central serous chorioretinopathy 

Retinal pigment epithelial tear involving the macula on Day 1

On FFA/CFP:
–
Subretinal hemorrhage of 50% of the total lesion area and/or that involves 
the fovea
–
Fibrosis or atrophy of 50% of the total lesion area and/or that involves 
the fovea

Any concurrent intraocular condition (e.g., amblyopia, aphakia, retinal detachment, 
cataract, diabetic retinopathy or maculopathy, or epiretinal membrane with traction) 
that, in the opinion of the investigator, could either reduce the potential for visual 
improvement or require medical or surgical intervention during the study

Current vitreous hemorrhage on Day 1

Uncontrolled glaucoma 


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
Spherical equivalent of refractive error demonstrating more than 8 diopters 
of myopia 
For patients who have undergone prior refractive or cataract surgery, the 
preoperative refractive error should not have exceeded 8 diopters of myopia.

Any prior or concomitant treatment for CNV or vitreomacular-interface abnormalities, 
including, but not restricted to, IVT treatment (e.g., anti-VEGF, steroids, tissue 
plasminogen activator, ocriplasmin, C3F8, air), periocular pharmacological 
intervention, argon laser photocoagulation, verteporfin photodynamic therapy, diode 
laser, transpupillary thermotherapy, or ocular surgical intervention

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, glaucoma surgery, 
corneal transplant, or radiotherapy)

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 exclusion criterion for the fellow eye (non-study eye) at 
both the screening and Day 1 visits will be excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of non-study eye (i.e., monocular)
4.1.2.4
Exclusion Criteria for Both Eyes 
Patients who meet the following exclusion criteria for either eye 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 ocular inflammation or suspected or active ocular or periocular infection 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 central reading center will evaluate CFPs, FFA, and 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 arms 


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(faricimab up to Q16W or aflibercept Q8W).  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 (the Day 1 visit).
Randomization will be stratified by the following baseline factors (Day 1):

Baseline BCVA ETDRS letter score (74 letters, 7355 letters, and 54 letters)

LLD (33 letters, and 33 letters) (adapted from Frenkel et al. 2016)

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.  
LLD may contribute to variability of BCVA outcomes in patients with AMD treated with 
anti-VEGF therapy. Data from the Harbor study have shown that LLD at baseline is 
inversely proportional to the change from baseline in BCVA in nAMD patients treated 
with ranibizumab (Frenkel et al. 2016).
Enrollment may be closed or temporarily paused by region or country to ensure 
sufficiently balanced recruitment of patients globally.
4.2.2
Masking
This is a double-masked study.  There must be a minimum of two investigators per site 
to fulfill the masking requirements of this study, and a masked and unmasked 
investigator are required to be present at each scheduled study visit.  
4.2.2.1
Masked Roles
Principal Investigator
The Principal Investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) must be in a masked role as he or she has to oversee the whole trial conduct 
at his or her site and must be masked to patients’ treatment assignment.  In addition, the 
Principal Investigator can assume any other masked role for which he or she qualifies 
except for tasks performed by the BCVA examiner. 
Assessor Physician
At least one investigator who will be a retina specialist (or the equivalent in ex-U.S. 
countries) will be designated as the assessor physician. He or she will be masked to 
patients’ treatment assignment and will evaluate all pre-treatment assessments, as well 
as all assessments performed at screening, Day 7, and at the final or early termination 
visit.  The assessor physician will also evaluate the causality of all adverse events 
reported by the treatment administrator physician.  If qualified, this role can take on any 
other masked role tasks except for tasks performed by the BCVA examiner.  


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Photographer(s) and OCT Technician(s)
If qualified, the photographers and OCT technicians can share any other masked role 
tasks except for tasks performed by the BCVA examiner.  
Study Coordinator(s)
If qualified, the study coordinator(s) can share any other masked role tasks except for 
tasks performed by the BCVA examiner.  
BCVA Examiner 
The BCVA examiner will be masked to both the assigned treatment arm and the location 
(right vs. left) of the study eye.  The BCVA examiner will have no access to patients’ 
medical charts or the VA scores from a patient’s previous visits and may have access 
only to a patient’s refraction data from previous visits.  The BCVA examiner is not 
allowed to perform any other task involving direct patient care.
Phlebotomist
The phlebotomist’s tasks can be performed by a qualified masked or unmasked role
individual except for tasks performed by the BCVA examiner. 
4.2.2.2
Unmasked Roles
Treatment Administrator
At least one investigator will be designated as the treatment administrator and will be 
unmasked to the patients’ treatment assignment.  The treatment administrator 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 the 
equivalent in ex-U.S. countries) may be permitted to perform the role of the treatment 
administrator following Sponsor approval.
The treatment administrator(s) performing the study treatment administration (faricimab, 
aflibercept, or sham) will also perform the post-treatment administration vision testing 
(finger counting and, if applicable, hand movement and/or light perception tests) and will 
treat adverse events that occur during or shortly after the study treatment administration.  
The person in this role, however, will not evaluate the causality of adverse events, which 
is the responsibility of the masked assessor physician(s).  The treatment administrator 
will also perform post-treatment IOP measurements, as well as optional aqueous humor
sample collection. 
In addition, the qualifying treatment administrator can assist with and perform the 
screening and Day 1 visit assessments.  The treatment administrator must not be 
involved in any other aspect of the study and must not divulge treatment assignment to 
anyone. 
Unmasked Assistant(s) and Pharmacist
If desired, sites may have designated qualified unmasked assistant(s) who can, for 
example, assemble study treatment supplies, prepare the sterile field, prepare the 


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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 assistant(s) can be assigned to measure post-dose IOP. If the site
uses a pharmacy, then the unmasked role is also assigned to the pharmacist who can 
perform study drugrelated tasks as applicable per the Delegation of Authority Log. In 
addition, qualifying unmasked assistant(s) 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 Sponsor. 
Please note that if the site is using a pharmacist(s), they are not included in the overall 
site unmasked headcount described above.  Thus, pharmacists may be in an unmasked 
role in addition to the above unmasked site staff.
Any other study assisting personnel not listed above will be in the masked roles.
4.2.2.3
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 a designated unmasked role perform any unmasked 
activities, 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 
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.  If the assessor physician is unavailable, then any clinic physician 
present, including the physician in the treatment administrator role, should see the 
patient. 
4.2.2.6
Masking of Vendors, Sponsor's Agents, and 
Laboratory Personnel 
Central reading center 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 this clinical trial.  These roles 
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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 Data Access Charter to audit the implementation of the randomization 
scheme and the treatment 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 
either 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.
4.2.2.7
Patient Masking
Patients will be masked to treatment assignment during the study and until 
study closeout, until the Sponsor indicates that the study can be unmasked. 
4.2.3
Unmasking
4.2.3.1
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 investigator will be able to break the treatment code by 
contacting the IxRS.  The 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.
4.2.3.2
Single-Patient Non-Emergency Unmasking
If the investigator wants 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 
investigator should document and provide an explanation for any non-emergency 
unmasking.  The investigator will be able to break the treatment code by contacting 
the IxRS. 
4.2.3.3
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 investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 


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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.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is faricimab (test product).
Aflibercept is being used as an active comparator in this study; therefore, aflibercept is 
also considered an IMP for this study when administered to the study eye.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Faricimab, Aflibercept, and Sham 
4.3.1.1.1
Faricimab Formulation
Faricimab will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials. 
4.3.1.1.2
Aflibercept (Active Comparator) Formulation
Aflibercept will be supplied by the Sponsor as a sterile liquid for IVT injection in 
single-use glass vials.   
4.3.1.1.3
Sham Formulation
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.
4.3.1.1.4
Faricimab, Aflibercept, and Sham Packaging and Handling
Faricimab, aflibercept, and sham packaging will be overseen by Roche's Clinical Trial 
Supplies Department and bear labels with the identification required by local law, the 
protocol number, drug identification, and its concentration.
The packaging and labeling of faricimab, aflibercept, and sham will be in accordance 
with Roche standards and local regulations.
Faricimab, aflibercept, and sham must be stored according to the details on the product 
label and the information provided in the pharmacy manual.
For more detailed information on the formulation and handling of faricimab, aflibercept,
and sham, see the pharmacy manual. 
Upon arrival of the masked investigational products at the site, site personnel should 
check individual carton boxes for damage and verify proper identity, quantity, integrity of 
seals and temperature conditions, and report any deviations or product complaints to the 
unmasked monitor upon discovery.  Any product under investigation for integrity or 


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temperature excursion should be quarantined by the IxRS, pending final assessment by 
the Sponsor.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.
4.3.2.1
Dosage
4.3.2.1.1
Intravitreal Faricimab Injections
Patients randomized to Arm A will receive 6 mg of IVT faricimab Q4W up to Week 12 
(4 injections). At Week 20, protocol-defined assessment of disease activity requires 
patients in Arm A with active disease (for the criteria, refer to Section 3.1.1.4) to be 
treated with a Q8W dosing regimen of 6 mg of faricimab (i.e., injections at Weeks 20, 28, 
36, 44, 52, and 60). 
A second protocol-defined assessment of disease activity at Week 24 requires patients 
in Arm A with active disease (see Section 3.1.1.4, excluding those with active disease at 
Week 20 and therefore receiving a Q8W dosing regimen of 6 mg of IVT faricimab) to be 
treated with a Q12W dosing regimen of 6 mg of IVT faricimab (i.e., injections at 
Weeks 24, 36, 48, and 60). 
Patients receiving faricimab who do not have active disease according to the protocol-
defined criteria (see Section 3.1.1.4) at Week 20 or Week 24 will be treated with 6 mg of 
IVT faricimab Q16W (i.e., injections at Weeks 28, 44, and 60).
From Week 60 (when all patients in Arm A are scheduled to receive study drug) to 
Week 108, patients in Arm A will be treated according to a PTI dosing regimen (between 
Q8W and Q16W). At study drug dosing visits, treatment intervals may be maintained or 
adjusted (i.e., increased by 4 weeks or decreased by 4 or 8 weeks), based on OCT, 
BCVA, and clinical assessment (for the criteria, refer to Section 3.1.1.5). Patients will 
therefore receive between 10 and 16 injections over the study treatment period (Day 1 to 
Week 108).
See the study schema in Figure 1.
4.3.2.1.2
Intravitreal Aflibercept (Active Comparator) Injections 
For patients randomized to the active comparator (Arm B), a 2-mg dose of aflibercept 
will be administered intravitreally Q8W after 3 consecutive monthly doses during the 
108-week treatment period (see Figure 1).  Patients will receive 15 IVT injections of 
aflibercept during the 108-week treatment period.  This will consist of three initiating 
injections (2 mg of aflibercept Q4W to Week 8), followed by 12 maintenance injections 
(2 mg of aflibercept Q8W at Weeks 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, and 104).
4.3.2.1.3
Sham Procedure
Both treatment arms (faricimab up to Q16W and aflibercept Q8W) will maintain Q4W 
study visits for the duration of the study.  To preserve masking of the randomized 


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treatment arm, patients will have the sham procedure performed at study treatment visits 
when they are not treated with either faricimab or aflibercept as applicable per their 
treatment arm schedule (see Figure 1).
4.3.2.2
Administration
4.3.2.2.1
Faricimab or Aflibercept Intravitreal Injections or 
Sham Procedure
See the pharmacy manual for the pre-treatment procedures, the administration of 
faricimab, aflibercept, or sham and the post-treatment procedures for all treated patients.
4.3.2.2.2
Study Treatment Preparation
The pharmacist responsible for dispensing the study drug or designated unmasked site
personnel will prepare the correct study drug (faricimab, aflibercept, or sham) as
assigned through the 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 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 or aflibercept vials, 
as well as administration material must not be reused.  
4.3.2.3
Compliance
Any medication error, including drug overdose, should be noted on the Adverse Event 
eCRF, even if it did not result in any adverse event (see Adverse Event eCRF 
completion guidance and Section 5.3.5.12).
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Table 3 and Section 5.1.4.1.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (faricimab, sham, and aflibercept) will be 
provided by the Sponsor.  The study site will acknowledge receipt of IMPs supplied by 
the Sponsor using the IxRS to confirm shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 


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with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to 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 would not 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for nAMD

The Sponsor has reasonable safety concerns regarding the IMP as treatment 
for nAMD 

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 prescription drugs or 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 preceding the Day 1 visit and through the conclusion of the patient’s study 


 
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participation or early termination visit.  Patients required to use therapy that is prohibited 
(see Section 4.4.3) will not be eligible for the study. 
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 
At the discretion of the investigator, patients may continue to receive medications and 
standard treatments administered for other conditions, with the exceptions listed in 
Section 4.4.3. 
Of note, the following are some common therapies that are permitted: 
 
Onset of ocular hypertension or glaucoma in the study eye during a patient’s study 
participation should be treated as clinically indicated. 
 
Onset of cataract or posterior capsular opacification in either eye during a patient’s 
study participation may be treated as clinically indicated.  Dose interruption criteria 
(see Section 5.1.4.1, Table 3) may apply with cataract surgery. 
 
Short-term use of topical corticosteroids after cataract surgery, yttrium-aluminum 
garnet laser capsulotomy, or peripheral iridotomy is permitted. 
 
Patients who require anti-VEGF treatment for their fellow eye should continue or 
initiate treatment according to instructions in Section 4.4.2. 
 
4.4.2 
Fellow (NonStudy) Eye Treatment with Anti-VEGF Therapy 
At the discretion of the masked physician, randomized patients may have their fellow 
(non-study) eye treated with anti-VEGF therapy licensed for ocular use if they are 
diagnosed with an ocular condition for which the selected anti-VEGF therapy is 
approved by the country regulatory agency.  Consult with the region-specific anti-VEGF 
prescribing information for the recommended dose and frequency of treatment.  The 
Sponsor will cover the cost of the approved licensed ocular anti-VEGF therapy in 
accordance with local regulations.  Note:  Avastin (bevacizumab) is not licensed for 
ocular use in any country; therefore, its use is prohibited. 
Note:  If (per the masked investigator's judgment) treatment with anti-VEGF therapy 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 
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Note:  If the fellow eye anti-VEGF treatment is performed outside of the study visit, 
then the qualified physician either in masked or unmasked role can administer the 
treatment. 
4.4.3
Prohibited Therapy
At the discretion of the investigator, patients may continue to receive medications and 
standard treatments administered for other conditions.  However, 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 the 
study eye 

IVT, periocular (subtenon), steroid implants (i.e., Ozurdex®, Illuvien®), or chronic 
topical (ocular) corticosteroids in the study eye 

Concurrent use of any macular photocoagulation or photodynamic therapy with 
verteporfin in the study eye

Other experimental therapies (except those comprising vitamins and minerals)
Note:  Patients who discontinue study treatment should be strongly encouraged to 
continue their study participation and undergo as many scheduled visits as possible, 
with emphasis on the Weeks 44, 48, 52, and 112 visits.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  Written informed 
consent will be obtained prior to initiation of any study procedures.  The screening 
evaluation will be performed within 28 days preceding the Day 1 visit (the day of the first 
study treatment).
Note:  Some patients may require an extended screening period as a result of repeated 
evaluation of images or other issues.  Upon agreement with the Medical Monitor, the 
screening period may be extended for up to 5 business days for such cases.
All assessments for a scheduled visit are to be performed on the same day, except 
those performed during the screening period (see Section 5.1.4.1, Table 3).
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 or re-screening 


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evaluations).  Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site.
All screening and Day 1 visit evaluations must be completed and reviewed to confirm
that patients meet all eligibility criteria before randomization at the Day 1 visit.  The 
investigator will maintain a screening log to record details about all patients screened 
and to confirm eligibility.  Reasons for screening failure have to be documented in 
patients' source documents.  
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, chronic and ongoing conditions 
(e.g., trauma, cancer, cardiovascular, cerebrovascular, and ophthalmic history), 
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 a patient within 7 days prior to initiation of 
study treatment (the Day 1 visit) and up to 28 days after the last drug dosing visit will 
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 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.
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
In addition, a patient’s height and weight will be recorded.  
4.5.4
Vital Signs
Vital signs will include measurements of temperature, respiratory rate, pulse rate, and 
systolic and diastolic blood pressure.  Vital signs will be taken with the patient in a 
seated position after resting for 5 minutes.


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4.5.5
Ocular Assessments
Ocular assessments include the following and will be performed on both eyes, unless 
otherwise indicated, at specified timepoints according to the schedule of activities in 
Appendix 1:

BCVA assessed on an ETDRS chart at a starting distance of 4 meters (performed
prior to dilating eyes; see Appendix 4)

Low-luminance BCVA, as assessed on the ETDRS chart at a starting distance of 
4 meters (performed prior to dilating eyes; see Appendix 5)

Pre-treatment IOP measurement of both eyes (performed prior to dilating eyes)

Slitlamp examination (for grading scales for anterior and vitreous cells, see 
Appendix 3)

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 by the unmasked treatment administrator.

Post-treatment IOP measurement only in the study eye after 30 (15) minutes of 
study treament administration by qualified personnel assigned to the unmasked role
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, the patient will remain in the clinic 
and will be managed in accordance with the treatment administrator’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 central reading center(s) will provide sites with the central reading center(s) 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 reading center(s) as specified in the central reading center 
manual.  All ocular images results will be obtained by trained site personnel at the study 
sites and forwarded to the central reading center(s) for independent analysis and/or 
storage (see Appendix 6, Appendix 7, and Appendix 8).
Note:  After randomization, if a patient misses a study visit when CFP, FFA, or ICGA (if 
applicable) ocular images are scheduled (see Appendix 1), the images should be 
obtained at the next scheduled visit the patient attends. 
Ocular images include the following:

CFP of both eyes (please note that ultra-wide photography [UWP)] is not 
permitted)


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
FFA of both eyes (performed after laboratory samples are obtained; please note that 
UWP is not permitted)

SD-OCT or swept-source OCT (SS-OCT) images of both eyes
Certain SS-OCT machines may be acceptable; consult the central reading 
center.  

Optional OCT-angiography (OCT-A) of both eyes at sites with agreed
OCT-A capabilities

Optional ICGA of both eyes at selected sites with agreed ICGA capabilities 
(performed after laboratory samples are obtained) and after all other imaging has 
been performed.  However, if a site’s standard of practice is to perform ICGA in 
parallel with FFA, this is also acceptable.  Please refer to the central reading center 
manual.
Additional details on obtaining these images are included in the central reading 
center manual.
4.5.6
Concurrent Ocular Procedures
Any ocular procedures performed on either eye during the study (starting on Day 1,
post-study treatment) 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-eye treatment and 
FFA assessments (if applicable).  Fasting is not required prior to specimen collection.
The specimens will be forwarded to the central laboratory.  The central laboratory will 
either perform the analysis or forward samples to the Sponsor or its designee for 
analysis and/or storage.  Instructions for obtaining, processing, storing, and shipping of 
all specimens are provided in the laboratory manual.  Laboratory supply kits will be 
provided to the sites by the central laboratory.  See Appendix 1 for sample collection 
timepoints and the laboratory manual for biological sample collection and shipping 
instructions.  Except as noted (see Appendix 9), all samples obtained during screening 
from patients who are not randomized will be discarded.
The following assessments will be performed:

Hematology:  hemoglobin, hematocrit, quantitative platelet count, RBC counts, 
WBC counts, and differentials, including neutrophils, bands, lymphocytes, basophils, 
eosinophils, and monocytes (absolute)

Serum chemistry:  sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, 
albumin, ALP, AST, ALT, and uric acid

Urinalysis:  specific gravity, pH, blood, protein, ketones, glucose, bilirubin, 
urobilinogen, and microscopic examination (if any of the preceding urinalysis tests, 
other than glucose and ketones, are abnormal)


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
Coagulation:  activated partial thromboplastin time and prothrombin time

Pregnancy test
All women of childbearing potential (including those who have had tubal ligation) 
will have a urine pregnancy test at screening and prior to each study treatment.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.  If the serum pregnancy test is positive, do not administer study treatment. 

Plasma samples for measurement of anti-drug (faricimab) antibodies (ADAs)

Plasma samples to measure faricimab or aflibercept concentration (mandatory and 
optional samples from patients who consent to aqueous humor sampling)

Plasma samples for analysis of systemic free VEGF-A, free Ang-2, and additional 
biomarkers (PD sample) (mandatory and optional samples from patients who 
consent to aqueous humor sampling)
Drug concentration, free VEGF-A, and free Ang-2 will be determined in plasma using a 
validated immunoassay method.  ADAs will be detected in plasma using a validated 
bridging ELISA.
Unless the patient gives specific consent for his or her leftover plasma samples to be 
stored for optional exploratory research (see Section 4.5.9.1), the samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed.  
The hematology, serum chemistry, urinalysis, coagulation, and serum and urine 
pregnancy test samples will be destroyed after their analysis during the study.
4.5.7.1
Optional Aqueous Humor and Optional Plasma Samples
Collection and submission of optional aqueous humor and optional plasma samples is 
contingent upon the 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 4.5.7.1) will not be applicable at that site.  
For patients who consent to provide aqueous humor sampling, the aqueous humor 
sample should be collected just prior to study treatment by a qualified unmasked 
treatment administrator, using an aseptic procedure and sterile field and according to 
local guidelines (see Appendix 9 and the laboratory manual for further details on sample 
collection, storage, and transfer). Samples should be frozen according to the 
instructions provided to sites. All efforts should be made to obtain a baseline aqueous 
humor sample on Day 1 (pre-dose).  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.  
Aqueous humor samples will be analyzed for faricimab or aflibercept, free VEGF-A, and 
free Ang-2 concentrations.  Remaining samples will be analyzed for additional 


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biomarkers, including those involved in angiogenesis
 
 and 
inflammation 
 
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.  
At Day 7, sites will collect optional PK plasma samples for measurement of faricimab or 
aflibercept concentrations and optional PD plasma sample for analysis of systemic free 
VEGF-A and free Ang-2 (see Appendix 1 and the laboratory manual for PK/PD samples 
collection, storage, and transfer).
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.5), biological samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.7.2
Optional Unscheduled Collection of Vitreous Samples
Elective vitrectomy for vitreous sample collection is not allowed in the study eye during a 
patient's study participation; however, if the surgery is medically necessary and the 
patient consents, a vitreous sample can be obtained from the study eye (see Appendix 9
for further details). Associated PK plasma samples will be collected to measure faricimab 
or aflibercept concentrations.  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 VEGF-A and free 
Ang-2 concentrations, as well as additional biomarkers, including those involved in 
angiogenesis 
 
 and inflammation 
 
 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.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.9.5), biological samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.8
Patient-Reported Outcomes
Patient-reported outcomes (PROs) will be assessed using the National Eye Institute 
Visual Function Questionnaire-25 (NEI VFQ-25; see Appendix 10).  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 
one item on general health.  In this study, an additional six items will be included for the 
Near Activities and Distance Activities subscales.  The composite score and subscale 


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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. 
The NEI VFQ-25 will be interviewer administered by the masked site staff (except for the 
VA examiner) prior to any other visit assessments being performed.  Interviews will be 
conducted in the local language of the patient using linguistically validated translations.  
Patients may be excluded from completing the NEI VFQ-25 if a translation is not 
available in their spoken language. 
4.5.9
Optional Samples for Research Biosample Repository
4.5.9.1
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 specimens will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow 
for individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.9.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection, and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB or 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 4.5.9) will not be applicable at that site.  The RBR portion of the 
Informed Consent Form has to be agreed to and signed by the consenting patient before 
these samples can be collected and/or mandatory residual samples used. 


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4.5.9.3
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 response to faricimab, to 
improve the understanding of the biology of VEGF-A and Ang-2, or to better understand 
the targets or diseases (nAMD):

Whole blood sample for DNA 

Residual aqueous humor sample

Residual vitreous sample 

Residual plasma PD sample

Residual PK sample

Residual ADA sample
The whole blood sample for DNA may be sent to one or more laboratories for analysis
via whole genome sequencing (WGS), next-generation sequencing, or other genomic 
analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.
Data will be analyzed in the context of this study but will also be explored in aggregate 
with data from other studies.  The availability of a larger dataset will assist in 
identification of important pathways guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  For all samples, the dates of consent and specimen collection should 
be recorded on the associated RBR eCRF.
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.9.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.


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Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.9.5
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 specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.9.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens 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 
specimens 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 specimens, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  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


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A patient's withdrawal from this study does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from this study.  
4.5.9.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP)
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Occurrence of any medical condition that the investigator or Sponsor determines 
may jeopardize the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced and will not be allowed to restart study treatment.  However, they should be 
strongly encouraged to continue their study participation and undergo as many 
scheduled visits as possible, with emphasis on the Week 40, 44, 48, 60, and 112 visits. 
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator and Sponsor has the right to withdraw a patient from the 
study at any time.  Reasons for withdrawal from the study may include, but are not 
limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues in the study 

Investigator or Sponsor determines it is in the best interest of the patient 


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
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.
If a patient discontinues from the study but has not withdrawn informed consent, the site 
should make every effort to continue to follow-up on serious adverse events, deaths, and 
adverse events of special interest.  In order to avoid loss to follow-up, the investigator 
should ask the patient at the study start for the contact information of 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 withdrawn.  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 but have not withdrawn consent should 
return for an early termination visit (see Appendix 1) after a minimum of 28 days have 
elapsed following the last study treatment.
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 
GCP

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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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 
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 
pre- and post-treatment antimicrobials, patients will also be asked whether they have 
self-administered pre- and/or post-treatment antimicrobials.  
A finger counting test will be conducted for each patient within 15 minutes following 
study treatment by the treatment administrator; 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, 
the patient will remain in the clinic and will be managed in accordance with the treatment 
administrator’s clinical judgment.  The adverse event will be recorded on the Adverse 
Event eCRF as applicable.  
Note:  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 4.4.2 for additional details).  
Detailed ocular examinations, including indirect ophthalmoscopy and slitlamp 
examination, will be performed throughout the study.  Blood samples for plasma study 
drug concentrations, antibodies to faricimab, and other biomarker samples (see 
Section 4.5.7) will be obtained from all patients at selected timepoints.  The optional 
aqueous humor and vitreous samples will be obtained from patients who consent to the 
procedure and sample collection.
An iDMC will monitor safety and study conduct on an ongoing basis (see Section 3.1.5
for additional details).


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Patients who are discontinued from the study prior to completion (Week 112) 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 Section 5.1.4.1, Table 3.
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 
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 the Comparator Aflibercept
Important risks associated with aflibercept IVT injections are infective 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)
Summary of Product Characteristics.
5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
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 3.  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 or discontinuation should be recorded on the appropriate eCRF and, if 
applicable, on the Adverse Event eCRF.


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Table 3
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 Medical Monitor and investigator.
Intraocular surgery in the 
study eye

Interrupt study treatment after intraocular surgery 
(e.g., cataract surgery) in the 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 or other intraocular, 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 30 letters in BCVA 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 investigator.
Elevated IOP

Interrupt study treatment if pre-treatment IOP in the study 
eye is 30 mmHg.

Treatment may be permitted when IOP has been lowered 
to 30 mmHg, either spontaneously or with treatment, as 
determined by 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 
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 infection

Interrupt study treatment if active or suspected ocular or 
periocular infections present (e.g., infectious 
conjunctivitis, infectious keratitis, infectious scleritis, or 
endophthalmitis) in either eye or if the patient requires 
treatment for an active non-ocular infection. 

Study treatment may be subsequently permitted after 
discussion with Medical Monitor.
On-study prohibited medications

See Section 4.4.3 for a list of prohibited therapies 
during the study.
BCVAbest-corrected visual acuity; IOPintraocular pressure.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9
and 5.3.5.10 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)
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)


 
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 
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 according to the Adverse 
Event Grading Scale; see Section 5.3.3, Table 4); 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) 
 
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: 


 
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– 
It causes a decrease of  30 letters in VA score (compared with the last 
assessment of VA 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 5.2.3 and Appendix 3 
for intraocular inflammation grading scales). 
 
All of the above-listed sight-threatening adverse events should 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 investigator who is 
in the masked role. 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until the final study visit 
at Week 112.  For patients who terminate study treatment and from the study early, all 
adverse events will be reported up to the early termination visit.  For patients who 
discontinue study treatment early (prior to Week 108 treatment) but continue to 
participate in the study, adverse events will be reported until their last or final study visit.   


 
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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 4 provides guidance for assessing adverse event severity. 
Table 4 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  Note:  Only the masked investigator will assess all adverse event causality.  
The following guidance should be taken into consideration (see also Table 5): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, 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 
 


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Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
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.

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.


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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.

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.


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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., ALP and bilirubin 5the upper limit of normal [ULN] associated with cholestasis), 
only the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 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 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by 
Hy's Law).  Therefore, investigators must report as an adverse event the occurrence of 
either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.4) 
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.


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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
Worsening of Neovascular Age-Related Macular Degeneration
in the Study Eye
Medical occurrences or symptoms of deterioration that are anticipated as part of nAMD 
in the 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 nAMD on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., "accelerated worsening of neovascular age-related 
macular degeneration"). The expedited reporting requirements for associated 
sight-threatening events (listed in the Section 5.2.3) will apply.
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


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5.3.5.11
Adverse Events Associated with an Overdose or Error in 
Drug Administration
No safety data related to overdosing of faricimab are available. See Section 5.3.5.12 for 
additional medication error reporting details. 
5.3.5.12
Reporting Requirements for Cases of Medication Error and 
Associated Adverse Events
Medication Error Definition and Reporting
Medication error, including the error intercepted prior to administration and accidental 
overdose (hereafter collectively referred to as "special situations"), are defined as 
follows: 

Medication error is 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 is 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 a masked manner as described below:
For medication error enter “Medication Error” on the Adverse Event eCRF as the 
primary event term and check the “Medication error” box (see eCRF Completion 
Guidelines for additional details).
For intercepted medication error enter “intercepted Medication Error” on the 
Adverse Event eCRF as the primary event term and check the “Medication Error” 
box (see eCRF Completion Guidelines for additional details).
Reporting of Adverse Events Resulting from Special Situation
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 it is 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:

Enter the adverse event caused by the medication error as primary adverse event 
term on Adverse Event eCRF.  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.






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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or for at least 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 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).


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5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
a minimum of 28 days after the final dose of study drug for patients who complete study 
treatment, i.e., the Week 108 visit; for the patients who discontinue study treatment early 
but continue to participate in the study, the adverse events reporting period is until their 
last or final study visit whichever is later), if the event is believed to be related to prior 
administration of study 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.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Faricimab (RO6867461) Investigator's Brochure

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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Approximately 640 patients will be randomized in the global enrollment phase of this 
study.
 
The primary and the final analyses of this study will include only patients enrolled during 
the global enrollment phase; 
 
The primary analysis will be performed when all patients from the global enrollment 
phase have either completed the study through Week 48 or have discontinued from the 
study prior to Week 48, whichever comes later (i.e., timing is defined as the primary 
analysis after 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. Additional 
analyses of key efficacy endpoints may be performed between the primary analyses and 
final analyses to support marketing applications.
Results of the primary analyses, 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 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 112 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 
. Details of 
the planned analyses, including any additional analyses needed to support


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country-specific or regional marketing applications, will be provided in the Statistical 
Analysis Plan.
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 640 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 Q8W) and the faricimab 
up to Q16W arm.
A sample size of approximately 320 patients in each arm will provide greater than 90% 
power to show non-inferiority of faricimab to aflibercept in the change in BCVA averaged 
over Weeks 40, 44, and 48 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 two treatment 
arms

Standard deviation (SD) of 14 letters for the change from baseline in BCVA 
averaged over Weeks 40, 44, and 48

Two-sample t-test

2.5% one-sided type I error rate

10% dropout rate
To ensure appropriate patient representation, the Sponsor may elect to cap the 
recruitment of patients in certain baseline BCVA strata.  If implemented, details of the 
cap will be described in the Statistical Analysis Plan. 
The sample size may be adjusted as appropriate based on a masked assessment of the 
pooled SD of the change in BCVA from baseline. The assessment will be performed by 
the Sponsor at a specified timepoint prior to completing enrollment. Details on the 
masked sample size re-estimation conducted, as well as actions and decisions taken 
regarding changes in sample size, will be documented in the Statistical Analysis Plan. 
The Sponsor will remain masked. Other factors external to the study may also trigger a 
decision to modify the sample size.
6.2
ANALYSIS POPULATIONS
The analysis populations used in this section, such as the ITT population, are based on 
patients enrolled during the global enrollment phase 
.


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6.2.1
Intent-to-Treat Population
The ITT population will comprise 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. 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 comprise all patients who receive at least one 
injection of active study drug (faricimab or aflibercept). For analyses based on this 
patient population, patients will be grouped according to the actual treatment received up 
to Week 48. 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.
6.2.4
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 the previous section).
6.2.5
Immunogenicity-Analysis Population
The immunogenicity-analysis population will consist of all patients 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.
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 


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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.
Exposure to study drug (number of study drug administrations and duration of treatment) 
will be summarized by treatment group 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.
The primary comparison will be between the active comparator (aflibercept Q8W) and 
the faricimab up to Q16W arm. 
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.
6.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in BCVA averaged over 
Weeks 40, 44, and 48. The BCVA outcome measure is based on the ETDRS VA chart 
assessed at a starting distance of 4 meters.
The primary comparison will be to test non-inferiority of faricimab compared with 
aflibercept in the ITT population. Additional analysis based on the per-protocol 
population will also be conducted.
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 averaged over 
Weeks 40, 44, and 48 for the faricimab up to Q16W arm and the active comparator 
(aflibercept Q8W), respectively.  
The change from baseline averaged over Weeks 40, 44, and 48 will be compared 
between the faricimab up to Q16W arm and the aflibercept Q8W arm using a MMRM 
model. The model will include the change from baseline at Weeks 448 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.  Comparisons between the two treatment arms will be made using a  
composite contrast over Weeks 40, 44, and 48. The MMRM model will assume an  


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unstructured covariance structure. If there are convergence problems with the model,  
then a heterogeneous compound symmetry or an AR(1) covariance structure may be fitted.
Missing data will be implicitly imputed by the MMRM model, assuming a missing at 
random missing data mechanism (i.e., the probability that missing data are dependent 
on other observed variables but not on the missing data). Data for patients who receive
prohibited therapy will be censored at the timing of use of prohibited therapy. Data for 
patients who discontinue from study drug and do not receive prohibited therapy after 
discontinuation of study drug will be included in the analysis.
Additional details about the planned analyses, as well as supplementary and sensitivity 
analyses using other imputation methods for missing data, analysis using the trimmed 
mean approach for patients who receive prohibited therapy or discontinue study drug
due to lack of efficacy or adverse events, analyses of the per-protocol population, and 
subgroup analyses to assess the robustness of the primary endpoint results will be 
provided in the Statistical Analysis Plan.
Non-Inferiority Margin
Non-inferiority hypothesis testing for the primary endpoint of the change from baseline in 
BCVA averaged over Weeks 40, 44, and 48 will be performed using a 4-letter 
non-inferiority margin. The non-inferiority margin is based on data from the MARINA 
ranibizumab pivotal nAMD study and is also supported by both data from the ANCHOR 
ranibizumab pivotal nAMD study and the VIEW1 and VIEW2 aflibercept pivotal nAMD 
studies.
The MARINA study compared ranibizumab with sham (placebo) control in 716 patients. 
At 1 year, in MARINA, patients receiving 0.5 mg of ranibizumab every month gained 
6.3 letters from baseline compared with a loss of 11.0 letters for patients in the control 
arm. The 4-letter non-inferiority margin preserves approximately 70% of the least 
estimated benefit of ranibizumab over sham control in the MARINA study.
Furthermore, the ANCHOR study compared ranibizumab to verteporfin photodynamic 
therapy control in 423 patients. At 1 year, in ANCHOR, patients receiving 0.5 mg of 
ranibizumab every month gained 11.0 letters from baseline compared with a loss of 
8.5 letters for patients in the control arm. 
The VIEW1 and VIEW2 studies compared different doses and regimens of aflibercept 
with an active control of 0.5 mg ranibizumab in 2412 patients. VIEW1 was conducted in 
the United States and Canada, and VIEW2 was conducted in Europe, Latin America, the 
Middle East, and the Asia-Pacific region. At 1 year, in VIEW1 and VIEW2, patients 
receiving 0.5 mg of ranibizumab every month gained 8.1 and 9.4 letters from baseline, 
respectively, and patients receiving 2 mg of aflibercept Q8W gained 7.9 and 9.4 letters 
from baseline, respectively, demonstrating the clinical equivalence of these treatments. 


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The non-inferiority 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, 
the non-inferiority margin should be fewer than 5 letters, given that a loss of 5 letters 
(one ETDRS line) between treatments would be considered clinically relevant.
6.5.2
Secondary Efficacy Endpoints
For all secondary endpoints measured on a continuous scale, the same analysis method 
and data handling rules as described in Section 6.5.1 for the primary endpoint will be 
used.  
For binary secondary endpoints, 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). 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 (Mehrota and Railkar 2000).
Additional details regarding the plan for the secondary endpoint analyses will be 
provided in the Statistical Analysis Plan.
6.5.3
Exploratory Efficacy Endpoints
Details regarding the exploratory efficacy endpoints will be provided in the Statistical 
Analysis Plan.
6.6
SAFETY ANALYSES
Safety analyses will be based on the safety-evaluable population.
Safety will be assessed through descriptive summary 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 48 data in the safety-evaluable population. In addition, summaries for 
ongoing safety data (after Week 48 and up to a single specified clinical cutoff date) in the 
safety-evaluable population will be summarized. At the time of the final analysis, safety 
summaries will be produced based on cumulative Week 112 data in the safety-evaluable 
population.
Verbatim descriptions of treatment-emergent adverse events will be mapped to Medical 
Dictionary for Regulatory Activities (MedDRA) thesaurus terms, and the incidence and 


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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.  
Separate summaries will be prepared for non-ocular and ocular adverse events.
Results of the ocular assessments will be summarized by eye (study vs. fellow) using 
descriptive summaries. In addition, changes from baseline in pre-dose IOP 
measurements and changes between pre-dose and post-dose IOP measurements will 
also be summarized.
Additional details regarding the safety analysis plan will be provided in the Statistical 
Analysis Plan.
6.7
PHARMACOKINETIC ANALYSES
PK analyses will be performed in the PK-evaluable population.  
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 and 
aflibercept. 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 to update the current population-PK model.  The model may be revised if 
necessary.  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 VEFG-A, and Ang-2 


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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
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 (post-baseline incidence) 
will be summarized by treatment group. When determining the post-baseline 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 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-dose samples is greater than the titer of the baseline sample by a 
scientifically reasonable margin (details to be provided in the Statistical Analysis Plan). 
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all post-baseline samples are negative, or if they are ADA positive 
at baseline but do not have any post-baseline samples with a titer that is greater than the 
titer of the baseline sample by a scientifically reasonable margin such as 4-fold (if 
1:2 dilution steps are applied).
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. 
Baseline values will be used to evaluate predictive biomarkers in the context of efficacy, 
PK, safety, and/or immunogenicity endpoints. Descriptive summaries will be presented 
by treatment and timepoint.
WGS 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.


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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 central
reading center 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.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the 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, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 


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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 
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 at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


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Roche will retain study data for 25 years after the Clinical Study Report has been 
completed for the length of time required by relevant medical or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the 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 will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/EC-approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. 
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient 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.


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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient.  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. 
HIPAA of 1996.  If the site utilizes a separate Authorization Form for patient 
authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that 
IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
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 


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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  
In addition, redacted clinical study reports and other summary reports will be provided 
upon request.
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 
study and for 1 year after completion of the study (see the 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.


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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored 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 640 patients.  
Enrollment will occur through an 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.  
9.5
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 of the U.S. National Institutes of Health and the 
European Medicines Agency, 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, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 


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has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
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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Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet 
age-related macular degeneration. Ophthalmology 2012;119:253748.


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Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular 
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ocular vascular endothelial growth factor levels by ranibizumab in patients with 
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Faricimab—F. Hoffmann-La Roche Ltd
111/Protocol GR40306, Version 3
Appendix 1
Schedule of Activities
Table 1
Screening through Week 48 Assessments
Screening a
Visit Day
Visit Week 
ET b
(28)
1 a
7
4
8
12
16
20
24
28
32
36
40
44
48
Day(s)
(Visit window)
–28 to 1
N/A
(3)
28
(7)
56
(7)
84
(7)
112
(7)
140
(7)
168
(7)
196
(7)
224
(7)
252
(7)
280
(7)
308
(7)
336
(7)
Informed consent c
x
Sample informed consent c for 
optional aqueous, vitreous, and blood
samples
x
Optional (RBR) residual samples and 
DNA whole blood sample informed 
consent c
x
Review of inclusion and exclusion 
criteria
x
x
Demographic data
x
Medical history d
x
Targeted physical examination e
x
x
Body weight and height
x
Vital signs f
x
x
x
x
NEI VFQ-25 g
x
x
x
x
BCVA h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Low-luminance BCVA
x
x
Pre-treatment IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


Appendix 1  
Schedule of Activities (cont.) 
Faricimab—F. Hoffmann-La Roche Ltd 
112/Protocol GR40306, Version 3 
Table 1 
Screening through Week 48 Assessments (cont.) 
 Screening a 
Visit Day 
Visit Week  
ET b 
( 28) 
1 a 
7 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day(s) 
(Visit window) 
–28 to 1 
N/A ( 3) 
28 
( 7) 
56 
( 7) 
84 
( 7) 
112 
( 7) 
140 
( 7) 
168 
( 7) 
196 
( 7) 
224 
( 7) 
252 
( 7) 
280 
( 7) 
308 
( 7) 
336 
( 7) 
Pregnancy test j 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Whole blood sample (hematology, 
chemistry panel, coagulation), and 
urinalysis k 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Optional aqueous humor sample l 
 
x 
x 
 
 
 
x 
x 
x 
x 
 
 
 
 
 
x 
Optional vitreous humor sample m 
 
If elective vitrectomy is performed m 
Optional PK plasma sample (if 
vitreous humor sample collected) m 
 
If elective vitrectomy is performed and vitreous humor sample collected  m 
Optional blood sample for RBR n 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory plasma PK sample o 
 
x 
 
x 
 
 
x 
x 
 
 
 
 
 
 
x 
x 
Optional PK plasma sample  
(if aqueous humor sample is collected) 
 
 
x p 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory plasma PD sample  o 
 
x 
  
x 
 
 
x 
x 
 
 
 
 
 
 
x 
x 
Optional PD plasma sample (if 
aqueous humor sample is collected) 
 
 
x p 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory plasma sample for ADAs o 
 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
x 
Slitlamp examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Appendix 1  
Schedule of Activities (cont.) 
Faricimab—F. Hoffmann-La Roche Ltd 
113/Protocol GR40306, Version 3 
Table 1 
Screening through Week 48 Assessments (cont.) 
 
Screening a 
Visit Day 
Visit Week  
ET b 
( 28) 
1 a 
7 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Day(s)  
(Visit window) 
–28 to 1 
N/A  ( 3) 
28 
( 7) 
56 
( 7) 
84 
( 7) 
112 
( 7) 
140 
( 7) 
168 
( 7) 
196 
( 7) 
224 
( 7) 
252 
( 7) 
280 
( 7) 
308 
( 7) 
336 
( 7) 
Indirect ophthalmoscopy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
OCT q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Optional OCT-A q, r 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FFA q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
CFP q 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Optional ICGA q, s 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Disease activity  
assessment t 
 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
Administration of study 
treatment 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Finger counting test u 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Post-treatment IOP v 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events w 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concurrent ocular procedures y 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA  anti-drug antibody; BCVA  best-corrected visual acuity; CFP  color fundus photograph; eCRF  electronic Case Report Form; ET  early 
termination; FFA  fundus fluorescein angiography; ICGA  indocyanine green angiography; IOP  intraocular pressure; NEI VFQ-25National Eye 
Institute 25-Item Visual Function Questionnaire; OCT  optical coherence tomography; OCT-A  optical coherence tomographyangiography; 
PD  pharmacodynamic; PK  pharmacokinetic; RBR  Research Biosample Repository; VA  visual acuity. 


Appendix 1
Schedule of Activities (cont.)
Faricimab—F. Hoffmann-La Roche Ltd
114/Protocol GR40306, Version 3
Table 1
Screening through Week 48 Assessments (cont.)
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 relative to the date of the Day 1 visit (first study treatment).  There must be a minimum of 21 days between 
all study visits occurring from Week 4 through Week 108.  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 4.4.2). 
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.  Informed consent must be administered and signed by a patient before any study-specific screening procedure is performed.  When 
screening and randomization are combined and performed on 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:  slitlamp examination, indirect ophthalmoscopy, and pre- and post-treatment IOP measurements (recorded 
on the Day 1 eCRF and dated accordingly).  Verify that the patient has not started any prohibited medication.
b Patients who discontinue from the study early (prior to the final study visit at Week 112) but have not withdrawn consent should return for an
ET visit after a minimum of 28 days have elapsed following their last study treatment.
c Informed consent must be administered and documented before any study-specific screening procedure is performed and may be obtained 
more than 28 days before initiation of study treatment at the Day 1 visit.  The Optional Blood, Aqueous Humor, Vitreous Humor Samples 
Informed Consent Form as well as Optional (RBR) Informed Consent Form for residual samples and whole blood DNA sample collection can be 
signed either at the screening or Day 1 visit prior to sample collection.
d Medical history, including clinically significant diseases, chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, cerebrovascular, 
and ophthalmic history), surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, and smoking history, 
will be recorded at baseline.  
e 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.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.
f
Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure.  Vital signs will be 
measured with the patient in a seated position after resting for 5 minutes.
g To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
h To be performed prior to other ocular assessments. Perform the assessments prior to dilating the eyes.
i
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.


Appendix 1
Schedule of Activities (cont.)
Faricimab—F. Hoffmann-La Roche Ltd
115/Protocol GR40306, Version 3
Table 1
Screening through Week 48 Assessments (cont.)
j
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, do not administer study treatment.  Perform urine pregnancy test before FFA (if applicable).
k Hematology includes hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC counts, and differentials, including neutrophils, 
bands, lymphocytes, basophils, eosinophils, and monocytes (absolute).  Serum chemistry panel includes sodium, potassium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALP, AST, ALT, and 
uric acid.  Coagulation includes activated partial thromboplastin time and prothrombin time.  Urinalysis includes specific gravity, pH, blood, 
protein, ketones, glucose, 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.
l
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.  Not applicable for a site that 
has not been granted approval by a site's Institutional Review Board or Ethics Committee. The sample at ET is not required if there are any 
safety concerns.
m If elective vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood 
sample (for plasma preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for 
faricimab concentrations or aflibercept concentrations.  The remaining samples may be analyzed for VEGF and Ang-2 concentrations and 
possibly other biomarkers.
n 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).
o Obtain prior to FFA (if applicable) and prior to study treatment. 
p PK and PD samples on Day 7 should be collected only from patients consenting to optional aqueous humor sampling.
q OCT and FFA images obtained at screening will be reviewed by the CRC to determine patient eligibility.  At all subsequent visits, please 
forward imaging outputs from all devices to the CRC.  Please see the CRC manual for further details on image requirements.  Please 
remember to forward all OCT images to the CRC as soon as possible.  If OCT imaging data is missing due to a missed visit or a
problem with the OCT device, please notify the CRC as soon as possible. Note:  After randomization, if a patient misses a study visit 
when ocular images are scheduled, the images should be obtained at the next scheduled visit the patient attends.


Appendix 1
Schedule of Activities (cont.)
Faricimab—F. Hoffmann-La Roche Ltd
116/Protocol GR40306, Version 3
Table 1
Screening through Week 48 Assessments (cont.)
r
Optional OCT-A of both eyes to be conducted at sites with agreed OCT-A capability.
s Optional ICGA of both eyes performed at sites with agreed ICGA capability.  ICGA should be performed after laboratory samples are obtained 
and, if images are taken sequentially, after all other imaging has been performed.  If standard of care at a site, it is acceptable to perform 
ICGA in parallel with FFA.
t
Assessment of disease activity should be conducted per the specified criteria outlined in Section 3.1.1.4.  
u The finger counting test should be conducted within 15 minutes of study drug or sham administration for the study eye only.
v Post-treatment 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 at 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 should be used throughout the 
study period.
w After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event(s) that are believed 
to be related to prior administration of study treatment.  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.
x All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment (the Day 1 visit) until 28 days after the final 
dose of study drug should be recorded. 
y 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 ET visit.


Appendix 1  
Schedule of Activities (cont.) 
Faricimab—F. Hoffmann-La Roche Ltd 
117/Protocol GR40306, Version 3 
Table 2 
Week 52 through Week 112 Assessments 
Day 
(Visit window) 
Visit Week 
ET b 
( 28) 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
364 
( 7) 
392 
( 7) 
420 
( 7) 
448 
( 7) 
476 
( 7) 
504 
( 7) 
532 
( 7) 
560 
( 7) 
588 
( 7) 
616 
( 7) 
644 
( 7) 
672 
( 7) 
700  
( 7) 
728  
( 7) 
756  
( 7) 
784 
( 7) a 
Targeted physical examination c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Vital signs d 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
NEI VFQ-25 e 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
BCVA f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
Low-luminance BCVA 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Pre-treatment IOP g 
x 
x 
x 
x 
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 
x 
x 
x 
x 
Optional aqueous humor 
sample i 
 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
x 
Optional vitreous humor sample j 
If elective vitrectomy is performed j 
Optional PK plasma sample (if 
vitreous humor sample is 
collected) j 
If elective vitrectomy is performed and vitreous humor sample collected j 
Plasma PK sample k 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
Plasma PD sample k  
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
Plasma sample for ADAs k 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
x 
x 
Slitlamp examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


Appendix 1
Schedule of Activities (cont.)
Faricimab—F. Hoffmann-La Roche Ltd
118/Protocol GR40306, Version 3
Table 2
Week 52 through Week 112 Assessments (cont.)
Day(s)
(Visit window)
Visit Week
ET b
(28)
52
56
60
64
68
72
76
80
84
88
92
96
100
104
108
112
364
(7)
392
(7)
420
(7)
448
(7)
476
(7)
504
(7)
532
(7)
560
(7)
588
(7)
616
(7)
644
(7)
672
(7)
700 
(7)
728 
(7)
756 
(7)
784
(7) a
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
OCT l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A l, m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA l
x
x
x
CFP l
x
x
x
Optional ICGA l, n
x
x
Administration of study 
treatment
x
x
x
x
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
x
x
x
x
Post-treatment IOP p
x
x
x
x
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
x
x
x
x
Concomitant medications r
x
x
x
x
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
x
x
x
x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; eCRFelectronic Case Report Form; ETearly
termination; FFAfundus fluorescein angiography; ICGAindocyanine green angiography; IOPintraocular pressure; NEI VFQ-25National Eye 
Institute 25-Item Visual Function Questionnaire; OCT optical coherence tomography OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PK pharmacokinetic; VAvisual acuity. 


Appendix 1
Schedule of Activities (cont.)
Faricimab—F. Hoffmann-La Roche Ltd
119/Protocol GR40306, Version 3
Table 2
Week 52 through Week 112 Assessments (cont.)
Notes:  There must be a minimum of 21 days between all study visits occurring from Week 4 through Week 108. All assessments should be 
performed prior to dosing, unless otherwise specified. Standard-of-care treatment for nAMD in the fellow eye may be covered by the Sponsor only 
as long as the patient remains in the study (for details, refer to Section 4.4.2). 
a The Week 112 visit must occur 28 days and 35 days after the actual date of the Week 108 visit.  
b Patients who discontinue from the study early but have not withdrawn consent should return for an ET visit 28 days following the last 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.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.
d Vital signs will include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure.  Vital signs will be 
measured with the patient in a seated position after resting for approximately 5 minutes.
e To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
f
To be performed prior to other ocular assessments. Perform the assessments prior to dilating the eyes.  
g The same method should be used throughout the study period.  Perform measurements prior to dilating the eyes.
h All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test performed at prior to each 
study treatment and at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  If 
positive, do not administer study treatment. Perform urine pregnancy test before FFA (if applicable). 
i
If a patient consents to collection of optional aqueous humor sample, collect the sample at the indicated timepoints prior to study treatment 
administration.  Not applicable for a site that has not been granted approval by a site's Institutional Review Board or Ethics Committee.   The 
sample at ET is not required if there are any safety concerns.
j
If elective vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood 
sample (for plasma preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for 
faricimab concentrations or aflibercept concentrations.  The remaining samples may be analyzed for VEGF and Ang-2 concentrations, and 
possibly other biomarkers.


Appendix 1
Schedule of Activities (cont.)
Faricimab—F. Hoffmann-La Roche Ltd
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Table 2
Week 52 through Week 112 Assessments (cont.)
k Obtain prior to FFA (if applicable) and prior to study treatment. 
l
Please forward imaging outputs from all devices to the CRC.  Please see the CRC manual for further details on image requirements. Please 
remember to forward all OCT images to the CRC as soon as possible, particularly from Week 60 onwards when images need to
be read and data submitted to IxRS before the next study visit.  If OCT imaging data is missing due to a missed visit or a 
problem with the OCT device, please notify the CRC as soon as possible so that they may update the IxRS system accordingly. 
Note: If a patient misses a study visit when ocular images are scheduled, the images should be obtained at the next scheduled visit the patient 
attends.
m Optional OCT-A of both eyes to be conducted at sites with agreed OCT-A capability.
n Optional ICGA of both eyes performed at sites with agreed ICGA capabilities.  ICGA should be performed after laboratory samples are 
obtained and if images are taken sequentially, after all other imaging has been performed.  If standard of care at a site, it is acceptable to 
perform ICGA in parallel with FFA.
o The finger counting test should be conducted within 15 minutes of study drug or sham administration for the study eye only.
p Post-treatment IOP measurement to be conducted in the study eye only within 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 should be 
used throughout the study period. 
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, all adverse events will be reported until 28 days after the final dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event(s) that are 
believed to be related to prior administration of study treatment.  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 All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by 
a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment (the Day 1 visit) until 28 days after the 
final dose of study drug should be recorded.
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 ET visit.


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Appendix 2
Unscheduled Safety Assessment Visit
Assessments a
Vital signs (blood pressure, respiration rate, pulse, and temperature)
Hematology, serum chemistry panel, and coagulation b
Best-corrected visual acuity (assessed at a 4-meter starting distance) c
Slitlamp examination
Dilated binocular indirect high-magnification ophthalmoscopy FFA, ICGA (if 
applicable), and OCT imaging (if required)
IOP d
Adverse events e
Concurrent ocular procedures
Concomitant medications
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 Hematology includes hemoglobin, hematocrit, quantitative platelet count, 
RBC counts, WBC counts, and differentials, including neutrophils, bands, 
lymphocytes, basophils, eosinophils, and monocytes (absolute.  Serum 
chemistry panel includes sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen, creatinine, calcium, phosphorus, total and direct 
bilirubin, total protein, albumin, ALP, AST, ALT, and uric acid.  Coagulation 
includes activated partial thromboplastin time and prothrombin time.
c Perform finger counting test followed by hand motion and light perception 
tests when necessary.
d The method used for the IOP measurement for a patient must remain 
consistent throughout the study.
e Adverse event causality to be evaluated by the masked physician in the 
assessor role.


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Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells
Table 1
Grading Scale for Anterior Chamber Flare or Cells
Grade
Description
Flare
0
None
1
Faint
2
Moderate (iris and lens details clear)
3
Marked (iris and lens details hazy)
4
Intense (fibrin or plastic aqueous)
Cells a
Grade
Number of Cells in Field
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.


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Appendix 3
Grading Scale for Assessment of Anterior Chamber Flare
or Cells and Vitreous Cells (cont.)
Table 2
Grading Scale for Vitreous Cells
Grade
Number of 
Vitreous Cells
0
No cells
0.5 
010
1 
1120
2 
2130
3 
31100
4 
 101
REFERENCES
Foster CS, Kothari S, Anesi SD, et al. The Ocular and Uveitis Foundation preferred 
practice patterns of uveitis management. Surv Opthalmol 2016;61:117.   
doi: 10.1016/j.survophthal.2015.07.001. Epub: 9 July 2015.


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Appendix 4
Best-Corrected Visual Acuity Testing
SCOPE
The best-corrected visual acuity (BCVA) assessment must be conducted before pupil 
dilation.  BCVA will be measured by trained and certified personnel at the study sites.  
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
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 VA examination room also must be certified before any VA examinations 
are performed.


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Appendix 5
Low-Luminance Best-Corrected Visual Acuity Testing
There are the same requirements as the best corrected visual acuity described in 
Appendix 4; however, low-luminance best-corrected visual acuity will be measured by 
placing a 2.0-log-unit neutral density filter (Kodak Wratten 2.0 neutral density filter) over 
the best correction for that eye and having the participant read the normally illuminated 
Early Treatment Diabetic Retinopathy Study chart. 


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Appendix 6
Color Fundus Photography
SCOPE
Monoscopic color fundus photographs will be obtained from both eyes by trained 
personnel at the study sites.  Fundus photography will be performed at the intervals 
specified in the schedule of activities (see Appendix 1).  Analysis (if applicable) of fundus 
photographs will be performed by the central reading center.
EQUIPMENT
See the central reading center manual.
PROCEDURE
The central reading center will provide a study manual and training materials.  The 
fundus photographer and photography equipment will be certified by the central reading 
center before any study images are obtained.  See the central reading center manual for 
further details.


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Appendix 7
Fundus Fluorescein Angiography and Optional Indocyanine 
Green Angiography
SCOPE
Fundus fluorescein angiography will be performed on both eyes at the study sites by 
trained personnel who are certified by the central reading center.  The fundus fluorescein 
angiograms will be obtained at the intervals specified in the protocol (see Appendix 1).  
FFA image analysis will be performed by the central reading center.
Indocyanine green angiography (ICGA) will be performed on both eyes at selected sites 
with agreed ICGA capabilities by trained personnel who are certified by the central 
reading center. At applicable sites, the indocyanine green angiograms will be obtained 
at the intervals specified in the protocol (see Appendix 1).  Analysis (if applicable) of 
indocyanine green angiograms will be performed by the central reading center.
EQUIPMENT
Digital angiograms must be used while conducting an angiographic evaluation for 
the study.
Film-based angiography is not acceptable.
DIGITAL IMAGING SYSTEMS AND CERTIFICATION
Digital imaging systems are required.  The system and software at the site will be 
certified by the central reading center prior to obtaining any study angiograms.  This 
certification and validation process will ensure that the central reading center will be able 
to correctly calculate the required measurements.
PROCEDURES
The central reading center will provide a study manual and training materials.  
Photographers, systems, and software will be certified prior to obtaining angiograms of 
patients.


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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.  SD-OCT 
imaging will be performed for each patient at the intervals specified in the protocol (see 
Appendix 1).
The SD-OCT images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center.
Note:  The optional images will be collected at the sites with agreed optical coherence 
tomographyangiography capabilities and forwarded to the central reading center.
EQUIPMENT
Equipment utilized during this study is described in the central reading center manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed OCT images will be sent to the central reading center).
Note: Certain swept source (SS)-OCT machines may be acceptable to use; see the
central reading center manual for further details.  
PROCEDURES AND CERTIFICATION
The central reading center will provide the study manual and training materials.  OCT 
operators, systems, and software will be certified prior to any evaluation of patients.


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Appendix 9
Biological Sample Collection and Shipping Instructions
BIOLOGICAL SAMPLES
Biological samples for the assessment of faricimab or aflibercept concentrations 
(pharmacokinetics), anti-faricimab antibodies, residual 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 4.5.5 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.  The aqueous humor sample collection 
consists of an anterior chamber paracentesis (removing approximately 0.1 mL of fluid 
from the anterior chamber of the eye).
The anterior chamber paracentesis will be performed by a qualified unmasked physician 
by placing a drop of topical anesthetic on the cornea, passing a 30-gauge needle 
through the limbus into the anterior chamber, and removing 0.1 mL of aqueous fluid.  
Samples will be collected with the kit provided by central laboratory and shipped on dry 
ice as specified in the central laboratory manual as soon as possible after the draw.
For administration of study treatment following the collection of the aqueous humor 
sample, use of additional anesthesia may be necessary prior to study treatment 
administration.  
OPTIONAL UNSCHEDULED COLLECTION OF VITREOUS HUMOR 
SAMPLE COLLECTION
Elective vitrectomy is not allowed in the study eye during a patient's study participation.  
However, if the surgery is medically necessary and the patient consents, a vitreous 
sample can be collected 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. 


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Appendix 9
Biological Sample Collection and Shipping Instructions (cont.)
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 concentrations or
aflibercept concentrations.  The remaining samples may be analyzed for VEGF and 
Ang-2 concentrations, as well as possibly other biomarkers.
Unless the patient gives specific Research Biosample Repository consent for his or her 
remaining samples to be stored for optional exploratory research (see Section 4.5.9.5), 
biological samples will be destroyed no later than 5 years after the final Clinical Study 
Report has been completed.


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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)


Faricimab—F. Hoffmann-La Roche Ltd
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Appendix 10
National Eye Institute 25-Item Visual Function Questionnaire
(cont.)

SAP_001.pdf: 
 
Official Title: 
A Phase Ill, Multicenter, Randomized, Double-Masked, Active 
Comparator-Controlled Study to Evaluate The Efficacy and Safety of 
Faricimab in Patients With Neovascular Age-Related Macular 
Degeneration (Tenaya And Lucerne) 
NCT Number: 
NCT03823287 
Document Date: 
SAP Version 1: 15-October-2020 
 
 
 




Faricimab—F. Hoffmann-La Roche Ltd
2/ Statistical Analysis Plan GR40306 and GR40844
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................. 10
2.2
Determination of Sample Size ............................................... 10
2.2.1
Sample Size for the Japan Extension (as part of 
GR40306 [TENAYA])............................................................. 11
2.2.2
Sample Size for the China Extension (as part of 
GR40844 [LUCERNE]).......................................................... 11
2.3
Analysis Timing ..................................................................... 11
2.3.1
Analysis Timing for the Japan Subpopulation 
Analysis (as part of GR40306 [TENAYA]) ............................. 12
2.3.2
Analysis Timing for the China Subpopulation 
Analysis (as part of GR40844 [LUCERNE])........................... 12
3.
STUDY CONDUCT..................................................................................... 12
3.1
Randomization....................................................................... 12
3.2
Independent Review Facilities............................................... 13
3.3
Data Monitoring ..................................................................... 13
4.
STATISTICAL METHODS .......................................................................... 14
4.1
Analysis Populations ............................................................. 14
4.1.1
Intent-to-Treat Population...................................................... 14
4.1.2
Per-Protocol Population......................................................... 14
4.1.3
Safety-Evaluable Population.................................................. 14
4.1.4
Pharmacokinetic-Evaluable Population ................................. 14
4.1.5
Immunogenicity-Analysis Population..................................... 14
4.2
Analysis of Study Conduct..................................................... 15
4.3
Analysis of Treatment Group Comparability .......................... 15
4.4
Efficacy Analysis.................................................................... 15
4.4.1
Primary Efficacy Endpoint...................................................... 16
4.4.1.1
Hypothesis Testing and Type I Error Control......................... 16
4.4.1.2
Analysis Methods .................................................................. 17
4.4.1.3
Sensitivity Analyses............................................................... 17
4.4.1.4
Supplementary Analyses....................................................... 17
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
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4.4.2
Secondary Endpoints ............................................................ 22
4.4.3
Exploratory Efficacy Endpoints.............................................. 25
4.4.4
Subgroup Analyses ............................................................... 25
4.5
Pharmacokinetic Analyses..................................................... 26
4.6
Pharmacodynamic Analyses ................................................. 27
4.7
Immunogenicity Analyses...................................................... 27
4.7.1
Sample Anti-Drug Antibody (ADA) Status.............................. 27
4.7.2
Patient ADA Status................................................................ 27
4.8
Biomarker Analyses............................................................... 28
4.9
Safety Analyses..................................................................... 29
4.9.1
Exposure of Study Medication............................................... 29
4.9.2
Adverse Events ..................................................................... 29
4.9.3
Ocular Assessments.............................................................. 30
4.9.4
Laboratory Data..................................................................... 31
4.9.5
Vital Signs.............................................................................. 31
4.10
Missing Data.......................................................................... 31
4.11
Interim Analyses .................................................................... 31
5.
JAPAN SUBPOPULATION ANALYSIS....................................................... 31
6.
CHINA SUBPOPULATION ANALYSIS....................................................... 32
7.
REFERENCES ........................................................................................... 33
LIST OF TABLES
Table 1
Personalized Treatment Interval Algorithm ................................... 9
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis (Study GR40306) .......................................... 34
Appendix 2
Protocol Synopsis (Study GR40844) .......................................... 48
Appendix 3
Schedule of Assessments........................................................... 62
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AE
adverse events
AMD
age-related macular degeneration
ANCOVA
analysis of covariance
Ang-2
angiopoietin-2 (protein)
Anti-VEGF
anti-vascular endothelial growth factor
APTC
Anti-Platelet Trialists’ Collaboration
BCVA
best-corrected visual acuity
BM
Bruch’s membrane
CDE
(China) Center for Drug Evaluation
CFP
color fundus photograph
CI
confidence interval
CMH
Cochran Mantel-Haenszel
CNV
choroidal neovascularization
CRC
central reading center
CSR
clinical study report
CST
central subfield thickness
EC
Ethics Committee
ETDRS
early treatment diabetic retinopathy study
FFA
fundus fluorescein angiography
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee 
ICGA
indocyanine green angiography
ILM
internal limiting membrane
IOI
intraocular inflammation
IOP
intraocular pressure
IRB
Institutional Review Board
ITT
intent-to-treat
IVT
intravitreal
IxRS
interactive voice or web-based response system 
LLD
low-luminance deficit
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
nAMD
neovascular age-related macular degeneration
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
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5/ Statistical Analysis Plan GR40306 and GR40844
NEI VFQ-25
National Eye Institute 25-Item Visual Function Questionnaire
OCT
optical coherence tomography
OCT-A
optical coherence tomographyangiography
PD
pharmacodynamic
PED
pigment epithelial detachment
PK
pharmacokinetic
PTI
personalized treatment interval
Q12W
every 12 weeks
Q16W
every 16 weeks
Q4W
every 4 weeks
Q8W
every 8 weeks
RPE
retinal pigment epithelium
SAE
serious adverse event
SD
standard deviation
SD-OCT
spectral-domain optical coherence tomography
U.S.
United States
VA
visual acuity
VEGF (A)
vascular endothelial growth factor (A)
Protocol Number: 
 Report Number: 
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1.
BACKGROUND
Neovascular age-related macular degeneration (nAMD) is a form of advanced AMD that 
causes rapid and severe visual loss and remains a leading cause of visual impairment in 
the elderly. In nAMD, choroidal neovascularization (CNV) leaks fluid, lipids, and blood 
into the outer retina causing severe, irreversible loss of central vision if left untreated.
Treatment of nAMD has been markedly improved by the introduction of biological 
molecules that target vascular endothelial growth factor (-A) (VEGF-A). The impressive 
benefit of anti-VEGF therapies and their ability to restore vision has been widely 
recognized since the first approval of Lucentis(ranibizumab) in 2006. A key challenge 
with currently available anti-VEGF treatments is the requirement for long-term frequent
administration to maintain vision gains. Real-world data suggest that many patients with 
nAMD do not receive treatment at the optimal frequency, and this under-treatment in 
clinical practice is associated with lower visual acuity (VA) gains compared with those 
observed in controlled clinical trials. Under-treatment of nAMD in clinical practice reflects 
the burden of frequent therapy on patients, caregivers, and the healthcare system.
Faricimab is a novel humanized bispecific immunoglobulin 1 monoclonal antibody that 
selectively binds to angiopoietin-2 (Ang-2) and VEGF-A. Nonclinical studies have shown 
that Ang-2 and VEGF-A act in concert to regulate the vasculature and to increase retinal 
endothelial cell permeability such that simultaneous inhibition of Ang-2 and VEGF-A with 
faricimab led to a greater reduction in the leakiness and severity of CNV lesions 
compared with inhibition of either target alone. Furthermore, data from the completed 
Phase II studies also support the hypothesis that targeting Ang-2 has the potential to 
extend the durability of effect beyond anti-VEGF therapy alone in nAMD. Taken 
together, data from earlier non-clinical and clinical studies, as well as the clear unmet 
need for less-frequent dosing in nAMD, support the evaluation of faricimab in a Phase III
study.
The purpose of this document is to provide details of the planned analyses for Phase III
studies GR40306 (TENAYA) and GR40844 (LUCERNE). The designs of these studies 
are identical with the exception of the country participating in the extension study. A 
Japan extension study is planned as part of GR40306 and a China extension is planned 
as part of GR40844 (refer to Section 2.2). In this Statistical Analysis Plan, study 
collectively refers to both studies GR40306 (TENAYA) and GR40844 (LUCERNE), and 
study drug refers to faricimab or aflibercept whereas study treatment refers to faricimab, 
aflibercept, or the sham procedure.
The analyses specified in this document supersede the analysis plan described in the 
study protocols.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
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2.
STUDY DESIGN
Studies GR40306 (TENAYA) and GR40844 (LUCERNE) are identical Phase III, 
multicenter, randomized, active comparator-controlled, double-masked, parallel-group, 
112-week studies, evaluating the efficacy, safety, durability, and pharmacokinetics of the 
6 mg dose of faricimab administered at up to 16-week intervals compared with 
aflibercept monotherapy every 8 weeks (Q8W) in patients with nAMD. For the study
schema, see Figure 1.
Patient recruitment is expected to take longer in Japan and China; therefore, a specific 
Japan and China enrollment plan has been established as part of Studies GR40306 and 
GR40844, respectively. After the global enrollment phase of these studies has been 
completed, additional patients will be enrolled in a Japan and China extension to ensure 
a total enrollment that is sufficient to support registration in Japan and in the People’s 
Republic of China, respectively (refer to Section 2.2.1 and Section 2.2.2).
Figure 1
Study Schema
BCVAbest-corrected visual acuity; ETDRSEarly Treatment Diabetic Retinopathy Study; IVTintravitreal; 
PTIpersonalized treatment interval; Q8Wevery 8 weeks; Q12Wevery 12 weeks; Q16Wevery 16 weeks; 
W=week.
a At Weeks 20 and 24, patients will undergo a disease activity assessment. Patients with 
anatomic or functional signs of disease activity at these timepoints will receive Q8W or Q12W 
dosing, respectively, rather than Q16W dosing.
b The primary endpoint is the change from baseline in BCVA (as assessed on the ETDRS chart 
at a starting distance of 4 meters) based on an average at Weeks 40, 44, and 48. 
c From Week 60 (when all patients in Arm A are scheduled to receive faricimab) onward, 
patients in Arm A will be treated according to a PTI dosing regimen (between Q8W and 
Q16W).
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Approximately 640 patients will be enrolled globally during the global enrollment phase
of the study and randomized in a 1:1 ratio to one of two treatment arms:

Arm A (n320): Patients randomized to Arm A will receive 6 mg of intravitreal (IVT)
faricimab every 4 weeks (Q4W) up to Week 12 (4 injections). At Week 20 and 
Week 24, protocol-defined assessment of disease activity determines patients’ 
treatment frequency (a fixed regimen every 8, 12, or 16 weeks) until Week 60. From 
Week 60 onward, all patients will be treated according to a personalized treatment 
interval (PTI) dosing regimen (up to Week 108).

Arm B (n320): Patients randomized to Arm B will receive 2 mg of IVT aflibercept 
Q4W up to Week 8 (3 injections), followed by 2 mg of IVT aflibercept Q8W up to 
Week 108.
Weeks 20 and 24 Disease Activity Criteria for Patients Randomized to Arm A
At Weeks 20 and 24, a protocol-defined assessment of disease activity performed for all 
patients. Patients in Arm A with active disease at Week 20 will be treated at that visit and 
continue with a Q8W dosing regimen of faricimab. Patients in Arm A with active disease 
at Week 24 (excluding those with active disease at Week 20) will be treated at that visit 
and to continue with a Q12W dosing regimen of faricimab. Patients in Arm A who do not 
have active disease at Week 20 and Week 24 will be treated with a Q16W dosing 
regimen of faricimab. Patients in Arm A will continue receiving faricimab on a fixed 
regimen every 8, 12, or 16 weeks until Week 60. Patients in Arm B will receive 
aflibercept Q4W up to Week 8, followed by Q8W up to Week 108.
Determination of active disease at Weeks 20 and 24 will be made if any of the following 
criteria are met:

Increase50 m in central subfield thickness (CST) compared with the average 
CST value over the previous two scheduled visits (Weeks 12 and 16 for the 
Week 20 assessment and Weeks 16 and 20 for the Week 24 assessment) Or

Increase75 m in CST compared with the lowest CST value recorded at either of 
the previous two scheduled visits Or

Decrease5 letters in best-corrected visual acuity (BCVA) compared with average 
BCVA value over the previous two scheduled visits, owing to nAMD disease activity 
(as determined by the investigator) Or

Decrease10 letters in BCVA compared with the highest BCVA value recorded at 
either of the previous two scheduled visits, owing to nAMD disease activity (as 
determined by the investigator) Or

Presence of new macular hemorrhage (as determined by the investigator), owing to 
nAMD activity
Additional considerations at Week 24: If there is significant nAMD disease activity at 
Week 24 that does not meet the criteria above, but which in the opinion of the 
investigator would otherwise warrant treatment, following Sponsor notification through 
the interactive voice or web-based response system (IxRS), patients randomized to 
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Arm A will receive 6 mg of faricimab at Week 24 and will continue to receive repeated 
12 weekly treatments until Week 60.
Personalized Treatment Interval Disease Activity Criteria for Patients Randomized 
to Arm A
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) to 
Week 108, patients in Arm A will be treated according to a PTI dosing regimen (Q8W, 
every 12 weeks [Q12W], or every 16 weeks [Q16W]). At study drug dosing visits, 
treatment intervals may be maintained or adjusted (i.e., increased by 4 weeks, or 
decreased by 4 or 8 weeks), based on CST, BCVA, and clinical assessment as 
mentioned below Table 1.
Table 1
Personalized Treatment Interval Algorithm
Dosing Interval
Criteria
Interval extended by 4 weeks
(to a maximum of Q16W)

Stable CSTa compared with the average of the last 
two study drug dosing visits, and no 
increase 50 m in CST (compared with the lowest 
on-study drug dosing visit measurement) and

No decrease 5 letters in BCVAb compared with the 
average from the last two study drug dosing visits, 
and no decrease 10 letters in BCVAb compared 
with the highest on-study drug dosing visit 
measurement and

No new macular hemorrhagec
Interval reduced (to a minimum 
Q8W)
If one of the criteria is met, the 
interval will be reduced by 
4 weeks. If two or more criteria 
are met or one criterion includes 
new macular hemorrhage, the 
interval will be reduced to an 
8-week interval. d
Increase50 m in CST compared with the average 
from the last two study drug dosing visits or 75 m 
compared with the lowest on-study drug dosing visit 
measurement or
Decrease5 letters in BCVA b compared with average 
of last two study drug dosing visits or decrease10 
letters in BCVA b compared with the highest on-study 
drug dosing visit measurement or
New macular hemorrhage c
Interval maintained
If extension or reduction criteria have not been met
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; nAMDneovascular 
age-related macular degeneration; Q8W every 8 weeks; Q16W every 16 weeks.
a Where stability is defined as a change of CST of less than 30 m.
b Change in BCVA should be attributable to nAMD disease activity (as determined by 
investigator).
c Refers to macular hemorrhage owing to nAMD activity (as determined by investigator).
d Patients whose treatment interval is reduced by 8 weeks from Q16W to Q8W will not be 
allowed to return to a Q16W interval during the study.
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Patients in both treatment arms will complete scheduled study visits Q4W for the entire 
study duration and return for a final visit at Week 112. A sham procedure will be 
administered to patients in both treatment arms at study visits with no study treatment 
administration to maintain masking among treatment arms. 
Refer to Section 3 of the Study Protocols for further details on study design and 
Appendix 3 of this document for the Schedule of Activities.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1 and Appendix 2.
2.2
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on patients enrolled in the global enrollment 
phase, which will enroll approximately 640 patients. 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 Q8W) and the faricimab 
up to Q16W arm.
A sample size of approximately 320 patients in each arm will provide greater than 90% 
power to show non-inferiority of faricimab to aflibercept in the change in BCVA averaged 
over Weeks 40, 44, and 48 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 two treatment 
arms

Standard deviation (SD) of 14 letters for the change from baseline in BCVA 
averaged over Weeks 40, 44, and 48

Two-sample t-test

2.5% one-sided type I error rate

10% dropout rate
For each unmasked independent Data Monitoring Committee (iDMC) safety review 
performed prior to the primary analysis, a nominal type I error penalty of 0.0001 will be 
taken such that efficacy analyses would be performed with a family wise significance 
level of 0.0497 (refer to Section 3.3). This type I error adjustment is not expected to 
impact the sample size or power.
The study protocol mentions that the Sponsor may elect to cap the recruitment of 
patients in certain baseline BCVA strata to ensure appropriate patient representation. In 
addition, it states that the Sponsor might re-estimate the sample size in a masked 
manner prior to completing enrollment. However, a recruitment cap was not introduced 
and the sample size re-estimation was not performed nor the sample size modified due 
to faster than anticipated enrollment.
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2.2.1
Sample Size for the Japan Extension (as part of GR40306 
[TENAYA])
After the global enrollment phase of the GR40306 (TENAYA) has been completed, 
additional patients will be enrolled in a Japan extension to ensure a total enrollment that 
is sufficient to support registration in Japan. It is anticipated that approximately 
132 patients will be enrolled at approximately 45 sites (including patients who have 
already enrolled during the global enrollment phase). The data from Japan 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 Japan extension will not be 
included in the primary analyses but will be considered in the Japan subpopulation 
analysis (see Section 5).
2.2.2
Sample Size for the China Extension (as part of GR40844
[LUCERNE])
After the global enrollment phase of the GR40844 (LUCERNE) has been completed, 
additional patients will 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 90 patients will be enrolled at approximately 15 sites (including patients 
who have already enrolled during the global enrollment phase). The China extension 
may include current residents of mainland China, Hong Kong, or Taiwan enrolled at 
China Center for Drug Evaluation (CDE) recognized sites. 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 considered in the China 
subpopulation analysis (see Section 6).
2.3
ANALYSIS TIMING
The primary analysis will be performed when all patients from the global enrollment 
phase have either completed the study through Week 48 or have discontinued from the 
study prior to Week 48, 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 have been cleaned and verified. At 
the time of the primary analysis, the study will be ongoing. Results of the primary 
analyses, summarized by treatment group, may be reported to the public before 
completion of the study. Patients, masked study site personnel, and central reading 
center (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 112 or have discontinued early from the 
study, all data from the global enrollment phase are in the database and have been 
cleaned and verified.
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Additional analyses of efficacy endpoints may be performed between the primary 
analysis and final analysis to support marketing applications.
2.3.1
Analysis Timing for the Japan Subpopulation Analysis (as part 
of GR40306 [TENAYA])
Primary analysis for the Japan subpopulation will be performed when all patients from 
Japan (i.e., during both the global enrollment phase and the Japan extension of 
GR40306 [TENAYA]) have either completed the study through Week 48 or have 
discontinued from the study prior to Week 48, whichever comes later, and all data 
collected are in the database, cleaned and verified.
A final analysis for the Japan subpopulation will be performed when all patients from 
Japan (i.e., during both the global enrollment phase and the Japan extension) have 
either completed the study through Week 112 or have discontinued early from the study, 
all data are in the database, and the database is locked.
2.3.2
Analysis Timing for the China Subpopulation Analysis (as part 
of GR40844 [LUCERNE])
Primary analysis for the China subpopulation will be performed when all patients from 
China (i.e., during both the global enrollment phase and the China extension of 
GR40844 [LUCERNE]) have either completed the study through Week 48 or have 
discontinued from the study prior to Week 48, whichever comes later, and all data 
collected are in the database, cleaned and verified. 
A final analysis for the China subpopulation will be performed when all patients from 
China (i.e., during both the global enrollment phase and the China extension) have 
either completed the study through Week 112 or have discontinued early from the study, 
all data are in the database, and the database is locked.
3.
STUDY CONDUCT
3.1
RANDOMIZATION
Using a stratified permuted block randomization method, patients will be randomized in a 
1:1 ratio so that approximately 320 patients are randomized to receive treatment with 
faricimab (Arm A) or aflibercept (Arm B). Randomization is stratified by baseline BCVA 
Early Treatment Diabetic Retinopathy Study (ETDRS) letter score as assessed on Day 1 
(74 letters, 7355 letters, and54 letters), low-luminance deficit(LLD;33 letters 
and33 letters), and region (United States [U.S.] and Canada, Asia, and the rest of the 
world). Randomization will be performed through an IxRS and the first study treatment
will be administered on the same day as randomization (i.e., at the Day 1 visit).
Subject randomization and study treatment kit number assignment were audited by an 
external and independent data coordinating center (iDCC) to ensure that randomization 
and kit assignment were carried out correctly by the IxRS. This randomization audit was 
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performed on August 14, 2019 (approximately six months after first patient in) with 
randomization information available for 230 patients available in TENAYA and 
277 patients in LUCERNE. No major issues were detected during the audit, and 
corresponding report will be provided by the iDCC at study unmasking for the primary 
analysis.
The same randomization method is implemented for the Japan extension (as part of 
GR40306 [TENAYA]) and for the China extension (as part of GR40844 [LUCERNE]).
3.2
INDEPENDENT REVIEW FACILITIES
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 color fundus photographs (CFPs), fundus fluorescein angiography 
(FFA), and optical coherence tomography (OCT) images to provide an objective, 
masked assessment of patient eligibility. During the study treatment period, the CRCs 
provide a masked evaluation of all ocular images including CFP, FFA, indocyanine 
green angiography (ICGA), OCT and optional OCTangiography (OCT-A). The data 
resulting from this masked review of ocular images are forwarded to the Sponsor and 
additionally, the spectral-domain optical coherence tomography (SD-OCT) CST values 
are forwarded to the IxRS for treatment interval determination.
Potential Anti-Platelet Trialists’ Collaboration (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.
3.3
DATA MONITORING
An iDMC monitors safety and study conduct on an ongoing basis throughout the study. 
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 outcomes 
of these data reviews that affect study conduct must 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 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 final significance level used in the analysis 
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will be adjusted based on the actual number of iDMC review meetings conducted during 
the study.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
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 Japan extension (as 
part of GR40306 [TENAYA]) or China extension (as part of GR40844 [LUCERNE]), 
unless otherwise specified. The analysis plans for the Japan and China extensions are 
presented in Section 5 and Section 6, respectively.
4.1.1
Intent-to-Treat Population
The ITT population will comprise 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.
4.1.2
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 or the treatment interval determination. For 
analyses based on this patient population, patients will be grouped according to the 
actual treatment received. 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 unblinding, protocol deviations will be reviewed and a determination of the 
definition of the population for per protocol analysis will be made.
4.1.3
Safety-Evaluable Population
The safety-evaluable population will comprise 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 as described in Section 4.1.2.
4.1.4
Pharmacokinetic-Evaluable Population
The pharmacokinetic (PK) analyses will include safety-evaluable patients with at least 
one plasma sample, provided sufficient dosing information (dose and dosing time) is 
available, and such patients will be grouped according to treatment received as 
described in Section 4.1.2.
4.1.5
Immunogenicity-Analysis Population
The immunogenicity prevalence set will consist of all patients randomized to faricimab 
with at least one determinant anti-drug antibody (ADA) assessment. Patients will be 
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grouped according to treatment received as described in Section 4.1.2. or if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The immunogenicity incidence set will consist of all patients receiving faricimab with at 
least one determinant post-baseline ADA assessment. Patients will be grouped 
according to treatment received as described in Section 4.1.2.
4.2
ANALYSIS OF STUDY CONDUCT
The analysis of study conduct 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 deviations and other major 
protocol deviations will be summarized by treatment arm. The impact of COVID-19 will 
be assessed by including major protocol deviations related to COVID-19 and by 
summarizing COVID-19 related intercurrent events by treatment arm.
4.3
ANALYSIS 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.
Exposure to study drug (number of study drug administrations and duration of treatment) 
will be summarized by treatment group for the safety-evaluable population.
Baseline is defined as the last available measurement obtained on or prior to 
randomization. Patients with missing baseline assessments will not be imputed.
4.4
EFFICACY ANALYSIS
Efficacy analyses will be based on the ITT population, unless otherwise specified. A 
supplemental 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 (74 letters, 7355 letters, 
and54 letters), LLD (33 letters and33 letters), and region (U.S. and Canada, Asia, 
and the rest of the world). The stratification factors as recorded in IxRS will be used.
The primary comparison will be between the active comparator (aflibercept Q8W) and 
the faricimab up to Q16W arm.
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Continuous outcomes will be analyzed using a mixed model for repeated measures 
(MMRM). Binary endpoints will be analyzed using stratified estimation for binomial 
proportions. The estimates and confidence intervals (CIs) will be provided for the mean 
(for continuous variables) or proportion (for binary variables) for each treatment group 
and the difference in means or proportions between two treatment groups. All CIs will be 
two-sided and at the 95.03% level.
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in BCVA averaged over 
Weeks 40, 44, and 48. The BCVA outcome measure is based on the ETDRS VA chart 
assessed at a starting distance of four meters.
The primary estimand is defined as follows:

Population: Adult treatment-naive patients with nAMD, as defined by the 
inclusion / exclusion criteria (see Section 4.1.1) (ITT Population)

Variable: Change in BCVA score from baseline averaged over Weeks 40, 44, and 
48. BCVA score is based on the ETDRS VA chart assessed at a starting distance of 
4 meters

Intercurrent events: 
–
Discontinuation of study treatment due to adverse events (AEs) or lack of 
efficacy not due to COVID-19: A treatment policy strategy will be applied where 
all observed values will be used regardless of the occurrence of the intercurrent 
event
–
Use of any prohibited systemic treatment or prohibited therapy in the Study eye 
(Section 4.4.3 of Protocol Version 3) not due to COVID-19: A treatment policy 
strategy will be applied where all observed values will be used regardless of the 
occurrence of the intercurrent event
–
Discontinuation of study treatment due to COVID-19: A hypothetical strategy 
will be applied where all values will be censored after the intercurrent event
–
Use of any prohibited systemic treatment or prohibited therapy in the study eye
due to COVID-19: A hypothetical strategy will be applied where all values will 
be censored after the intercurrent event
–
Missed dose(s) with potentially major impact on efficacy due to COVID-19: A 
hypothetical strategy will be applied where all values will be censored after the 
intercurrent event
–
COVID-19 death: A hypothetical strategy will be applied

Population-level summary: Difference in adjusted mean between faricimab (up to 
Q16W) and aflibercept (Q8W) arms
4.4.1.1
Hypothesis Testing and Type I Error Control
The primary comparison will be to test non-inferiority of faricimab (up to Q16W) 
compared with aflibercept (Q8W) in the ITT population. The non-inferiority test will be 
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conducted with a non-inferiority margin of four letters at the one-sided 0.02485 
significance level. For the primary efficacy endpoint, if the lower bound of a two-sided 
95.03% CI for the difference in adjusted means of the two treatments is greater than 4 
letters (the non-inferiority margin), then faricimab is considered non-inferior to 
aflibercept.
4.4.1.2
Analysis Methods
The primary analysis will be performed using a MMRM. The model will include the 
change from baseline at Weeks 448 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. Comparisons between the two treatment arms will be made using a composite 
contrast over Weeks 40, 44, and 48. The MMRM model will assume an unstructured 
covariance structure. If there are convergence problems with the model, then a 
heterogeneous compound symmetry or an AR (1) covariance structure may be fitted.
Missing data will be implicitly imputed by the MMRM model, assuming a missing at 
random (MAR) missing data mechanism. Non-standard BCVA data (assessed by 
ETDRS BCVA testing with prior visit refraction, test performed by unmasked certified 
ETDRS BCVA assessor, or by uncertified experienced ETDRS BCVA assessor) will be 
excluded from the analyses.
4.4.1.3
Sensitivity Analyses
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 primary 
analysis finding:
a)
Last observation carried forward:  
The estimand and analysis method will be the same as the primary analysis 
(Section 4.4.1), with the exception that any missing BCVA assessments due to any 
reason will be imputed using the last available post-baseline observation prior to the 
occurrence of missing data. Additionally, BCVA assessments after the COVID-19 related 
intercurrent event will be censored and will be imputed using the last available post-
baseline observation prior to the COVID-19 intercurrent event.
4.4.1.4
Supplementary Analyses
The following supplementary analyses will be performed for the primary efficacy 
endpoint to provide further understanding of treatment effect:
a)
Per-protocol analysis:
The per-protocol analysis will follow the same intercurrent events, handling of 
intercurrent events, and analysis method as the primary analysis (Section 4.4.1) with the 
exception that the analysis will be based on the per-protocol population (Section 4.1.2). 
Patients with major protocol deviations that impact the efficacy evaluation or the 
treatment interval determination, whether or not related to COVID-19, will be excluded 
from the analysis.
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b)
Analysis using treatment policy strategy for all intercurrent events:
The analysis method, population, and definition of intercurrent events will be the same 
as the primary analysis (Section 4.4.1). However, all intercurrent events will follow a 
treatment policy strategy, where all observed values will be used regardless of the 
occurrence of the intercurrent event.
c)
Analysis using hypothetical strategy for all intercurrent events: 
The analysis method, population, and definition of intercurrent events will be the same 
as the primary analysis (Section 4.4.1). However, all intercurrent events will follow a 
hypothetical strategy, where all values will be censored after the occurrence of the 
intercurrent event.
d)
ANCOVA analysis:
The analysis of covariance (ANCOVA) analysis will use the same population, 
intercurrent events, and handling of intercurrent events as in the primary analysis. The 
analysis will be conducted using an 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 average of 
non-missing values of Weeks 40, 44, and 48 assessments in change from baseline in 
BCVA score (if at least one assessment is available then the average of the non-missing 
assessments will be used; assessments after the COVID-19 related intercurrent events 
will be excluded before taking the average). Missing observations will not be imputed.
e)
Trimmed Mean Analysis: 
The analysis will be used to assess the difference in BVCA between two treatment
groups using a truncated distribution, truncating patients with the worst outcome, with 
the assumption that patients have the worst outcome after non-COVID-19 related
intercurrent events. The estimand is defined as follows:

Population: Adult treatment-naive patients with nAMD, as defined by the 
inclusion / exclusion criteria (see Section 4.1.1) (ITT Population)

Variable: Change in BCVA score from baseline averaged over Weeks 40, 44, and 
48. BCVA score is based on the ETDRS VA chart assessed at a starting distance of 
4 meters

Intercurrent events: 
–
Discontinuation of study treatment due to AEs or lack of efficacy not due to 
COVID-19: Assume patients have the worst outcome after the intercurrent 
event
–
Use of any prohibited systemic treatment or prohibited therapy in the Study eye
(Section 4.4.3 of Protocol Version 3) not due to COVID-19: Assume patients 
have the worst outcome after the intercurrent event
–
Discontinuation of study treatment due to COVID-19: A hypothetical strategy 
will be applied where all values will be censored after the intercurrent event
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–
Use of any prohibited systemic treatment or prohibited therapy in the study eye 
due to COVID-19: A hypothetical strategy will be applied where all values will 
be censored after the intercurrent event
–
Missed dose(s) with potentially major impact on efficacy due to COVID-19: A 
hypothetical strategy will be applied where all values will be censored after the 
intercurrent event
–
COVID-19 death: A hypothetical strategy will be applied

Population-level summary: Difference in adjusted trimmed mean between faricimab 
(up to Q16W) and aflibercept (Q8W) arms
The trimmed mean analysis (Permutt and Li 2017) 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 average of non-missing values of 
Weeks 40, 44, and 48 assessments in change from baseline in BCVA score (if at least 
one assessment is available then the average of the non-missing assessments will be 
used; assessments after the COVID-19 related intercurrent events will be excluded 
before taking the average).
Patients with intercurrent events that are not related to COVID-19 will be considered to 
have the worst outcomes and will be trimmed from analysis if any of the following 
occurs:

They have a non-COVID-19 related intercurrent event prior to Week 40

They have missing assessment at Week 40 and have a non-COVID-19 related 
intercurrent event at Week 40

They have missing assessments at Weeks 40 and 44, and have a non-COVID-19 
related intercurrent event at either one of these two visits

They have missing assessments at Weeks 40, 44 and 48, and have a non-COVID-
19 related intercurrent event at either one of these three visits
Such patients will be referred to as "must be trimmed patients”. 
Of note, patients in the following scenario will not be considered as “must be trimmed 
patients”. If a patient has a non-missing Week 40 assessment and has a non-COVID-19 
related intercurrent event at Week 40, then the change in BCVA from baseline will be 
calculated using Week 40 assessment only (since BCVA is assessed prior to any 
treatment administration, it is not expected to have an impact on BCVA even if they 
occur at the same study visit), and this patient will not be considered a as "must be 
trimmed patient”. Similarly, if a patient has a non-missing Week 44 assessment and has 
a non-COVID-19 related intercurrent event at Week 44, then the change in BCVA from 
baseline will be calculated using Week 40 and 44 assessments only. If a patient has a 
non-missing Week 48 assessment and has a non-COVID-19 related intercurrent event 
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at Week 48, then the change in BCVA from baseline will be calculated using Weeks 40, 
44 and 48 assessments only. 
For the remaining patients without COVID-19 related intercurrent events, if they have at 
least one BCVA assessment for Weeks 40, 44, and 48, they will be considered 
"completers". If they have missing assessments at all three visits (Weeks 40, 44, and 
48), the missing data will be considered MAR and these patients will be removed from 
the analysis.
Patients with intercurrent events due to COVID-19 will be censored after the intercurrent 
event. If they have at least one BCVA assessment for Weeks 40, 44, and 48 prior to any 
COVID-19 related intercurrent event, they will be considered "completers". Otherwise, 
the missing data will be considered MAR and these patients will be removed from the 
analysis.
The inferential statistics (i.e., 95.03% CI) for the trimmed mean will be based on the 
permutation test. The treatment assignments will be permuted in a sufficiently large 
random sample of possible ways (~30,000 random samples will be generated). The 
method can be stated in the following four steps:
1.
Remove patients whose missing assessments are considered MAR (see definition 
above) from the analysis.
2.
Order the data based on adjusted values from the ANCOVA model, and trim equal 
fractions (the trimming fraction will be finalized based on a masked assessment 
prior to the primary analysis) from both treatment arms.
The adjusted values are determined as follows. An ANCOVA model as specified 
above will be fitted for all completers. The estimated treatment effect will be 
discarded and the coefficients for the covariates will be kept to calculate the 
adjusted value Y ' X for each patient, for which Y is the change in BCVA score 
averaged over Weeks 40, 44, and 48; X is the matrix for the covariates baseline 
BCVA (continuous), and randomization stratification factors of baseline BCVA 
score, LLD, and region, and is the estimated coefficient matrix for the covariates.
These adjusted values will be used to rank the data within each treatment group. 
The “must be trimmed” patients will always be ranked the lowest (regardless of 
whether their adjusted values are available) and trimmed from the analyses. The 
best (10.1)*100%(90%) in each group will be used for the analysis specified in 
Step 3. If multiple patients have the same adjusted values, they will be ranked 
randomly relative to each other prior to trimming.
3.
Refit the ANCOVA model (as specified above) to the trimmed data set, and compute 
the difference in trimmed mean between two treatment groups.
4.
Repeat steps 2 and 3, 30,000 times based on augmented datasets with the 
treatment assignment randomly permuted according to the original randomization 
procedures (blocked randomization stratified by baseline BCVA score, LLD, and 
region).
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When the proportion of the "must be trimmed patients" in either treatment group in the 
permuted data exceeds the planned trimmed fraction, the trimming fraction will be
chosen adaptively as the greater of the proportions of the "must be trimmed patients" in 
the two treatment groups.
f)
Multiple imputation:
The population, intercurrent events, and handling of intercurrent events will be the same 
as in the primary analysis, however missing primary endpoint BCVA data will be imputed 
via multiple imputation. As in the primary analysis, intercurrent events related to COVID-
19 will follow a hypothetical strategy where all values are censored after the intercurrent 
event, and intercurrent events not related to COVID-19 will follow a treatment policy 
strategy where all observed values are used regardless of the occurrence of the 
intercurrent event. The analysis will be performed using an ANCOVA model in the same 
way as described above for the ANCOVA analysis (item d in Section 4.4.1.4).
Missing BCVA data resulting from intercurrent events related to COVID-19 will be 
assumed to be MAR. Missing BCVA data for reasons that have not been specified as an 
intercurrent event will also be assumed MAR. Intercurrent events not related to COVID-
19 that result in missing data will be assumed to be missing not at random (MNAR). 
Each arm will be imputed separately. The missing BCVA values for patients with MAR 
data will be imputed first while excluding the patients with MNAR data; the MNAR values 
will then subsequently be imputed. Imputation will only be performed for patients with 
missing BCVA data at all three primary endpoint timepoints (Weeks 40, 44, and 48), 
where a single value for each patient will be imputed. If at least one of the primary 
endpoint timepoint values is available after censoring from COVID-19 related 
intercurrent events, the averaged value will be used in the ANCOVA analysis and no 
imputation will be conducted.
For BCVA data that is MAR, the fully conditional specification (FCS) predicted mean 
matching method will be used for imputation (SAS Institute 2018). This method imputes
by selecting a value from a set of observed values whose predicted values are closest to 
the predicted value for the missing value from a simulated regression model. The 
regression model will be fit with observed values of BCVA at each timepoint j as the 
dependent variable, and BCVA at each prior timepoint, baseline BCVA (continuous), and 
the stratification factors as covariates. The BCVA values that are missing will be imputed 
sequentially.
BCVAj = β0 + (β1*BCVA1) + … + (βj-1*BCVAj-1) + (βj*baseline BCVA [continuous]) + 
(βj+1*baseline BCVA (74 letters, 7355 letters, 54 letters)]) + (βj+2*LLD) + (βj+3*region) 
where j=1, 2, …, 10 such that BCVAj is the BCVA value at Week 4*j. 
The number of observations whose corresponding predicted values are closest to the 
predicted values of the missing data will be set to 30 patients in the relevant treatment 
arm. 
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For BCVA data that is MNAR, 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 at least one assessment from Weeks 40, 44, and 48
(i.e. patients with non-missing primary endpoint data after censoring for COVID-19 
related intercurrent events), and n0 patients that are missing all three assessments. The 
imputation steps will be as follows:
1.
Among patients with at least one assessment from Weeks 40, 44, and 48, 
identify 10% of the patients with the worst values for change in BCVA score 
from baseline averaged over the non-missing values of Weeks 40, 44, and 48. 
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 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.
4.4.2
Secondary Endpoints
The continuous secondary endpoints will be analyzed using the estimand, analysis 
method and data handling rules following those for the primary endpoint (Section 4.4.1),
as well as using descriptive statistics after censoring observations following COVID-19 
related intercurrent events as described in Section 4.4.1.
The binary secondary endpoints will be analyzed using the population, intercurrent 
events, and handling of intercurrent events as described in Section 4.4.1 with the 
following analysis method.
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 
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the observed proportions and the differences in observed proportions over the strata 
defined by randomization stratification factor of baseline BCVA score (74 letters, 
7355 letters, and54 letters), LLD (33 letters and33 letters), and region (U.S. and 
Canada, Asia, and the rest of the world) using the Cochran Mantel-Haenszel (CMH) 
weights (Cochran 1954; Mantel and Haenszel 1959). 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). If the response rate is low, an 
unstratified analysis may also be performed. Due to a small number of patients enrolled 
from Asia, the Asia and rest of the world regions will be combined to calculate the CMH 
weighted estimates and for the CMH analyses.
In addition, the binary endpoints will be summarized using descriptive statistics after
censoring observations following COVID-19 related intercurrent events as described in
Section 4.4.1.
The primary comparison for the following secondary endpoints will be faricimab (up to 
Q16W) vs. aflibercept (Q8W)
The secondary endpoints are:

Proportion of patients gaining: 
–
15 letters in BCVA from baseline averaged over Weeks 40, 44 and 48
–
10 letters in BCVA from baseline averaged over Weeks 40, 44 and 48
–
5 letters in BCVA from baseline averaged over Weeks 40, 44 and 48
–
0 letters in BCVA from baseline averaged over Weeks 40, 44 and 48

Proportion of patients avoiding a loss of:
–
15 letters in BCVA from baseline averaged over Weeks 40, 44 and 48
–
10 letters in BCVA from baseline averaged over Weeks 40, 44 and 48
–
5 letters in BCVA from baseline averaged over Weeks 40, 44 and 48

Proportion of patients gaining 15 letters from baseline or achieving BCVA of 84 
letters averaged over Weeks 40, 44 and 48

Proportion of patients with BCVA Snellen equivalent of 20/40 (BCVA-ETDRS 69 
letters) or better averaged over Weeks 40, 44 and 48
–
Different strata will be used for the CMH analyses: the difference between the 
two treatment groups will be estimated using the same approach as described 
above but stratified by baseline BCVA (Snellen equivalent of 20/40 or better vs. 
worse than 20/40).

Proportion of patients with BCVA Snellen equivalent of 20/200 (BCVA-ETDRS 38 
letters) or worse averaged over Weeks 40, 44 and 48
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
Proportion of patients in the faricimab arm on a Q8W, Q12W, and Q16W treatment 
interval at Weeks 48, 60, and 112 
–
For the faricimab arm, treatment interval will be defined as follows:
At Week 48: the treatment interval decision followed at Week 48
At Week 60: the treatment interval decision followed at Week 60
At Week 112: the treatment interval decision followed at Week 112

Number of study drug injections received through Weeks 48, 60, and 112 

Change from baseline in CST (ILM-RPE) based on an average at Weeks 40, 44, 
and 48 
–
CST is defined as the distance between internal limiting membrane (ILM) and 
retinal pigment epithelium (RPE), as measured in m as assessed by CRC.

Change from baseline in total area of CNV lesion at Week 48 and Week 112

Change from baseline in total area of leakage at Week 48 and Week 112
Additionally, the following secondary endpoints will be assessed over time, with results 
presented for each study visit:

Change from baseline in BCVA over time 

Proportion of patients gaining 15, 10, 5, 0 letters in BCVA from baseline over 
time

Proportion of patients avoiding a loss of 15, 10, 5 letters in BCVA from baseline 
over time

Proportion of patients gaining 15 letters from baseline or achieving BCVA of 84 
letters over time

Proportion of patients with BCVA Snellen equivalent of 20/40 (BCVA-ETDRS 69 
letters) or better over time
–
Different strata will be used for the CMH analyses: the difference between the 
two treatment groups will be estimated using the same approach as described 
above but stratified by baseline BCVA (Snellen equivalent of 20/40 or better vs. 
worse than 20/40).

Proportion of patients with BCVA Snellen equivalent of 20/200 (BCVA-ETDRS 38 
letters) or worse over time

Change from baseline in CST (ILM-RPE) over time

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 intraretinal and subretinal fluid over time
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
Proportion of patients with absence of pigment epithelial detachment (PED) over 
time 
–
PED is as measured in the central subfield (center 1 mm)
The following efficacy endpoints are considered for the purpose of the marketing 
authorization application for European Medicine Agency (EMA):

Change from baseline in BCVA averaged over Weeks 52, 56, and 60

Change from baseline in CST (ILM-RPE) averaged over Weeks 52, 56, and 60

Proportion of patients gaining15 letters in BCVA from baseline averaged over 
Weeks 52, 56, and 60

Proportion of patients avoiding a loss of15 letters in BCVA from baseline averaged 
over Weeks 52, 56, and 60
4.4.3
Exploratory Efficacy Endpoints
The following exploratory endpoints will be summarized using descriptive statistics by 
including the mean, standard deviation, median, and range for continuous endpoints, 
and counts and percentages for categorical endpoints. Patients with COVID-19 related 
intercurrent events will be censored after the intercurrent event.

Change from baseline in National Eye Institute 25-Item Visual Function 
Questionnaire (NEI VFQ-25) composite score over time

Change from baseline in CST (ILM-BM) based on an average at Weeks 40, 44, and 
48
–
CST is defined as the distance between ILM and Bruch’s membrane (BM), as 
measured in m as assessed by CRC.

Change from baseline in CST (ILM-BM) over time

Change from baseline in PED height over time
–
PED height is defined as RPE + PED thickness at the foveal center, as 
measured in m
Analysis for the following endpoints will be presented by pooling across machine type 
used to obtain the images. If enough gradable images available, analysis may be 
conducted by machine type.

Proportion of patients with choriocapillaris drop out dropout over time assessed using 
OCT-A

Change from baseline in lesion area over time, as assessed using OCT-A

Change from baseline in vascular density over time, as assessed using OCT-A
4.4.4
Subgroup Analyses
The following subgroups will be analyzed with respect to the primary efficacy endpoint 
using the same method as specified above for each respective endpoint. Forest plots will 
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be presented to summarize the results. The subgroup categories may be combined if 
there is not enough representation of a specific subpopulation.

Baseline BCVA (74 letters, 7355 letters, and 54 letters)

Region (U.S. and Canada, Asia, and the rest of the world)

Low-luminance deficit (33 letters and 33 letters)

CNV lesion subtype (classic, predominantly classic, minimally classic, and occult)

CNV lesion area (1 mm2, 1-3 mm2 and 3 mm2)

Total CNV lesion area (1 mm2, 1-3 mm2 and 3 mm2)

Age (75 years and 75 years)

Gender (female and male)

Race (White, Asian, and other)
4.5
PHARMACOKINETIC ANALYSES
PK analyses will be based on the pharmacokinetic-evaluable population.
Listings 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, the population PK analysis will be performed. The previous Population PK 
analysis of plasma and aqueous humor of faricimab (RDR 1092579) that was conducted 
on the data from Phase II Studies BP29647 and CR39521 in patients with neovascular 
age related macular degeneration and from the Phase II Study BP30099, in patients with 
diabetic macular edema will be updated with the PK data from the present Studies 
GR40306 and GR40844. Structural model refinement will be driven by the data and will 
be based on various goodness of fit indicators. 
The model may be revised if necessary. 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). The potential effect of ADA on the 
kinetics of faricimab will be assessed. 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 may be conducted as 
appropriate.
Details of the population PK analyses will be described in a Modeling and Simulation 
Analysis Plan. The result of the population PK analyses will be reported in a document 
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separate from the clinical study report (CSR) and may include data from the Japan and 
China extensions.
4.6
PHARMACODYNAMIC ANALYSES
Pharmacodynamic (PD) analyses will be based on the safety-evaluable population.
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 baselines (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.
4.7
IMMUNOGENICITY ANALYSES
Immunogenicity analyses will be based on the immunogenicity-analysis population
(immunogenicity prevalence set or immunogenicity incidence set, as appropriate, as 
defined in Section 4.1.5).
4.7.1
Sample Anti-Drug Antibody (ADA) Status
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.
4.7.2
Patient ADA Status
The ADA status will be listed by patient using the Immunogenicity incidence set and 
summarized according to treatment received.

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 any 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.

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 
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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 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 post-baseline having titer 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.
The following summaries, both overall and by time point (including baseline) will be 
provided using the Immunogenicity prevalence set, according to treatment received or, if 
no treatment is received prior to study discontinuation, according to treatment assigned. 
For summaries by time point, the numerator is the number of patients at that time point 
with determinant samples:

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 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.
4.8
BIOMARKER ANALYSES
Biomarker analyses will be based on the safety-evaluable population. 
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.
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4.9
SAFETY ANALYSES
Safety analyses will be based on the safety-evaluable population. 
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 time of the primary analysis, safety summaries will be summarized based on the 
complete Week 48 data in the safety-evaluable population. For the purpose of the 
marketing authorization application for EMA, safety summaries will also be summarized 
based on the cumulative Week 60 data in the safety-evaluable population. At the time of 
the final analysis, safety summaries will be produced based on cumulative Week 112 
data in the safety-evaluable population.
Baseline for safety analyses is defined as the last available measurement prior to first 
exposure to study drug.
4.9.1
Exposure of Study Medication
Exposure to study drug (number of study drug administrations and duration of treatment) 
will be summarized by treatment group for the study eye in the safety-evaluable 
population.
Duration of treatment is the time from first study drug (faricimab or aflibercept) to the 
earlier of 

Date of treatment discontinuation or date of study treatment completion

The analysis cutoff date
Pre-randomization and concomitant systemic medications, ocular medications for the 
study eye, and ocular medications for the fellow eye will be summarized separately by 
treatment group.
4.9.2
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. 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 
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when the month (if it was recorded) and the year occur on or later than the month and 
year of the study treatment start date.
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 defined as follows:
–
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 Version 3)
–
Suspected transmission of an infectious agent by the study drug
–
Sight-threatening AEs

AEs leading to discontinuation of study treatment

Treatment related ocular AEs and SAEs as determined by the Investigator

Externally adjudicated APTC events

Intraocular inflammation (IOI)

Retinal vascular occlusive disease

Deaths
Adverse events associated with suspected or confirmed COVID-19 will also be provided.
4.9.3
Ocular Assessments
Results of the following ocular assessments will be summarized by treatment group, by 
timepoint using descriptive summaries and graphical presentations (as applicable):

intraocular pressure (IOP)

slitlamp examination

indirect ophthalmoscopy
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 3 of Protocol Version 3). 
The presence of retinal break or detachment as determined from ophthalmoscopy will be 
tabulated.
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4.9.4
Laboratory Data
Laboratory data will be collected at baseline and Week 48 only (Section 4.5.7 of Protocol 
Version 3). Laboratory assessments will be summarized by treatment group, by 
timepoint, using descriptive summaries.
4.9.5
Vital Signs
Vital signs will be collected at screening, randomization, Week 48, Week 60 and Week 
112 or early termination visit. Vital signs will be summarized by treatment group, by 
timepoint, using descriptive summaries.
4.10
MISSING DATA
For efficacy analyses, the handling of missing data during analysis is specified in the 
efficacy analysis section (Section 4.4.1.2).
For safety analyses, missing data will not be imputed.
4.11
INTERIM ANALYSES
No interim efficacy or futility analyses are planned. The iDMC will review the interim 
safety analyses approximately every 6 months.
5.
JAPAN SUBPOPULATION ANALYSIS
A separate analysis will be performed for the Japan subpopulation, where data from all 
patients enrolled in Japan (i.e., during both the global enrollment phase and the Japan 
extension of GR40306 [TENAYA]) will be combined and summarized.
Analyses described in this section will include all data from the Japan subpopulation as 
defined in Section 2.3.1.
The analysis populations will be equally defined as per Section 4.1 but will be based only 
on patients who enroll in Japan. Analyses of study conduct will be performed as 
described in Section 4.2. Summaries of demographics, stratification factors, disease 
history, baseline disease characteristics, and patient treatment history will be produced 
as described in Section 4.3. Primary and key efficacy endpoints for the Japan
subpopulation will be summarized using descriptive statistics after censoring 
observations following COVID-19 related intercurrent events. Similarly, key PK, ADA and 
safety data for the Japan subpopulation will also be summarized.
No formal statistical testing of the comparison between faricimab (up to Q16W) and the 
active comparator aflibercept (Q8W) is planned for the Japan subpopulation and the 
clinical data will be descriptively summarized. The Japan subpopulation results will be 
interpreted in the context of results from the global enrollment phase. Thus, the 
consideration of whether the Japan subpopulation data is consistent with the results 
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from the primary analysis will be based on the totality of the data, including the direction 
of efficacy and safety profiles.
6.
CHINA SUBPOPULATION ANALYSIS
A separate analysis will be performed for the China subpopulation, where data from all 
patients enrolled in China (i.e., during both the global enrollment phase and the China 
extension of GR40844 [LUCERNE]) will be combined and summarized.
Analyses described in this section will include all data from the China subpopulation as 
defined in Section 2.3.2.
The analysis populations will be equally defined as per Section 4.1 but will be based only 
on patients who enroll at a CDErecognized site in mainland China, Hong Kong, or 
Taiwan. Analyses of study conduct will be performed as described in Section 4.2. 
Summaries of demographics, stratification factors, disease history, baseline disease 
characteristics, and patient treatment history will be produced as described in 
Section 4.3. Primary and key efficacy endpoints for the China subpopulation will be
summarized using descriptive statistics after censoring observations following COVID-19 
related intercurrent events. Similarly, key PK, ADA and safety data for the China 
subpopulation will also be summarized.
No formal statistical testing of the comparison between faricimab (up to Q16W) and the 
active comparator aflibercept (Q8W) 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 primary analysis will be based on the totality of the data, including the direction of 
efficacy and safety profiles.
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7.
REFERENCES
Cochran WG. Some methods for strengthening the common chi-square tests. Biometrics 
1954;10:41751.
Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective 
studies of disease. J Natl Cancer Inst 1959;22:719–48.
Mehrotra DV and Railkar R. Minimum risk weights for comparing treatments in stratified 
binomial trials. Stat Med 2000;19:811–25.
Permutt T and Li F. Trimmed means for symptom trials with dropouts. Pharm Stat 
2017;16:20-8.
Rubin DB. Multiple imputation for nonresponse in surveys. John Wiley and Sons, New 
York, 1987.
SAS Institute Inc. 2018. SAS/STAT® 15.1 User’s Guide. Cary, NC: SAS Institute Inc.
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Appendix 1
Protocol Synopsis (Study GR40306)
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATORCONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF FARICIMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION 
(TENAYA)
PROTOCOL NUMBER:
GR40306
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-002152-32
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
PHASE:
Phase III
INDICATION:
Neovascular age-related macular degeneration
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of the 6-mg dose 
of faricimab administered at up to 16-week intervals compared with aflibercept monotherapy 
every 8 weeks (Q8W) in patients with choroidal neovascularization (CNV) secondary to 
age-related macular generation (AMD), also known as neovascular AMD (nAMD). Specific 
objectives and corresponding endpoints for the study are outlined in the following table. 
In this protocol, study drug refers to faricimab or aflibercept and study treatment refers to 
faricimab, aflibercept, or the sham procedure.
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Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint

To evaluate the efficacy of IVT 
injections of the 6-mg dose of 
faricimab on BCVA outcomes 
compared with aflibercept 

Change from baseline in BCVA (as measured on 
the ETDRS chart at a starting distance of 
4 meters) based on an average at Weeks 40, 44, 
and 48 
Secondary Efficacy Objectives
Corresponding Endpoints

To evaluate the efficacy of faricimab
on additional BCVA outcomes 

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 loss of 15, 10
5, or 0 letters in BCVA from baseline over 
time

Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time

Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time

Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time

To evaluate the frequency of study 
drug administration

Proportion of patients on a Q8W, Q12W, and 
Q16W treatment interval at Weeks 48, 60, 
and 112 

Number of study drug injections received through 
Weeks 48, 60, and 112 

To evaluate the efficacy of faricimab
on anatomic outcome measures using 
OCT

Change from baseline in CST based on an 
average at Weeks 40, 44, and 48

Change from baseline in CST 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 intraretinal 
and subretinal fluid over time

Proportion of patients with absence of intraretinal 
cysts over time

Proportion of patients with absence of pigment 
epithelial detachment over time 

To evaluate the efficacy of faricimab 
on anatomic outcome measures 
using FFA

Change from baseline in total area of CNV lesion 
at Week 48 and Week 112

Change from baseline in total area of CNV 
leakage at Week 48 and Week 112
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Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints

To evaluate the ocular and non-
ocular safety and tolerability of 
faricimab

Incidence and severity of ocular adverse events

Incidence and severity of non-ocular adverse 
events
Exploratory Efficacy Objectives
Corresponding Endpoint

To evaluate the efficacy of 
faricimab on patient-reported vision-
related functioning and quality of life 
using the NEI VFQ-25

Change from baseline in NEI VFQ-25 composite 
score over time 
Pharmacokinetic Objectives
Corresponding Endpoints

To characterize the systemic 
pharmacokinetics of faricimab

Plasma concentration of faricimab over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response 
to faricimab

To evaluate potential effects of 
ADAs

Presence of ADAs during the study relative to the 
presence of ADAs at baseline

Relationship between ADA status and efficacy, 
safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints

To evaluate potential relationships 
between selected covariates and 
exposure to faricimab 

Relationship between selected covariates and 
plasma or aqueous humor (optional) 
concentration or PK parameters for faricimab

To evaluate the drug concentration 
(exposure)-effect relationship for 
free Ang-2 and free VEGF-A 

To characterize the aqueous humor 
(optional) and vitreous (optional) 
pharmacokinetics of faricimab

Relationship between pharmacokinetics of 
faricimab and concentration of free Ang-2 and
VEGF-A in aqueous humor (optional), plasma, 
and/or vitreous (optional) over time

Aqueous humor (optional) and vitreous (optional) 
concentration of faricimab over time

To explore concentration-effect 
relationship for visual acuity and 
other endpoints (e.g., anatomical 
markers)

Pharmacokinetics of faricimab and the change in 
BCVA or other endpoints (e.g., anatomical 
markers) over time
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Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker Objectives 
(cont.)
Corresponding Endpoints

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
Concentration of biomarkers of 
angiogenesis and inflammation in 
aqueous humor (optional) at 
baseline and over time and their 
correlation with PK and/or primary 
and secondary endpoints at 
baseline and over time
Relationship between efficacy, 
safety, PK, immunogenicity, or other 
biomarker endpoints and genetic 
polymorphisms at loci, including, but 
not limited to, Ang-2 and VEGF-A
Relationship between baseline 
anatomic measures and the change 
in BCVA or other endpoints (e.g., 
frequency of study drug 
administration) over time
Relationship between anatomic 
measures and visual acuity
Relationship between LLD and/or 
low-luminance BCVA and BCVA or 
other endpoints (e.g., anatomical 
markers) at baseline, Week 48, and 
Week 112
ADAanti-drug antibody; Ang-2angiopoietin-2; BCVAbest-corrected visual acuity; 
CNVchoroidal neovascularization; CSTcentral subfield thickness; ETDRSEarly Treatment 
Diabetic Retinopathy Study; FFAfundus fluorescein angiography; IVTintravitreal; 
LLDlow-luminance deficit; NEI VFQ-25National Eye Institute 25-Item Visual Function 
Questionnaire; OCToptical coherence tomography; PKpharmacokinetic; Q8W every 
8 weeks; Q12W every 12 weeks; Q16W every 16 weeks; VEGF-Avascular endothelial 
growth factorA.
Note:  Additional exploratory efficacy objectives may be evaluated using color fundus 
photographs, OCT, FFA, optional OCT-angiography, and optional indocyanine green 
angiography and will be detailed in the Statistical Analysis Plan.
Study Design
Description of Study
This is a Phase III, multicenter, randomized, active comparatorcontrolled, double-masked, 
parallel-group, 112-week study to investigate the efficacy, safety, durability, and 
pharmacokinetics of faricimab administered at up to 16-week intervals to treatment-naive 
patients with nAMD. 
Overview of Study Design
Approximately 640 patients will be enrolled globally and randomized in a 1:1 ratio to one of two 
treatment arms: 

Arm A (faricimab up to every 16 weeks [Q16W]) (n320):  Patients randomized to Arm A will 
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receive 6 mg of intravitreal (IVT) faricimab every 4 weeks (Q4W) up to Week 12 
(4 injections). At Week 20, a protocol-defined assessment of disease activity requires 
patients in Arm A with active disease to be treated at that visit and to continue with a Q8W 
dosing regimen of faricimab. A second protocol-defined assessment of disease activity at 
Week 24 requires patients in Arm A with active disease (excluding those with active disease 
at Week 20 and therefore receiving a Q8W dosing regimen of faricimab) to be treated at 
that visit and to continue with an every 12-week (Q12W) dosing regimen of faricimab. 
Patients receiving faricimab who do not have active disease according to the 
protocol-defined criteria at Week 20 and Week 24 will be treated with a Q16W dosing 
regimen of faricimab. Patients will continue receiving faricimab on a fixed regimen every 8, 
12, or 16 weeks until Week 60 according to the disease activity assessments made at 
Weeks 20 and 24. 
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) onward, all 
patients in Arm A will be treated according to a personalized treatment interval (PTI) dosing 
regimen (up to Week 108). 

Arm B (comparator arm) (Q8W) (n320):  Patients randomized to Arm B will receive 2 mg 
of IVT aflibercept Q4W up to Week 8 (3 injections), followed by 2 mg of IVT aflibercept 
Q8W up to Week 108. 
Patients in both treatment arms will complete scheduled study visits Q4W for the entire study 
duration (112 weeks). A sham procedure will be administered to patients in both treatment arms 
at study visits with no study treatment administration to maintain masking among treatment 
arms.
Only one eye will be assigned as the study eye. If both eyes are considered eligible (per the 
inclusion and exclusion criteria), the eye with the worse best-corrected visual acuity (BCVA), as 
assessed at screening, will be selected as the study eye (unless based on medical reasons, 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. 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length and an 
approximately 108-week treatment period, followed by the final study visit at Week 112 (at least 
28 days after the last study treatment administration). A unique screening number will be 
assigned to each screened patient through an interactive voice or web-based response system 
(IxRS).
Screening
Informed consent must be administered and signed by each patient 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. 
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 on the same day or within 2 business days. 
During screening, a patient’s eligibility will be assessed, including a central reading center 
review of color fundus photographs (CFPs), optical coherence tomography (OCT), and fundus 
fluorescein angiography (FFA), to ensure that CNV secondary to AMD meets the ocular criteria 
for the study. 
After screening and pre-treatment Day 1 assessments have been completed, eligible patients 
will have a randomization identification number assigned to them through the IxRS and will be 
randomized in a 1:1 ratio in order that approximately 320 patients are randomized to each of the 
two treatment arms. Randomization will be stratified by baseline best-corrected visual acuity 
(BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score as assessed on 
Day 1 (74 letters, 7355 letters, and 54 letters), low-luminance deficit (LLD; 33 letters and 
33 letters), and region (United States and Canada, Asia, and the rest of the world).
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Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which will be 
performed through the IxRS (i.e., at the Day 1 visit). 
Note:  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 administration:  
urine pregnancy test (if appropriate), slitlamp examination, indirect ophthalmoscopy, and 
pre-treatment IOP measurements (recorded on the Day 1 eCRF and dated accordingly).
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger counting test and post-dose
IOP measurement). Afterward, all study patients will have a safety assessment visit on 
Day 7 (3 days) evaluated by the masked investigator. At subsequent scheduled visits, patients 
will have safety assessments evaluated by the masked investigator prior to receiving study 
treatment (for additional details about masking). Study treatment administration and study-
related assessments will occur Q4W (starting on Day 1), as outlined in the schedule of 
activities). The sham procedure will be delivered to patients in all arms throughout the study as 
applicable. 
At Weeks 20 and 24, a protocol-defined assessment of disease activity performed for all 
patients in the study requires patients with active disease receiving faricimab (Arm A) to be 
treated with an 8 weekly or 12 weekly dosing regimen, respectively, until Week 60. Patients 
receiving faricimab who do not have active disease according to the protocol-defined criteria will 
be treated with a 16 weekly dosing regimen until Week 60.
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) to Week 108, 
patients in Arm A will be treated according to a PTI dosing regimen (Q8W, Q12W, or Q16W). At 
study drug dosing visits treatment intervals may be maintained or adjusted (i.e., increased by 4 
weeks, or decreased by 4 or 8 weeks), based on OCT, BCVA, and clinical assessment.
Patients in Arm B will receive aflibercept Q4W up to Week 8, followed by Q8W up to Week 108.
Patients will receive the assigned therapy up to and including Week 108 and return for a final 
visit at Week 112. After the final visit, adverse events should be followed. Assessments 
performed in case of an unscheduled safety visit(s) are at the discretion of the investigator. 
Patients who prematurely discontinue 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 40, 44, 48, 60, and 112 visits.
Patients who wish to discontinue from the study prior to completion but have not withdrawn 
consent will be asked to return for an early termination visit after a minimum of 28 days have 
elapsed following their last study treatment for monitoring of adverse events and early 
termination visit assessments.
Weeks 20 and 24 Disease Activity Criteria
Determination of active disease at Weeks 20 and 24 will be made if any of the following criteria 
are met:

Increase 50 m in central subfield thickness (CST) compared with the average CST value
over the previous two scheduled visits (Weeks 12 and 16 for the Week 20 assessment and 
Weeks 16 and 20 for the Week 24 assessment)
Or

Increase 75 m in CST compared with the lowest CST value recorded at either of the 
previous two scheduled visits
Or

Decrease 5 letters in BCVA compared with average BCVA value over the previous two 
scheduled visits, owing to nAMD disease activity (as determined by the investigator)
Or
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
Decrease 10 letters in BCVA compared with the highest BCVA value recorded at either of 
the previous two scheduled visits, owing to nAMD disease activity (as determined by the 
investigator)
Or

Presence of new macular hemorrhage (as determined by the investigator), owing to nAMD 
activity
Additional considerations at Week 24:  If there is significant nAMD disease activity at 
Week 24 that does not meet the criteria above, but which in the opinion of the investigator 
would otherwise warrant treatment, following Sponsor notification through the IxRS, patients 
randomized to Arm A will receive 6 mg of faricimab at Week 24 and will continue to receive 
repeated 12 weekly treatments. Patients randomized to Arm A who meet the disease activity 
criteria at Week 20 will remain on their Q8W dosing schedule and will not receive treatment at 
Week 24. Patients randomized to Arm B will remain on their Q8W dosing schedule and will 
receive aflibercept at Week 24.
Personalized Treatment Interval Disease Activity Criteria
Starting at Week 60, when all patients in Arm A are scheduled to receive faricimab, the study 
drug dosing interval for patients in Arm A will be extended, reduced, or maintained based on 
assessments made at study drug dosing visits. Study drug dosing interval decisions during the 
PTI regimen phase for Arm A are automatically calculated by the IxRS based on the algorithm 
described in the following table. The decision will be made based on data from visits at which 
patients received study drug. Patients will receive a sham procedure at study visits when 
they are not receiving treatment with faricimab.
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Personalized Treatment Interval Algorithm
Dosing Interval
Criteria
Interval extended by 4 weeks (to a 
maximum of Q16W)
Stable CSTa compared with the average of the 
last 2 study drug dosing visits, and no 
increase 50 m in CST (compared with the 
lowest on-study drug dosing visit 
measurement) and 
No decrease 5 letters in BCVA b compared 
with the average from the last two study drug 
dosing visits, and no decrease 10 letters in 
BCVA b compared with the highest on-study 
drug dosing visit measurement and 
No new macular hemorrhage c
Interval reduced (to a minimum Q8W)
If one of the criteria is met, the interval will 
be reduced by 4 weeks. If two or more 
criteria are met or one criterion includes 
new macular hemorrhage, the interval will 
be reduced to an 8-week interval. d
Increase 50 m in CST compared with the 
average from the last two study drug dosing 
visits or 75 m compared with the lowest on-
study drug dosing visit measurement or
Decrease 5 letters in BCVA b compared with 
average of last two study drug dosing visits or 
decrease 10 letters in BCVA b compared 
with the highest on-study drug dosing visit 
measurement or
New macular hemorrhage c
Interval maintained
If extension or reduction criteria have not been 
met
BCVAbest-corrected visual acuity; CSTcentral subfield thickness; nAMDneovascular age-
related macular degeneration; Q8W every 8 weeks; Q16W every 16 weeks.
a Where stability is defined as a change of CST of less than 30 m.
b Change in BCVA should be attributable to nAMD disease activity (as determined by 
investigator).
c Refers to macular hemorrhage owing to nAMD activity (as determined by investigator).
d Patients whose treatment interval is reduced by 8 weeks from Q16W to Q8W will not be 
allowed to return to a Q16W interval during the study.
Japan Enrollment Plan
Patient recruitment is expected to take longer in Japan; therefore, a specific Japan enrollment 
plan has been established. After the global enrollment phase of the study has been completed, 
additional patients may be enrolled in a Japan extension to ensure a total enrollment that is 
sufficient to support registration in Japan. It is anticipated that approximately 110 patients 
will be enrolled at approximately 45 sites. All Japanese 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 Japan extension will not be included in the primary analyses.
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study conduct on an 
ongoing basis throughout the study. Members of the iDMC will be external to the Sponsor and 
will follow a charter that outlines the iDMC's roles and responsibilities.
The iDMC will meet approximately every 6 months (frequency adjustable as required) to 
evaluate unmasked ocular and non-ocular safety events, with emphasis on the evaluation of the 
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rate of ocular inflammation, increased IOP, endophthalmitis, arterial thromboembolic events, 
and clinically significant decreases in BCVA, which will be prepared for the committee by an 
independent Data Coordinating Center. The iDMC may recommend stopping the study early for 
safety reasons.
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.
Number of Patients
Approximately 640 patients will be enrolled at approximately 200 sites globally. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent  
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act authorization, and in other countries, as applicable according to 
national laws.

Age 50 years on Day 1

Ability to comply with the study protocol, in the investigator’s judgment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive measures that result in failure 
rate 1% per year during the treatment period and for at least 3 months after the final dose 
of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of acceptable contraceptive methods include bilateral tubal ligation, male 
sterilization; hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices; and copper intrauterine devices. 
Contraception methods that do not result in a failure rate of 1% per year such as male 
or female condom with or without spermicide; and cap, diaphragm, or sponge with 
spermicide are not acceptable.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception. 

For patients enrolled in the Japan extension at Japanese sites:  current residents of Japan
Ocular Inclusion Criteria for Study Eye
Patients must meet the following ocular criteria for study entry:

Treatment-naive CNV secondary to AMD (nAMD)

Subfoveal CNV or juxtafoveal/extrafoveal CNV with a subfoveal component related to the 
CNV activity identified by FFA or OCT (where CNV activity is defined as showing 
evidence of subretinal fluid, subretinal hyper-reflective material, or leakage)
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
CNV lesion of any type (i.e., predominantly classic, minimally classic, or occult [including 
polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) that exhibits all of 
the following characteristics:
–
A total lesion size (including blood, atrophy, fibrosis, and neovascularization) of 9 disc 
areas on FFA
–
A CNV component area of 50% of the total lesion size on FFA
–
Active CNV confirmed on FFA (evidence of leakage)
–
CNV exudation confirmed on OCT (presence of fluid)

BCVA of 78 to 24 letters, inclusive (20/32 to 20/320 approximate Snellen equivalent), using 
the ETDRS protocol and assessed at the initial testing distance of 4 meters on Day 1

Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
General Exclusion Criteria
Patients who meet any of the following general exclusion 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 prohibited medications and treatments 

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

Uncontrolled blood pressure, defined as systolic blood pressure 180 mmHg and/or 
diastolic blood pressure 100 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

Pregnancy or breastfeeding, or intention 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 treatment. 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 by a patient 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 
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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:

CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, pathological 
myopia, angioid streaks, choroidal rupture, or uveitis 

Any history of macular pathology unrelated to AMD affecting vision or contributing to the 
presence of intraretinal or subretinal fluid  

Presence at screening of central serous chorioretinopathy 

Retinal pigment epithelial tear involving the macula on Day 1

On FFA/CFP: 
–
Subretinal hemorrhage of 50% of the total lesion area and/or that involves 
the fovea
–
Fibrosis or atrophy of 50% of the total lesion area and/or that involves the fovea

Any concurrent intraocular condition (e.g., amblyopia, aphakia, retinal detachment, cataract, 
diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the 
opinion of the investigator, could either reduce the potential for visual improvement or 
require medical or surgical intervention during the study

Current vitreous hemorrhage on Day 1

Uncontrolled glaucoma 

Spherical equivalent of refractive error demonstrating more than 8 diopters of myopia 
For patients who have undergone prior refractive or cataract surgery, the preoperative 
refractive error should not have exceeded 8 diopters of myopia.

Any prior or concomitant treatment for CNV or vitreomacular-interface abnormalities, 
including, but not restricted to, IVT treatment (e.g., anti-vascular endothelial growth factor 
[VEGF], steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular 
pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic 
therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention

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, glaucoma surgery, corneal 
transplant, or radiotherapy)

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 exclusion criterion for the fellow eye (non-study eye) at both the 
screening and Day 1 visits will be excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of non-study eye (i.e., monocular)
Exclusion Criteria for Both Eyes 
Patients who meet the following exclusion criteria for either eye 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 ocular inflammation or suspected or active ocular or periocular infection in either eye 
on Day 1
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End of Study
The study consists of two enrollment phases:  the global enrollment phase, during which 
patients will be recruited globally, and an optional Japan extension, during which additional 
patients may be enrolled to support registration in Japan.
The end of this study is defined as the date when the last patient, last visit occurs, including 
patients from the optional Japan extension. The end of the study is expected to occur 
approximately 112 weeks after the last patient is randomized. 
Length of Study
The total length of the study (excluding the Japan extension) from screening of the first patient 
to the end of the study is expected to be approximately 48 months.
Investigational Medicinal Products
Test Products (Investigational Drugs)
Intravitreal Faricimab
Patients randomized to Arm A will receive 6 mg of IVT faricimab Q4W up to Week 12 
(4 injections). At Week 20, protocol-defined assessment of disease activity requires patients in 
Arm A with active disease to be treated with a Q8W dosing regimen of 6 mg of faricimab 
(i.e., injections at Weeks 20, 28, 36, 44, 52, and 60). 
A second protocol-defined assessment of disease activity at Week 24 requires patients in 
Arm A with active disease, excluding those with active disease at Week 20 and therefore 
receiving a Q8W dosing regimen of 6 mg of IVT faricimab) to be treated with a Q12W dosing 
regimen of 6 mg of IVT faricimab (i.e., injections at Weeks 24, 36, 48, and 60). 
Patients receiving faricimab who do not have active disease according to the protocol-defined 
criteria at Week 20 or Week 24 will be treated with 6 mg of IVT faricimab Q16W (i.e., injections 
at Weeks 28, 44, and 60). 
From Week 60 (when all patients in Arm A are scheduled to receive study drug) to Week 108, 
patients in Arm A will be treated according to a PTI dosing regimen (between Q8W and Q16W). 
At study drug dosing visits, treatment intervals may be maintained or adjusted (i.e., increased 
by 4 weeks or decreased by 4 or 8 weeks), based on OCT, BCVA, and clinical assessment. 
Patients will therefore receive between 10 and 16 injections over the study treatment period 
(Day 1 to Week 108).
Comparator
Intravitreal Aflibercept (Active Comparator) Injections 
For patients randomized to the active comparator (Arm B), a 2-mg dose of aflibercept will be 
administered intravitreally Q8W after 3 consecutive monthly doses during the 108-week 
treatment period. Patients will receive 15 IVT injections of aflibercept during the 108-week 
treatment period. This will consist of three initiating injections (2 mg of aflibercept Q4W to Week 
8), followed by 12 maintenance injections (2 mg of aflibercept Q8W at Weeks 16, 24, 32, 40, 48, 
56, 64, 72, 80, 88, 96, and 104).
Non-Investigational Medicinal Products
Sham Procedure
Both treatment arms (faricimab up to Q16W and aflibercept Q8W) will maintain Q4W study 
visits for the duration of the study. To preserve masking of the randomized treatment arm, 
patients will have the sham procedure performed at study treatment visits when they are not 
treated with either faricimab or aflibercept as applicable per their treatment arm schedule.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in BCVA averaged over Weeks 40, 
44, and 48. The BCVA outcome measure is based on the ETDRS visual acuity chart assessed 
at a starting distance of 4 meters.
The primary comparison will be to test non-inferiority of faricimab compared with aflibercept in 
the intent-to-treat (ITT) population. Additional analysis based on the per-protocol population will 
also be conducted. 
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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 averaged over Weeks 40, 44, and 48 
for the faricimab up to Q16W arm and the active comparator (aflibercept Q8W), respectively. 
The change from baseline averaged over Weeks 40, 44, and 48 will be compared between the 
faricimab up to Q16W arm and the aflibercept Q8W arm using a mixed model for repeated 
measures (MMRM). The model will include the change from baseline at Weeks 448 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. 
Comparisons between the two treatment arms will be made using a composite contrast over 
Weeks 40, 44, and 48. The MMRM model will assume an unstructured covariance structure. 
If there are convergence problems with the model, then a heterogeneous compound symmetry 
or an AR(1) covariance structure may be fitted.
Missing data will be implicitly imputed by the MMRM model, assuming a missing at random 
missing data mechanism (i.e., the probability that missing data are dependent on other 
observed variables but not on the missing data). Data for patients who receive prohibited 
therapy will be censored at the timing of use of prohibited therapy. Data for patients who 
discontinue from study drug and do not receive prohibited therapy after discontinuation of 
study drug will be included in the analysis.
Additional details about the planned analyses, as well as supplementary and sensitivity 
analyses using other imputation methods for missing data, analysis using the trimmed mean 
approach for patients who receive prohibited therapy or discontinue study drug due to lack of 
efficacy or adverse events, analyses of the per-protocol population, and subgroup analyses to 
assess the robustness of the primary endpoint results will be provided in the Statistical Analysis 
Plan.
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 640 patients. 
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 
Q8W) and the faricimab up to Q16W arm. 
A sample size of approximately 320 patients in each arm will provide greater than 90% power to 
show non-inferiority of faricimab to aflibercept in the change in BCVA averaged over Weeks 40, 
44, and 48 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 two treatment arms

Standard deviation (SD) of 14 letters for the change from baseline in BCVA averaged over 
Weeks 40, 44, and 48

Two-sample t-test

2.5% one-sided type I error rate

10% dropout rate
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To ensure appropriate patient representation, the Sponsor may elect to cap the recruitment of 
patients in certain baseline BCVA strata. If implemented, details of the cap will be described 
in the Statistical Analysis Plan.
The sample size may be adjusted as appropriate based on a masked assessment of the pooled 
SD of the change in BCVA from baseline. The assessment will be performed by the Sponsor at 
a specified timepoint prior to completing enrollment. Details on the masked sample size 
re-estimation conducted, as well as actions and decisions taken regarding changes in sample 
size, will be documented in the Statistical Analysis Plan. The Sponsor will remain masked. 
Other factors external to the study may also trigger a decision to modify the sample size. 
Additional patients may be randomized during the Japan extension to support a Japan marketing 
application. If implemented, details of the Japan extension will be described in the Statistical 
Analysis Plan.
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Appendix 2
Protocol Synopsis (Study GR40844)
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
ACTIVE COMPARATORCONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF FARICIMAB IN PATIENTS WITH 
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
(LUCERNE)
PROTOCOL NUMBER:
GR40844
VERSION NUMBER:
3
EUDRACT NUMBER:
2018-004042-42
IND NUMBER:
119225
TEST PRODUCT:
Faricimab (RO6867461)
PHASE:
Phase III
INDICATION:
Neovascular age-related macular degeneration
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of the 6-mg dose 
of faricimab administered at up to 16-week intervals compared with aflibercept monotherapy 
every 8 weeks (Q8W) in patients with choroidal neovascularization (CNV) secondary to 
age-related macular generation (AMD), also known as neovascular AMD (nAMD). Specific 
objectives and corresponding endpoints for the study are outlined in the following table. 
In this protocol, study drug refers to faricimab or aflibercept and study treatment refers to 
faricimab, aflibercept, or the sham procedure.
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Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint

To evaluate the efficacy of IVT injections 
of the 6-mg dose of faricimab on BCVA 
outcomes compared with aflibercept 

Change from baseline in BCVA (as measured 
on the ETDRS chart at a starting distance of 
4 meters) based on an average at Weeks 40, 
44, and 48 
Secondary Efficacy Objectives
Corresponding Endpoints

To evaluate the efficacy of faricimab on 
additional BCVA outcomes 

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 loss of 15, 
105, or 0 letters in BCVA from baseline 
over time

Proportion of patients with BCVA Snellen 
equivalent of 20/40 or better over time

Proportion of patients gaining 15 letters or 
achieving BCVA of 84 letters over time

Proportion of patients with BCVA Snellen 
equivalent of 20/200 or worse over time

To evaluate the frequency of study drug 
administration

Proportion of patients on a Q8W, Q12W, and 
Q16W treatment interval at Weeks 48, 60, 
and 112 

Number of study drug injections received 
through Weeks 48, 60, and 112 

To evaluate the efficacy of faricimab on 
anatomic outcome measures using OCT

Change from baseline in CST based on an 
average at Weeks 40, 44, and 48

Change from baseline in CST 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 
intraretinal and subretinal fluid over time

Proportion of patients with absence of 
intraretinal cysts over time

Proportion of patients with absence of pigment 
epithelial detachment over time 

To evaluate the efficacy of faricimab on 
anatomic outcome measures using FFA

Change from baseline in total area of CNV 
lesion at Week 48 and Week 112

Change from baseline in total area of CNV 
leakage at Week 48 and Week 112
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Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints

To evaluate the ocular and non-ocular 
safety and tolerability of faricimab

Incidence and severity of ocular adverse 
events

Incidence and severity of non-ocular 
adverse events
Exploratory Efficacy Objectives
Corresponding Endpoint

To evaluate the efficacy of faricimab on 
patient-reported vision-related functioning 
and quality of life using the NEI VFQ-25

Change from baseline in NEI VFQ-25 
composite score over time 
Pharmacokinetic Objectives
Corresponding Endpoints

To characterize the systemic 
pharmacokinetics of faricimab

Plasma concentration of faricimab over time
Immunogenicity Objectives
Corresponding Endpoints

To evaluate the immune response to 
faricimab

To evaluate potential effects of ADAs

Presence of ADAs during the study relative 
to the presence of ADAs at baseline

Relationship between ADA status and 
efficacy, safety, or PK endpoints
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker 
Objectives
Corresponding Endpoints

To evaluate potential relationships 
between selected covariates and 
exposure to faricimab 

Relationship between selected covariates 
and plasma or aqueous humor (optional) 
concentration or PK parameters for 
faricimab

To evaluate the drug concentration 
(exposure)-effect relationship for free 
Ang-2 and free VEGF-A To characterize 
the aqueous humor (optional) and 
vitreous (optional) pharmacokinetics of 
faricimab

Relationship between pharmacokinetics of 
faricimab and concentration of free Ang-2 
and free VEGF-A in aqueous humor 
(optional), plasma, and/or vitreous 
(optional) over time

Aqueous humor (optional) and vitreous 
(optional) concentration of faricimab 
over time

To explore concentration-effect 
relationship for visual acuity and other 
endpoints (e.g., anatomical markers)

Pharmacokinetics of faricimab and the 
change in BCVA or other endpoints 
(e.g., anatomical markers) over time
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Objectives and Corresponding Endpoints (cont.)
Exploratory Pharmacokinetic, 
Pharmacodynamic, and Biomarker Objectives 
(cont.)
Corresponding Endpoints

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
Concentration of biomarkers of 
angiogenesis and inflammation in 
aqueous humor (optional) at baseline 
and over time and their correlation 
with PK and/or primary and 
secondary endpoints at baseline and 
over time
Relationship between efficacy, safety, 
PK, immunogenicity, or other 
biomarker endpoints and genetic 
polymorphisms at loci, including, but 
not limited to, Ang-2 and VEGF-A
Relationship between baseline 
anatomic measures and the change 
in BCVA or other endpoints (e.g., 
frequency of study drug 
administration) over time
Relationship between anatomic 
measures and visual acuity
Relationship between LLD and/or 
low-luminance BCVA and BCVA or 
other endpoints (e.g., anatomical 
markers) at baseline, Week 48, and 
Week 112
ADAanti-drug antibody; Ang-2angiopoietin-2; BCVAbest-corrected visual acuity; 
CNVchoroidal neovascularization; CSTcentral subfield thickness; ETDRSEarly Treatment 
Diabetic Retinopathy Study; FFAfundus fluorescein angiography; IVTintravitreal; 
LLDlow-luminance deficit; NEI VFQ-25National Eye Institute 25-Item Visual Function 
Questionnaire; OCToptical coherence tomography; PKpharmacokinetic; Q8W every 
8 weeks; Q12W every 12 weeks; Q16W every 16 weeks; VEGF-Avascular endothelial 
growth factorA.
Note:  Additional exploratory efficacy objectives may be evaluated using color fundus 
photographs, OCT, FFA, optional OCT-angiography, and optional indocyanine green 
angiography and will be detailed in the Statistical Analysis Plan. 
Study Design
Description of Study
This is a Phase III, multicenter, randomized, active comparatorcontrolled, double-masked, 
parallel-group, 112-week study to investigate the efficacy, safety, durability, and 
pharmacokinetics of faricimab administered at up to 16-week intervals to treatment-naive 
patients with nAMD. 
Overview of Study Design
Approximately 640 patients will be enrolled globally and randomized in a 1:1 ratio to one of two 
treatment arms: 

Arm A (faricimab up to every 16 weeks [Q16W]) (n320):  Patients randomized to Arm A will 
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receive 6 mg of intravitreal (IVT) faricimab every 4 weeks (Q4W) up to Week 12 
(4 injections). At Week 20, a protocol-defined assessment of disease activity requires 
patients in Arm A with active disease to be treated at that visit and to continue with a Q8W 
dosing regimen of faricimab. A second protocol-defined assessment of disease activity at 
Week 24 requires patients in Arm A with active disease (excluding those with active disease 
at Week 20 and therefore receiving a Q8W dosing regimen of faricimab) to be treated at 
that visit and to continue with an every 12-week (Q12W) dosing regimen of faricimab. 
Patients receiving faricimab who do not have active disease according to the 
protocol-defined criteria at Week 20 and Week 24 will be treated with a Q16W dosing 
regimen of faricimab. Patients will continue receiving faricimab on a fixed regimen every 8, 
12, or 16 weeks until Week 60 according to the disease activity assessments made at 
Weeks 20 and 24. 
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) onward, all 
patients in Arm A will be treated according to a personalized treatment interval (PTI) dosing 
regimen (up to Week 108). 

Arm B (comparator arm) (Q8W) (n320):  Patients randomized to Arm B will receive 2 mg 
of IVT aflibercept Q4W up to Week 8 (3 injections), followed by 2 mg of IVT aflibercept 
Q8W up to Week 108. 
Patients in both treatment arms will complete scheduled study visits Q4W for the entire study 
duration (112 weeks). A sham procedure will be administered to patients in both treatment arms 
at study visits with no study treatment administration to maintain masking among treatment 
arms.
Only one eye will be assigned as the study eye. If both eyes are considered eligible (per the 
inclusion and exclusion criteria), the eye with the worse best-corrected visual acuity (BCVA), as 
assessed at screening, will be selected as the study eye (unless based on medical reasons, 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. 
The study will consist of a screening period of up to 28 days (Days 28 to 1) in length and an 
approximately 108-week treatment period, followed by the final study visit at Week 112 (at least 
28 days after the last study treatment administration). A unique screening number will be 
assigned to each screened patient through an interactive voice or web-based response system 
(IxRS).
Screening
Informed consent must be administered and signed by each patient 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. 
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 on the same day or within 2 business days. 
During screening, a patient’s eligibility will be assessed, including a central reading center 
review of color fundus photographs (CFPs), optical coherence tomography (OCT), and fundus 
fluorescein angiography (FFA), to ensure that CNV secondary to AMD meets the ocular criteria 
for the study. 
After screening and pre-treatment Day 1 assessments have been completed, eligible patients 
will have a randomization identification number assigned to them through the IxRS and will be 
randomized in a 1:1 ratio in order that approximately 320 patients are randomized to each of the 
two treatment arms. Randomization will be stratified by baseline best-corrected visual acuity 
(BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score as assessed on 
Day 1 (74 letters, 7355 letters, and 54 letters), low-luminance deficit (LLD; 33 letters and 
33 letters), and region (United States and Canada, Asia, and the rest of the world).
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Randomization and Visit Schedule
The first study treatment will be administered on the same day as randomization, which will be 
performed through the IxRS (i.e., at the Day 1 visit). 
Note:  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 administration:  
urine pregnancy test (if appropriate), slitlamp examination, indirect ophthalmoscopy, and
pre-treatment IOP measurements (recorded on the Day 1 eCRF and dated accordingly).
Randomized patients will have the first study treatment administered by the unmasked 
investigator on Day 1, followed by the safety assessments (finger counting test and post-dose 
IOP measurement). Afterward, all study patients will have a safety assessment visit on 
Day 7 (3 days) evaluated by the masked investigator. At subsequent scheduled visits, patients 
will have safety assessments evaluated by the masked investigator prior to receiving study 
treatment (for additional details about masking). Study treatment administration and study-
related assessments will occur Q4W (starting on Day 1), as outlined in the schedule of 
activities). The sham procedure will be delivered to patients in all arms throughout the study as 
applicable. 
At Weeks 20 and 24, a protocol-defined assessment of disease activity performed for all 
patients in the study requires patients with active disease receiving faricimab (Arm A) to be 
treated with an 8 weekly or 12 weekly dosing regimen, respectively, until Week 60. Patients 
receiving faricimab who do not have active disease according to the protocol-defined criteria will 
be treated with a 16 weekly dosing regimen until Week 60.
From Week 60 (when all patients in Arm A are scheduled to receive faricimab) to Week 108, 
patients in Arm A will be treated according to a PTI dosing regimen (Q8W, Q12W, or Q16W). At 
study drug dosing visits treatment intervals may be maintained or adjusted (i.e., increased by 4 
weeks, or decreased by 4 or 8 weeks), based on OCT, BCVA, and clinical assessment.
Patients in Arm B will receive aflibercept Q4W up to Week 8, followed by Q8W up to Week 108.
Patients will receive the assigned therapy up to and including Week 108 and return for a final 
visit at Week 112. After the final visit, adverse events should be followed. Assessments 
performed in case of an unscheduled safety visit(s) are at the discretion of the investigator. 
Patients who prematurely discontinue 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 40, 44, 48, 60, and 112 visits.
Patients who wish to discontinue from the study prior to completion but have not withdrawn 
consent will be asked to return for an early termination visit after a minimum of 28 days have 
elapsed following their last study treatment for monitoring of adverse events and early 
termination visit assessments.
Weeks 20 and 24 Disease Activity Criteria
Determination of active disease at Weeks 20 and 24 will be made if any of the following criteria 
are met:

Increase 50 m in central subfield thickness (CST) compared with the average CST value 
over the previous two scheduled visits (Weeks 12 and 16 for the Week 20 assessment and 
Weeks 16 and 20 for the Week 24 assessment)
Or

Increase 75 m in CST compared with the lowest CST value recorded at either of the 
previous two scheduled visits
Or

Decrease 5 letters in BCVA compared with average BCVA value over the previous two 
scheduled visits, owing to nAMD disease activity (as determined by the investigator)
Or
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
Decrease 10 letters in BCVA compared with the highest BCVA value recorded at either of 
the previous two scheduled visits, owing to nAMD disease activity (as determined by the 
investigator)
Or

Presence of new macular hemorrhage (as determined by the investigator), owing to nAMD 
activity
Additional considerations at Week 24:  If there is significant nAMD disease activity at 
Week 24 that does not meet the criteria above, but which in the opinion of the investigator 
would otherwise warrant treatment, following Sponsor notification through the IxRS, patients 
randomized to Arm A will receive 6 mg of faricimab at Week 24 and will continue to receive 
repeated 12 weekly treatments. Patients randomized to Arm A who meet the disease activity 
criteria at Week 20 will remain on their Q8W dosing schedule and will not receive treatment at 
Week 24. Patients randomized to Arm B will remain on their Q8W dosing schedule and will 
receive aflibercept at Week 24.
Personalized Treatment Interval Disease Activity Criteria
Starting at Week 60, when all patients in Arm A are scheduled to receive faricimab, the study 
drug dosing interval for patients in Arm A will be extended, reduced, or maintained based on 
assessments made at study drug dosing visits. Study drug dosing interval decisions during the 
PTI regimen phase for Arm A are automatically calculated by the IxRS based on the algorithm 
described in the following table. The decision will be made based on data from visits at which 
patients received study drug. Patients will receive a sham procedure at study visits when 
they are not receiving treatment with faricimab.
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Personalized Treatment Interval Algorithm
Dosing Interval
Criteria
Interval extended by 4 weeks (to a 
maximum of Q16W)
Stable CSTa compared with the average of the 
last 2 study drug dosing visits, and no 
increase 50 m in CST (compared with the 
lowest on-study drug dosing visit 
measurement) and 
No decrease 5 letters in BCVA b compared 
with the average from the last two study drug 
dosing visits, and no decrease 10 letters in 
BCVA b compared with the highest on-study 
drug dosing visit measurement and 
No new macular hemorrhage c
Interval reduced (to a minimum Q8W)
If one of the criteria is met, the interval will 
be reduced by 4 weeks. If two or more 
criteria are met or one criterion includes 
new macular hemorrhage, the interval will 
be reduced to an 8-week interval. d
Increase 50 m in CST compared with the 
average from the last two study drug dosing 
visits or 75 m compared with the lowest on-
study drug dosing visit measurement or
Decrease 5 letters in BCVA b compared with 
average of last two study drug dosing visits or 
decrease 10 letters in BCVA b compared with 
the highest on-study drug dosing visit 
measurement or
New macular hemorrhage c
Interval maintained
If extension or reduction criteria have not been 
met
BCVAbest-corrected visual acuity; CST central subfield thickness; nAMDneovascular 
age-related macular degeneration; Q8W every 8 weeks; Q16W every 16 weeks. 
a Where stability is defined as a change of CST of less than 30 m.
b Change in BCVA should be attributable to nAMD disease activity (as determined by 
investigator).
c Refers to macular hemorrhage owing to nAMD activity (as determined by investigator).
d Patients whose treatment interval is reduced by 8 weeks from Q16W to Q8W will not be 
allowed to return to a Q16W interval during the study.
China Enrollment Plan
Patient recruitment is expected to take longer in China; therefore, a specific China enrollment 
plan has been 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 the People’s Republic of China. It is anticipated that 
approximately 64 patients will be enrolled at approximately 15 sites. The China extension 
may include current residents of mainland China, Hong Kong, or Taiwan enrolled at China 
Center for Drug Evaluation (CDE)recognized sites. The data from those China patients who 
are 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.
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will monitor safety and study conduct on an 
ongoing basis throughout the study. 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 adjustable as required) to 
evaluate unmasked ocular and non-ocular safety events, with emphasis on the evaluation of the 
rate of ocular inflammation, increased IOP, endophthalmitis, arterial thromboembolic events, 
and clinically significant decreases in BCVA, which will be prepared for the committee by an 
independent Data Coordinating Center. The iDMC may recommend stopping the study early for 
safety reasons.
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.
Number of Patients
Approximately 640 patients will be enrolled at approximately 200 sites globally. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
General Inclusion Criteria
Patients must meet the following general criteria for study entry:

Signed Informed Consent  
Additionally, at U.S. sites, patients must provide Health Insurance Portability and 
Accountability Act authorization, and in other countries, as applicable according to 
national laws.

Age 50 years on Day 1

Ability to comply with the study protocol, in the investigator’s judgment

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive measures that result in failure 
rate 1% per year during the treatment period and for at least 3 months after the final dose 
of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of acceptable contraceptive methods include bilateral tubal ligation, male 
sterilization; hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices; and copper intrauterine devices. 
Contraception methods that do not result in a failure rate of 1% per year such as male 
or female condom with or without spermicide; and cap, diaphragm, or sponge with 
spermicide are not acceptable.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception. 

For patients enrolled in the China extension at China CDErecognized sites:  current 
residents of mainland China, Hong Kong, or Taiwan
Ocular Inclusion Criteria for Study Eye
Patients must meet the following ocular criteria for study entry:

Treatment-naive CNV secondary to AMD (nAMD)

Subfoveal CNV or juxtafoveal/extrafoveal CNV with a subfoveal component related to the 
CNV activity identified by FFA or OCT (where CNV activity is defined as showing 
evidence of subretinal fluid, subretinal hyper-reflective material or leakage)
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
CNV lesion of any type (i.e., predominantly classic, minimally classic, or occult [including 
polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) that exhibits all of 
the following characteristics:
–
A total lesion size (including blood, atrophy, fibrosis, and neovascularization) of 9 disc 
areas on FFA
–
A CNV component area of 50% of the total lesion size on FFA
–
Active CNV confirmed on FFA (evidence of leakage)
–
CNV exudation confirmed on OCT (presence of fluid)

BCVA of 78 to 24 letters, inclusive (20/32 to 20/320 approximate Snellen equivalent), using 
the ETDRS protocol and assessed at the initial testing distance of 4 meters on Day 1

Sufficiently clear ocular media and adequate pupillary dilatation to allow acquisition of good 
quality retinal images to confirm diagnosis
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
General Exclusion Criteria
Patients who meet any of the following general exclusion 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 prohibited medications and treatments 

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

Uncontrolled blood pressure, defined as systolic blood pressure 180 mmHg and/or 
diastolic blood pressure 100 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

Pregnancy or breastfeeding, or intention 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 treatment. 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 by a patient 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 
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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:

CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, pathological 
myopia, angioid streaks, choroidal rupture, or uveitis 

Any history of macular pathology unrelated to AMD affecting vision or contributing to the 
presence of intraretinal or subretinal fluid  

Presence at screening of central serous chorioretinopathy 

Retinal pigment epithelial tear involving the macula on Day 1

On FFA/CFP: 
–
Subretinal hemorrhage of 50% of the total lesion area and/or that involves 
the fovea
–
Fibrosis or atrophy of 50% of the total lesion area and/or that involves the fovea

Any concurrent intraocular condition (e.g., amblyopia, aphakia, retinal detachment, cataract, 
diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the 
opinion of the investigator, could either reduce the potential for visual improvement or 
require medical or surgical intervention during the study

Current vitreous hemorrhage on Day 1

Uncontrolled glaucoma 

Spherical equivalent of refractive error demonstrating more than 8 diopters of myopia 
For patients who have undergone prior refractive or cataract surgery, the preoperative 
refractive error should not have exceeded 8 diopters of myopia.

Any prior or concomitant treatment for CNV or vitreomacular-interface abnormalities, 
including, but not restricted to, IVT treatment (e.g., anti-vascular endothelial growth factor 
[VEGF], steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular 
pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic 
therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention

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, glaucoma surgery, corneal 
transplant, or radiotherapy)

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 exclusion criterion for the fellow eye (non-study eye) at both the 
screening and Day 1 visits will be excluded from study entry:

Non-functioning nonstudy eye, defined as either:
–
BCVA of hand motion or worse
–
No physical presence of non-study eye (i.e., monocular)
Exclusion Criteria for Both Eyes 
Patients who meet the following exclusion criteria for either eye 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 ocular inflammation or suspected or active ocular or periocular infection in either eye 
on Day 1
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End of Study
The study consists of two enrollment phases:  the global enrollment phase, during which 
patients will be recruited globally, and an optional China extension, during which additional 
patients may be enrolled to support registration in the People’s Republic of China.
The end of this study is defined as the date when the last patient, last visit occurs, including 
patients from the optional China extension. The end of the study is expected to occur 
approximately 112 weeks after the last patient is randomized. 
Length of Study
The total length of the study (excluding the China extension) from screening of the first patient 
to the end of the study is expected to be approximately 48 months.
Investigational Medicinal Products
Test Products (Investigational Drugs)
Intravitreal Faricimab
Patients randomized to Arm A will receive 6 mg of IVT faricimab Q4W up to Week 12 
(4 injections). At Week 20, protocol-defined assessment of disease activity requires patients in 
Arm A with active disease to be treated with a Q8W dosing regimen of 6 mg of faricimab 
(i.e., injections at Weeks 20, 28, 36, 44, 52, and 60). 
A second protocol-defined assessment of disease activity at Week 24 requires patients in 
Arm A with active disease, excluding those with active disease at Week 20 and therefore 
receiving a Q8W dosing regimen of 6 mg of IVT faricimab) to be treated with a Q12W dosing 
regimen of 6 mg of IVT faricimab (i.e., injections at Weeks 24, 36, 48, and 60). 
Patients receiving faricimab who do not have active disease according to the protocol-defined 
criteria at Week 20 or Week 24 will be treated with 6 mg of IVT faricimab Q16W (i.e., injections 
at Weeks 28, 44, and 60). 
From Week 60 (when all patients in Arm A are scheduled to receive study drug) to Week 108, 
patients in Arm A will be treated according to a PTI dosing regimen (between Q8W and Q16W). 
At study drug dosing visits, treatment intervals may be maintained or adjusted (i.e., increased 
by 4 weeks or decreased by 4 or 8 weeks), based on OCT, BCVA, and clinical assessment. 
Patients will therefore receive between 10 and 16 injections over the study treatment period 
(Day 1 to Week 108).
Comparator
Intravitreal Aflibercept (Active Comparator) Injections 
For patients randomized to the active comparator (Arm B), a 2-mg dose of aflibercept will be 
administered intravitreally Q8W after 3 consecutive monthly doses during the 108-week 
treatment period. Patients will receive 15 IVT injections of aflibercept during the 108-week 
treatment period. This will consist of three initiating injections (2 mg of aflibercept Q4W to Week 
8), followed by 12 maintenance injections (2 mg of aflibercept Q8W at Weeks 16, 24, 32, 40, 48, 
56, 64, 72, 80, 88, 96, and 104).
Non-Investigational Medicinal Products
Sham Procedure
Both treatment arms (faricimab up to Q16W and aflibercept Q8W) will maintain Q4W study 
visits for the duration of the study. To preserve masking of the randomized treatment arm, 
patients will have the sham procedure performed at study treatment visits when they are not 
treated with either faricimab or aflibercept as applicable per their treatment arm schedule.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in BCVA averaged over Weeks 40, 
44, and 48. The BCVA outcome measure is based on the ETDRS visual acuity chart assessed 
at a starting distance of 4 meters.
The primary comparison will be to test non-inferiority of faricimab compared with aflibercept in 
the intent-to-treat (ITT) population. Additional analysis based on the per-protocol population will 
also be conducted. 
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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 averaged over Weeks 40, 44, and 48 
for the faricimab up to Q16W arm and the active comparator (aflibercept Q8W), respectively. 
The change from baseline averaged over Weeks 40, 44, and 48 will be compared between the 
faricimab up to Q16W arm and the aflibercept Q8W arm using a mixed model for repeated 
measures (MMRM). The model will include the change from baseline at Weeks 448 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. 
Comparisons between the two treatment arms will be made using a composite contrast over 
Weeks 40, 44, and 48. The MMRM model will assume an unstructured covariance structure. 
If there are convergence problems with the model, then a heterogeneous compound symmetry 
or an AR(1) covariance structure may be fitted.
Missing data will be implicitly imputed by the MMRM model, assuming a missing at random 
missing data mechanism (i.e., the probability that missing data are dependent on other 
observed variables but not on the missing data). Data for patients who receive prohibited 
therapy will be censored at the timing of use of prohibited therapy. Data for patients who 
discontinue from study drug and do not receive prohibited therapy after discontinuation of 
study drug will be included in the analysis.
Additional details about the planned analyses, as well as supplementary and sensitivity 
analyses using other imputation methods for missing data, analysis using the trimmed mean 
approach for patients who receive prohibited therapy or discontinue study drug due to lack of 
efficacy or adverse events, analyses of the per-protocol population, and subgroup analyses to 
assess the robustness of the primary endpoint results will be provided in the Statistical Analysis 
Plan.
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 640 patients. 
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 
Q8W) and the faricimab up to Q16W arm. 
A sample size of approximately 320 patients in each arm will provide greater than 90% power to 
show non-inferiority of faricimab to aflibercept in the change in BCVA averaged over Weeks 40, 
44, and 48 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 two treatment arms

Standard deviation (SD) of 14 letters for the change from baseline in BCVA averaged over 
Weeks 40, 44, and 48

Two-sample t-test

2.5% one-sided type I error rate

10% dropout rate
To ensure appropriate patient representation, the Sponsor may elect to cap the recruitment of 
patients in certain baseline BCVA strata. If implemented, details of the cap will be described 
in the Statistical Analysis Plan.
The sample size may be adjusted as appropriate based on a masked assessment of the pooled 
SD of the change in BCVA from baseline. The assessment will be performed by the Sponsor at 
a specified timepoint prior to completing enrollment. Details on the masked sample size 
re-estimation conducted, as well as actions and decisions taken regarding changes in sample 
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size, will be documented in the Statistical Analysis Plan. The Sponsor will remain masked. 
Other factors external to the study may also trigger a decision to modify the sample size. 
Additional patients may be randomized during the China extension to support a China 
marketing application. If implemented, details of the China extension will be described in the 
Statistical Analysis Plan.
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Appendix 3
Schedule of Assessments
Screening through Week 48 Assessments
Screening a
Visit Day
Visit Week 
ET b
(28
)
1 a
7
4
8
12
16
20
24
28
32
36
40
44
48
Day(s)
(Visit window)
–28 to 1
N/A
(3)
28
(7)
56
(7)
84
(7)
112
(7)
140
(7)
168
(7)
196
(7)
224
(7)
252
(7)
280
(7)
308
(7)
336
(7)
Informed consent c
x
Sample informed consent c for 
optional aqueous, vitreous, and blood 
samples
x
Optional (RBR) residual samples and 
DNA whole blood sample informed 
consent c
x
Review of inclusion and exclusion 
criteria
x
x
Demographic data
x
Medical history d
x
Targeted physical examination e
x
x
Body weight and height
x
Vital signs f
x
x
x
x
NEI VFQ-25 g
x
x
x
x
BCVA h
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Low-luminance BCVA
x
x
Pre-treatment IOP i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
62


Faricimab—F. Hoffmann-La Roche Ltd
63/ Statistical Analysis Plan GR40306 and GR40844
Screening through Week 48 Assessments (cont.)
Screening a
Visit Day
Visit Week 
ET b
(28)
1 a
7
4
8
12
16
20
24
28
32
36
40
44
48
Day(s)
(Visit window)
–28 to 1
N/A (3)
28
(7)
56
(7)
84
(7)
112
(7)
140
(7)
168
(7)
196
(7)
224
(7)
252
(7)
280
(7)
308
(7)
336
(7)
Pregnancy test j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Whole blood sample (hematology, 
chemistry panel, coagulation), and 
urinalysis k
x
x
Optional aqueous humor sample l
x
x
x
x
x
x
x
Optional vitreous humor sample m
If elective vitrectomy is performed m
Optional PK plasma sample (if 
vitreous humor sample collected) m
If elective vitrectomy is performed and vitreous humor sample collected m
Optional blood sample for RBR n
x
Mandatory plasma PK sample o
x
x
x
x
x
x
Optional PK plasma sample 
(if aqueous humor sample is collected)
x p
Mandatory plasma PD sample o
x
x
x
x
x
x
Optional PD plasma sample (if 
aqueous humor sample is collected)
x p
Mandatory plasma sample for ADAs o
x
x
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
63


Faricimab—F. Hoffmann-La Roche Ltd
64/ Statistical Analysis Plan GR40306 and GR40844
Screening through Week 48 Assessments (cont.)
Screening a
Visit Day
Visit Week 
ET b
(28
)
1 a
7
4
8
12
16
20
24
28
32
36
40
44
48
Day(s)
(Visit window)
–28 to 1
N/A
(3)
28
(7)
56
(7)
84
(7)
112
(7)
140
(7)
168
(7)
196
(7)
224
(7)
252
(7)
280
(7)
308
(7)
336
(7)
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
OCT q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A q, r
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA q
x
x
x
CFP q
x
x
x
Optional ICGA q, s
x
x
Disease activity 
assessment t
x
x
Administration of study 
treatment
x
x
x
x
x
x
x
x
x
x
x
x
x
Finger counting test u
x
x
x
x
x
x
x
x
x
x
x
x
x
Post-treatment IOP v
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant medications x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concurrent ocular procedures y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; eCRFelectronic Case Report Form; ETearly
termination; FFAfundus fluorescein angiography; ICGAindocyanine green angiography; IOPintraocular pressure; NEI VFQ-25National 
Eye Institute 25-Item Visual Function Questionnaire; OCToptical coherence tomography; OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PK pharmacokinetic; RBRResearch Biosample Repository; VAvisual acuity.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
64


Faricimab—F. Hoffmann-La Roche Ltd
65/ Statistical Analysis Plan GR40306 and GR40844
Screening through Week 48 Assessments (cont.)
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 relative to the date of the Day 1 visit (first study treatment).  There must be a minimum of 21 days between all 
study visits occurring from Week 4 through Week 108.  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 4.4.2). 
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.  Informed consent must be administered and signed by a patient before any study-specific screening procedure is performed.  When 
screening and randomization are combined and performed on 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:  slitlamp examination, indirect ophthalmoscopy, and pre- and post-treatment IOP measurements (recorded 
on the Day 1 eCRF and dated accordingly).  Verify that the patient has not started any prohibited medication.
b Patients who discontinue from the study early (prior to the final study visit at Week 112) but have not withdrawn consent should return for an 
ET visit after a minimum of 28 days have elapsed following their last study treatment.
c Informed consent must be administered and documented before any study-specific screening procedure is performed and may be obtained more 
than 28 days before initiation of study treatment at the Day 1 visit.  The Optional Blood, Aqueous Humor, Vitreous Humor Samples Informed 
Consent Form as well as Optional (RBR) Informed Consent Form for residual samples and whole blood DNA sample collection can be signed 
either at the screening or Day 1 visit prior to sample collection.
d Medical history, including clinically significant diseases, chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, cerebrovascular, 
and ophthalmic history), surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, and smoking history, 
will be recorded at baseline.  
e 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.  Changes from baseline abnormalities should be recorded in patient notes.  New or worsened 
clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.
f
Vital signs include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure.  Vital signs will be 
measured with the patient in a seated position after resting for 5 minutes.
g To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day.
h To be performed prior to other ocular assessments.  Perform the assessments prior to dilating the eyes.
i
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.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
65


Faricimab—F. Hoffmann-La Roche Ltd
66/ Statistical Analysis Plan GR40306 and GR40844
Screening through Week 48 Assessments (cont.)
j
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, do not administer study treatment.  Perform urine pregnancy test before FFA (if applicable).
k Hematology includes hemoglobin, hematocrit, quantitative platelet count, RBC counts, WBC counts, and differentials, including neutrophils, 
bands, lymphocytes, basophils, eosinophils, and monocytes (absolute).  Serum chemistry panel includes sodium, potassium, chloride, 
bicarbonate, glucose, blood urea nitrogen, creatinine, calcium, phosphorus, total and direct bilirubin, total protein, albumin, ALP, AST, ALT, and 
uric acid.  Coagulation includes activated partial thromboplastin time and prothrombin time.  Urinalysis includes specific gravity, pH, blood, 
protein, ketones, glucose, 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.
l
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.  Not applicable for a site that 
has not been granted approval by a site's Institutional Review Board or Ethics Committee.  The sample at ET is not required if there are any 
safety concerns.
m If elective vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood 
sample (for plasma preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for 
faricimab concentrations or aflibercept concentrations.  The remaining samples may be analyzed for VEGF and Ang-2 concentrations and 
possibly other biomarkers.
n 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).
o Obtain prior to FFA (if applicable) and prior to study treatment. 
p PK and PD samples on Day 7 should be collected only from patients consenting to optional aqueous humor sampling.
q OCT and FFA images obtained at screening will be reviewed by the CRC to determine patient eligibility. At all subsequent visits, please 
forward imaging outputs from all devices to the CRC. Please see the CRC manual for further details on image requirements. Please 
remember to forward all OCT images to the CRC as soon as possible.  If OCT imaging data is missing due to a missed visit or a
problem with the OCT device, please notify the CRC as soon as possible. Note:  After randomization, if a patient misses a study visit 
when ocular images are scheduled, the images should be obtained at the next scheduled visit the patient attends.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
66


Faricimab—F. Hoffmann-La Roche Ltd
67/ Statistical Analysis Plan GR40306 and GR40844
Screening through Week 48 Assessments (cont.)
r
Optional OCT-A of both eyes to be conducted at sites with agreed OCT-A capability.
s Optional ICGA of both eyes performed at sites with agreed ICGA capability.  ICGA should be performed after laboratory samples are obtained 
and, if images are taken sequentially, after all other imaging has been performed.  If standard of care at a site, it is acceptable to perform ICGA 
in parallel with FFA.
t
Assessment of disease activity should be conducted per the specified criteria outlined in Section 3.1.1.4.  
u The finger counting test should be conducted within 15 minutes of study drug or sham administration for the study eye only.
v Post-treatment 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 at 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 should be used throughout the 
study period.
w After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event(s) that are believed 
to be related to prior administration of study treatment.  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.
x All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment (the Day 1 visit) until 28 days after the final 
dose of study drug should be recorded. 
y 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 ET visit.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
67


Faricimab—F. Hoffmann-La Roche Ltd
68/ Statistical Analysis Plan GR40306 and GR40844
Week 52 through Week 112 Assessments
Day
(Visit window)
Visit Week
ET b
(28)
52
56
60
64
68
72
76
80
84
88
92
96
100
104
108
112
364
(7)
392
(7)
420
(7)
448
(7)
476
(7)
504
(7)
532
(7)
560
(7)
588
(7)
616
(7)
644
(7)
672
(7)
700 
(7)
728 
(7)
756 
(7)
784
(7) a
Targeted physical examination c
x
x
Vital signs d
x
x
x
NEI VFQ-25 e
x
x
x
BCVA f
x
x
x
x
x
x
x
x
x
x
X
x
x
x
x
x
x
Low-luminance BCVA
x
x
Pre-treatment IOP g
x
x
x
x
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
x
x
x
x
Optional aqueous humor 
sample i
x
x
x
x
x
Optional vitreous humor sample j
If elective vitrectomy is performed j
Optional PK plasma sample (if 
vitreous humor sample is 
collected) j
If elective vitrectomy is performed and vitreous humor sample collected j
Plasma PK sample k
x
x
x
Plasma PD sample k
x
x
x
Plasma sample for ADAs k
x
x
x
Slitlamp examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
68


Faricimab—F. Hoffmann-La Roche Ltd
69/ Statistical Analysis Plan GR40306 and GR40844
Week 52 through Week 112 Assessments (cont.)
Day(s)
(Visit window)
Visit Week
ET b
(28)
52
56
60
64
68
72
76
80
84
88
92
96
100
104
108
112
364
(7)
392
(7)
420
(7)
448
(7)
476
(7)
504
(7)
532
(7)
560
(7)
588
(7)
616
(7)
644
(7)
672
(7)
700 
(7)
728 
(7)
756 
(7)
784
(7) a
Indirect ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
OCT l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Optional OCT-A l, m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FFA l
x
x
x
CFP l
x
x
x
Optional ICGA l, n
x
x
Administration of study 
treatment
x
x
x
x
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
x
x
x
x
Post-treatment IOP p
x
x
x
x
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
x
x
x
x
Concomitant medications r
x
x
x
x
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
x
x
x
x
ADAanti-drug antibody; BCVAbest-corrected visual acuity; CFPcolor fundus photograph; eCRFelectronic Case Report Form; ETearly
termination; FFAfundus fluorescein angiography; ICGAindocyanine green angiography; IOPintraocular pressure; NEI VFQ-25National 
Eye Institute 25-Item Visual Function Questionnaire; OCToptical coherence tomography OCT-Aoptical coherence tomographyangiography; 
PDpharmacodynamic; PK pharmacokinetic; VAvisual acuity. 
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
69


 
Faricimab—F. Hoffmann-La Roche Ltd 
70/ Statistical Analysis Plan GR40306 and GR40844 
Week 52 through Week 112 Assessments (cont.) 
Notes:  There must be a minimum of 21 days between all study visits occurring from Week 4 through Week 108.  All assessments should be 
performed prior to dosing, unless otherwise specified.  Standard-of-care treatment for nAMD in the fellow eye may be covered by the Sponsor only 
as long as the patient remains in the study (for details, refer to Section 4.4.2 ).   
a The Week 112 visit must occur 28 days and 35 days after the actual date of the Week 108 visit.   
b Patients who discontinue from the study early but have not withdrawn consent should return for an ET visit 28 days following the last 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.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
d Vital signs will include measurement of temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure.  Vital signs will be 
measured with the patient in a seated position after resting for approximately 5 minutes. 
e To be administered by the masked site staff (except for the VA examiner) prior to any other visit assessments being performed on that day. 
f To be performed prior to other ocular assessments.  Perform the assessments prior to dilating the eyes. 
g The same method should be used throughout the study period.  Perform measurements prior to dilating the eyes. 
h All women of childbearing potential (including those who have had a tubal ligation) will have a urine pregnancy test performed at prior to each 
study treatment and at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  If 
positive, do not administer study treatment.  Perform urine pregnancy test before FFA (if applicable).  
i If a patient consents to collection of optional aqueous humor sample, collect the sample at the indicated timepoints prior to study treatment 
administration.  Not applicable for a site that has not been granted approval by a site's Institutional Review Board or Ethics Committee.   The 
sample at ET is not required if there are any safety concerns. 
j If elective vitrectomy is medically necessary and the patient consents, a vitreous sample can be obtained from the study eye.  A PK blood 
sample (for plasma preparation) should also be collected and shipped to the Sponsor.  Vitreous humor samples will be analyzed primarily for 
faricimab concentrations or aflibercept concentrations.  The remaining samples may be analyzed for VEGF and Ang-2 concentrations, and 
possibly other biomarkers. 
 
 
 
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
70


Faricimab—F. Hoffmann-La Roche Ltd
71/ Statistical Analysis Plan GR40306 and GR40844
Week 52 through Week 112 Assessments (cont.)
k Obtain prior to FFA (if applicable) and prior to study treatment. 
l
Please forward imaging outputs from all devices to the CRC. Please see the CRC manual for further details on image requirements. Please 
remember to forward all OCT images to the CRC as soon as possible, particularly from Week 60 onwards when images need to 
be read and data submitted to IxRS before the next study visit. If OCT imaging data is missing due to a missed visit or a 
problem with the OCT device, please notify the CRC as soon as possible so that they may update the IxRS system accordingly. 
Note: If a patient misses a study visit when ocular images are scheduled, the images should be obtained at the next scheduled visit the patient 
attends.
m Optional OCT-A of both eyes to be conducted at sites with agreed OCT-A capability.
n Optional ICGA of both eyes performed at sites with agreed ICGA capabilities.  ICGA should be performed after laboratory samples are 
obtained and if images are taken sequentially, after all other imaging has been performed.  If standard of care at a site, it is acceptable to 
perform ICGA in parallel with FFA.
o The finger counting test should be conducted within 15 minutes of study drug or sham administration for the study eye only.
p Post-treatment IOP measurement to be conducted in the study eye only within 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 should be 
used throughout the study period. 
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, all adverse events will be reported until 28 days after the final dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event(s) that are believed 
to be related to prior administration of study treatment.  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 All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by 
a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment (the Day 1 visit) until 28 days after the final 
dose of study drug should be recorded.
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 ET visit.
Protocol Number: 
 Report Number: 
Clinical Study Report: faricimab - F. Hoffmann-La Roche Ltd.
GR40306
1102954
71